WO2008089034A2 - Cytokine inhibitors - Google Patents

Cytokine inhibitors Download PDF

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Publication number
WO2008089034A2
WO2008089034A2 PCT/US2008/050723 US2008050723W WO2008089034A2 WO 2008089034 A2 WO2008089034 A2 WO 2008089034A2 US 2008050723 W US2008050723 W US 2008050723W WO 2008089034 A2 WO2008089034 A2 WO 2008089034A2
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WIPO (PCT)
Prior art keywords
compound
alkyl
substituted
group
butyl
Prior art date
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PCT/US2008/050723
Other languages
French (fr)
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WO2008089034A3 (en
Inventor
Antonio Garrido Montalban
Russell Dahl
Erik Boman
Justin Ernst
Christopher Lum
Zhijun Wang
Jan Urban
Yazhong Pei
Original Assignee
Kemia, Inc.
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Publication of WO2008089034A2 publication Critical patent/WO2008089034A2/en
Publication of WO2008089034A3 publication Critical patent/WO2008089034A3/en

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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
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    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2529/00—Catalysts comprising molecular sieves
    • C07C2529/04—Catalysts comprising molecular sieves having base-exchange properties, e.g. crystalline zeolites, pillared clays
    • C07C2529/06—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof
    • C07C2529/40—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof of the pentasil type, e.g. types ZSM-5, ZSM-8 or ZSM-11

Definitions

  • the present invention relates to low molecular weight compounds and compositions thereof, useful as cytokine inhibitors, and their preparation.
  • the invention further relates to methods of treating, preventing, modifying and managing a variety of conditions, including cytokinc-mediated disorders or related disorders, which comprise the administration of a cytokine inhibitor, alone or in combination with known therapeutics.
  • the invention also relates to pharmaceutical compositions and dosing regimens using the disclosed compounds, optionally in conjunction with other therapies, for the treatment of a variety of conditions, including autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancer, and the like.
  • cytokines The functioning of the immune system is finely balanced by the activities of pro-inflammatory and anti-inflammatory mediators or cytokines.
  • Some cytokines promote inflammation and are called pro-inflammatory cytokines, whereas other cytokines suppress the activity of pro-inflammatory cytokines and are referred to as anti-inflammatory cytokines.
  • IL-4, IL-10, and IL-I 3 are potent activators ofB lymphocytes, but are also potent anti-inflammatory agents. They are anti-inflammatory cytokines by virtue of their ability to suppress genes for pro-inflammatory cytokines such as IL-I, TNF, and chemokines (CA. Dinarello, Chest. 2000, 118, 503).
  • autoimmune diseases arise when immune system cells (lymphocytes, macrophages) become sensitized against the "self. Lymphocytes as well as macrophages are usually under control in this system. However, a misdirection of the system toward the body's own tissues may happen in response to still unexplained triggers.
  • lymphocytes recognize an antigen which mimics the "self and a cascade of activation of different components of the immune system takes place, ultimately leading to tissue destruction. Genetic predisposition has also been postulated to be responsible for autoimmune disorders.
  • Tumor necrosis factor- ⁇ (TNF- a) and interleukin-1 (IL-I ) are proinflammatory cytokines that mediate inflammatory responses associated with infectious agents and other cellular stresses.
  • Overproduction of cytokines such as IL-I and TNF-G! is believed to underlie the progression of many inflammatory diseases including rheumatoid arthritis (RA), Crohn's disease, inflammatory bowel disease, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, congestive heart failure, and psoriasis among others (Dinarello, CA. et al., Rev. Infect. Diseases 1984, 6, 51 ; Salituro et al., Curr. Med.
  • RA rheumatoid arthritis
  • Crohn's disease inflammatory bowel disease
  • multiple sclerosis multiple sclerosis
  • endotoxin shock osteoporosis
  • Alzheimer's disease congestive heart failure
  • TNF- ⁇ also referred to as TNFa
  • IL-Ib interleukin-1 ⁇
  • the present invention provides low molecular weight compounds and pharmaceutical compositions thereof.
  • compounds of the invention are useful for a variety of applications including, e.g., as cytokine release inhibitory agents.
  • methods for the preparation of such compounds and for the use of these compounds alone, in mixtures thereof, or in mixtures with other therapeutic agents, in the preparation of medicaments for use in treating various disease states are provided.
  • methods for the use of compounds of the invention in the prevention and treatment of various disorders mediated by cytokines such as inflammatory, cardiovascular, and autoimmune disorders, cancer, pain, and others.
  • G is phenyl or pyrazolyl, wherein G is substituted by one or more R 1 , R 2 or R 3 ;
  • X is C(O) or C(S);
  • Ar is (Y)-naphthyl;
  • Y is C(O) or C(NOR);
  • L-Q is selected from:
  • each R is independently F, Cl, Br, I, NR 2 , CN, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heterocyclylalkyl group; each R' is independently F, Cl, Br.
  • each R is independently a substituted or unsubstituted alkyl, alkenyl, or alkynyl group, or an 0(C 1 ⁇ alkyl) group, wherein each alkyl group is optionally partially or fully halogenated;
  • R 4 is a substituted or unsubstituted C 1-4 alkyl, NH-(C 1 -8 alkyl), NH-aralkyl, or NH-heterocyclylalkyl group;
  • R 5 is selected from substituted or unsubstituted -NH-(C 1 -8 alkyl) group or a substituted or unsubstituted heterocyclyl selected from:
  • R is selected from a substituted or unsubstituted C 1 -4 alkyl, heterocyclyl, NH-(C M alkyl), Nll-alkylaryl, or NH-heterocyclylalkyl group;
  • R 7 is selected from F or Cl, or a substituted or unsubstituted NH-(C 2 . 8 alkyl) group; each R is independently hydrogen or a substituted or unsubstituted C ⁇ 6 alkyl group; each R' is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclyl, aralkyl, or heterocyclylalkyl group; each R" is independently a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl group; and each m is independently 0, 1 or 2.
  • G is
  • L-Q is O-(C 2 -3 alkyl)-Q
  • Q is -N(C 2-3 alkyl-OR) 2 ,
  • L-Q is
  • R 4 is a substituted or unsubstituted C 1-4 alkyl or -NH-(C 1-5 alkyl) group. In some such embodiments, R is
  • R is selected from substituted or unsubstituted
  • R is F, or a 3,3-dimethylbutan-l -amine- 1 -yl group
  • R 1 is a substituted or unsubstituted C ⁇ ⁇ , alkyl, or heterocyclyl group.
  • R 1 is a substituted or unsubstituted methyl, isopropyl, tert-butyl, isobutyl, sec-butyl, neopentyl, cyclohexyl, pyrrohdinyl, piperidinyl, piperazinyl, oxazepanyl, morpholinyl, or thiomorpholinyl group.
  • R 2 is a substituted or unsubstituted (CV 6 alkyl), heterocyclyl, or hcterocyclylalkyl group, F, Br, CN, C(O)NR' 2 , C(O)R", S(O) 111 R", NR'SO 2 R", or SO 2 NR' 2
  • R 2 is F, Br, CN, CF 3 , imidazolyl, triazolyl, tetrazolyl, C(O)NH 2 , C(O)NH(C 5 alkyl), C(O)NH(C 3 6 cycloalkyl), C(0)NH(heterocyclyl), C(O)NH(heterocyclylalkyl), (CH 2 ) 1-3 -heteroeyclylalkyl), C(O)-hetcrocyclyl, NHSO 2 (CV 6 alkyl), NHSO 2 (CV 6 cycloalkyl), NHSO 2 (CV 6 cycloalkyl), NHSO
  • 6 cycloalkyl, heterocyclyl, and heterocyclylalkyl gi * oup is substituted or unsubstituted.
  • 6 cycloalkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherem the alkyl or cycloalkyl group is optionally substituted by OH or N(C 1-3 alkyl) 2 .
  • the heterocyclyl group is a pyrrohdinyl, piperidinyl, piperazinyl, azepanyl, or 3,8-diazabicyclo[3.2.1]octanyl group.
  • the heterocyclylalkyl group is a (CH 2 ) 1-3 -pyrrolidinyl, (CH 2 ) ! _ 3 -piperidinyl, (CH 2 )i_ 3 -piperazinyl, (CH 2 )i_ 3 -furanyl, (CH 2 )i_ 3 -oxazolyl, or (CH 2 )i_ 3 -isoxazolyl group.
  • the heterocyclyl and heterocyclylalkyl group is substituted with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, neopentyl, (CH 2 ) 0 . 3 -cyclopropyl, (CH 2 ) 0 . 3 -cyclobutyl, (CH 2 ) 0-3 -cyclopentyl, (CH 2 ) 0 -3-cyclohexyl, (CH 2 ) 2 . 3 -OH, (CH 2 ) 0-3 NH(C 1-3 alkyl), (CH 2 ) O - ⁇ N(C L3 alkyl) 2 , and (CH 2 ) 1-3 -pyrrolidinyl.
  • a substituent selected from the group consisting of methyl, ethyl, n-propyl, is
  • R 3 is a substituted or unsubstituted C 1-4 alkyl or O(C ⁇ alkyl) group, or is a partially or fully halogenated 0(C 1-2 alkyl) group.
  • G is phenyl and R 1 a substituted or unsubstituted methyl, isopropyl, tert-butyl, isobutyl, sec-butyl, neopentyl, cyclohexyl, pyrrolidinyl, pipcridinyl, piperazinyl, oxazepanyl, morpholinyl, or thiomorpholinyl group.
  • R" is a substituted or unsubstituted (C 1-6 alkyl) or heterocyclylalkyl group, F, Br, CN, C(O)NR' 2 , C(O)R", S(O) m R", NR 1 SO 2 R' or SO 2 NR' 2 .
  • R 2 is F, Br, CN, CF 3 , imidazolyl, triazolyl, tetrazolyl, C(O)NH 2 , C(O)NH(C 1-6 alkyl), C(O)NH(C 3-6 cycloalkyl), C(O)NH(heterocydyl), C(O)NH(hetcrocyclylalkyl), (CH 2 ) 1-3 -heterocyclylalkyl), C(0)-heterocyclyl, NHSO 2 (C 1-6 alkyl), NHSO 2 (C 3-6 cycloalkyl), NHSO 2 (heterocyclyl), SO 2 NH(C 1-6 alkyl), SO 2 N(C 1-6 alkyl) 2 , wherein each C 1-6 alkyl, C 3-6 cycloalkyl, hcterocyclyl, and heterocyclylalkyl group is substituted or unsubstituted.
  • theC 1-f i alkyl or C 3-6 cycloalkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,.
  • the heterocyclyl group is a pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, or 3,8-diazabicyclo[3.2.1 ]octanyl group.
  • the heterocyclylalkyl group is a (CH 2 ) 1-3 -pyrrolidinyl, (CH 2 ) 1-3 -piperidinyl, (CH 2 ) 1-3 -piperazinyl, (CH 2 ) 1-3 -ruranyl, (CH 2 ) 1-3 -oxazolyl, or (CH 2 ) 1-3 -isoxazolyl group.
  • the C 1-6 alkyl, C 3-6 cycloalkyl, heterocyclyl, and heterocyclylalkyl group is substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, neopentyl, (CH 2 ) 0 .
  • R 3 is a substituted or unsubstituted C 1-4 alkyl or O(C M alkyl) group, or is a partially or fully halogenated 0(C 1-2 alkyl) group.
  • Table 1 Exemplary combinations of G and L-Q for Formula I.
  • Table 2 sets forth various combinations of substituents X and Y of Formula I.
  • combination 2000 describes those embodiments in which X is C(O) and Y is C(O).
  • a combination of substituents is permissible only if such a combination results in a chemically stable compound, and that any combination from Table 1, describing G and L-Q, may be combined with any combination from Table 2, describing X and Y.
  • combination 1006 from Table 1 and combination 2000 from Table 2 describe those embodiments of Formula I in which G is phenyl, L-Q is O-(C,_ 4 alkyl)- N(C 1-4 alkyl-OR) 2 , X is C(O) and Y is C(O).
  • each G and L-Q in the tables is understood to be optionally substituted as described herein.
  • each value of R 1 F, Cl, Br, I, NR 2 , CN, or a substituted or unsubstituted alkyl, alkcnyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heterocyclylalkyl group
  • R 1 F, Cl, Br, I, NR 2 , CN, or a substituted or unsubstituted alkyl, alkcnyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heterocyclylalkyl group
  • combination 2000 describes those embodiments in which R 1 is F, X is C(O) and Y is C(O), as well as those where R 1 is -NR 2 , X is C(O) and Y is C(O), etc.
  • Table 2 Exemplary combinations of X and Y for Formula I.
  • the cytokine inhibitor is selected from List I.
  • the compounds of the invention at a concentration of
  • 10 ⁇ M inhibit induced TNFa-release from a cell by about 50% or greater than 50%.
  • compositions comprising a compound as described herein and a pharmaceutically acceptable carrier.
  • the invention provides methods of treating disorders mediated by cytokines, including but not limited to inflammatory disorders, autoimmune disorders, cardiovascular disorders, cancer and pain.
  • the methods include administering to a subject in need of such treatment a therapeutically effective amount of a compound as described herein.
  • the cytokine-mcdiated disorder is a p38 MAPK-mcdiatcd disorder.
  • the cytokine is selected from TNFa, IL-I , IL-6, IL-S, GM-CSF, and IFN-gamma, or a combination of any two or more thereof.
  • the cytokine is TNFa or IL-I .
  • the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A), as described herein.
  • Cytokine-mediated disorders include rheumatoid arthritis, osteoarthritis,
  • cytokine-mediated disorders are stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, coronary heart disease, coronary artery disease, acute coronary syndrome, 1 akayasu arteritis, cardiac failure such as heart failure, cardiomyopathy, myocaiditis.
  • DIC disseminated intravascular coagulation
  • cardiomyopathy venoocclusive disease of the liver, hypotension, decreased cardiac output, decreased vascular resistance, pulmonary hypertension, diminished lung compliance, leucopenia or thrombocytopenia, or atherosclerosis
  • Cytokine-mediated disorders further include allergic lhimtis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, obhterative bronchiolitis, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection and respiratory tract inflammation
  • pso ⁇ asis pemphigus, eczema, atopic dermatitis, contact dermatitis, or acne
  • the cytokine-mediated disorders include bone resorption diseases such as osteopetrosis, osteoporosis, or osteoarthritis
  • the cytokine-mediated disease can be sepsis, HIV infection, HCV infection, malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer, including but not limited to breast cancer, colon cancer, lung cancer, prostatic cancer, multiple myeloma, and others.
  • the cytokine mediated disorder is a neutrophil-mediated disorder, such as, for example, bronchial asthma, rhinitis, influenza, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis, hemodialysis, lcukopheresis, granulocyte transfusion associated syndromes, 01 necrotizing enterocolitis
  • ARDS adult respiratory distress syndrome
  • the cytokine mediated disorder is or results from abnormal bleeding, an abscess, actinic reticuloid syndrome, acute confusional migraine, acute confusional senile dementia, acute hepatocellular injury, acute tubular necrosis, adenohypophyseal diseases, adenovirus infections, adhesions, adhesive capsulitis, adnexitis, agammaglobulinemia, allergy, alopecia, fibrosing alveolitis, amyloidosis, angioplasty, angor pectoris, antiphosphohpid syndrome, arteriosclerotic dementia, arteritis temporal, arthropod-borne encephalitis, asphyxia, atopic hypersensitivity, atrial fibrillation, beaver fever, biliary cirrhosis, bone loss, bronchiolitis, cancer of endocrine gland, cancer of larynx, candidiasis, small cell lung carcinoma, cardiac hypertrophy,
  • cytokine in another aspect of the invention, there are provided methods of reducing levels of a cytokine in a subject
  • the methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein or a steieoisomer, tautomer, soK ate, prodrug, or pharmaceutically acceptable salt thereof, effective to reduce a level of a cytokine relative to the level p ⁇ or to administration of the compound
  • the reduction in cytokine levels is at least 10%, at least 30%, at least 50%, or at least 90%
  • the subject suffers from or is at risk for a cytokine mediated disorder, as described herein
  • the cytokine is selected from TNFa, IL-I , IL-6, IL-8, GM-CSF, IFN-gamma, or a combination of an> two or more thereof
  • the cytokine is TNFa or IL-I
  • the cytokine is TNFa or
  • cytokine levels are at least 10%, at least 30%, at least 50%, or at least 90%.
  • the pro-inflammatory stimulus results from the presence of TNFa, IL-I, IL-6, IL-8, GM-CSF, IFN-gamma, LPS, or a combination of any two or more thereof.
  • the cytokine level is the level of TNFa, IL-I, IL-6, IL-8, GM-CSF, IFN-gamma, or a combination of any two or more thereof.
  • the method further includes exposing the cell to additional therapeutic ingredients (hereafter referred to as ingredient A), as described herein.
  • methods of inhibiting p38 activity comprise contacting p38 with an amount of a compound as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof effective to inhibit p38 activity, the phosphorylation of p38, or both.
  • the inhibition of p38 activity or phosphorylation of p38 is at least 10%, at least 30%, at least 50%, or at least 90%.
  • the p38 may be isolated such as in a cell-free in vitro system, a cellular preparation or it may be in a cell. In some other embodiments, the p38 is in a subject.
  • the subject suffers from, or is at risk for, a cytokine mediated disorder as described herein.
  • the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A) to the subject, as described herein.
  • the methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein or a stereoisomer tautomer, soh atc, prodrug, or pharmaceutically acceptable salt thereof effective to reduce the activity of a pro-inflammatory mediator telatrve to the activity prior to the administration of the compound
  • the reduction in pro-inflammatory mediator activity is at least 10%, at least 30%, at least 50%, or at least 90%
  • the subject suffers from or is at ⁇ sk for a cytokine mediated disorder as described heiein
  • the reduction in activity results from a decrease in circulating levels of a pro-inflammatory mediator relative to the circulating levels p ⁇ or to administration of the compound as described herein
  • the decrease in circulating pro-inflammatory mediator level is at least 10%, at least 30%, at least 50%.
  • the pro-inflammatory mediator is a prostaglandin or a leukot ⁇ ene, or a combination of two or more thereof
  • the reduction in activity results from an inhibition of the production of a proinflammatory mediator
  • the inhibition of pro-inflammatory mediator production is at least 10%, at least 30% at least 50%, or at least 90%
  • the pro-inflammatory mediator is a prostaglandin, leukot ⁇ ene, COX-2, NO- synthdse, or a combination of any two or more thereof
  • the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient ⁇ ), as described herein
  • methods of reducing the circulating levels of C-Reactive Protein or Rheumatoid Factor, or both comprise administering to a subject, such as a subject m need thereof, an amount of compound as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof effective to reduce the circulating levels of C- Reactive Protein or Rheumatoid Factoi, or both, in the subject's blood relative to the level p ⁇ or to the administration of the compound
  • the circulating C- React ⁇ e Protein levels before administration are higher than about 2 87 mg/1
  • the reduction m circulating level is at least 10%, at least 30%, at least 50%, or at least 90%
  • the subject suffers from, or is at ⁇ sk for, a cytokine mediated disorder as described herein
  • the method furthei includes administration of additional therapeutic ingredients (he
  • methods of reducing at least one indicium of rheumatoid arthritis comprise administering to a subject exhibiting one or more indicia of iheumatoid arth ⁇ tis, an amount of a compound as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to reduce at least one of the indicia to a level below that which exists p ⁇ or to the administration of the compound, wherein the indicia are selected from erythrocyte sedimentation rate (FSR), number of painful and tender joints, level of joint pain, joint tenderness, Ritchie articular index, duration of morning stiffness, joint immobility, joint swelling, and/or circulating C-reactive protein level
  • the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A), as desc ⁇ bed herein
  • kits for reducing the number or severity of clinical signs of psoiiasis comprise administering to a subject exhibiting one or more clinical signs of psoriasis an amount of a compound as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to reduce the number or severity of clinical signs of psoriasis relative to those present in the subject p ⁇ or to the administration of the compound, wherein the clinical signs of psoiiasis are the percentage of total body surface area (BSA) affected by psoriasis, pso ⁇ asis plaque thickness, level of lymphocytes within pso ⁇ atic lesions, epidermal thickness, T-cell infiltration, pathological epidermal hyperplasia, cell-mediated immunity reactions, tetanus antibody response, lymphocyte subpopulations, or any two or more thereof.
  • BSA total body surface area
  • the method further includes administration of additional therapeutic ingredients (heieaftei referred to as mgiedient A), as desc ⁇ bed herein
  • the invention provides methods that further include administering to a subject one or more, typically one, of the ingredients ⁇ described herein together with one or more, typically one, compound of the invention.
  • the methods are for treating cytokine-mediated disorders or conditions
  • a combination of any two or more ingredients A are administered with a compound as desc ⁇ bed herein
  • An additive or over-additive e g synergistic
  • a va ⁇ ety ot ingredients A arc contemplated for use in the combinations of the invention
  • non-steroidal anti-inflammatory drugs NSAIDs
  • NSAIDs include acetaminophen, aspi ⁇ n, lbuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac.
  • ⁇ ngiogenesis inhibitors may serve as ingredient A, such as VEGF inhibitors, taxol, pentoxyfyllinc and/or thalidomide
  • ingredient A includes biological agents, such as etanercept, infliximab, alefacept adahmumab, efahzumab, anakmra, IL-IRA, alpha-interferon, interferon beta 1 -B CTLA-4, and other antibodies or receptor constructs directed against TNFa.
  • ingredient A also within the scope of the invention for ingredient A are steroids, such as glucocorticoids, and vitamin D3 and analogs thereof (cholccalciferols), alone (the latter being used mostly for psoriasis) or in combination Steroids include budesonidc, dcxamethasone, fluocmomde, hydrocortisone, betamethasone, halobetasol (ulobetasol), methylprednisolone, prednisolone, prednisone, clobetasone, deflazacort, fluocmolone acetonide, fluticasone, triamcinolone acetonide, mometasone and diflucortolone
  • vitamin D3 derivatives are calcipotnol, tacalcitol, maxacalcitol, and tacalitol, the calciotropic hormones, l ⁇ ,2,5- dihydroxyvitamm D ⁇ ,
  • immunomodulatory immunosuppressive or cytostatic drugs can be used in combination with the compounds as described herein
  • Exemplary agents include hydroxychloroquine, D-penicillamme, sulfasalazine, auranofin, gold sodium thiomalatc, minocycline, dapsone, chlorambucil, mercaptopu ⁇ ne, tacrolimus, sirohmus, pimecrolimus, mycophcnolate mofetil, cyclospo ⁇ ne, leflunomide, methotrexate, azathioprme, cyclophosphamide, macrolides, ascomycin, hydroxyurea, 6-thioguanine, (Orfanos C E , 1999, Cutis 64 (5) 347), alefacept, leflunomide, infliximab, etanercept, etahzumab, anti-CD4, anti- CD25.
  • agents or therapies which act on other targets or immune mediated pioducts are suitable as the ingredient A
  • agents or therapies which act on other targets or immune mediated pioducts include, for example, inhibitors of protein tyrosine kinases (PTKs) such as epidermal growth factor receptor (FGFR), E-selectm inhibitors, and therapies widely used for pso ⁇ asis such as anthrahn, coal tar, phototherapies including ultraviolet B (UVB) or psoialens ultraviolet A (PUVA), photodynamic therapy and laser theiapy [0044]
  • PTKs protein tyrosine kinases
  • FGFR epidermal growth factor receptor
  • UVB ultraviolet B
  • PUVA psoialens ultraviolet A
  • Retinoid therapy can also be used as ingredient A
  • Retinoid therapy can also be used as ingredient A
  • Retinoid therapy can also be used as ingredient A
  • Ingredients A useiul in the invention further include small molecule inhibitors directed against enzymes involved in signal transduction pathways or to cell adhesion molecules like LFA-I or ICAM 1
  • Statins and HMG-CoA. reductase inhibitors may also be employed as ingredients A including, e g , atorvastatin (LIPI I OR, I ORV AS I ), flm astatin (LESCOL), lovastatin (MEVACOR, ALTOCOR), mevastatin, pravastatin (LIVALO, PITAVA), pravastatin (PRA VACHOL, SELEKTINE, LIPOSTAT), losuvastatin (CRESTOR) or sim ⁇ astatin (ZOCOR, LIPEX)
  • Other ingredients A contemplated for use in methods ot the invention include fibrates, such as bezafibrate (e g , BEZALIP), ciprofibrate (e g , MODALIM), clofibrate, chnofibrate, gemfibrozil (e g , LOPID) or fenofibrate, cholesterol absorption inhibitors, such as, ezetimibe
  • combinations comprising ingredient A and one or more compounds as described herein, typically in therapeutically effective amounts, for use as pharmaceutical compositions with anti-cytokine activ ity
  • Moreo ⁇ ei combinations comprising ingiedient A and a compound as desc ⁇ bed herein can be used for preparing a pharmaceutical composition for the treatment and or prevention of a cytokme-mediated disorder or condition
  • the pharmaceutical preparations, containing as the active substance one or more compound combinations comprising ⁇ ngredient(s) A and the compound as described herein may further include the phaimaceutically acceptable de ⁇ vatives theieot, and may be optionally combined with a conventional e ⁇ cipient, carrier, or combination thereof
  • UVB ultraviolet B
  • PUVA psoralens ultraviolet A
  • a typical combination for treating psoriasis is the compound as described herein compound in combination with immunotherapy drugs which include cyclospo ⁇ ne, pimeciohmus, tacrolimus, ascomycine, anti-CD4, anti-CD25, peptide T, LhA3TlP, DAB3 S 9, Cl LA-4Ig, E-selectm inhibitors, alefacept, infliximab etaneicept, efalizumab, and those disclosed in Griffiths, Christopher E M , 1998 Hospital Medicine, VoI 59 No 7, and the obvious variants thereof
  • Another typical combination for treating psoriasis is the compound as described herein as described herein with methotrexate (MTX) It is expected this combination will be effective because of the good tolerability of MTX in the short term and because of the acceptability if maintenance of remission is obtained with good quality of life
  • Another typical combination for treating psoriasis is the compound as described herein with cyclo
  • Another typical combination for treating psoriasis is the compound as described herein with another anti- 1 NFa ingredient
  • a typical embodiment is one wherein the other anti- I NFa ingredient is selected from infliximab oi etanercept, typically infliximab Infliximab is believed to have a higher rate of response for induction of remission, which recently was suggested to be maintained on the long term
  • topical or general antisense inhibitors of TNFa such as ahcaforsen
  • Another typical combination lor treating psoriasis is the compound as desc ⁇ bed herein with anti-CD4, anti-CD80 (IDEC-1 14 or ABX-1L8), DAB 1L-2, DAB 389 IL-2, CTLA4-Ig, IL-I O, the IL2 receptor inhibitors such as dach/umab (anti-TAC), or basihximab (
  • DMARDs Disease Modifying Antirheumatic Drugs
  • SAARDs Slow Acting Antirheumatic Drugs
  • a typical combination for treating rheumatoid arthritis is the compound as described herein combined with one or more of the following immunosuppressive, immunomodulatory, or cytostatic drugs, such as, for example, hydroxychloroquine, D-penicillaminc, sulfasalazine, auranofm, gold sodium thiomalatc, minocycline, dapsonc, chlorambucil, mercaptopurine, tacrolimus, sirolimus, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate, azathioprine or cyclophosphamide.
  • immunosuppressive immunomodulatory
  • cytostatic drugs such as, for example, hydroxychloroquine, D-penicillaminc, sulfasalazine, auranofm, gold sodium thiomalatc, minocycline, dapsonc, chlorambucil, mercaptopurine, tacrol
  • Another typical combination for treating rheumatoid arthritis is the compound as described herein combined with angiogenesis inhibitors, such as compounds directed against VEGF, taxol, pentoxyfylline, thalidomide, interferon beta- IB and alpha-interferon.
  • angiogenesis inhibitors such as compounds directed against VEGF, taxol, pentoxyfylline, thalidomide, interferon beta- IB and alpha-interferon.
  • Yet another typical combination for treating rheumatoid arthritis is the compound as described herein in combination with inhibitors of cell adhesion, such as inhibitors of LFA-I or inhibitors of ICAM-I .
  • Another typical combination for treating rheumatoid arthritis is the compound as described herein combined with anti-TNFa antibodies or TNFa-receptor antagonists such as etanercept, infliximab, adalimumab (D2E7), or biological agents such as CTLA-4, or biological agents directed against targets such as CD-4, LFA- 1 , IL-6, ICAM- 1 , C5, or IL-I receptor
  • the compound as desc ⁇ bed herein is combined with infliximab alone or infliximab and methotrexate
  • Another typical combination for treating rheumatoid arthritis is the compound as desc ⁇ bed herein in combination with IL-I receptor antagonists, such as anakmra (KINERET)
  • NSAIDs including acetaminophen, aspi ⁇ n, lbuprofen, choline magnesium sal
  • the follow ing groups of drugs combined with the compound as desc ⁇ bed herein may be effective steroids such as budesomde, 5-ASA drugs like mesalamme, immunosuppressants, biological agents and adhesion molecule inhibitors
  • a typical combination for treating Crohn's disease is the compound as described herein with one or more of the following steroids including all those listed herein, 5-ASA, methotrexate and a/athioprme
  • Anothei typical combination for treating Crohn's disease is the compound as described herein combined with IL-I receptor antagonists, such as anakmra (K1NERET)
  • Yet another typical combination for treating Crohn's disease is the compound as described herein with anti-TNFa antibodies or TNFa-receptor antagonists, such as etanercept, infliximab, adalimumab (D2E7), or biological agents such as CTLA -4, or biological agents directed against targets such as CD-4, LFA- I , IL
  • the compound as described herein is combined with infliximab and methotrexate. More typically, the compound as described herein is combined with infliximab.
  • Another typical combination for treating Crohn's disease is the compound as described herein combined with IL-IO, alicaforsen (anti ICAM 1), or antegren (VCAM receptor antagonist).
  • methods of increasing the HDL-lcvels of a subject comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to increase the HDL-level of the subject relative to the level prior to the administration of the compound.
  • the compound is a p38 inhibitor.
  • the subject suffers from or is at risk for a cytokine mediated disorder as described herein.
  • the HDL level prior to administration is less than about 70 mg/dl, less than about 65 mg/ml, less than about 60 mg/dl, less than about 55 mg/dl, less than about 50 mg/dl, less than about 45 mg/dl or less than about 40 mg/dl.
  • the HDL level prior to administration is less than about 55 mg/dl.
  • the HDL is HDL2, while in others it is HDL3.
  • the subject has an LDL level less than about 150 mg/ml.
  • the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis.
  • the vascular event is a cardiovascular event or a cerebrovascular event.
  • a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound as described herein.
  • the subject is suffering from or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome.
  • the methods of increasing HDL-levels in a subject additionally comprise administration of statins or HMG-CoA reductase inhibitors, such as, atorvastatin (LIPITOR. TORVAST), fluvastatin (LESCOL), lovastatin (MEVACOR, ALTOCOR), mcvastatin, pravastatin (LIVALO, PITAVA), pravastatin (PRAVACHOL, SELEKTINE, LIPOSTAT), rosuvastatm (CRESTOR), or simvastatin (ZOCOR, LIPEX); fibrates, such as, gemfibrozil, fenofibrate, bezafibrate, ciprot ⁇ brate, clofibrate, or clinofibrate; bile acid sequestrants, such as, cholestyramine (QUESTRAN); cholesterol absorption inhibitors, such as colestipol (COLESTID), or ezetimibe (ZETIA); ni
  • the HDL level of the subject is increased by at least about 5%, by at least about 7%, by at least about 10%, or by at least about 15%.
  • the HDL level of the subject is increased by at least about 12%.
  • the HDL level of the subject may be increased by about 5% to about 20%.
  • methods of increasing Apo-Al -levels of a subject comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to increase the Apo-A l -level of the subject relative to the level prior to the administration of the compound.
  • the Apo-Al -level is increased by at least about 5% or by at least about 10%.
  • the subject's HDL level prior to administration is less than about 70 mg/dl, less than about 65 mg/dl, less than about 60 mg/dl, less than about 55 mg/dl, less than about 50 mg/dl, less than about 45 mg/dl or less than about 40 mg/dl. In other embodiments, the HDL level prior to administration is less than about 55 mg/dl; or the subject's LDL level prior to administration is less than about 150 mg/ml.
  • the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis.
  • a vascular event can be a cardiovascular event or a cerebrovascular event.
  • a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound as described herein.
  • the subject is suffering from or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome.
  • the HDL level of the subject is increased by at least about 5%, by at least about 7%, by at least about 1 0%, or by at least about 15%.
  • the HDL level of the subject is increased by at least about 12%.
  • the HDL level of the subject may be increased by about 5% to about 20%.
  • methods of decreasing or preventing from increasing the systolic or diastolic blood pressure of a subject in need thereof comprise administering to a subject an amount of a compound effective to decrease or to prevent from increasing the systolic or diastolic blood pressure of the subject relative to the blood pressure prior to the administration of the compound, wherein the compound is as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof.
  • the blood pressure is the systolic blood pressure. In others, the blood pressure is the diastolic blood pressure.
  • the subject's systolic blood pressure prior to administration is above 140 mm Hg, and the diastolic blood pressure prior to administration of the compound is above 90 mm Hg. In others, the diastolic blood pressure prior to administration of the compound is higher than 85 mm Hg. In some embodiments, the decrease in systolic or diastolic blood pressure, or both, is at least about 5 mm Hg, at least about 3 mm Hg or at least about 2 mm Hg.
  • the subject's HDL level prior to administration is less than about 70 mg/dl, less than about 65 mg/dl, less than about 60 mg/dl, less than about 55 mg/dl, less than about 50 mg/dl, less than about 45 mg/dl or less than about 40 mg/dl. In other embodiments, the HDL level prior to administration is less than about 55 mg/dl; or the subject ' s LDL level prior to administration is less than about 150 mg/ml.
  • the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis.
  • a vascular event for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis.
  • the vascular event may be a cardiovascular event or a cerebrovascular event.
  • the present methods produce a reduction of the occurrence or severity of the vascular event in the subject, relative to a subject who is at risk of a vascular event who has not been administered a compound described herein.
  • the subject is suffering from or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome.
  • the HDL level of the subject may be increased by at least about 5%, by at least about 7%, by at least about 10%, or by at least about 15%
  • the HDL level of the subject is increased by at least about 12%
  • the HDL level of the subject may be increased by about 5% to about 20%
  • Compounds disclosed herein may be used in combination therapv with one or more anti-hypertensive agents, for example, ACE inhibitors, calcium channel blockers, aldosterone antagonists, angiotensin Il antagonists, diuretics, benzodiazepine dc ⁇ vativcs, beta blocking agents, dihydropyridine derivatives, potassium- sparing agents, urologicals, sulfonamides, or thiazides
  • anti-hypertensive agents for example, ACE inhibitors, calcium channel blockers, aldosterone antagonists, angiotensin Il antagonists, diuretics, benzodiazepine dc ⁇ vativcs, beta blocking agents, dihydropyridine derivatives, potassium- sparing agents, urologicals, sulfonamides, or thiazides
  • anti-hypertensive agents for example, ACE inhibitors, calcium channel blockers, aldosterone antagonists, angiotensin Il antagonists, diuretics,
  • methods of decreasing or preventing an elevation in PAI-I levels comprise administering to a subject at risk for increased PAI-I levels (for example in a subject suffe ⁇ ng from, or at risk of obesity, metabolic syndrome or inflammatory conditions) an amount of a compound effective to decrease or prevent an elevation in the PAI-1-level of the subject relative to the level in the untreated subject, wherein the compound is as desc ⁇ bed herein, or a stereoisomer, tautomer, soh ate prodrug, or pharmaceutically acceptable salt thereof
  • methods of decreasing the t ⁇ glvceride-level of a subject comprise administering to a subject, such as a subject in need thereof, an amount of a compound as desc ⁇ bed herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to decrease the t ⁇ glycc ⁇ dc-lcvel of the subject relative to the level prior to the administration of the compound as described herein
  • the t ⁇ glycc ⁇ de- level p ⁇ or to administration is abov e 500 mg/dl, above 200 mg/dl, or above 150 mg/dl
  • the t ⁇ glyce ⁇ de-level p ⁇ or to administration is above 200 mg/dl
  • the subject suffers from or is at risk for a cytokine mediated disorder as described heiein
  • the subject is at ⁇ sk of a vascular event
  • methods of decreasing the fasting glucose-level in a subject comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein, or a stereoisomer, tautomcr, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to decrease the fasting glucose-level in a subject relative to the level prior to the administration of the compound
  • the glucose level p ⁇ or to the administration is above about 130 mg/dl
  • the glucose level is decreased by about 5%, about 10%, about 20% or about 30%
  • the subject suffers from, or is at ⁇ sk for, a cytokine mediated disorder as described herein
  • the subject suffers from, or is at ⁇ sk of suffering from diabetes, insulin resistance, or metabolic syndrome
  • the method further comprises administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide,
  • the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis.
  • the vascular event is a cardiovascular event or a cerebrovascular event.
  • a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound as described herein.
  • methods of decreasing the HbAIc value in a subject comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to decrease the HbAI c value in the subject relative to the level prior to the administration of the compound.
  • the subject has a HbAI c value above about 8%, above about 7.5%, or above about 7%.
  • the HbAI c level is decreased to between about 4% and about 6.5%.
  • the subject suffers from, or is at risk for, a cytokine mediated disorder as described herein. In other embodiments, the subject suffers from, or is at risk of suffering from, or is at risk for, diabetes, insulin resistance or metabolic syndrome.
  • the method further comprises administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, repaglinide, nateglinide, metformin, miglitol, acarbose, exendin, pramlintide, insulin, or combinations of two or more thereof.
  • the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis.
  • the vascular event is a cardiovascular event or a cerebrovascular event.
  • a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound as described herein.
  • methods for decreasing the insulin level in a subject comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to decrease the insulin-level in the subject relative to the level prior to the administration of the compound,
  • the subject has a fasting insulin level prior to administration of above about 100 pmol/1, above about 150 pmol/1, above about 200 pmol/1, above about 250 pmol/1, above about 300 pmol/1, above about 350 pmol/1, above about 400 pmol/1, or above about 500 pmol/1.
  • the subject has a postprandial insulin level of above about 400 pmol/1, above about 500 pmol/1, above about 600 pmol/1, above about 700 pmol/1, or above about 800 pmol/1. In some embodiments, the insulin level is reduced by about 10%, about 20%, about 30%, or about 40%. In certain embodiments, the subject suffers from or is at risk for a cytokine mediated disorder as described herein. In yet other embodiments, the subject suffers from, or is at risk of suffering from diabetes, insulin resistance or metabolic syndrome.
  • the method further comprises administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, repaglinide, nateglinide, metformin, miglitol, acarbose, exendin, pramlintide, insulin, or a combination of two or more thereof.
  • the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis.
  • the vascular event is a cardiovascular event or a cerebrovascular event.
  • a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound as desc ⁇ bed herein.
  • a subject in another aspect of the invention, there arc provided methods for decreasing the HOMA Insulin Resistance Index in a subject.
  • the methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to decrease the HOMA Insulin Resistance Index in the subject relative to the Index prior to the administration of the compound.
  • the Insulin Resistance Index is reduced to below about 2 5, below about 2 0 or below about 1 8 In some embodiments, the Insulin Resistance Index, is reduced by about 10%, about 20% or about 30% In certain embodiments, the subject is in need of a decreased HOMA Insulin Resistance Index because, e g , the subject suffeis from, or is at risk tor a cytokine mediated disorder as desc ⁇ bed herein In others the subject buffers from or is at ⁇ sk of suffering from diabetes, insulin resistance or metabolic syndrome In some embodiments of the in ⁇ ention the method further comp ⁇ ses administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glybu ⁇ de, ghmepinde, gliclazide, repaghnide, nateglinide metformin, miglitol, acaibose, exendm, pramhntide, insulin, or a combination of two or more thereof In some embodiments
  • the methods compose administering to a subject such as a subject in need thereof, an amount of a compound as desc ⁇ bed herein, or a stereoisomer, tautomei, solvate prodrug, or pharmaceutically acceptable salt thereof, effective to increase the indirect bilirubin level in the subject relative to the le ⁇ el p ⁇ or to the administration of the compound
  • the indirect bilirubin level is increased to about 0 4 mg/dl, to about 0 5 mg/dl, to about 0 6 mg/dl, or to about 0 7 mg/dl
  • the indirect bilirubin level is increased by about 10%, about 20%, or about 30%
  • the bilirubin level is increased w ithout causing jaundice
  • the subject is in need of increased indirect bilirubin level because, e g the subject suffer
  • the vascular event is a cardiovascular event or a cerebrovascular event.
  • a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound as described herein.
  • compounds as described herein possess inhibitory effects on the procoagulant and pro fibrinolytic responses during human endotoxemia.
  • the invention therefore also provides a method of anticoagulant and fibrinolytic therapy for a disease or condition relating to blood coagulation or fibrinolysis, comprising administering to a subject in need thereof a pharmaceutically effective amount of the compound as described herein.
  • This administration may be of benefit given either prophylactically to subjects at risk or therapeutically to subjects who have developed complications related to these pathways.
  • Compounds disclosed herein may be used in combination therapy with one or more other anticoagulant or fibrinolytic agents.
  • these include recombinant tissue plasminogen activator (rtPA), streptokinase (SK), urokinase (UK), proUK, heparin, enoxoparin, dalteparin, coumarin anticoagulants, aspirin, dipyrimidamole, aggrennox, ticlopidine, clopidogrel (Plavix), abciximab, RheoPro, integrilin, aggrestat, and the like.
  • rtPA tissue plasminogen activator
  • SK streptokinase
  • UK urokinase
  • proUK proUK
  • heparin heparin
  • enoxoparin dalteparin
  • coumarin anticoagulants aspirin, dipyrimidamole, aggrennox, ticlopidine
  • a method comprising administering to a subject a combination of a compound as described herein and one or more ingredients A, in an amount effective to control, treat or prevent obesity or obesity-related conditions or disorders in a subject in need thereof, wherein ingredient A is selected from agents useful in the treatment of obesity or an obesity-related condition or disorder.
  • the obesity-related disorder is selected from overeating, binge eating, bulimia, diabetes, elevated plasma insulin concentrations, insulin resistance, metabolic syndrome, dyslipidemias, hyperlipidemia, lipodystrophy, osteoarthritis, arthritis deformans, lumbodyma, emmeniopathy.
  • obstructive sleep apnea cholelithiasis, gallstones, nonalcoholic steatohepatitis
  • heart disease abnormal heart rhythms and abnormal heart arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, coronary artery disease, angina pectoris, hypertension, sudden death, stroke, cerebral infarction, cerebral thrombosis, transient ischemic attack, polycystic ovary disease, craniopharyngioma, Pickwickian syndrome, fatty liver.
  • the subject desires to lose body weight relati ⁇ e to the subject's body weight prior to administration of the combination
  • the method additionally comp ⁇ ses treatment of the subject with hpoplasty, gast ⁇ c bypass, laparoscopic adjustable gast ⁇ c binding, biliopancreatic diversion or vertical banded gastroplasty.
  • both the compound as described herein and ingredient A are administered intravenously, subcutaneously or by inhalation
  • the compound as described herein is administered orally and the ingredient A is administered mtra ⁇ enously, subcutaneously, or by inhalation
  • the cytokine inhibitor may be administered intravenously, subcutaneously, or by inhalation and the ⁇ ngredient(s) A may be administered orally
  • agents useful in the treatment of obesity or an obesity-related condition or disorder as ingredients A include an insulin sensitizer, an insulin or insulin mimetic, a sulfonylurea, an oglucosidase inhibitor, a cholesterol lowering agent, a PPAR ⁇ agonist, a CB receptor hgand, a serotonergic agent, an adrenoceptor agonist, a pancreatic lipase inhibitor, an ApoB/MTP inhibitor, a MCH receptor antagonist, an amylin and'or calcitonin receptor agonist, an NPY antagonist, an orexin antagonist, a GLP-I agonist, an MC agonist a ghrehn antagonist, a leptm agonist, a CCK agonist, a PYY agonist, a CNTF, a GII secretagogue a GH secretagogue receptor modulator, a DP-IV inhibitor, a H3 antagonist or inverse
  • ingredient A is a MCH receptor antagonist, an NPY antagonist, an orexm antagonist, a GLP-I agonist, an MC agonist, a ghrehn antagonist, a leptm agonist, a CCK agonist a PYY agonist, a CNTF, a GH secretagogue, or a GH secretagogue receptor modulator
  • ingredient A is ⁇ monabant, sibutramine, fluoxetine,
  • ingredients A, and combinations of any two or more thereof, that may be combined with the compounds as desc ⁇ bcd herein, for the treatment or pievention of obesity, diabetes and/or obesity-related disorders, either administered separately or in the same pharmaceutical compositions include, but are not limited to
  • insulin sensitizers including (i) peroxisome prohlerator activated receptors
  • PPAR PPAR ⁇ agonists
  • ghtazones e g isaglitazone, pioghtazone. rosightazone, rivoglitazone, netoglitazone
  • naveglitazar farglitazar
  • metaglidasen GW6779542, CSO38
  • MBX2044 AZD6610
  • PLX204 LBM642
  • AMG131 , AVE0847, AVE5376, ONO5129, TAK654, CLX0921 , and the like
  • biguanides such as metformin and phenformin
  • insulin or insulin mimetics such as insulin aspart, insulin glulisine, insulin glargine, insulin lispro, insulin detemir, NN5401 , NN9101, NN344, AT1391 , DTYOOl , betaRx, insulin zinc suspension (lente and ultralente); insulintropin (by "insulin” is meant a polypeptide or its equivalent useful in regulation of blood glucose levels. A general description of such insulins is provided in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th Rd., Pergamon Press (1990). Such insulins can be fast acting, intermediate acting, or long acting. Various derivatives of insulin exist and arc useful in this invention. Such compositions can be administered by any standard route, including oral, nasal, pulmonary, or transdermal administration.);
  • sulfonylureas such as acetohexamide; chlorpropamide; glibenclamide; glipizide; glyburidc; glimepiride; gliclazide; glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide;
  • oglucosidase inhibitors such as alglucosidase alfa, voglibosc, cclgosivir, miglitol, acarbose, and the like;
  • cholesterol lowering agents such as (i) 3-hydroxy-3-methylglutaryl-
  • Cocnzyme A HMG-CoA reductase inhibitors (atorvastatin, pravastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, lovastatin and other statins); (ii) bile acid absorbers/sequestrants, such as colesevelam, colestipol, cholestyramine, dialkylaminoalcyl derivatives of a cross-inked dextran, and the like; (ii) nicotinyl alcohol, nicotinic acid or a salt thereof; (iii) PPAR ⁇ agonists such as fen ⁇ fibric acid derivatives (ciprofibrate, gemfibrozil, clofibrate, fenofibrate and benzafibrate), GW677954, CSO38, ABT335, LY674, GFT14, PLX204, Kl 1 1 , naveglitazar,
  • CB receptor ligands such as CB-I receptor antagonists or inverse agonists, for example rimonabant, surinabant, AVE 1625, CP945598, and SLV-319, and those disclosed in U.S. Pat. Nos. 6,344,474, 6,028,084, 5,747,524, 5,596,106, 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,1 12,820, 5,292,736, 5,624,941 , PCT Application Nos.
  • anti-obesity serotonergic agents such as fenfluramine, dexfenfluramine, phentermine, DOVl 02677, zimeldine, and sibutramine;
  • adrenoceptor agonists including /53-adrenoreceptor agonists, such as solabregon, YM 178, amibregon, tesofensince, fenfluramine, amphetamine, phenmetrazine, phentermine, and N5984;
  • pancreatic lipase inhibitors such as orlistat, cetilistat, and GT389255;
  • apolipoprotein-B secretion/microsomal triglyceride transfer protein apo-
  • B/MTP inhibitors such as ISIS301012, ISIS301012, JTT130, and SLx4090;
  • MCH melanin-concentrating hormone
  • MCH l R and MCH2R antagonists for example, 856464, and AMG076, and those described in U.S. Patent Application Publication Nos. 2005/0009815, 2005/0026915, 2004/0152742, 2004/0209865; PCT Patent Application Publication Nos. WO 01/82925, WO 01/87834, WO 02/06245, WO 02/04433, and WO 02/51809; and Japanese Patent Application No.
  • neuropeptide Y (NPY) antagonists such as NPYl antagonists, for example, BIBP3226, Jl 15814, B1BO3304, LY357897, CP671906, GI264879A, and those disclosed in U.S. Pat, No. 6,001,836 and PCT Application Nos. WO 96/14307, WO 01/23387.
  • NPY5 antagonists for example, S2367, FMS586, GW569180A, GW r 594884A, GW587081, GW5481 18..
  • WO 97/ 19682 WO 97/20820, WO 97/20821 , WO 97/20822, WO 97/20823, WO 98/27063, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01 /07409.
  • WO 01/02379, WO 01 /23388, WO 01/23389, WO 01/44201 WO 01/62737, WO 01 /62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648;
  • peptide YY (PYY) agonists such as PYY, PYY 3-36, peptide YY analogs, and PYY agonists, for example, AC162352, N-Acetyl [Leu(28,31)]NPY 24-36, and PYY(3-36)NH 2 , cyclo-(28/32)- ⁇ c-[Lys28- Glu32]-(25-36)-pNPY, TASP-V, pancreatic peptide (PP), 122U91, and those disclosed in U.S. Pat. Publication No. 2002/0141985 and PCT Application Publication No. WO 2005/077094, WO 03/026591 , WO 03/057235, and WO 03/027637;
  • GLP-I agonists including GLP-I , GLP- I analogs and derivatives, such as exenatide, exenatide-LAR, liraglutide, CJCl 134PC, LY548806, 716155, and AVEOOlO;
  • melanocortin (MC) agonists including MC4 agonists and MC4R agonists, such as Melanotan II, PT15, BL3020, AP1030, or those described in PCT Application Nos. WO 99/64002, WO 00/74679, WO 01/991752, WO 01/74844,
  • ghrelin receptor antagonists such as NOXBl 1, CYT009GhrQb,
  • leptin agonists including recombinant human leptin and recombinant methionyl human leptin, and leptin derivatives, such as OB3, and those disclosed in U.S. Pat. Nos. 5,552,524, 5,552,523, 5,552,522, 5,521 ,283, 6,777,388 and 6,936,439, and PCT Application Nos.
  • WO 97/38014, WO 98/08512, WO 98/284427 U.S. patent publications 2004/0072219, 2003/049693, 2003/0166847, and 2003/0092126;
  • cholccystokinin (CCK) agonists such as ARRl 5849, GIl 81771 ,
  • ciliary neurotrophic factors including CNTF, CNTF modulators, and CNTF derivatives, such as Axokine and NT501, and those disclosed in U.S. Pat. Nos. 6,680,291 and 6,767,894 and in PCT Application Nos. WO 94/09134, WO 98/22128, and WO 99/43813;
  • growth hormone (GH) secretagogues growth hormone secretagogues
  • growth hormone secretagogue receptor modulators such as SUNl 1031 , RC1291, tesamorelin, scrmorelin, examorelin, NN703, hexarelin, MK677, SM-130686, CP-424,391 , L-692,429 and L-163,255:
  • dipeptidyl peptidase IV (DP-IV or DPP-IV) inhibitors such as denaghptm, sitagliptin, SYR322, RO0730699, TS021 , ALS20426, vidagliptin. GRC8200, MP513.
  • 5HT 5-hydroxytryptamine
  • 5HT2C serotonin receptor 2C
  • lorcaserin vabicaserin
  • APD356 5-hydroxytryptamine receptor 2C
  • 5HT6 agonists such as PRX07034
  • PRX07034 5-hydroxytryptamine agonists
  • serotonin transport or serotonin reuptake inhibitors such as nefazodone, citalopram, dapoxetine, duloxetine, desvenlafaxine, fluvoxamine, escitalopram, sibutramine, venlafaxine, vilazodone, DOV21947, LUAA21004, BGC201259, NS2359, UK416244, DOV102677.
  • dopamine agonists for example dopamine D2 agonists, such as, ropinirole, bifeprunox, aripiprazole, pergolide, talipexole, ACP 104, quinagolide, nolomirole, NHOO l , SLV3O8, piribedil, lisuride, bromocriptine, aplindore, tesofensine, and preclamol;
  • dopamine D2 agonists such as, ropinirole, bifeprunox, aripiprazole, pergolide, talipexole, ACP 104, quinagolide, nolomirole, NHOO l , SLV3O8, piribedil, lisuride, bromocriptine, aplindore, tesofensine, and preclamol;
  • norepinephrine (NE) transport inhibitors such as lisdexamfctaminc, atomoxetine, duloxetine, SLE381 , desvenlafaxine, amfebutamone, sibutramine, venlafaxine, DOC21947, radafaxine, bupropion, DOV216303, reboxetine, AD337, NS2359, DOVl 02677, SEP225289, Xen2174, indeloxazine, protriptyline, and S33005;
  • NE transport inhibitors such as lisdexamfctaminc, atomoxetine, duloxetine, SLE381 , desvenlafaxine, amfebutamone, sibutramine, venlafaxine, DOC21947, radafaxine, bupropion, DOV216303, reboxetine, AD337, NS2359, DOVl 02677, SEP225289,
  • DAG diacyl glycerol acyltransferase
  • glucose transporter inhibitors for example, sodium glucose cotransporter
  • (SGLT) inhibitors such as, KGTl 251 , 189075, AVE2268, and SGLOOl O;
  • glucocorticoid antagonists for example, mifepristone, Org34517, and
  • PDE3B PDE3B inhibitors
  • tetomilast for example, tetomilast, tadalafil, atopik, vardenat ⁇ l, tipelikast, HT0712, QADl 71 A, SK3530, oglemilast, acanafil, cilostazol, roflumilast, parogrelil, udenafil, EHT0202, dasantafil, MEM1414, SLx2101, CC10004, 256066, cilomilast, vinpocetine, ibudilast.
  • pimobendan ND7001 , LAS37779, Kl 23, UK357903, NDl 251 , tofimilast, UK169003, senazodan, trapidil, arofylline, theophylline, doxofylline.
  • olprinone pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast;
  • antiplatelet agents such as, limaprost, clopidogrel, felbinac, eptifibatide,
  • Kl 34 triflusal, YY280, xemilofiban, ozagrel, alprostadil alfadex. TP9201 , procainamide, AT1015, Z335.
  • angiotensin converting enzyme (ACE) inhibitors such as peridopril, enalapril, ramipril, fosinopril, quinapril, lisinopril, imidapril, benazepril, ilepatril, captopril, trandolapril, temcapil, cilazapril, MC4232, CHFl 521 , omapatrilat, spirapril, moexipril, zofcnopril, delapril, alacepril, S5590, and fasidotril;
  • ACE angiotensin converting enzyme
  • angiotensin II receptor antagonists for example, losartan, candcsartan, tcmisartan, coaprovel, imidapril, azilsartan, valsartan, irbesartan, olmesartan, CYT006AngQb, TAK491.
  • UCP uncoupling protein
  • activators such as phytanic acid
  • thyroid hormone ⁇ agonists such as thyroid hormone, levo thyroxine,
  • cyclo-oxygcnase (COX)-2 inhibitors such as etoricoxib, GW406381 , meloxicam, lumiracoxib, diclofenac, valdecoxib, parecoxib, PMIOOl , 6444784, SVT2016, nimesulfide, CS706, cimicoxib, LR3001 , LAS34475, P54, rofecoxib, celecoxib, and arcoxia;
  • metabotropic glutamate 5 (mGlu5) receptor antagonists such as
  • acyl-estrogens such as oleoyl-estrone, disclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001);
  • FAS fatty acid synthase
  • urocortin binding protein antagonists and urocortin ligands such as urocortin II;
  • BDC03 BDC03, S2367, AOD9604, fluasterone, GT389255, QCBTl 6, MK0916, MK0493, MK0364, PD6735, c2735, and adiponectin.
  • Obesity and weight loss treatments also include surgery. Typically the weight loss surgical procedure is liposuction or lipoplasty. Surgical obesity treatments include gastric bypass, laparoscopic adjustable gastric binding, biliopancreatic diversion or vertical banded gastroplasty.
  • a method comprising administering a compound as described herein, or is a mixture of any two or more thereof and/or a stereoisomer, tautomcr, solvate, prodrug, or pharmaceutically acceptable salt thereof, and one or more ingredients A to a subject in need thereof, in an amount effective to increase or enhance the effectiveness of the ingredient A when used alone, wherein ingredient A is selected fiom agents useful in the treatment of obesity or an obesity-related condition or disorder
  • the effectiveness enhancement is obtained by allowing administration of lower dosages of one or more of the ingredient A used in combination as relatn e to the use of either agent alone
  • a method comprising administering to a subject a compound as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, and an ingredient A, in an amount effective to ieduce the risk ol metabolic disorders in a sub
  • the reduction in risk of metabolic disorders is obtained by reducing the body weight of the subject, relative to the subject's body weight prior to administration of the combination of the compound as described herein and ⁇ ngredient(s) A
  • routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intiasynovial, by infusion, sublingual, transdermal, oral, topical and by inhalation Typical modes of administiation aie oial, topical or intrav enous
  • the pharmaceutical combinations of ingredient A and the compound(s) as described herein may be administered separately, or in a combination formulation with other ingiedients or adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutical compositions containing them, provide increased dissolution or dispersion, muease inhibitory activity, provide adjunct therapy, or provide like advantages
  • Such combination therapies typically utilize lowei dosages of the conventional therapeutics, and av oid the possible toxicity and adverse side effects incurred when those agents aie used as monotherapies
  • Pharmaceutical combinations of ingredient A and the compound as described herein may therefore be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition
  • the ingredient A and 'or the compound as described herein may be used in the combination as a salt, solvate, tautomer and/or prodrug and as a single stereoisomer or mixtures of stereoisomers, including racemates.
  • ingredient A and the compound as described herein may be used in the combinations according to the invention are variable.
  • Ingredient A and the compound as described herein are optionally present in the form of their solvates or hydrates.
  • the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various compounds and their different potencies. Determination of ratios by weight is dependent on the particular ingredient A and the compound as described herein, and are within the skill in the art.
  • a method of treating a cancer which comprises administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the method of treating cancer further comprises treating the subject with surgery, radiation, cryotherapy, or one or more antiproliferative agents or a combination thereof.
  • the antiproliferative agent is an alkylating agent, platinum agent, antimetabolite, topoisomerase inhibitor, antitumor antibiotic, antimitotic agent, aromatase inhibitor, thymidylate synthase inhibitor, DNA antagonist, farnesyltransferase inhibitor, pump inhibitor, histone acetyltransferase inhibitor, metalloproteinase inhibitor, ribonucleoside reductase inhibitor, endothelin A receptor antagonist, retinoic acid receptor agonist, immunomodulator, hormonal or antihormonal agent, photodynamic agent, angiogenesis inhibitor, or a tyrosine kinase inhibitor.
  • the alkylating agent is busulfan, procarbazine, ifosfamide, altretamine, hexamethylmclaminc, estramustine phosphate, thiotepa, mechlorethamine, dacarbazine, streptozocin, lomustine, temozolomidc, cyclophosphamide, semustine, or chlorambucil.
  • platinum agents examples include spiroplatin, lobaplatin (Aeterna), tetraplatin, satraplatin (Johnson Matthey), ormaplatin, iproplatin, miriplatin (Sumitomo), nexplatin (AnorMED), polymer platinate (Access), oxaliplatin, or carboplatin.
  • the antimetabolite is azacytidine, trimetrexate. floxu ⁇ dme, deox>cofomiycin, 2-chlorodeoxyadenosine, pentostatm, 6-mercaptopu ⁇ ne, hydroxyurea.
  • 6-thioguanine decitabine (SuperGen), cytarabme, cl ⁇ farabine (Bioenvision), 2-fluorodeoxy cytidine, irofulven (MGI Pharma), methotrexate, tomudex.
  • the topoisomerase inhibitor is amsac ⁇ ne, exatecan mesylate (Daiichi), epirubicm, qumamed (ChemGenex), etoposide, gimatccan (Sigma-Tau), tcniposidc, mitoxantrone, diflomotecan (Beaufour-Ipscn), 7-cthyl- 10-hydroxy-camptothecin, dexrazoxanet (TopoTarget), elsamitrucm (Spectrum), pixantrone (NO ⁇ uspharma), edotecarin (Merck & Co), becateca ⁇ n (Exehxis), karenitecm (BioNume ⁇ k), BBR-3576 (Novuspharma), belotecan (Chong Kun Dang), rub
  • daunorubicin (daunomycin), oxantrazole, thcrarubicin, losoxantronc, ldarubicin, blcomycimc acid, rubidazonc, sabarubicin (Menarini), phcamycinp, 13-deoxydoxorubicin hydrochloride (Gem Pharmaceuticals), porf ⁇ romycm, epirubicm, mitoxantrone (novantrone) or amonafide
  • antimitotic agents are colchicines, ABT-751 (Abbott), vinblastine, xyotax (Cell Therapeutics), vindesine, IDN 5109 (Bayer), dolastatin 10 (NCI), A 105972 (Abbott), rhizoxm (Fujisawa), A 204197 (Abbott), mivobuhn (Warner-Lambert), synthadotin (BASF), cemadotm (BASF), m
  • the DNA antagonist is trabectedin (PharmaMar), edotreotide (Novartis), glufosfamide (Baxter International), mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals), or thymectacin (NewBiotics)
  • the farnesyltransferase inhibitor is arglabin (NuOncology Labs), tipifarnib (Johnson & Johnson), lonafarnib (Schcring-Plough), perillyl alcohol (DOR BioPharma), or sorafenib (Bayer).
  • Examples of pump inhibitors are zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova). biricodar dicitrate (Vertex), or MS-209 (Schering AG).
  • Examples of histone acetyltransferase inhibitors include tacedinaline (Pfizer), pivaloyloxymethyl butyrate (Titan), AP-CANC-03 and AP-CANC-04 (Aton Pharma). depsipeptide (Fujisawa), or MS-275 (Schering AG).
  • the metalloproteinase inhibitor is neovastat (Aeterna Laboratories), rnetastat (CollaGcncx), or marimastat (British Biotech).
  • the ribonucleoside reductase inhibitor is gallium maltolate (Titan), tezacitabine (Aventis), triapine (Vion), or didox (Molecules for Health).
  • the endothelin A receptor antagonist is atrasentan (Abbott), bosentan (Roche), ambrisentan (BASF), sitaxsentan (Encysive), clazosentan (Roche), darusentan (Knoll), and ZD-4054 (AstraZeneca).
  • the retinoic acid receptor agonist is fenretinide (Johnson & Johnson), alitretinoin (Ligand), tazarotenc (Allcrgan), tctrinoin (Roche), isotretinoin (Roche), I3-cis-rctinoic acid (UCSD), or LGD- 1550 (Ligand).
  • the immuno-modulator is interferon, Roferon-A (Roche), dex ⁇ some therapy (Anosys), onc ⁇ phage (Antigenics), pentrix (Australian Cancer Technology), GMK vaccine (Progenies), CDl 54 cell therapy (Tragen), adenocarcinoma vaccine (Biomira), transvax (Intercell), avicine (AVI BioPharma), norelin (Biostar), IRX-2 (lmmuno-Rx), BLP-25 liposome vaccine (Biomira), PEP-005 (Peplin Biotech), multiganglioside vaccine (Progenies), synchrovax vaccine (CTL Immuno), ⁇ -alethine (Dovetail), melanoma vaccine (CTL Immuno), vasocare (Vasogen), rituximab (Genentech/Biogen pou), or p21 RAS vaccine (GemVax).
  • the hormonal agent is an estrogen, dexamethasone, a conjugated estrogen, prednisone, ethinyl estradiol, methylprednisolone, chlortrianisen.
  • the photodynamic agent is talaporf ⁇ n (Light Sciences), Pd-bacteriophcophorbidc (Yeda), thcralux (Theratechnologies), lutetium texaphyrin (Pharmacyclics), motexafin, gadolinium (Pharmacyclics), or hypericin.
  • the angiogenesis inhibitor is neovastat (AEterna Zentaris), ATN-224 (Attenuon), sorafenib (Bayer), thalidomide, bevacizumab (Genentech), ranibizumab (Genentech), benefin (Lane Labs), L-651582 (Merck & Co), vatalanib (Novartis), or sutent (Pfizer).
  • tyrosine kinase inhibitors include imatinib (Novartis), leflunomide (Aventis), kahalide F (PharmaMar) iressa (AstraZeneca), lestaurtinib (Cephalon), erlotinib (Oncogene Science), canertinib (Pfizer), tandutinib (Millenium), squalamine (Genaera), midostaurin (Novartis), phenoxodiol, SLJ6668 (Pharmacia), cetuximab (ImClone), rhu-Mab (Genentech), ZD6474 (AstraZeneca), MDX-H210 (Mcdarcx), vatalanib (Novartis), omnitarg (Genentech), lapatimb (GlaxoSmithKline), panitumumab (Abgenix), IMC-I Cl 1 (ImClone
  • the anti -proliferative agent is melphalan, carmustine, cisplatin, 5-fluorouracil, mitomycin C, adriamycin (doxorubicin), bleomycin, or paclitaxel (Taxol*).
  • the cancer is osteosarcoma, Kaposi's sarcoma, colorectal cancer, brain cancer, epithelial cell-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, gastric cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamus cell cancer, basal cell cancer, prostate cancer, renal cell carcinoma; leukemia, lymphoma, erythroblastoma, glioblastoma, glioma, meningioma, astrocytoma, myoblastoma, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, or follicular lymphoma.
  • the cancer is acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadcnoma, endode ⁇ nal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperp
  • osteosarcoma pancreatic polypeptide, papillary serous adenocarcinoma, pineal cell, pituitary tumor, plasmacytoma, pseudosarcoma.
  • pulmonary blastoma renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatm-secreting tumor, squamous carcinoma, squamous cell carcinoma, submesothehal, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, ⁇ ipoma, well differentiated carcinoma, or Wilm's tumor
  • the cancer is leukemia, erythroblastoma, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-hodgkm's lymphoma or follicular lymphoma
  • the cancer is follicular lymphoma, acute myelogenous leukemia, multiple myeloma or non-hodgkin's lymphoma
  • the cancer is bram cancer, glioblastoma, meningioma, astocytoma, medulloblastoma, neuroblastoma or retinoblastoma In some such embodiments, the cancer is glioma or glioblastoma
  • the cancer is osteosarcoma, Kaposi's sarcoma, chondosarcoma, Ewing's sarcoma or myoblastoma. In some such embodiments, the cancer is osteosarcoma bone cancer
  • the cancer is breast, lung, kidney or prostate cancer metastasis
  • the neoplasm is bone metastasis
  • a method ol treating, modifying or managing pain which comp ⁇ ses administering to a patient in need of such treatment, modification or management, a composition comp ⁇ sing a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof
  • the composition further comp ⁇ ses an antidepressant, antihypertensive, anxiolytic, calcium channel blocker, ⁇ -adrenergic receptor agonist, ⁇ -adrenergic receptor antagonist, ketamme, anesthetic, muscle relaxant, non-narcotic analgesic opioid analgesic, NSAID, immunomodulatory agent, immunosuppressive agent, corticosteroid, anticonvulsant, hyperbaric oxygen, ⁇ .2 ⁇ hgand, NMDA receptor antagonist, or a combination of any two or more thereof
  • the antidepressant is nortriptyline, amit ⁇
  • the anxiolytic is fluoxetine, paroxetine, sertraline, or venlafaxine
  • calcium channel blockers include nifedipine, verapamil and clomdme
  • the ⁇ -adrenergic receptor agonist is clomdme or midod ⁇ ne
  • the ⁇ -adrenergic receptor antagonist is terazosin, prazosin, or doxasozm
  • the anesthetic is procaine, hdocame, mepivacame, articame, p ⁇ locaine, etidocaine, bupu acaine, or ropivacame
  • opioid analgesic include hydromorphone, oxycodone, morphine sulfate, meperidine, and tentanyl transdermal patch
  • the opioid analgesic include hydromorphone, oxycodone, morphine sulfate, meperidine, and tentanyl transdermal patch
  • the opioid analgesic include hydromorph
  • the NMDA receptor antagonist is dextromethorphan, dextrorphan, ketamine, memantme, amantadine, agmatine, aptiganel, gavestinel, selfotel, 7-chlorokynuratc, rcmacemide, riluzole, pyrroloquinolme qumone or cis-4-(phosphonomethyl)-2-pipe ⁇ dmecarboxylic acid
  • the pain is acute pam, chrome pain, pain resulting from soft tissue and peripheral damage from acute trauma, neuropathic pain.
  • post-stroke pam postherpetic neuralgia, occipital neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgias, pain associated w ith osteoarthritis and rheumatoid arthritis, musculoskeletal pain, spinal pain, central nervous system pain, lower back pain, sciatica, dental pam, myofascial pain syndiomes, episiotomy pam, gout pam, and pain resulting from burns, deep and visceral pain, muscle pain, eye pain, inflammatory pain, orofacial pain, abdominal pain, and gynecological pain, somatogenic pain, pain associated with nerve and root damage, pain associated with hmb amputation, tic douloureux, neuroma, or vasculitis, diabet
  • the musculoskeletal pam is pain associated with strains, sprains or broken bones
  • the central nervous system pam is pain due to spinal cord or brain stem damage.
  • the deep and visceral pain is heart pain.
  • the orofacial pain is odontalgia.
  • the gynecological pain is dysmenorrhoea, labour pain and pain associated with endometriosis.
  • the pain associated with nerve and root damage is pain associated with peripheral nerve disorders.
  • the peripheral nerve disorder is nerve entrapment or brachial plexus avulsions.
  • the headache is migraine with aura, migraine without aura, vascular headaches, acute or chronic tension headache, sinus headache or cluster headache.
  • the chronic non-neuropathic pain is pain associated with HIV, anthralgia, vasculitis or fibromyalgia.
  • the complex regional pain syndrome is type I or type II.
  • the pain is nociceptive pain or neuropathic pain.
  • the nociceptive pain is associated with chemical or thermal burn, cut of the skin, contusion of the skin, osteoarthritis, rheumatoid arthritis, systemic lupus erthrematosis (SLE), tendonitis, or myofascial pain.
  • the neuropathic pain is diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, post-stroke pain, complex regional pain syndrome, sympathetic maintained pain syndrome, reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, spinal cord injury pain, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, pain related to cancer or metastases, phantom limb pain, fibromyalgia, chronic fatigue syndrome, radiculopathy, luetic neuropathy, or painful neuropathic condition induced by a drug.
  • the cancer is osteosarcoma, colorectal cancer, brain cancer, epithelial call-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamus cell and/or basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body; leukemia; lymphoma; or angiogenesis including neoplasia.
  • the metastases are breast, lung, kidney or prostate cancer metastases.
  • a method of treating pemphigus which comprises administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of a compound as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof.
  • the pemphigus is pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus, bullous pemphigoid, paraneoplastic pemphigus, cicatricial pemphigoid, bullous impetigo, or staphylococcal scalded-skin syndrome.
  • methods comprising administering to a subject in need thereof a combination of (i) an effective amount of a compound of the invention and (ii) an effective amount of one or more therapeutic Ingredients A useful in the treatment of pemphigus as described herein, wherein the effective amount of Ingredients A is less than the effective amount of Ingredient A when used alone.
  • kits comprising administering to a subject exhibiting one or more clinical indicia of pemphigus an amount of a compound as described herein effective to reduce the number and/or severity of clinical indicia of pemphigus relative to those present in the subject prior to the administration of the compound as described herein, wherein the clinical indicia of pemphigus include the percentage of total body surface area (BSA) affected by pemphigus, pemphigus lesion thickness, the number of new pemphigus lesions, the number of active pemphigus lesions (including blisters and erosions), the healing time of active lesions (for example, time to 80% healing), serum anti-desmoglein-1 (DSGl) antibody levels, serum anti-DSG3 antibody levels, serum TNFa-levels, serum IL6 levels, skin TNFa-mRNA levels, skin IL6 mRNA levels, or any two or more thereof.
  • BSA total body surface area
  • DSGl serum anti-desmoglein-1
  • the methods additionally comprise administering to the subject an effective amount of one or more Ingredients A, useful in the treatment of pemphigus, as described herein.
  • the effective amount of Ingredients A is less than the effective amount of Ingredient A when used alone.
  • the methods further comprise administering to the subject an Ingredient A, wherein the Ingredient A is an antiinflammatory agent, an immunosuppressant, an anti-infective, an antibiotic, a gold salt, an alkylating agent, an immunoglobulin, or a combination of two or more thereof.
  • the Ingredient A is an antiinflammatory agent, an immunosuppressant, an anti-infective, an antibiotic, a gold salt, an alkylating agent, an immunoglobulin, or a combination of two or more thereof.
  • the anti-inflammatoiy may be a corticosteroid, a COX-2 inhibitor, a non-steroidal antiinflammatory drug (NSAID), a TNFa antagonist, or an IL-I antagonist
  • the corticosteroid can be prednisone, prednisolone, or methylprednisolone Corticosteroids such as these may also be administered with either chlorambusil 01 mycophenylate mofetil
  • the TNFa antagonist is infliximab, etanercept, or adalimumab
  • the IL- I antagonist is anakinra
  • the immunosuppressant is mycophenylate mofetil, cyclosporin, azathi ⁇ pnne, methotrexate, alefacept, ⁇ tuximab, anti-interferon gamma, or cyclophosphamide
  • the anti-mfective is dapsonc, or hydroxychloroquine
  • the gold salt is myochrysme, oi solganal
  • the alkylating agent is lukeran
  • the antibiotic is tetiacychne, minocycline, or doxycychne
  • the method further comprises administration of nicotinamide, or niacinamide
  • the methods of the invention further comprise administering plasmaphe ⁇ sis therapy or photophoresis therapy to the subject
  • Ingredient A is reduced by from about 10% to about 90% in comparison to the dosage used to achieve the same therapeutic effect with Ingredient A alone In some embodiments, the dosage is reduced by at least about 10%, about 20%, about 30%, about 40%, about 50%. or about 60%
  • Ingiedient A is a corticosteroid, for example, prednisone or prednisolone
  • Ingredient A comprises a corticosteroid and cither chlorambusil or mycophenylate mofetil
  • the dosage of prednisone is reduced to less than about 70 mg/day, less than about 50 mg/day, less than about 30 mg/day, less than about 20 mg/day, less than about 15 mg/ day, or less than about 10 mg/day
  • the compound as described herein is administered orally or topically
  • Ingredient A is a corticosteroid or antibiotic and is administered orally, topically, in a mouthwash or in a mouth spray DETAILED DESCRIPTION OF THE INVENTION
  • '"substituted refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to atoms other than hydrogen or unsubstituted carbon.
  • Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom arc replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • a substituted group will be substituted with one or more substituents, unless otherwise specified.
  • a substituted group is substituted with 1 , 2, 3, 4, 5, or 6 substituents.
  • substituent groups include halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclyl alkoxy groups; carbonyls (oxo); carboxyls; esters; urethanes; oximes; hydroxyl amines; alkoxyamines; aralkoxyamincs; thiols; sulfides: sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides: isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitriles (i.e.,
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.
  • Alkyl groups include straight chain and branched alkyl groups having from
  • Alkyl groups further include cycloalkyl groups as defined below. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tcrt-butyl, ncopcntyl, isopentyl, and 2,2-dimethylpropyl groups.
  • Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above,
  • Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl. cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group has 3 to 10 or 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7.
  • Cycloalkyl groups further include mono-, bicyclic and polycyclic ring systems, such as, for example bridged cycloalkyl groups as described below, and fused rings, such as, but not limited to, decalinyl, and the like.
  • polycyclic cycloalkyl groups have three rings. Substituted cycloalkyl groups may be substituted one or more times with non- hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that arc substituted with straight or branched chain alkyl, alkenyl or alkynyl groups as defined above. Representative substituted cycloalkyl groups may be mono- substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents such as those listed above.
  • Bridged cycloalkyl groups are cycloalkyl groups in which two or more hydrogen atoms arc replaced by an alkylcnc bridge, wherein the bridge can contain 2 to 6 carbon atoms if two hydrogen atoms are located on the same carbon atom, or 1 to 5 carbon atoms if the two hydrogen atoms are located on adjacent carbon atoms, or 2 to 4 carbon atoms if the two hydrogen atoms are located on carbon atoms separated by 1 or 2 carbon atoms.
  • Bridged cycloalkyl groups can be bicyclic, such as, for example bicyclo[2.1.1]hexane, or tricyclic, such as. for example, adamantyl.
  • Representative bridged cycloalkyl groups include bicyclo[2.1.1]hexyl. bicyclo[2.2.1 ]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1 ]nonyl, bicyclo[3.3.2]decanyl, adamantyl, noradamantyl, bornyl, or n ⁇ rbornyl groups.
  • Substituted bridged cycloalkyl groups may be substituted one or more times with substituents as defined above, including straight or branched chain alkyl, alkenyl, or alkynyl groups.
  • Representative substituted bridged cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono- di- or tri-substitutcd adamantyl groups, which may be substituted with substituents such as those listed abo ⁇ e
  • Cycloalkylalkyl groups are alkyl groups as defined abo ⁇ e m which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cvcloalkyl group as defined above
  • cy cloalkylalkyl groups have from 4 to 20 carbon atoms, 4 to 16 carbon atoms, and typically 4 to 10 carbon atoms
  • Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl or both the alkyl and cycloalkyl portions of the group
  • Representative substituted cycloalkylalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tii-substituted with substituents such as those listed above
  • Alkenyl groups include straight and branched chain and cycloalkyl groups as defined above, except that at least one double bond exists between two carbon atoms Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments from 2 to 8, 2 to 6, or 2 to 4 caibon atoms In some embodiments, alkenyl groups include cycloalkenyl groups having from 4 to 20 carbon atoms, 5 to 20 carbon atoms.
  • substituted alkenyl groups may be mono- substituted oi substituted more than once, such as, but not limited to, mono-, di- or tri- substituted with substituents such as those listed above
  • Cycloalkenylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above Substituted cycloalkenylalkyl groups may be substituted at the alkyl, the cvcloalkenyl or both the alkyl and cycloalkenyl portions of the group Representative substituted cycloalkenylalkyl groups mav be substituted one or more times with substituents such as those listed above
  • Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms Thus, alkynyl groups have from
  • 2 to about 20 carbon atoms and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms.
  • Examples include, but arc not limited to -C ⁇ CH, -CsC(CH 3 ), -CsC(CH 2 CH 3 ), -CH 2 C ⁇ CH, -CH 2 CsC(CH 3 ). and -CH 2 CsC(CH 7 CH 3 ), among others.
  • Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • Aryl groups include monocyclic, bicyclic and polycyclic ring systems.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenylenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups.
  • aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms in the ring portions of the groups.
  • aryl groups includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups.
  • Representative substituted aryl groups may be mono-substituted or substituted more than once.
  • monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.
  • Aralkyl groups arc alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • aralkyl groups contain 7 to 20 carbon atoms, 7 to 14 carbon atoms or 7 to 10 carbon atoms.
  • Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group.
  • Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above.
  • Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non- aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S.
  • heterocyclyl groups include 3 to 20 ⁇ ng membeis, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 15 ⁇ ng members
  • Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, lmidazolyl, lmidazolinyl and lmidazolidinyl groups
  • the phrase "heterocyclyl group” includes fused ring species including those comprising fused aromatic and non-aromatic groups, such as, for example, bcnzotnazolyl, 2,3-dihydrobenzo[l ,4]dioxinyl, and benzo[1.3]dioxolyl
  • the phrase also includes bridged polycyclic ⁇ ng systems containing a heteroatom such as, but not limited to.
  • Heterocyclyl groups include, but are not limited to, azi ⁇ dinyl, azetidinyl, pyrrolidinyl, lmidazolidinyl, pyrazolidinyl, thiazohdmyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrohnyl, imida7olyl, imidazohnyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiaz
  • substituted heterocyclyl groups may be mono- substituted or substituted more than once, such as, but not limited to, py ⁇ dyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents suLh as those listed above [00176]
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ⁇ ng membeis, of which, one or more is a heteroatom such as, but not limited to, N.
  • O, and S Heteroaryl groups include but aie not limited to, groups such as pyrrolyl, pvrazolyl, lmidaz ⁇ lyl, triaz ⁇ lyl, tetrazolyl, oxazolvl, lsoxazolyl, thiazolyl.
  • heteroaryl groups includes fused img compounds such as indolyl and 2,3-dihydro indolyl, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups Rather, heteroaryl groups with such substitution are
  • Heter ⁇ cyclylalkyl groups are alkyl groups as defined above in which a hydiogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above
  • Substituted heterocyclylalkyl groups may be substituted at the alkvl, the heterocyclyl or both the alkyl and heterocyclyl portions of the group
  • Representative heterocyclyl alkyl groups include, but arc not limited to, 4-ethyl-morpholinyl, 4-ptopylmorphohnyl, furan-2-yl methyl furan-3-yl methvl, py ⁇ dine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indoI-2-yl propyl
  • Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those listed above
  • Heteroaralkyl groups are alkyl groups as defined abo ⁇ e in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined abov e
  • Substituted heteroaralkyl groups may be substituted at the alkyl, the heteroaryl, or both the alkyl and heteroaryl portions of the group
  • Representative substituted heteioaialkyl groups may be substituted one or more times with substituents such as those listed above
  • Alkoxy groups arc hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy. propoxy, butoxy, pentoxy, hexoxy, and the like.
  • branched alkoxy groups include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like.
  • cycloalkoxy groups include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.
  • aryloxy and arylalkoxy refer to, respectively, a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those listed above.
  • Alkyl, alkenyl, and alkynyl groups may be divalent as well as monovalent.
  • alkyl, alkenyl, or alkynyl group will be readily apparent from the context to those of skill in the art.
  • the alkyl group in an aralkyl group is divalent.
  • divalency is expressly indicated by appending the suffix "ene” or "ylene” to terms defined herein.
  • alkylene refers to divalent alkyl groups
  • alkcnylcnc refers to divalent alkcnc groups.
  • R 30 is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • amide (or “amido”) includes C- and N-amide groups, i.e.,
  • R 31 and R 32 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH 2 ) and formamide groups (-NHC(O)H).
  • Urethane groups include N- and O-urethane groups, i.e., -NR 33 C(O)OR 34 and
  • R 33 and R j4 arc independently hydrogen, or a substituted or un substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • amine refers to -NHR 35 and -NR 36 R 37 groups, wherein R 35 , R 36 and R 37 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • the amine is NHi, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.
  • sulfonamido includes S- and N-sulfonamide groups, i.e.,
  • R 38 and R 19 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-SO 2 NH 2 ).
  • thiol refers to -SH groups
  • sulfides include -SR 40 groups
  • sulfoxides include -S(O)R 41 groups
  • sulfones include -SO 2 R 42 groups
  • sulfonyls include -SO 2 OR 43 .
  • R 40 , R 41 , R 42 , and R 43 are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • urea refers to -NR 44 -C(O)-NR 45 R 46 groups.
  • R 44 , R 45 , and R 46 groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.
  • amidine refers to -C(NR 47 )NR 4S R 49 and -NR 47 C(NR 4S )R 49 , wherein R 47 , R 4 ⁇ and R 49 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • guanidine refers to -NR 50 C(KR 51 )NR 52 R 53 , wherein R 50 , R 51 , R 52 and R 33 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl. alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • R 54 , R 55 , R 56 and R 57 are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • the te ⁇ n "imide” refers to -C(O)NR 58 C(O)R 59 , wherein R 58 and R 59 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • the term "imine” refers to -CR 6(J (NR 61 ) and -N(CR 60 R 61 ) groups, wherein R 60 and R 61 are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R 60 and R 61 are not both simultaneously hydrogen.
  • protected with respect to hydroxyl groups, amine groups, carboxy groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction by means of protecting groups.
  • Protecting groups are known to those skilled in the art and can be added or removed using well-known procedures, such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
  • Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methyfhiom ethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyefhoxymethyl ether, tetrahydropyranyl ethers, 1 -ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoyl formate, fo ⁇ nate, acetate, trichloroacetate, and trifluoroacetate.
  • N-Protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butyl acetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloro acetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl.
  • acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butyl acetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloro
  • carbamate forming groups such as benzyl oxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2- - nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3, 5-dimethoxybenzyl oxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybcnzyloxycarbonyl, l-(p-biphenylyl)-l -methyl ethoxycarbonyl, ( ⁇ -dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropyl
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl. phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • Examples of protected sulfhydryl groups include, but are not limited to, thioethcrs such as S-benzyl thioether, S-t-butylthioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
  • Representative carboxy protecting groups arc C 1 to C 8 alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cyclopentyl, and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cyclopentylmethyl, and the like; arylalkyl, for example, phcncthyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups, and the like; arylalkcnyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g...).
  • alkyl e.g., methyl, eth
  • alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valerytoxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1 -(propionyloxy)- 1 -ethyl, 1 -(pivaloyloxyl)-l -ethyl, 1 -methyl- 1 -(propionyloxy)- 1 -ethyl, pivaloyloxymethyl, propionyloxymethyl, and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymcthyl, and the like; aroyloxyalkyl.
  • alkoxycarbonylalkyl such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-l -ethyl, and the like
  • alkoxycarbonyloxyalkyl such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1-ethoxycarbonyloxy-l -ethyl, 1-cyclohexyloxycarbonyloxy-l - ethyl, and the like
  • alkoxycarbonylaminoalkyl such as t-butyloxycarbonylaminomethyl, and the like
  • alkylaminocarbonylaminoalkyl such as methylaminocarbonylamino
  • Tautomers refers to isomeric forms of a compound that are in equilibrium with each other.
  • concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution.
  • triaz ⁇ les may exhibit the following isomeric forms, which are referred to as tautomers of each other:
  • a solvate is an aggregation of a molecule and one or moie molecules of solvent Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the solid state
  • the solvent molecules may interact with the non-solvent molecule by dipole-dipole interactions, ion-dipole interactions, coordinate bonds, and the like
  • the solvate is a hydrate
  • Many oiganic solvents can also form solvates, including, e g , ethers, such as diethyl ether and tetrahydrofuran, alcohols, such as methanol and ethanol ketones such as acetone, DMF, DMSO and others
  • Solvates may be identified by various methods known in the art For example, solvates in which the solvent molecules contain hydrogen may be observable by 1 H NMR Additional methods useful in identifying solvates include thei ⁇ nogra ⁇ imet ⁇ c analysis, differential scanning calo ⁇ metry, X-ray analysis and element
  • prodrug' denotes a derivative of a known direct acting drug, e.g.. esters and amides, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process; see Notari, R. E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology /72:309-323 (1985); Bodor, N., “Novel Approaches in Prodrug Design," Drugs of the Future 6: 165-182 (1981); and Bundgaard, H., “Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H.
  • compositions are considered within the scope of the present invention.
  • pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., formic acid, acetic acid, trifluoroacctic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methancsulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid).
  • inorganic acids such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid
  • organic acids e.g., formic acid, acetic acid, trifluoroacctic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid,
  • the compound of the invention when it has an acidic group, such as for example, a carboxyhc acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g., Na ⁇ , Li + , K + , Ca + , Mg" + , Zn 2' ), ammonia, organic amines (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolaminc, dicthanolamine, triethanolamine), or basic amino acids (e.g., arginine, lysine and ornithine).
  • alkali and earth alkali metals e.g., Na ⁇ , Li + , K + , Ca + , Mg" + , Zn 2'
  • ammonia e.g., organic amines (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolaminc, dicthano
  • C-reactive protein is a plasma protein, and an acute phase protein produced by the liver.
  • CRP is a member of the class of acute phase reactants as its levels rise dramatically during inflammatory processes occurring in the body.
  • CRP is used mainly as a marker of inflammation. Measuring and charting C-reactive protein values can prove useful in determining disease progress or the effectiveness of treatments.
  • Blood usually collected in a serum-separating tube, is analyzed in a medical laboratory or at the point of testing.
  • Various analytical methods are available for CRP determination, such as ELISA, immunoturbidimetry. rapid immunodiffusion and visual agglutination. Research suggests that patients with elevated basal levels of CRP are at an increased risk for diabetes, hypertension and cardiovascular disease. It is thought that CRP levels ⁇ lmg/l represent low cardiovascular risk, while levels >3mg/l represent high risk.
  • Lipoproteins are complexes which contain both a lipid and protein. Most of the lipids in plasma are present as lipoproteins and are transported as such. Lipoproteins are characterized by their flotation constants (e.g., densities). Various classes of lipoproteins exist and include high density lipoproteins (HDL) and low density lipoproteins (LDL). The HDL fraction comprises two major fractions, namely HDL 2 (large, buoyant HDL, density 1.063 - 1 , 125 g/ml) and HDL 3 (small, dense HDL, density 1.125-1.21 g/ml). LDLs are particularly rich in cholesterol esters.
  • HDL 2 large, buoyant HDL, density 1.063 - 1 , 125 g/ml
  • HDL 3 small, dense HDL, density 1.125-1.21 g/ml
  • LDL and/or low levels of HDL are associated with coronary artery disease.
  • Epidemiological studies have shown that high concentrations of HDL (over 60 mg/dl) have protective value against cardiovascular diseases.
  • Low concentrations of HDL (below 40 mg/dl for men, below 50 mg/dl for women) are a positive risk factor for atherosclerotic diseases.
  • a near optimal level of LDL is considered to be between 100 to 129 mg/dl, with levels below 100 mg/dl considered optimal, while very high LDL levels (above 190 mg/dl) correspond to the highest increased risk of heart disease.
  • the second method based on density gradient ultracentrifugation, measures the amount of cholesterol across a range of densities and utilizes deconvolution to determine the amount of cholesterol in each traction (HDL, including HDL 2 and HDL 3 , LDL, IDL, VLDL)
  • Apohpoprotein A-I is the major protein component of HDL in plasma The protein promotes cholesterol efflux from tissues to the liver tor excretion and helps to clear cholesterol from arteries
  • Glucose or "blood sugar" is normally present in humans at concentrations of about 80- 120 mgvdl and is the principal source of carbohydrate energy for man and many other organisms Excess glucose is stored in the body (especially in the liver and muscles) as glycogen, a starch-like substance which is, essentially, polymerized glucose Glycogen is metabolized into glucose as needed to meet bodily requirements
  • Glucose normally stimulates both the secretion and biosynthesis of insulin
  • basal insulin secretion namely the biological process by which insulin is released into the circulation in the absence of stimulation by levels of glucose, or other agents that promote insulin secretion, that are elevated above their "fasting" or non-fed levels
  • fasting and postprandial (after a meal) insulin are about 14 to 145 pmol/1, and 100 to 300 pmol/1 respectively in healthy people, with perhaps 3 -to 4-fold higher levels in insulin-resistant people
  • HgA Ic is a form of hemoglobin used primarily to identify the plasma glucose concentration over time
  • the normal range that found in healthy subjects
  • the normal range is 4% to 5 9%
  • People with diabetes melhtus often have higher levels of HbA 1 c
  • diabetic subject treatment goals vary, many include a target range of HbAI c values
  • a diabetic with good glucose control has a HbAIc level that is close to or within the reference range
  • the International Diabetes Federation and Ame ⁇ can College of Endoc ⁇ nology recommends HbAI c values below 6 5%, while the range recommended by the Ame ⁇ can Diabetes Association extends to 7%
  • a very high HbAIc represents poor glucose control
  • Insulin resistance is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells Insulin resistance in fat cells results m hydrolysis of stored triglycerides, which elevates free fatty acids in the blood plasma Insulin resistance in muscle reduces glucose uptake whereas insulin resistance in liver reduces glucose storage, with both effects serving to ele ⁇ ate blood glucose High plasma levels of insulin and glucose due to insulin resistance often leads to metabolic syndrome and type 2 diabetes Metabolic syndrome, also known as Syndrome X, metabolic syndrome X, insulin resistance syndrome, is a combination of medical disorders, having at least three of the following symptoms and features fasting hyperglycemia (including diabetes melhtus type 2 or impaired fasting glucose, impaired glucose tolerance or insulin resistance), high blood pressure, central obesity (also known as visceral adiposity), decreased HDL cholesterol, and elevated triglycerides
  • Insulin resistance can be detected by the follow ing indications as an increased le ⁇ el of blood insulin, increased blood level of glucose in response to oral glucose tolerance test (OGTT), decreased level of phosphorylated protein kinase B (AKT) in response to insulin administration, and the like Insulin resistance may be caused by decreased sensitivity of the insulin receptor-related signaling system in cells and/or by loss of beta cells in the pancreas through apoptosis There is also evidence that insulin resistance can be characterized as having an underlying inflammatory component
  • Bilirubin is formed when red blood cells die and their hemoglobin is broken down within the macrophages to heme and globins The heme is further degraded to Fe "+ , carbon monoxide and bilirubin via the intermediate compound bihverdin Since bilirubin is poorly soluble in water, it is carried to the liver and bound to albumin Bilirubin is made water-soluble in the liver bv conjugation with glucuronic acid Conjugated bilirubin, or bihrubinglucuronide, moves into the bile canahculi of the liver and then to the gall bladder Bilirubin is found in blood either in the conjugated form (also called direct bilirubin), or in the unconjugated form (also called indirect bilirubin) The reference range for total bilirubin is 0 3 - 1 0 mg/dl For direct bilirubin, it is 0 1 - 0 3 mg/dl, while for indirect bilirubin
  • Treating within the context of the instant invention, means an alleviation, in whole or in part, of symptoms associated with a disorder or disease, or slowing, or halting of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder in a subject at risk for developing the disease or disorder.
  • a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with a disorder or disease, or slows or halts further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disease or disorder in a subject at risk for developing the disease or disorder.
  • the therapeutically effective amount of a compound disclosed herein may vary depending on the indication being treated, e.g., the therapeutically effective amount of a compound described herein would likely be different for treating subjects suffering from, or at risk for, cytokine- mediated disorders relative to the therapeutically effective amount of the compound for treating subjects suffering from, or at risk of, a different disorder, e.g., vascular event(s), diabetes, insulin resistance, or metabolic syndrome.
  • a different disorder e.g., vascular event(s), diabetes, insulin resistance, or metabolic syndrome.
  • the therapeutically effective amount of a compound for decreasing CRP-levels in a subject would likely be different from the therapeutically effective amount for raising
  • HDL-levels in a subject determining a therapeutically effective amount of a compound described herein for treating a particular disorder or disease is well within the skill in the art in view of the present disclosure.
  • a subject is any animal that can benefit from the administration of a compound as described herein.
  • the subject is a mammal, for example, a human, a primate, a dog, a cat, a horse, a cow, a pig, a rodent, such as for example a rat or mouse.
  • the subject is a human.
  • Subjects who are at risk for a cardiovascular and/or cerebrovascular event are also subjects who manifest at least one symptom indicative of a vascular disorder/event.
  • Symptoms that are indicative of a coronary-related vascular event include chest pain, abnormal electrocardiograms, elevated levels of ischemic markers, necrosis markers, or thrombin/fibrin generation markers.
  • Such markers include, but are not limited to, Creatine Kinase with Muscle and/or Brain subunits (CKMB), D-Dimer, F 1.2, thrombin anti-thrombin (TAT), soluble fibrin monomer (SFM), fibrin peptide A (FPA), myoglobin, thrombin precursor protein ( TPP), platelet monocyte aggregate (PMA) and troponin (cTn).
  • Subjects who are at risk also include subjects having a history of a thrombotic event (e.g., disorder), including coronary heart disease (CHD), stroke, or transient ischemic attacks (TIA).
  • a thrombotic event e.g., disorder
  • CHD coronary heart disease
  • TIA transient ischemic attacks
  • a history of CHD can include, for example, a history of MI, coronary revascularization procedure, angina with ischemic changes, or a positive coronary angiogram (e.g., showing greater than about 50% stenosis of at least one major coronary artery).
  • carcinomas Malignancies of epithelial glandular tissue such as are found in the breast, prostate, and colon, are known as adenocarcinomas.
  • sarcomas Malignant growths of connective tissue, e.g., muscle, cartilage, lymph tissue, and bone, are called sarcomas. Lymphomas and leukemias are malignancies arising among the white blood cells.
  • inhibition may be assessed by delayed appearance ot primary or secondary tumors, slowed development of primary or secondary tumors, decreased occuiience of primary or secondary tumors, slowed or decreased seventy of secondary effects of disease, arrested tumor growth and regression of tumors, among others In the extreme, complete inhibition, is referred to herein as prevention or chemoprev ention
  • prevention or chemoprev ention the term "prevention" includes either preventing the onset of clinically evident neoplasia altogether or preventing the onset ot a prcclinically evident stage of neoplasia in individuals at risk Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or to arrest or reverse the progression of
  • nociceptive pain includes, but is not limited to, pain associated with chemical or thermal burns, cuts of the skin, contusions of the skin, osteoarthritis, rheumatoid arthritis, tendonitis, and myofascial pain
  • neuroopathic pain includes, but is not limited to, CRPS (Complex
  • Regional Pain Syndrome type I.
  • CRPS type II reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy, reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, sympathetically maintained pam syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia, post herpetic neuralgia, cancer and metastases related pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, spinal cord injury pam, central post-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pam, luetic neuropathy, and other painful neuropathic conditions such as those induced by drugs such as vincristine, velcade and thalidomide
  • the neuropathic pain can result from a mononeuropathy, polyneuropathy, complex regional pain syndromes or dcaffcrcntation.
  • neuroopathy includes, but is not limited to, a functional distuibaiice oi pathological change in the nervous system, especially in the peripheral nervous system, and is characte ⁇ zed clinically by sensory or motor neuron abnormalities
  • mononeuropathy indicates that a single nerve is affected, while the term polyneuropathy indicates that several nerves are affected.
  • Deafferentation indicates a loss of the sensory input from a portion ol the body, and can be caused by interruption of either penphei al sensory fibers or nerv es from the central nervous s>
  • I he etiology of a neuropathy can be known or unknown
  • Known etiologies include complications of a disease or toxic state such as diabetes, which is the most common metabolic disorder causing neuropathy, or irradiation, ischemia or ⁇ asculitis It is understood that the methods of the invention can be used to treat chronic pain of these or other chronic neuropathies of known or unknown etiology
  • a therapeutically effective amount of a compound as described herein used in the present invention may ⁇ ary depending upon the ioute of administration and dosage form
  • Effective amounts of invention compounds typically fall in the range of about 0 001 up to 100 mg/kg/day, and more typically in the range of about 0 05 up to 10 mg/kg/day
  • the compound or compounds used in the instant invention are selected to provide a formulation that exhibits a high therapeutic index
  • the therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD 5 O and ED 50
  • the LD 50 is the dose lethal to 50% of the population and the EDso is the dose therapeutically effective in 50% of the population
  • the LD 50 and ED 50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals
  • Treatment ma> also include administering the compounds or pharmaceutical formulations of the present invention in combination with other therapies
  • Combinations of the invention may be administered simultaneously, separately or sequentially
  • the compounds and pharmaceutical formulations of the piesent invention ma ⁇ be administered before, during, or after surgical procedure and'Or radiation therapy
  • the compounds of the invention can also be administered in conjunction with other anti-inflammatory agents, anticancer agents and other agents described herein
  • many types of immunomodulatory, immunosuppressive or c>tostatic drugs as described heiein can be used in combination with the compounds as described heiein
  • the specific amount of the additional active agent will depend on the specific agent used, the type of condition being tieated or managed, the severity and stage of the condition, and the amount(s) of compounds and any optional additional active agents concurrently administered to the subject.
  • one or more compounds of the invention and an additional active agent are administered to a subject, more typically a human, in a sequence and within a time interval such that the compound can act together with the other agent to provide an enhanced benefit relative to the benefits obtained if they were administered otherwise.
  • the additional active agents can be coadminstered by coformulation, administered at the same time or administered sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect.
  • the compound and the additional active agents exert their effects at times which overlap.
  • Each additional active agent can be administered separately, in any appropriate form and by any suitable route.
  • the compound is administered before, concurrently or after administration of the additional active agents.
  • the compound and the additional active agents are administered less than about 1 hour apart, at about 1 hour apart, at about 1 hour to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 1 1 hours apart, at about 1 1 hours to about 12 hours apart, no more than 24 hours apart or no more than 48 hours apart.
  • the compound and the additional active agents are administered concurrently.
  • the compound and the additional active agents are administered concurrently by coformulation.
  • the compound and the additional active agents are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.
  • the inventive compound and optionally the additional active agents are cyclically administered to a subject.
  • Cycling therapy involves the administration of a first agent for a period of time, followed by the administration of a second agent and-Or third agent for a period of time and repeating this sequential administration. Cycling therapy can provide a variety of benefits, e.g., reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one or more of the therapies, and/or improve the efficacy of the treatment.
  • the inventive compound and optionally the additional active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week.
  • One cycle can comprise the administration of an inventive compound and optionally the second active agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle, about 30 minutes every cycle or about 15 minutes every cycle.
  • Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest.
  • the number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.
  • Courses of treatment can be administered concurrently to a subject, i.e., individual doses of the additional active agents are administered separately yet within a time interval such that the inventive compound can work together with the additional active agents.
  • one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks.
  • the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.
  • the additional active agents can act additively or, more typically, synergistically with the inventive compound.
  • the inventive compound is administered concurrently with one or more second active agents in the same pharmaceutical composition.
  • the inventive compound is administered concurrently with one or more second active agents in separate pharmaceutical compositions.
  • the inventive compound is administered prior to or subsequent to administration of a second active agent.
  • the invention contemplates administration of an inventive compound and a second active agent by the same or different routes of administration, e.g., oral and parenteral.
  • the inventive compound when administered concurrently with a second active agent that potentially produces adverse side effects including, but not limited to, toxicity, the second active agent can ad ⁇ antageously be administered at a dose that falls below the threshold that the adverse side effect is elicited
  • the instant invention also provides for pharmaceutical compositions and medicaments which may be prepaied by mixing one or more compounds of the invention, prodrugs thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to prevent and treat disorders associated with excess cytokine production
  • the compounds and compositions of the invention may be used to prepare formulations and medicaments that prevent or treat a variety of disorders associated with excess cytokine production as disclosed herein, e g , diseases and pathological conditions involving inflammation, pain, cancer, etc
  • Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions
  • the instant compositions can be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration,
  • oral dosage forms are acceptable as solid dosage forms These can be prepared, for example, by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitms, chitosans, pectins, tragacanth gum, gum arable, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glyce ⁇ des
  • oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, oi preservatives such as paraben or sorbic acid, or
  • suspensions may include oils
  • oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olrv e oil
  • Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopiopyl my ⁇ state fatty acid glyce ⁇ des and acetylated fatty acid glyce ⁇ des
  • Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol Ethers, such as but not limited to. poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum, and water may also be used in suspension formulations
  • Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent Acceptable solv ents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution Alternatively, ste ⁇ le oils may be employed as solvents or suspending agents Typically, the oil or fatty acid is nonvolatile, including natural or synthetic oils, fatty acids, mono-, di- or t ⁇ -glyce ⁇ des
  • the pharmaceutical formulation and/or medicament may be a pow der suitable for rcconstitution with an approp ⁇ ate solution as desc ⁇ bed above Examples of these include but are not limited to, freeze dried, rotary d ⁇ ed or spray d ⁇ ed powders, amorphous powders, granules precipitates, or particulates
  • the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these
  • the pharmaceutical formulations and medicaments may be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum.
  • Rectal suppositories are prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum.
  • Oils may also be employed in the preparation of formulations of the soft gelatin type and suppositories.
  • Water, saline, aqueous dextrose and related sugar solutions, and glycerols may be employed in the preparation of suspension formulations which may also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.
  • Compounds of the invention may be administered to the lungs by inhalation through the nose or mouth.
  • suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • Formulations for inhalation administration contain as excipients, for example, lactose, polyoxyethylcne-9- lauryl ether, glycocholate and deoxycholate.
  • Aqueous and nonaquous aerosols are typically used for delivery of inventive compounds by inhalation.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of the compound together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens. Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • a nonaqueous suspension e.g., in a fluorocarbon propellant
  • Aerosols containing compounds for use according to the present invention are conveniently delivered using an inhaler, atomizer, pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, pressurized dichlorodifluoromethane, trichlorotluoromcthane, dichlorotetrafluoroethane, nitrogen, air, or carbon dioxide.
  • a suitable propellant e.g., without limitation, pressurized dichlorodifluoromethane, trichlorotluoromcthane, dichlorotetrafluoroethane, nitrogen, air, or carbon dioxide.
  • the dosage unit may be controlled by pro ⁇ idmg a vah e to deliv er a metered amount
  • Capsules and cartridges of for example, gelatin tor use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch
  • Delivery of aerosols of the present invention using sonic nebulizers is advantageous because nebulizers minimize exposure of the agent to shear, which can result in degradation of the compound
  • the pharmaceutical formulations and medicaments ma ⁇ be a spray, nasal drops or aerosol containing an approp ⁇ atc solvcnt(s) and optionally other compounds such as, but not limited to stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these
  • the compounds may be formulated in oily solutions or as a gel
  • any suitable propellant may be used including compressed air, nitrogen carbon dioxide, or a hydrocarbon based low boiling solvent
  • Dosage forms for the topical (including buccal and sublingual) or transdermal administration of compounds of the invention include powders, sprays, ointments, pastes ci earns, lotions, gels, solutions, and patches
  • the active component may be mixed undei sterile conditions with a pharmaceutical ly-acceptable earner or excipient, and with any preservatives, or buffers, which may be required
  • Powders and sprays can be prepared, for example, with excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances
  • the ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils waxes paraffins, staich, tragacanth, cellulose derivatives, polyethylene glycols silicones, bentomtes, silicic acid talc and zinc oxide, or mixtures thereof
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the inv ention to the body
  • dosage forms can be made by dissolving or dispersing the agent in the proper medium
  • Absorption enhancers can also be used to increase the flux of the inventive compound across the skin The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel
  • Ophthalmic formulations, eye ointments, powders, solutions and the like are also contemplated as being within the scope of this invention.
  • the compounds of this invention can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant).
  • the compounds are typically incorporated into topical ophthalmic formulations for delivery to the eye.
  • the compounds may be combined with one or more ophthalmologically acceptable preservatives, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution.
  • Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound.
  • the ophthalmic solution may contain an agent to increase viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylccllulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac.
  • Gelling agents can also be used, including, but not limited to, gellan and xanthan gum.
  • the compound of the invention is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
  • Sterile ophthalmic gel formulations may be prepared by suspending the invention compound in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic preparations. Preservatives and tonicity agents can be optionally incorporated.
  • Intrathecal administration via bolus dosage or constant infusion, allows the local administration of a compound to a region of the spinal cord, such as the dorsal horn regions, delivering the compound directly to the subarachnoid space containing the CSF (cerebrospinal fluid).
  • a region of the spinal cord such as the dorsal horn regions
  • Central delivery to the spinal cord regions can also be performed by epidural injection to a region of the spinal cord exterior to the arachnoid membrane. Enhancing permeation of the active compound through meningeal membranes may be achieved by using hypertonic dosing solutions that increase permeability of meningeal membranes, or by addition of permeation enhancers, such as, but not limited to, liposomal encapsulation, surfactants, or ion-pairing agents.
  • formulations of the invention may be designed to be short-acting, fast- releasing long-acting, and sustained-releasing as desc ⁇ bed below
  • pharmaceutical lormulations may also be formulated for controlled release or for slow release
  • compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect Therefore, the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents Such implants may employ known inert materials such as silicones and biodegradable polymers
  • the present disclosure also provides medical devices mcorpoiatmg the compounds as desc ⁇ bed herein A.
  • representative device includes a vascular stent coated or impregnated w ith the compounds as described herein
  • the device can be configured to be inserted into a blood vessel where it can release the compounds as desc ⁇ bed herein to help reduce or prevent vascular inflammation, for example vascular inflammation
  • Other embodiments disclose medical devices that include compounds as described herein, or a combination of the compounds with additional ingredients A, as described herein
  • the compounds as described herein can be coated on the surface of the medical device or the device can be saturated with the compounds such that the compounds are released from the device, for example over a pe ⁇ od of time
  • Exemplary medical devices including the compounds as disclosed herein include but are not limited to, vascular medical devices such as vascular stents
  • Stents and methods for making and using stents coated or impregnated with therapeutic agents are well-known in the art see, e g , U S Application No US20050181977 and U S Application No US20050129729
  • Specific dosages may be adjusted depending on conditions of disease, the age, bod ⁇ weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention.
  • a therapeutically effective amount of a compound of the present invention may ⁇ ary depending upon the route of administration and dosage form.
  • Effective amounts of invention compounds typically fall in the range of about 0 001 up to 100 mg/kg/day, and more typically in the range of about 0.05 up to 10 mg/kg/day
  • the compound or compounds of the instant invention are selected to provide a formulation that exhibits a high therapeutic index.
  • the therapeutic index is the dose ratio between toxic and therapeutic eifccts which can be expressed as the ratio between LD ⁇ o and ED 50
  • the LDs 0 is the dose lethal to 50% of the population and the ED5 0 is the dose therapeutically effective in 50% of the population.
  • the LD 50 and ED 50 are determined by standard pharmaceutical procedures in animal cell cultures or expe ⁇ mental animals.
  • the compounds as desc ⁇ bed herein can be used in the methods and compositions of the invention either alone or together with additional treatments or active ingredients or a combination thereof.
  • Additional treatments comprise treatment by smgery, radiation, or cryotherapy, while treatment with additional active ingiedients comprises the use of antiproliferative agents
  • Combinations of drugs are administered in an attempt to obtain a synergistic cytotoxic effect on most cancers, e g , carcinomas, melanomas, lymphomas and sarcomas, and to reduce or eliminate emergence of drug- resistant cells and to reduce side effects to each drug.
  • the additional active agent will depend on the specific agent used, the type of cancer being treated or managed, the seventy and stage of the cancer, and the amount(s) of compounds as described herein and any optional additional active agents concurrently administered to the subject Typically, the additional active ingredients that can be used in combination with the compounds as desc ⁇ bed herein are used at dosages well known in the art. [00262] In general, surgery and radiation therapy are employed as potentially curative therapies foi humans under 70 years of age who present with clinically localized disease and are expected to live at least 10 years
  • antiproliferativ e agents includes agents that prevent the development, maturation, or spread of cells, by acting directly on the cell, e g , by cytostatic or cytocidal effects, and not indirectly through mechanisms such as biological response modification
  • antiproliferative agents available in commercial use, in clinical evaluation and in pre-clmical development, which could be included in the present invention for treatment of cancel by combination drug chemotherapy
  • Typical antiproliferative agents can be categorized as alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltiansterase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ⁇ bonucleoside reductase inhibitors, endofhehn A receptor antagonists, retinoic acid receptor agonists, lmmunomodulators, hormonal or antihormonal agents, photodynamic agents, angiogenesis inhibitors, tyiosme kinase inhibitors, and the like
  • Some antiproliferative agents operate through multiple or unknown mechanisms and can thus be classified into more than one category
  • a family of antiproliferative agents which may be used in combination with the present invention includes alkylatmg-type agents
  • the alkylating agents are believed to act by alkylating and cross-linking guanine and possibly other bases in DNA, arresting cell division
  • Typical alkylating agents include nitrogen mustards, ethyl eneimine compounds, alkyl sulfates, cisplatin, and various nitrosoureas
  • a disadvantage with these compounds is that they not only attack malignant cells, but also other cells which are naturally dividing, such as those of bone marrow, skm, gastro-mtestinal mucosa, and fetal tissue
  • Suitable alkylating-type agents that may be used in the present invention include, but are not limited to, busulfan, procarbazine, lfosfamide, altretamine, hexamethylmelamine, estramustme phosphate, thiotepa, mechlorethamme,
  • An additional family of antiproliferative agents which may be used in combination with the present invention includes antimetabohte-type agents
  • Antimetabolites are typically reversible or irreversible enzyme inhibitors, or compounds that otherwise interfeie with the replication, translation or transcription of nucleic acids
  • Suitable antimetabolite agents include, but are not limited to azacvtidine t ⁇ metrexate, floxu ⁇ dine, deoxycoformvcin, 2-chlorodeoxyddenosine, pentostatin, 6-mercaptopu ⁇ ne, hydroxyurea, 6-thioguamne, decitabine (SuperGen), cytarabine, clofarabine (Bioenvision), 2-fluorodeoxy cytidine, irofulven (MGI Pharma), methotrexate, tomudex, ethynylcytidinc ( 1 aiho), fludarabine gemcitabine, raltitrexed
  • topoisomerase inhibitors include, but are not limited to amsac ⁇ ne, exatecan mesylate (Daiichi), cpirubicm, quinamed (ChemGenex), etoposide, gimatecan (Sigma-Tau) temposide, mitoxantrone, diflomotecan (Bcaufour-Ipscn), 7-ethyl-l O-hydroxy-camptothecin, dexrazoxanet (TopoTarget), elsamitrucin (Spectium), pixantrone (Novuspharma), edoteca ⁇ n (Merck & Co), becateca ⁇ n (Exehxis), karemtecin (BioNume ⁇ k), BBR-1576 (Novuspharma), belotecan (Chong
  • antibiotic-type antiproliferative agents which may be used in combination with the present invention includes antibiotic-type antiproliferative agents Suitable antibiotic-type antiproliferatn e agents that may be used in the present invention include, but are not limited to dactmomycm (actinomycin D), azonafide, valrubicin, anthrapyrazole, daunorubicin (daunomycin), oxantrazole, therarubicin, losoxantrone, idarubicin, bleomycinic acid, rubidazone, sabarubicin (Mena ⁇ ni), plicamycinp, 13-deoxydoxorubicin hydrochlo ⁇ de (Gem Pharmaceuticals), porfiromycin, epirubicin, mitoxantrone (novantrone) or amonafide [00270] Another family ot antiproliferative agents which may be used in combination with the present invention includes antimitotic agents
  • aromatase inhibitors include, but are not limited to ammoglutethimide, atamestane (BioMedicmes), formestane, fadrozole, letrozole, exemestane, or anastra/ole
  • An additional family of antiproliferative agents which may be used in combination with the present invention includes the thymidylate synthase inhibitors Suitable thymidylate synthase inhibitors that may be used in the present invention include, but are not limited to, pemetrexed (Eh Lilly), nolatrexed (Eximias), ZD-9331 (BTG), doxiflu ⁇ dme (Nippon Roche), or 5,10-methylenetetrahydrofolate (BioKeys)
  • DNA antagonists that may be used in the present invention include, but arc not limited to trabectedm (PharmaMar). edotreotide glufosfamide (Baxter International), mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals), or thymectacin (IsewBiotics)
  • Another family of antiproliferative agents which may be used in combination with the present invention includes farnesyltransferase inhibitors Suitable farnesyltransfcrasc inhibitors that may be used in the present invention include, but are not limited to arglabin (NuOncology Labs), tipif ' arnib (Johnson & Johnson), lonafarnib (Schering-Plough), perillyl alcohol (DOR BioPharma), or sorafenib (Bayer).
  • An additional family of antiproliferative agents which may be used in combination with the present invention includes pump inhibitors.
  • Suitable pump inhibitors that may be used in the present invention include, but are not limited to zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova), biricodar dicitrate (Vertex), or MS-209 (Schering AG).
  • An alternative family of antiproliferative agents which may be used in combination with the present invention includes histone acetyltransferase inhibitors.
  • Suitable histone acetyltransferase inhibitors include, but are not limited to tacedinaline (Pfizer), pivaloyloxymethyl butyrate (Titan), AP-CANC-03 and AP-CANC-04 (Aton Pharma), depsipeptide (Fujisawa), or MS-275 (Schering AG).
  • Another family of antiproliferative agents which may be used in combination with the present invention includes metalloproteinase inhibitors.
  • Suitable metalloproteinase inhibitors that may be used in the present invention include, but are not limited to neovastat (Aeterna Laboratories), metastat (CollaGenex), or marimastat (British Biotech).
  • the family of antiproliferative agents which may be used in combination with the present invention includes ribonucleoside reductase inhibitors.
  • ribonucleoside reductase inhibitors include, but are not limited to gallium maltolate (Titan), tezacitabine (A vends), triapine (Vion), or didox (Molecules for Health).
  • Another family of antiproliferative agents which may be used in combination with the present invention includes endothelin A receptor antagonists.
  • Suitable endothelin A receptor antagonists include, but arc not limited to atrasentan (Abbott), bosentan (Roche), ambrisentan (BASF), sitaxsentan (Encysive), claz ⁇ sentan (Roche), darusentan (Knoll), and ZD-4054 (AstraZeneca).
  • retinoic acid receptor agonists include compounds which are natural and synthetic analogues of retinol (Vitamin A).
  • the retinoids bind to one or more retinoic acid receptors to initiate diverse processes such as reproduction, development bone formation, cellular proliferation and differentiation, apoptosis, hematopoiesis, immune function and vision.
  • Retinoids are required to maintain normal differentiation and proliferation of almost all cells and have been shown to reverse/suppress carcinogenesis in a variety of in vitro and in vivo experimental models of cancer, see (Moon et al., Ch.
  • Suitable retinoic acid receptor agonists that may be used in the present invention include, but are not limited to fenretinide (Johnson & Johnson), alitretinoin (Ligand), tazarotene (Allergan), tetrinoin (Roche), isotretinoin (Roche), 13-cis-retinoic acid (UCSD), or LGD- 1550 (Ligand).
  • immunomodulators Another family of antiproliferative agents which may be used in combination with the present invention includes immunomodulators.
  • Suitable immunomodulators that may be used in the present invention include, but are not limited to interferon, Roferon-A (Roche), dexosome therapy (Anosys), oncophage (Antigenics), pent ⁇ x (Australian Cancer Technology), GMK vaccine (Progenies), CDl 54 cell therapy (Tragen), adenocarcinoma vaccine (Biomira).
  • transvax (Intercell), avicine (AVI BioPharma), norelin (Biostar), IRX-2 (Immuno-Rx), BLP-25 liposome vaccine (Biomira), PEP-005 (Peplin Biotech), multiganglioside vaccine (Progenies), synchrovax vaccine (CTL Immuno), ⁇ -alethine (Dovetail), melanoma vaccine (CTL Immuno), vasocare (Vasogen), rituximab (Genentech/Biogen pou), or p21 RAS vaccine (GemVax).
  • hormonal agents include, but are not limited to an estrogen, dexamethasone, a conjugated estrogen, prednisone, ethinyl estradiol, methylprednisolonc, chlortrianisen, prednisolone, idenestrol, aminoglutethimide, hydroxyprogesterone caproate, leuprolide, medroxyprogesterone, octreotide, testosterone, mitotane, testosterone propionate, fluoxymesterone, methyltestosterone, 2-methoxyestradiol (EntreMed), diethylstilbestrol, arzoxifene (Eli Lilly), megcstrol, tamoxifen, bicalutamide, toremofme, flutamide, goserelin, nilutamide, or leupore
  • photodynamic agents that may be used in the present inv ention include, but are not limited to talaporfm (Light Sciences), Pd-bacte ⁇ opheophorbide (Yeda), theralux (Theratechnologies), lutetium texaphyim (Pharmacychcs), motexafln, gadolinium (Pharmacychcs). or hype ⁇ cm
  • angiogenesis inhibitors include, but are not limited to neovastat (AEterna Zenta ⁇ s), ATN-224 (Attention), sorafemb (Bayer) thalidomide, bevdcizumab (Genentech). ranibizumab (Genentech), benefm (Lane Labs), L-651582 (Merck & Co), vatalanib (Novartis), or sutent (Pfizer)
  • Tyrosine Kinase Inhibitors include, but are not limited to imatinib (Novartis), leflunomide (Aventis), kahahde F (PharmaMar) iressa (AstraZeneca), lestaurtmib (Cephalon), erlotinib (Oncogene Science), canertmib (Pfizer), tandutinib (Millenium) squalamine (Genaera), midostau ⁇ n (Novartis), phenoxodiol, SU6668 (Pharmacia), cetuximab (ImClone), rhu-Mab (Genentech), ZD6474 (AstraZeneca), MDX-H210 (Medarex), vatalanib (Novartis), imatinib (Novartis), leflunomide (Aventis), kahahde F (PharmaMar) iressa (AstraZeneca),
  • Additional antiproliferative agents which may be used in combination with the present invention include melphalan, carmustme, cisplatin, 5-fluorouracil, mitomycin C, ad ⁇ amycin (doxorubicin), bleomycin, paclitaxel (Taxol ), and the like
  • the comopounds of the invention can be used in methods and compositions together with additional active ingredients or agents
  • the additional active agents are capable of relieving pain, inhibiting inflammatory reactions, prov iding a sedative effect or an antineuralgic effect, or ensuring patient comfort
  • the additional active agents include, but are not limited to.
  • opioid analgesics non-narcotic analgesics, anti-inflammatones, COX-2 inhibitors, ⁇ -adrcnergic receptor agonists or antagonists, ketamine, anesthetic agents, NMDA antagonists, u2 ⁇ hgands, immunomodulatory agents, immunosuppressive agents, antidepiessants, anticonvulsants, antihypertensives, anxiolytics, calcium channel hlockers, muscle relaxants, corticosteroids, hyperbaric oxygen other therapeutics known to relieve pain, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, prodrugs and pharmacologically active metabolites thereof
  • Opioids can be used to treat severe pam
  • opioid analgesics include, but are not limited to, oxycodone (OxyContinTM), morphine sulfate (MS ContinTM, DuramorphTM, AstramorphTM), meperidine (Demerol rM ), and fcntanyl transdermal patch (DuragesicTM) and other known conventional medications [See, e g , Physicians' Desk Reference, 594-595, 2851 and 2991 (57 th ed .
  • Oxycodone (Ox>ContmTM) is a long- dcting form of an opioid and may be used usually in initial and later stages of CRPS Morphine sulfate ma> be used for analgesia due to reliable and predictable effects, safety profile, and ease of reversibility with naloxone Morphine sulfate is sold in the United States under the trade name MS ContinTM, DuramorphTM or AstramorphTM [See, e g , Physicians' Desk Reference, 594-595 (57 th ed , 2003)]
  • Fentanyl transdermal patch (DuragesicTM) is a potent narcotic analgesic with much shorter half-life than morphine sulfate Meperidine (Demerol TM) and hydromorphone (DilaudidTM) may also be used for pain management [See, e g , Ph>sicians' Desk Reference, 2991 (57 th ed , 2003)]
  • Non-narcotic analgesics and antiinflammatories are preferably used foi treatment of pam du ⁇ ng pregnancy and breastfeeding
  • Antiinflammatories such as nonsteroidal anti-inflammatory drugs (NSAIDs) and cox-2 inhibitors typically inhibit inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis NSAIDs may proude pam relief in the early stage of pam syndrome
  • Fxamples of antiinflammatories include, but are not limited to, salicylic acid acetate (AspirinTM) ibuprofen (MotrinTM, AdvilTM), ketoprofcn (OruvailTM), rofecoxib (Vioxx' M ), naproxen sodium (Anapr ⁇ xTM, NaprelanTM, NaprosynTM), ketorolac (Acular r 1 ), and other known conventional medications
  • a specific cox-2 inhibitor is celecoxib (CelebrexTM) [See,
  • Antidepressants increase the synaptic concentration of serotonin and/or norepinephrine in the CNS by inhibiting their reuptake by presynaptic neuronal membrane. Some antidepressants also have sodium channel blocking ability to reduce the firing rate of injured peripheral afferent fibers.
  • antidepressants include, but are not limited to, nortriptyline (PamelorTM), amitriptyline (ElavilTM), imipramine (Tofranill), doxepin (SinequanTM), clomipramine ( ⁇ nafranilTM), fluoxetine (Prozac' M ), sertraline (Zoloft I M ), nefazodone (SerzoneTM), venlafaxine (Effexor % ), trazodone (DesyrelTM), bupropion (WellbutrinTM) and other known conventional medications [See. e.g., Physicians' Desk Reference, 329, 1417, 1831 and 3270 (57 th ed., 2003)].
  • Anticonvulsant drugs may also be used in embodiments of the invention.
  • anticonvulsants include, but are not limited to, carbamazepine, oxcarbazepine, gabapentin (NeurontinTM), phenytoin, sodium valproate, clonazepam, topiramate, lamotrigine, zonisamide, and tiagabine [Sec, e.g., Physicians' Desk Reference, 2563 (57 th ed., 2003)].
  • Corticosteroids e.g., prednisone, dexamethasone or hydrocortisone
  • orally active class Ib anti-arrhythmic agents e.g.. mexiletine
  • calcium channel blockers e.g., nifedipine
  • beta-blockers e.g., propranolol
  • ⁇ -blockers e.g., phenoxybenzamine
  • ⁇ 2- adrenergic agonists e.g., clonidine
  • a compound as described herein See, e.g., Physicians' Desk Reference, 1979, 2006 and 2190 (57 th ed., 2003)].
  • the specific amount of the additional active agent will depend on the specific agent used, the type of pain being treated or managed, the severity and stage of pain, and the amount(s) of compounds as described herein and any optional additional active agents concurrently administered to the patient.
  • Hydromorphone (Dilaudid ) is typically administered in an initial dose of about 2 mg orally, or about 1 mg intravenously to manage moderate to severe pain [See, e.g., Physicians' Desk Reference, 2991 (57* ed., 2003)].
  • Morphine sulfate (DuramorphTM, AstramorphTM, MS ContinTM) is typically administered in an initial dose of about 2 mg 1V/SC/1M, depending on whether a patient has already taken narcotic analgesics [Sec, e.g.,
  • Oxycodone (OxyContinTM) is a long-acting form of an opioid and may be used in initial and later stages of pain syndrome. Oxycodone (OxyContin 7 ' ) is usually administered in an amount of about 10-160 mg twice a day [See, e.g., Physicians' Desk Reference, 2851 (57 th ed., 2003)]. Meperidine (DemerolTM) is typically administered in an amount of about 50-150 mg PO/IWIM/SC every 3-4 hours. A typical pediatric dose of meperidine (DemerolTM) is 1-1.8 mg/kg (0.5-0.8 mg/lb) PO/IV/IM/SC every 3-4 hours [See, e.g...
  • Fentanyl transdermal patch (DuragesicTM) is available as a transdermal dosage form. Most patients are administered the drug in 72 hour dosing intervals; however, some patients may require dosing intervals of about 48 hours. A typical adult dose is about 25 mcg/h (10 cm 2 ), 50 mcg/h (20 cm 2 ), 75 mcg/h (75 cm 2 ), or 100 mcg/h (100 cm 2 ) [See, e.g., Physicians' Desk Reference, 1775 (57 lh ed., 2003)].
  • Non-narcotic analgesics and anti-inflammatories such as NSAIDs and cox-2 inhibitors may be used to treat patients suffering from mild to moderate pain.
  • Ibuprofen MotrinTM, AdvilTM
  • Naproxen sodium (AnaproxTM.
  • NaprclanTM, NaprosynTM may also be used for relief of mild to moderate pain in an amount of about 275 mg thrice a day or about 550 mg twice a day [See, e.g., Physicians' Desk Reference, 1417,2193 and 2891 (57 th ed., 2003)].
  • Antidepressants e.g., nortriptyline (PamelorTM) may also be used in the invention to treat patients suffering from chronic and/or neuropathic pain.
  • the oral adult dose is typically in an amount of about 25-100 mg, and usually does not exceed 200 mg/d.
  • a typical pediatric dose is about 0.1 mg/kg PO as initial dose, increasing, as tolerated, up to about 0 5-2 mg'd
  • Amit ⁇ ptyline (Etraton M ) is typically used tor neuropathic pain m an adult dose of about 25-100 mg PO [See, e g , Physicians' Desk Reference, 1417 and 2193 (57 lh ed , 2003)]
  • Anticonvulsants such as gabapentm (NeurontinTM) may also be used to treat patients suffe ⁇ ng from chronic and neuropathic pain
  • gabapentm is orally administered in an amount of about 100-1 ,200 mg three times a day
  • Carbamazepine (TegretolTM) is used to treat pain associated with true trigeminal neuralgia
  • the oral adult dose is typically in an amount of about 100 mg twice a day as initial dose, increasing, as tolerated, up to about 2,400 mg/d [See. e g , Physicians' Desk Reference, 2323-25 (57 th ed , 2003)]
  • agents which may be used in combination with the novel compounds of the invention include, but are not limited to, antiinflammatory agents, immunosuppressants, anti-infectives, antibiotics, gold salts, alkylating agents, immunoglobulins, or a combination of two or more thereof
  • antiinflammatory agents include corticosteroids, COX-2 inhibitors, non-steroidal antiinflammatory drugs (NSAID), TNFa antagonists, and IL-I antagonists
  • the corticosteroid can be prednisone, prednisolone, or mefhylprednisolone Corticosteroids such as these may also be administered with either chlorambusil or mycophenylate mofetil
  • TNFa antagonists are infliximab, etanercept, and adalimumab
  • An example of an IL-I antagonist is anakinra
  • immunosuppiessants are mycophenylate mofetil, cyclospor
  • Treatment of pemphigus can also include plasmapheiisis therapy or photophoresis therapy to the subject
  • BINAP 2,2'-Bis(diphenylphosphmo)- 1 , 1 '-binaphthyl
  • IC 1 o value The concentration of an inhibitor that causes a 50 % reduction in a measured activity.
  • PE Petroleum ether
  • Step 2 To a solution of the compound obtained above (75 mg, 0.17 mmol) in
  • Step 2 The target compound was prepared as above the compound obtained above (220 mg, 0.64 mmol). The target compound (181 mg, 90% yield, >90% pure by LC- MS) was obtained as a thick yellow oil, which was used in the next step without further purification. (Calculated mass: 316.4, observed mass: 317.1 ). pyrrolidi ⁇ -1-yl
  • Butyl 3-morpholino-5-(trifluoromethyl)phenylcarbaniate To a 2 dram vial containing 3- morpb.olino-5-(trifluoromethyl)benzoic acid (100 mg, 360 ⁇ mol) (prepared as in International Application No. PCT/US06/042679) was added a 1.3 M solution diphenylphosphorylazide in DMF (360 ⁇ l, 468 ⁇ mol), and a 2.6 M solution of NMM in tert-butanol (360 ⁇ l, 0.94 mmol). Additional tert-butanol (1 ml) was added and the reaction was capped and heated at 70°C for 16 hr.
  • Step 2 The compound obtained above (61 mg, 176 ⁇ mol), was treated with
  • Step 2 Using the same procedure as above, starting from tert-butyl 3- piperidino-5-(trifluoromethyl)phenylcarbamatc (42 mg, 122 ⁇ mol) afforded 36 mg (120% yield) of 3-piperidino-5-(trifluoromethyl)aniline.
  • Step 2 Using the same procedure as above, starting from tert-butyl 3- pyrrolidino -5-(trifluoromethyl)phenyl-carbamate (52 mg. 157 ⁇ mol), afforded 36 mg (105% yield) of 3- pyrrolidino-5-(trifluoromethyl)aniline.
  • Step 3 Methyl 5-tert-butyl-3-cyano-2-methoxybenzoate. To a solution of
  • Step 4 To a solution of 5-tert-butyl-2-methoxy-3-cyanobenzoic acid methyl ester (40 mg, 0.16 mmol) in 1 : 1 THF/MeOH (1 ml) mixture, 2N NaOH (0.35 ml) was added. The mixture was stirred at room temperature for 1 hr. neutralized with IN HCl and extracted with approx. 20 ml of EtOAc. The organic layer was dried over MgS ⁇ 4 and concentrated to give intermediate J (quantitative) as a white solid which was used in the next step without further purification.
  • Step 1 Methyl 3-tert-butyl-S-formylbenzoate.
  • Methyl 3-tert-butyl-5- (hydroxymethyl)benzoate (444 mg, 2 mmol), dissolved in DCM (4 ml), was treated with pyridinium chlorochromate (1.72 g, 8 mmol) at r.t. for 2.5 hr. Completion of the reaction was monitored by TLC. Upon completion, the mixture was filtered through silica gel, using DCM as the eluent. Concentration of the filtrate afforded 440 mg of the target compound as a colorless oil, which was used in the next step without purification.
  • Step 2 Methyl 3-tert-butyl-5-((4-methylpiperazin-l-yl)methyl)benzoate.
  • Step 3 3-tert-Butyl-5-((4-methylpiperazin-l-yl)methyl)benzoic acid.
  • the compound obtained above (268 mg, ca. 0.88 mmol) was dissolved in EtOH (2 ml), THF (1.6 ml), and water (0.4 ml), and was treated with 2 N NaOH (1.6 ml) at r.t. for 2 hr and 50 0 C for 30 min.
  • the reaction mixture was neutralized with aq. HCl, evaporated to dryness and used as such in the next step.
  • Step 4 tert-Butyl 3-tert-butyl-5-((4-niethylpiperazin-l- yl) ⁇ icthyl)phcnylcarbamate.
  • the compound obtained above was dissolved in t-BuOH (10 ml) and DPPA (379 ⁇ l, 1.8 mmol) and NMM ( 143 ⁇ l, 1.8 mmol) were added. The mixture was stirred at 8O 0 C overnight. The reaction mixture was diluted with EtOAc, and the organic layer was washed with aq. NaHC ⁇ 3 , dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by HPLC to afforded 258 mg of a orange oil. (Calculated mass: 362, observed mass: 3262.1).
  • Step 2 5-tert-Butyl-2-methoxy-3-nitrobenzene-l-sulfonyl chloride.
  • the compound obtained above (21.45 g, 82 mmol) was dissolved in nitric acid (85 ml, 1.34 mol).
  • Sulfuric acid (50 ml, 0.9 mol) was added dropwise over 40 min to control the exothermic reaction.
  • the reaction mixture was heated to 90 - 1 10 0 C for 85 min, then stirred overnight at r.t.
  • the yellow precipitate was filtered, washed with water and dried in vacuo, yielding 19.3 g of the target product.
  • Step 4 The compound obtained above (0.96 mmol) was dissolved in MeOH and Raney nickel (catalytic amount) was added. The reaction was stirred under hydrogen atmosphere for 17 hr at r.t.. The catalyst was removed by filtration and the solvent was evaporated. The residue was obtained in 257 mg yield and was used as such in the next reaction.
  • Step 2 N-(5-tert-ButyI-2-methoxy-3-nitrophenyI)-4-methyIpiperazine-l- sulfonamide.
  • the compound obtained above (1 14 mg, 213 ⁇ mol) was place in a 50 ml round-bottomed flask and suspended in DCM (5 ml).
  • DCM 5 ml
  • PCI5 222 mg, 1.07 mmol
  • the flask was fitted with a condenser and a CaSO 4 drying tube and heated at reflux for 3hr.
  • the reaction was treated with 1 drop of brine and the solution was stirred for 15 min.
  • the suspension was diluted with DCM and filtered.
  • Step 3 The compound obtained above (22 mg, 57 ⁇ mol) was dissolved in
  • Step 1 4-tert-Butyl-2,6-dinitrophenoI. 4-tert-Butylphenol (30 g, 0.2 mol) in glacial acetic acid (50 ml) was added dropwise to a stirred solution of 90% nitric acid (48 ml) and glacial acetic acid (100 ml) at -15°C to -10 0 C over one hr. After the addition was complete, the mixture was stirred at r.t. for 1 hr and then poured into cracked ice. The mixture was diluted with water, cooled and extracted with DCM. The combined organic layers were dried and concentrated.
  • Step 2 5-tert-Butyl-2-chloro-l,3-dinitrobenzene.
  • 1 H NMR 300MHz, CDCl 3 ) ⁇ (ppm) 7.9 (s, 2H), 1.38 (s, 9H).
  • Step 3 5-tert-Butylbenzene-l,3-diamine.
  • the compound obtained above (3 g, 1 1.6 mmol), methanol (300 ml) and 10% Pd/C (1 g) were placed in an autoclave. The mixture was hydrogenated under 3 MPa for 1 hr. Solid K 2 CO 3 (4 g, 29 mmol) and 10% Pd/C ( 1 g) were added to the above reactor. The mixture was again hydrogenated under 1.5 MPa overnight, filtered and evaporated to provide the target compound (1.5 g, 79% yield).
  • 1 H NMR 300 MHz. CDCl 3 ) ⁇ (ppm) 6.2 (m, 2H), 5.9 (d, IH), 3.5 (s, 4H), 1.2(s, 9H).
  • 5-tert-Butyl-2-methoxy-3-nitrobenzenesulfInic acid A solution OfNa 2 SO 3 (580 mg, 4.6 mmol) and NaHCO 3 (420 mg, 5.0 mmol) in water (2.5 ml) was heated at 80 0 C. Solid 5-tert- butyl-2-methoxy-3-nitrobenzene-l-sulfonyl chloride (539 mg, 1.751 mmol) (obtained as described above) was added over 2 min, with evolution of gas. After 80 mm, the solution was allowed to cool to r.t. and stirring was continued overnight, resulting in a very viscous mixture.
  • Step 2 5-tert-Butyl-2-methoxy-l-(methylsulfinyl)-3-nitrobenzene.
  • NaHCO 3 400 mg, 4.76 mmol
  • water 2.5 ml
  • Dimethylsulfate 0.5 ml, 5.3 mmol
  • More dimethylsulfate was added in 2 portions (0.2 ml) each at 3 and 4 hr.
  • the reaction was allowed to cool to r.t. and stirred overnight.
  • the crystalline product was filtered, washed with water and dried.
  • 1 H NMR 500 MHz, CDCl 3 ) ⁇ (ppm) 8.25 (d, IH), 8.14 (d, I H), 4.08 (s, 3H), 3.31 (s, 3H), 1.40 (s, 9H).
  • Step 3 The compound obtained above (155 mg, 0.539 mmol) was dissolved in 12M HCl (1.5 ml) and treated with SnCl 2 .2H 2 O (400 mg, 1.77 mmol) for 40 min. The precipitated was filtered, washed with IM aq. HCl and dried. The residue was triturated with DCM and the solution was evaporated. The combined HCl washes were neutralized with 45% NaOH and the product was extracted into DCM. The organic layer was dried over MgSO 4 , filtered, and evaporated to yield the target compound.
  • 1 H NMR 500 MHz, CDCl 3 ) ⁇ (ppm) 7.82 (bs, IH), 7.68 (bs, IH). 4.14 (s, 3H), 3.25 (s, 3H), 1.35 (s, 9H). Synthesis of heteroaryl amine intermediates.
  • Step 2 To a solution of the compound obtained above (561 mg, 3 mmol) in heptane/THF (30 ml) cooled to -78 ° C under N 2 atmosphere, a solution of t-BuLi 1.7 M (3.4 ml, 6.6 mmol) was added. After 30 minutes ClSnBu 3 (1.8 g, 6.6 mmol) in THF (3 ml) was added and the reaction mixture was stirred for 2 hr at -78 C. Then a solution of 5% AcOH/THF (20 ml) was added and the mixture was allowed to warm up to room temperature. The solvents were evaporated and the residue was dissolved in EtOAcZH 2 O.
  • Step 2 Methyl 2-(4-(3-cyanopropoxy)naphthalen-l-yl)-2-oxoacetate.
  • the title compound was prepared from the compound above (106 mg, 0.5 mmol) using the procedure described in WO2005023761. Briefly, AlCh (1.5 eq.) was mixed with methyl 2- chloro-2-oxoacetate (1.4 eq. an stirred for 5 min. and then added to the starting material, which was suspended in DCM and cooled. The mixture was stirred for 2 hr and then quenched with H 2 O. The organic layer was washed with NaHCO ⁇ , dried and evaporated. The residue was purified over silica gel using EtOAc/Hex.
  • Step 3 Intermediate a was prepared from the compound obtained in the previous step, using the procedure described in WO2005023761, by suspending the material in THF, and treating with LiOH (3-4 eq.) for 2 hr. The compound was extracted into DCM, which was dried, evaporated and used as such in the next step.
  • Step 2 Methyl 2-oxo-2-(4-(2-(2,2,6,6- tetramethylniorphulino)ethoxy)naphthalen-l-yl)acetate.
  • Methyl 2-oxo-2-(4-(2-(2,2,6,6- tetramethylmorpholino)ethoxy)-naphthalen-l -yl)acetate was prepared from the compound obtained above using a similar procedure to that described to above and in WO2005023761.
  • the crude yellow oil (69 mg, 87% yield, >95% pure by LC-MS) was of sufficient purity to be used in the next step. (Calculated mass: 399.5, observed mass: 400.3).
  • Step 3 The target compound was prepared from the compound obtained above using a similar procedure to described in WO2005023761. Specifically, a solution of the compound obtained above was dissolved in THF ⁇ McOH (1/ 1 , 2 ml) and 2 N NaOH (2 eq.) was added. The reaction mixture was stirred at r.t. for 30 min, neutralized with 1 N HCl, and evaporated. The pale brown solid obtained was used in next step without further purification. (Calculated mass: 385.5, observed mass: 386.2).
  • Step 2 Methyl 2-(4-(2-(8-oxa-3-azabicyclo[3.2.11octan-3- yl)ethoxy)naphthalen-l-yl)-2-oxoacetatc.
  • Step 3 The target compound was prepared as above from methyl 2-(4-(2-(8- oxa-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)naphthalen-l-yl)-2-oxoacetate and was obtained as a pale brown solid, which was used in next step without further purification. (Calculated mass: 355.4. observed mass: 356.1). [00367] Intermediate e was similarly prepared using 10-Oxa-4-aza- tricyclo[5.2.1.0 ⁇ 2-,6°]' decane (see WO2004009589).
  • Step 1 tert-Butyl 4-(2-(2,2,6,6-tetramethylmorpholino)ethoxy)naphthalen-l- ylcarbamate.
  • tert-butyl 4-(2-chloroethoxy)naphthalen-l-ylcarbamate 50 mg, 0.16 mmol, prepared as in WO2006010082
  • DMF 2 ml
  • 2,2,6,6-tetramethylmorpholine hydrochloride 29 mg, 0.16 mmol, prepared as in WO2006066174
  • K 2 CO 3 107 mg, 0.78 mmol
  • Step 2 The title compound was prepared by treating the compound obtained above with a 1 :1 mixture of DCM:TFA and was used in the next step without further purification.
  • Step 2 The target compound was prepared as above, from tert-butyl 4-(2-(8- oxa-3-azabicyclo[3.2. l]octan-3-yl)ethoxy)naphthalen-l -ylcarbamate, and was used in the next step without further purification.
  • Example 1 Formation of target compounds via coupling reaction with naphthalenyl oxoacetic acid compounds.
  • the TFA-salt of the final product (58 mg, 14%) was obtained after RP-HPLC (gradient; 10 to 95% AcN in H 2 O), followed by a second RP-HPLC purification (gradient; 40 to 99% AcN in H 2 O) as a thick brown oil. (Calculated mass: 627.7, observed mass: 628.7).
  • Example 2 Formation of target compounds via crosscoupling reaction with bromonaphthalenyl compounds.
  • the intermediate product was prepared from 2-(4-bromonaphthalen-l -yl)-2-oxoacetyl chloride (41 mg, 0.14 mmol, prepared as in WO2006091862) and Intermediate A (24 mg, 0.14 mmol) via an acid chloride coupling reaction similar to described above, using TEA as a base.
  • the title compound was prepared from 2-(4-bromonaphthalen-l-yl)-N- (3-/erf-butyl-5-cyanophcnyl)-2-oxoacetamide (73 mg, 0.17 mmol) (as obtained in step 1 above) and 2-(pyrrolidin-l -yl)p> ⁇ imidin-4-amino (30 mg, 0.19 mmol, prepared as in WO200609186), using the procedure described in W 02006091862. Briefly, the compound obtained above was dissolved in toluene/dioxane 1/1 and BINAP (0.2 eq.), Cs 2 CO 3 (2 eq.) and Pd(II)OAc 2 (0.1 eq.) were added.
  • R 2 NHSO 2 Me
  • R 3 OMe
  • NR 2 4-methylpiperazinyl
  • 2-(4-bromonaphthalen-l -yl)-N-(5-tert-butyl-2- mcthoxy-3-(mcthylsulfonamido)phenyl)-2-oxoacetamide 26 mg, 49 ⁇ mol, see WO2006091862 A2
  • Intermediate IH-A 49 ⁇ mol
  • the pure compound (8.1 mg, 25%) was obtained after RP-HPLC and silica gel purification. (Calculated mass: 645.3, observed mass: 646.3).
  • the target compound was prepared using 2-(4-bromonaphthalen-l-yl)-N-(5-tert-butyl-2- mcthoxy-3-(methylsulfonamido)phenyl)-2-oxoacetamide (prepared as in WO2006091862) and Intermediate IV-B using a similar procedure to that described in WO2006091862. followed by Boc-deprotection as above. (Calculated mass: 631.3, observed mass: 632.1 ).
  • the target compound was prepared from Intermediate Vl (0.1 mmol) and 2-(4-bromonaphthalen-l-yl)- ⁇ r -(5-tcrt-butyl-3-cyano-2-methoxyphenyl)-2-oxoacetamide (32 mg, 0.07 mmol), using a palladium-mediated coupling procedure similar to above (see also WO2006091862).
  • the TFA-salt of the title compound (25.5 mg. 53%) was obtained after preparative LC-MS (gradient: 40 to 100% AcN in H 2 O) as an orange-red solid. (Calculated mass: 577.7, observed mass: 578.2).
  • the reaction was placed under N 2 atmosphere and was heated to 100 0 C for 3 hr.
  • the mixture was filtered through a silica gel column, which was washed with DMF.
  • the resulting solution was purified via preparative LC-MS (gradient: 10-60% AcN/H 2 O over 8.5 min), yielding the target product in 17.1 mg yield. (Calculated mass: 520.7, observed mass: 521.1).
  • the target compound was prepared from 2-(4- bromonaphthalen-l-yl)-2-oxoacetyl chloride (1 12 mg, 0.38 mmol, prepared as in WO2006091862) and 3-tert-butyl-l -p-tolyl-lH-pyrazol-5-amine (87 mg, 0.38 mmol, prepared as in WO2005023761 ) using the acid chloride procedure described above (see also WO2006091862). The residue was chromatographcd over silica gel (gradient: 0 to 50% EtOAc'Hex) to give the final product (72 mg, 39%).
  • the compound was prepared similarly, starting from 2-(4-bromonaphthalen-l-yl)-N-(3-tert-butyl-l-m-tolyl-lH- pyrazol-5-yl)-2-oxoacetamide (36 mg, 0.073 mmol).
  • the title compound was prepared from N-(4-(2-(8-oxa-3-azabicyclo[3.2.1 ]octan-3-yl)ethoxy)naphthalen-l-yl)-2-(5- tert-butyl-2-methylfuran-3-yl)-2-oxoacetamide (itself prepared from 2-(5-tert-butyl-2- methylfuran-3-yl)-2-oxoacetic acid, synthesized as described in WO2006091862, and intermediate g via BOP coupling as described above) using the procedure described in WO2005023761 : namely the starting material was treated with hydroxylamine hydrochloride in EtOH containing catalytic pyridine.
  • N-(3-Azido-5-tert-butyl-2-methoxyphenyl)-2-(4-(2- morpholinocthoxy)naphthalen-l-yl)-2-oxoacetaniide In a 250 ml round-bottomed flask containing the compound obtained above (245 mg, 0.38 mmol), dissolved in 10% H 2 SO 4 (10 ml) in an ice bath, was added sodium nitrite (35 mg, 0.51 mmol). After 10 min stirring, sodium nitrite (50 mg, 0.76 mmol) was added and the reaction was allowed to warm to r.t. The reaction was quenched with solid Na 2 CO 3 and extracted with DCM and dried over Na 2 SO 4 . The solvent was removed to afford 188 mg (103% yield) of the target compound. (Calculated mass: 531.2, observed mass: 532.1).
  • N-(5-tert-Butyl-2-methoxy-3-(lH-l,2,3-triazol-l-yI)phenyl)-2-(4-(2- morpholinoethoxy)naphthaIen-l-yl)-2-oxoacetamide To the compound obtained above (24 mg. 0.038 mmol) in AcN (4 ml) and water (400 ⁇ l) was added TMS-acetylene (700 ⁇ l) and copper wire. After heating at 5U 0 C for seven days, the solvent was evaporated and the reaction was treated with 2M HCl in dioxane (4 ml) and THF (2 ml) for 2 days.
  • N-(5-tcrt-butyl- 2-methoxy-3-(l H-l ,2,3-triazol-l -yl)phenyl)-2-(4-(2-mo ⁇ holinoethoxy)naphthalen-l -yl)-2- oxoacetamide (7.8 mg, 31%yield) (Calculated mass: 557.3, observed mass: 558.1), and N-(5- tert-butyl-2-methoxy-3-(4-(trimethylsilyl)-l H-1.2,3-triazol-l-yl)phenyl)-2-(4-(2- morpholinoethoxy)naphthalen-l -yl)-2-oxoacetamide (8.7 mg, 31 % yield) (Calculated mass: 629.3, observed mass: 630.1).
  • the target compound was prepared using an analogous procedure ( 1 1 mg, 41 % yield) starting from propargyl alcohol (26 mg, 0.45 mmol) and the compound obtained above (24 mg, 0.038 mmol), heating at 100 0 C overnight. (Calculated mass: 587.3, observed mass: 588.1).
  • THP-I cells (ATCC TIB 202, American Type Culture Collection, Rockville, MD) were maintained at 37°C, 5% CO 2 in RPMI 1640 media with 10% fetal bovine serum, 10 mM Hepes, 1 mM sodium pyruvate, 4.5 g/1 glucose and 0.05 mM 2-mercaptoethanol as suggested by ATCC.
  • the cells and compounds were diluted in the media above except with 1% fetal bovine serum (assay media).
  • Test compound stocks in DMSO were diluted into assay media to 6x the final assay concentration, with a final DMSO concentration of less than 0.3% in the assay.
  • THP-I cells were plated at lxl O7well in 96 well tissue culture plates. Diluted compounds (or DMSO control) were added and allowed to preincubate with the cells at 37°C, 5% CO 2 for 30 minutes prior to the addition of LPS (Sigma) to a final concentration of 1 ⁇ g/ml. Cells were then incubated 1 8-20 hours at 37 ° C/5% CO 2 . The assay was terminated by centrifuging the plates for 10 min at r.t.
  • IC50 is the concentration of the test compound that caused a 50% decrease in the maximal TNFa production.
  • the demyelinating disease is induced by administration of myelin basic protein (see Paterson, Textbook of lmmuopathology, Mischer et al., eds., Grune and Stratton, New York, 1986, pp. 179-213; McFarlin et al., Science, 1973, 179, 478: and Satoh et al., J. Immunol., 1987, 138, 179). Examples are described in more detail below.
  • mice with murine type II collagen induces a chronic relapsing polyarthritis that provides a strong model for human autoimmune arthritis.
  • the model is described, for example, by Courtenay et al., Nature, 1980, 282, 666; Kato ct al., Ann. Rheum. Dis., 1996, 55, 535; and Myers et al., Life Sci., 1997, 61, 1861-1878, each of which is incorporated herein by reference. Briefly, mice are quarantined for at least three days. On day 0, the mice are weighed and separated into treatment groups. The non-diseased control group animals receive no adjuvant (10 mice), in contrast to diseased mice (20 mice/treatment group).
  • mice are anesthetized, shaved at the base of tail, and injected (id) with adjuvant (50 ⁇ l/mouse; 100 ⁇ g/mouse collagen; lOO ⁇ g/mouse M. tuberculosis H37Ra), using a 1 ml syringe fitted with a 26 G needle.
  • the adjuvant is prepared by emulsifying (in an homogenizer) a 1 : 1 combination of collagen and M. tuberculosis H37Ra.
  • the adjuvant is injected (id) (50 ⁇ l/mouse; 100 ⁇ g/mouse collagen; 100 ⁇ g/mouse M.
  • tuberculosis H37Ra tuberculosis H37Ra
  • the macroscopic signs of arthritis are scored daily.
  • the mouse weights arc recorded and the macroscopic signs of arthritis are scored.
  • mice are sorted into treatment groups ( 10 mice/group) based upon their arthritic index, Each treatment group is designed to have a similar average Arthritic Index and a similar range of arthritic indices.
  • the dosing regimen by oral route is initiated. On day 29-42 the mice are dosed and any adverse effects of test agent administration are recorded. The macroscopic signs of arthritis for each paw are scored daily. On day 43 the macroscopic signs of arthritis are scored, the mice are exsanguinated and their blood is collected in heparinized tubes. The hindlimbs and/or forelimbs are removed and immersed in four volumes of 10% buffered formalin. The paws are evaluated for decalcification and histology. Livers are removed and their weights are recorded.
  • Total disease score per mouse is calculated by summation of the acute inflammatory or chronic inflammatory scores for each mouse.
  • Efficacy in the TNF A model of Crohn's disease is shown by any of: i) a failure to develop disease symptoms when administered to animals beginning at 3 weeks of age; ii) lessened severity of disease symptoms appearing when administered starting at 3 weeks of age, relative to control animals; iii) failure to progress to more severe disease or progression at a lower rate relative to control animals when administered beginning at 6 weeks of age; iv) reversal of symptoms at any of 7, 8, 9, 10, 1 1 , 12, or 14 weeks when administered to an animal beginning at 6 weeks of age.
  • treatment is considered effective if the average histopathological disease score is lower in treated animals (by a statistically significant amount) than that of a vehicle control group.
  • Treatment is also considered effective if the average histopathological score is lower by at least 0.5 units, at least 1.0 units, at least 1.5 units, at least 2.0 units, at least 2.5 units, at least 3.0 units, or by at least 3.5 units relative to the vehicle-only control group.
  • the treatment is effective if the average histopatholigical score remains at or is lowered to 0 to 0.5 throughout the course of the therapeutic regimen.
  • BALB/c mice The DSS model was originally described by Okayasu et al.. Gastroenterology, 1990, 98, 694 and was modified by Kojouharoff et al., Clin Exp. Immunol. 1997, 107, 353 (sec also WO 2004/041 862, incorporated herein by reference).
  • BALB/c mice weighing 21 -22 g are treated to induce chronic colitis by the administration of DSS in their drinking water at 5% w/v in cycles of 7 days of treatment and 12 days recovery interval without DSS.
  • the 4 th recovery period can be extended from 12 to 21 days to represent a chronic inflammation status, rather than the acute status modeled by shorter recovery.
  • treatment with a compound of the invention, optionally with one or more ingredient(s) A, is initiated.
  • Weekly administration is recommended initially, but can be adjusted by one of skill in the art as necessary.
  • animals are killed, the intestine is dissected and histopathological scores are assessed as described herein or as described in Kojouharoff et al., 1997, supra.
  • Other animal models of inflammatory bowel disease include the chronic intestinal inflammation induced by rectal instillation of 2,4,6-Trinitrobenzene sulfonic acid (TNBS; method described by Neurath et al., J. Exp. Med.. 1995, 182, 1281 ; see also U.S. Patent No. 6,764,838, incorporated herein by reference). Histopathological scoring can be performed using the same standard described above.
  • Ex-vivo LPS challenge endotoxemia model Ex-vivo treatment of blood from patients treated with anti-inflammatory compounds with endotoxin represents a safe, well-defined model of acute inflammation in humans. It is also an excellent tool to study the mechanisms contributing to inflammatory responses in man in vivo. Given the importance of the balance of inflammatory and anti-inflammatory cytokines and other factors in the etiology of inflammatory diseases such as rheumatoid arthritis and Crohn's disease, evaluation of compounds as described herein in a human LPS model could prove beneficial in elucidating potential effects of anti-inflammatory compounds in human inflammatory processes.
  • Compounds described herein are administered orally at different doses to human volunteers. After 1 to 24 hours, blood samples are collected via venepuncture into vacutainer tubes and heparinized. Prior to the stimulation assay, a monocyte count is performed for each individual's undiluted heparinized whole blood sample (Cell Dyn 3500 SL). For this purpose a small volume (100-200 ⁇ l) is aspirated directly form the whole blood sample into the analyzer. For each sample and for each subject the following stimulation assays are performed: a. Unstimulated control (only vehicle) and b. Stimulated: 10 ng/ml LPS (final concentration). The stimulation assays are performed within one hour after withdrawal of the whole blood samples. The stimulation assay procedure is as follows.
  • TNF- ⁇ , IL-1 / 3, IL-6 or other cytokines arc analyzed using validated ELISA methods.
  • Rheumatoid Arhritis disease assessment Rheumatoid arthritis is clinically scored on the basis of several clinically accepted scales, such as those described in U.S. Patent No. 5,698, 195, which is incorporated herein by reference, and Alctaha et al., Clin. Exp. Rheumatol. 2005, 23 (suppl. 39), S 100.
  • Disease activity and change effected with treatment can be evaluated using the disease activity score (DAS) and/or the chronic arthritis systemic index (CASI), see Carotti et al., 2002, Ann. Rheum. Dis. 61:877-882, and Salaffi et al., 2000, Rheumatology 39: 90-96.
  • DAS disease activity score
  • CASI chronic arthritis systemic index
  • Clinical response studies can assess the following parameters: A. Number of tender joints ; B. Number of swollen joints (Both tenderness and swelling are evaluated for each joint separately); and C. Visual analog pain scale (0-10 cm). Clinical response is assessed using a subjective reporting system as follows: Without any difficulty, With some difficulty, With much difficulty, or Unable to do.
  • the visual analog scale for pain is a straight line with the left end of the line representing no pain and the right end of the line representing the worst pain. Patients are asked to mark on the line where they think their pain is.
  • CDAI scores > 150 indicate active disease with a poorer prognosis than scores ⁇ 150.
  • Psoriasis disease assessment Efficacy of psoriasis treatment can be monitored by changes in clinical signs and symptoms of the disease, including Psoriasis Area and Severity Index (PASI) scores, physician's global assessment (PGA) of the patient compared with the baseline condition. A decrease in PASI score indicates a therapeutic effect. Psoriatic disease activity can also be determined based on Overall Lesion Severity (OLS) scale, percentage of total body surface area (BSA) affected by psoriasis, and psoriasis plaque thickness. Skin biopsies are studied for the effects of the drug on lymphocytes within psoriatic lesions.
  • PESI Psoriasis Area and Severity Index
  • PGA physician's global assessment
  • a decrease in PASI score indicates a therapeutic effect.
  • Psoriatic disease activity can also be determined based on Overall Lesion Severity (OLS) scale, percentage of total body surface area (BSA) affected by psorias
  • Histological analysis of skin biopsies can be performed to look for reduction in epidermal thickness and T-cell infiltration and reversal of pathological epidermal hyperplasia. Immunological activity can be monitored by testing for the effects of treatment on cell-mediated immunity reactions (delayed hypersensitivity), tetanus antibody responses, and lymphocyte subpopulations (flow cytometry).
  • Lipid determinations The anti -atherosclerotic activity of compounds may be demonstrated by determining the amount of agent required to alter plasma lipid levels, for example HDL cholesterol levels, LDL cholesterol levels, VLDL cholesterol levels or triglycerides, in the plasma of certain animals, for example marmosets (Crook et al. Arteriosclerosis 10, 625, 1990) or Golden Syrian Hamsters (Goulinet et al., J. Lipid Res., 34, 943, 1993). and others, that possess a plasma lipoprotein profile similar to that of humans.
  • 16 female cynomolgous monkeys are assigned to four dose groups.
  • a compound is formulated in a suitable vehicle at low, medium, and high concentrations.
  • the three dosages of the compound and vehicle alone are administered once daily by oral gavagc for 90 consecutive days to all male and female monkeys in the corresponding dose group.
  • Blood samples (4 to 6 ml) are collected from the femoral vein at days 0, 28, and 90.
  • the blood samples are processed for serum, and clinical chemistry values, including, for example, HDL cholesterol, triglyceride and total bilirubin levels, which are determined by standard methods.
  • Wistar rats are assigned to four dose groups.
  • a compound is formulated in a suitable vehicle at low, medium, and high concentrations.
  • the three dosages of the compound and vehicle alone are administered once daily by oral gavage for 90 consecutive days to all male and female rats in the corresponding dose group.
  • Blood samples (2 to 3 ml) arc collected via the orbital sinus at days 0, 28, and 90.
  • the blood samples are processed for serum, and clinical chemistry values, including, for example, HDL cholesterol levels, which are determined by standard methods.
  • Rabbit Atherosclerosis Assay Anti-atherosclerotic effects of the compounds may be determined by the amount of compound required to reduce the lipid deposition in rabbit aorta. Male New Zealand White rabbits are fed a diet containing 0.2% cholesterol and 10% coconut oil for 4 days (meal-fed once per day). Rabbits are bled from the marginal ear vein and total plasma cholesterol values are determined from these samples. The rabbits are then assigned to treatment groups so that each group has a similar mean.
  • mice are dosed daily with compound given as a dietary admix or on a small piece of gelatin based confection. Control rabbits receive only the dosing vehicle, be it the food or the gelatin confection. The cholesterol/coconut oil diet is continued along with the compound administration throughout the study. Plasma cholesterol values may be determined at any point during the study by obtaining blood trom the marginal ear vein. After 3-5 months, the rabbits are sacrificed and the aortae are removed from the thoracic arch to the branch of the iliac arteries.
  • the aortae are cleaned of adventitia, opened longitudinally and then analyzed unstained or stained with Sudan IV as described by Holman et. al. (Lab. Invest. 1958, 7, 42- 47).
  • the percent of the lesioned surface area is quantitated by densitometry using an Optimas Image Analyzing System (Image Processing Systems). Reduced lipid deposition is indicated by a reduction in the percent of lesioned surface area in the compound-receiving group in comparison with the control rabbits.
  • Cuff induced accelerated atherosclerosis The compounds are tested in a mouse model for restenosis and accelerated atherosclerosis based on cuff placement around the femoral artery in ApoE3 Leiden mice (Lardenoye et al. Circ Res. 2000, 87(3):248-53).
  • fhe model is highly regulated by inflammatory factors (Pires et al. Cardiovasc Res, 68 (2005) 415 ⁇ 424) including TNFa (Monraats et al. FASEB J 2005;19: 1998-2004) and MCP-I, as has been demonstrated by Egashira et al (Circ Res 2002; 90: 1 167-72).
  • Cuff placement in ApoE3 Leiden mice receiving a mild hypcrcholesterolemic diet results in a rapid adhesion and infiltration of monocytes, followed by a rapid induction of neointima formation, and in the induction in foam cell accumulation within the cuffed vessel segment.
  • mice Male ApoE3 Leiden mice (age 12 weeks) are fed a mildly hypercholesterolemic diet for 3 weeks prior to surgical cuff placement. After 3 weeks mice are divided in 3 groups, matched for plasma cholesterol levels. The mice either receive daily (from day-1 on) a control gavage solution or a gavage solution containing test compound (typically at a concentration of 30 mg/kg). On day 0 surgery is performed, i.e. a non- constricting cuff (2-3 mm in length) is placed around both the femoral arteries of the mice.
  • mice are sacrificed after 2 days for analysis of monocyte adhesion and infiltration, and additional mice are sacrificed after 2 weeks for histomorphometric analysis to quantify the (inhibition of) accelerated atherosclerotic lesions and neointima formation.
  • Example 9 Clinical Cardiovascular and Metabolic Disease Assessments
  • BMI body mass index
  • WHR waist to hip ratio
  • OGTT Oral glucose tolerance testing
  • w r hich may be used to diagnose diabetes mellitus
  • Blood glucose levels are then measured over the following 2 hours.
  • glycemia greater than or equal to 1 1 . lmmol/1 at 2 hours or greater than or equal to 7.0mmol/L fasting is diagnostic for diabetes mellitus.
  • OGTT can be normal or mildly abnormal in simple insulin resistance. Often, there are raised glucose levels in the early measurements, reflecting the loss of a postprandial (after the meal) peak in insulin production. Extension of the testing (for several more hours) may reveal a hypoglycemic "dip", which is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response.
  • Iiyperinsulinemic cuglycemic clamp The standard for investigating and quantifying insulin resistance is the "hyperinsulinemic euglycemic clamp," so called because it measures the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia. The procedure takes about 2 hours. Through a peripheral vein, insulin is infused at 10-120 mU per m * per minute. In order to compensate for the insulin infusion, glucose 20% is infused to maintain blood sugar levels between 5 and 5.5 mmol, 1. The rate of glucose infusion is determined by checking the blood sugar levels every 5-10 minutes. Low dose insulin infusions are more useful for assessing the response of the liver whereas high dose insulin infusions are useful for assessing peripheral (i.e.
  • glucose infusion determines insulin sensitivity. If high levels (7.5 mg/min or higher) are required, the subject is insulin-sensitive. Very low levels (4.0 mg/min or lower) indicate that the body is resistant to insulin action. Levels between 4.0 and 7.5 mg/min are not definitive and suggest "impaired glucose tolerance," an early sign of insulin resistance.
  • insulin resistance is quantified using the following formula:
  • HOMA IR values between 1.7 and 2.5 are seen in subjects with normal glucose tolerance
  • Example 10 Analysis of biomarkers in clinical samples.
  • lipid-lowering therapy e.g., statins, bile acid sequestrants, or cholesterol absorption inhibitors
  • a compound as described herein administered orally once daily for 6 weeks.
  • a fasting lipid panel total cholesterol, HDL-C, LDL-C, TG
  • CRP and general laboratory parameters CBC, general chemistry panel
  • CBC general laboratory parameters
  • Week 1 patients have a general chemistry panel assessed.
  • Weight, and waist and hip circumference are assessed at each visit, other than Week 1.
  • Lipid/metabolic, inflammatory, and prothrombotic biomarkers are assessed at Baseline, Week 2, Week 4, Week 6 and Follow-up.
  • Urinalysis and coagulation parameters are assessed at baseline and at the end of dosing.
  • Assay plates are incubated for 72-80 hours at 37°C +/-0.5 0 C with 5% CO 2 .
  • Twenty microliters of 20% Alamar Blue warmed to 37°C +/- 0.5 0 C is added to each assay well following the incubation period.
  • Alamar Blue metabolism is quantified by the amount of fluorescence intensity 3.5-5.0 hours after addition.
  • Quantification using an LJL Analyst AD reader (LJL Biosystems), is taken in the middle of the well with high attenuation, a 100 msec read time, an excitation filter at 530 nm, and an emission filter at 575 nm. For some experiments, quantification is performed using a Wallac
  • Victor reader Measurements are taken at the top of the well with stabilized energy lamp control; a 100 msec read time, an excitation filter at 530 nm, and an emission filter at 590 nm. Ko significant differences between plate readers are measured.
  • the average untreated well value (avg. untreated wells) is the arithmetic mean of 40 wells from the same assay plate treated with vehicle alone. Negative inhibition values result from local variations in treated wells as compared to untreated wells.
  • the anti-cancer effect that can be demonstrated with the tumor cell lines refered to herein can be similarly demonstrated using other cancer cell lines, such as, for example, NSC lung carcinoma, MCF7 mammary adenocarcinoma, PA-I ovarian tcratocarcinoma, HT29 colorectal adenocarcinoma, H 1299 large cell carcinoma, U -2 OS osteogenic sarcoma, U-373 MG glioblastoma, U-1 18 MG glioblastoma, U-138 MG glioblastoma, LN-229 glioma, Hep-3B hepatocellular carcinoma, BT-549 mammary carcinoma, T-24 bladder cancer, C-33A cervical carcinoma, HT- 3 metastatic cervical carcinoma, SiHa squamous cervical carcinoma, CaSki epidermoid cervical carcinoma, NCI- H292 mucoepidermoid lung carcinoma, NCI-2030, non small cell lung carcinoma, HeLa, epit
  • the specificity can be tested by using cells such as NHLF lung fibroblasts, NHDF dermal fibroblasts, HMEC mammary epithelial cells, PrEC prostate epithelial cells, HRE renal epithelial cells, NHBE bronchial epithelial cells, CoSmC Colon smooth muscle cells, CoEC colon endothelial cells, NHEK epidermal keratinocytcs, and bone marrow cells as control cells.
  • cells such as NHLF lung fibroblasts, NHDF dermal fibroblasts, HMEC mammary epithelial cells, PrEC prostate epithelial cells, HRE renal epithelial cells, NHBE bronchial epithelial cells, CoSmC Colon smooth muscle cells, CoEC colon endothelial cells, NHEK epidermal keratinocytcs, and bone marrow cells as control cells.
  • cancer cell lines such as those available from American Type Culture Collection (ATCC) (P.O. Box 1549 Manassas, VA 20108, USA), can be used similarly.
  • ATCC American Type Culture Collection
  • Table 3 lists compounds of the invention prepared using the methods of
  • Example 5 Each compound was analyzed by LCMS and displayed the expected molecular ion. Each of the compounds in Table 3 was tested in the TNFa ELlSA assay (Example 5) and found to have activity therein, with some compounds having IC 5 ⁇ S below 10 ⁇ M in this assay.
  • a range includes each individual member.
  • a group having 1-3 atoms refers to groups having 1 , 2, or 3 atoms.
  • a group having 1-5 atoms refers to groups having 1 , 2, 3, 4, or 5 atoms, and so forth.

Abstract

The present invention provides low molecular weight compounds useful as cytokine inhibitors, and compositions thereof. In particular, compounds of the invention are useful as anti-inflammatory agents. There are further provided methods for the preparation of such agents and their use in preventing or treating conditions mediated by cytokines, such as for example arthritis, pain, cardiovascular disease and cancer.

Description

CYTOKINE INHIBITORS
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application
No. 60/884,571, entitled "Cytokine Inhibitors", filed January 1 1, 2007, and U.S. Provisional Application No. 60/950,091, entitled "Cytokine Inhibitors", filed July 16, 2007, the entire contents of each of which arc incorporated herein by reference. This application is related to U.S. Application No 10/939,324, filed September 10, 2004, entitled "Cytokine Inhibitors", International Application No. PCT/US2006/006682, filed February 23, 2006, entitled "Cytokine Inhibitors and Their Use in Therapy", and International Application No. PCT/US2007/070547, filed June 8, 2007, entitled "Therapy using Cytokine Inhibitors," the entire contents of each of which is incorporated by reference.
EIELD OF THE INVENTION
[0002] The present invention relates to low molecular weight compounds and compositions thereof, useful as cytokine inhibitors, and their preparation. The invention further relates to methods of treating, preventing, modifying and managing a variety of conditions, including cytokinc-mediated disorders or related disorders, which comprise the administration of a cytokine inhibitor, alone or in combination with known therapeutics. The invention also relates to pharmaceutical compositions and dosing regimens using the disclosed compounds, optionally in conjunction with other therapies, for the treatment of a variety of conditions, including autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancer, and the like.
BACKGROUND OF THE INVENTION
[0003] The functioning of the immune system is finely balanced by the activities of pro-inflammatory and anti-inflammatory mediators or cytokines. Some cytokines promote inflammation and are called pro-inflammatory cytokines, whereas other cytokines suppress the activity of pro-inflammatory cytokines and are referred to as anti-inflammatory cytokines. For example, IL-4, IL-10, and IL-I 3 are potent activators ofB lymphocytes, but are also potent anti-inflammatory agents. They are anti-inflammatory cytokines by virtue of their ability to suppress genes for pro-inflammatory cytokines such as IL-I, TNF, and chemokines (CA. Dinarello, Chest. 2000, 118, 503).
[0004] Unregulated activities of these mediators can lead to the development of serious inflammatory conditions. For example, autoimmune diseases arise when immune system cells (lymphocytes, macrophages) become sensitized against the "self. Lymphocytes as well as macrophages are usually under control in this system. However, a misdirection of the system toward the body's own tissues may happen in response to still unexplained triggers. One hypothesis is that lymphocytes recognize an antigen which mimics the "self and a cascade of activation of different components of the immune system takes place, ultimately leading to tissue destruction. Genetic predisposition has also been postulated to be responsible for autoimmune disorders.
[0005] Tumor necrosis factor-α (TNF- a) and interleukin-1 (IL-I ) are proinflammatory cytokines that mediate inflammatory responses associated with infectious agents and other cellular stresses. Overproduction of cytokines such as IL-I and TNF-G! is believed to underlie the progression of many inflammatory diseases including rheumatoid arthritis (RA), Crohn's disease, inflammatory bowel disease, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, congestive heart failure, and psoriasis among others (Dinarello, CA. et al., Rev. Infect. Diseases 1984, 6, 51 ; Salituro et al., Curr. Med. Chem. 1999, 6, 807; Henry et al., Drugs Fut. 1999, 24,1345). Recent data from clinical trials support the use of protein antagonists of cytokines, for example soluble TNF-α receptor fusion protein (etanercept) (Moreland et al., Ann. Intern. Med. 1999, 130, 478) or the monoclonal TNFa antibody (infliximab), for the treatment of rheumatoid arthritis, Crohn's disease, juvenile chronic arthritis and psoriatic arthritis (Rankin et al., Br. J. Rheumatol. 1995, 34, 334; Galadaπ et al. Int J Dermatol. 2003, 42,231 ; Reimold, Am J Med Sci. 2003, 325(2), 75). Thus, the reduction of pro-inflammatory cytokines such as TNF-α (also referred to as TNFa) and interleukin-1 β (IL-Ib) has become an accepted therapeutic approach for potential drug intervention in these conditions.
SUMMARY OF THE INVENTION
[0006] The present invention provides low molecular weight compounds and pharmaceutical compositions thereof. In particular, compounds of the invention are useful for a variety of applications including, e.g., as cytokine release inhibitory agents. There are further provided methods for the preparation of such compounds and for the use of these compounds alone, in mixtures thereof, or in mixtures with other therapeutic agents, in the preparation of medicaments for use in treating various disease states. For example, methods are provided for the use of compounds of the invention in the prevention and treatment of various disorders mediated by cytokines such as inflammatory, cardiovascular, and autoimmune disorders, cancer, pain, and others.
[0007] Thus, there are provided in accordance with one aspect of the invention a compound of Formula I:
I stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is phenyl or pyrazolyl, wherein G is substituted by one or more R1, R2 or R3; X is C(O) or C(S); Ar is (Y)-naphthyl; Y is C(O) or C(NOR); L-Q is selected from:
1) -O-(CM alkyl)-Q, wherein Q is CN, 0-(C)-4 alkyl)-OR, N(C, _4 alkyI-OR)2, or a heterocyclyl group selected from
Figure imgf000004_0002
Figure imgf000005_0001
, i each R is independently F, Cl, Br, I, NR2, CN, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heterocyclylalkyl group; each R' is independently F, Cl, Br. I, CN, NO2, a substituted or unsubstituted alkyl, heterocyclyl, or heterocyclylalkyl group, OR', C(O)R", C(O)OR', C(O)NR'2, NR'2, NRC(O)R", NR'C(O)OR", NR'SO2R", NR'C(0)NR'2, NR'C(S)NR'2, S(O)mR", or
SO2NR'2; each R is independently a substituted or unsubstituted alkyl, alkenyl, or alkynyl group, or an 0(C1^ alkyl) group, wherein each alkyl group is optionally partially or fully halogenated;
R4 is a substituted or unsubstituted C1-4 alkyl, NH-(C1 -8 alkyl), NH-aralkyl, or NH-heterocyclylalkyl group;
R5 is selected from substituted or unsubstituted -NH-(C1 -8 alkyl) group or a substituted or unsubstituted heterocyclyl selected from:
Figure imgf000005_0002
R is selected from a substituted or unsubstituted C1 -4 alkyl, heterocyclyl, NH-(CM alkyl), Nll-alkylaryl, or NH-heterocyclylalkyl group;
R7 is selected from F or Cl, or a substituted or unsubstituted NH-(C2.8 alkyl) group; each R is independently hydrogen or a substituted or unsubstituted C^6 alkyl group; each R' is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclyl, aralkyl, or heterocyclylalkyl group; each R" is independently a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl group; and each m is independently 0, 1 or 2.
[0008] In some embodiments of compounds of Formula I, G is
Figure imgf000006_0001
[0009] In other embodiments of compounds of Formula I, Ar is
Figure imgf000006_0002
[0010] In other embodiments of compounds of Formula I, L-Q is O-(C2-3 alkyl)-Q, and
Q is -N(C2-3 alkyl-OR)2,
Figure imgf000006_0003
[001 1] In some such embodiments, L-Q is
Figure imgf000007_0001
[UOl 2J In some embodiments of compounds of Formula I. L-Q is
Figure imgf000007_0002
and R4 is a substituted or unsubstituted C1-4 alkyl or -NH-(C1-5 alkyl) group. In some such embodiments, R is
Figure imgf000007_0003
[0013] In some embodiments of compounds of Formula I, L-Q is
Figure imgf000007_0006
and R is selected from substituted or unsubstituted
Figure imgf000007_0004
[0014] In some other embodiments of compounds of Formula I, L-Q is
Figure imgf000007_0005
and R6 is
or
Figure imgf000008_0002
Figure imgf000008_0003
[0015J In other embodiments of compounds of Formula I, L-Q is
Figure imgf000008_0001
and R is F, or a 3,3-dimethylbutan-l -amine- 1 -yl group,
[0016] In some embodiments of compounds of Formula 1, R1 is a substituted or unsubstituted C\^, alkyl, or heterocyclyl group. For example, R1 is a substituted or unsubstituted methyl, isopropyl, tert-butyl, isobutyl, sec-butyl, neopentyl, cyclohexyl, pyrrohdinyl, piperidinyl, piperazinyl, oxazepanyl, morpholinyl, or thiomorpholinyl group.
[0017] In some embodiments of compounds of Formula I, R2 is a substituted or unsubstituted (CV6 alkyl), heterocyclyl, or hcterocyclylalkyl group, F, Br, CN, C(O)NR'2, C(O)R", S(O)111R", NR'SO2R", or SO2NR'2 For example, R2 is F, Br, CN, CF3, imidazolyl, triazolyl, tetrazolyl, C(O)NH2, C(O)NH(C5 alkyl), C(O)NH(C3 6 cycloalkyl), C(0)NH(heterocyclyl), C(O)NH(heterocyclylalkyl), (CH2)1-3-heteroeyclylalkyl), C(O)-hetcrocyclyl, NHSO2(CV6 alkyl), NHSO2(CV6 cycloalkyl), NHSO2(heterocyclyl), SO2NH(C1^6 alkyl), SO2N(C1^6 alkyl)2, wherein each C,_ή alkyl, C3.6 cycloalkyl, heterocyclyl, and heterocyclylalkyl gi*oup is substituted or unsubstituted. In some such embodiments, the C].6 alkyl or C3.6 cycloalkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherem the alkyl or cycloalkyl group is optionally substituted by OH or N(C1-3 alkyl)2 . In others, the heterocyclyl group is a pyrrohdinyl, piperidinyl, piperazinyl, azepanyl, or 3,8-diazabicyclo[3.2.1]octanyl group. In still others, the heterocyclylalkyl group is a (CH2) 1-3-pyrrolidinyl, (CH2)!_3-piperidinyl, (CH2)i_3-piperazinyl, (CH2)i_3-furanyl, (CH2)i_3-oxazolyl, or (CH2)i_3-isoxazolyl group. In some such embodiments, the heterocyclyl and heterocyclylalkyl group is substituted with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, neopentyl, (CH2)0.3-cyclopropyl, (CH2)0.3 -cyclobutyl, (CH2)0-3-cyclopentyl, (CH2)0-3-cyclohexyl, (CH2)2.3-OH, (CH2)0-3NH(C1-3 alkyl), (CH2)O-^N(CL3 alkyl)2, and (CH2)1-3-pyrrolidinyl.
[0018] In some embodiments of compounds of Formula 1, R3 is a substituted or unsubstituted C1-4 alkyl or O(Cμ alkyl) group, or is a partially or fully halogenated 0(C1-2 alkyl) group.
[0019] In some embodiments of compounds of Formula I, G is phenyl and R1 a substituted or unsubstituted methyl, isopropyl, tert-butyl, isobutyl, sec-butyl, neopentyl, cyclohexyl, pyrrolidinyl, pipcridinyl, piperazinyl, oxazepanyl, morpholinyl, or thiomorpholinyl group. In some such embodiments, R" is a substituted or unsubstituted (C1-6 alkyl) or heterocyclylalkyl group, F, Br, CN, C(O)NR'2, C(O)R", S(O)mR", NR1SO2R' or SO2NR'2. For example, R2 is F, Br, CN, CF3, imidazolyl, triazolyl, tetrazolyl, C(O)NH2, C(O)NH(C1-6 alkyl), C(O)NH(C3-6 cycloalkyl), C(O)NH(heterocydyl), C(O)NH(hetcrocyclylalkyl), (CH2)1-3-heterocyclylalkyl), C(0)-heterocyclyl, NHSO2(C1-6 alkyl), NHSO2(C3-6 cycloalkyl), NHSO2(heterocyclyl), SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, wherein each C1-6 alkyl, C3-6 cycloalkyl, hcterocyclyl, and heterocyclylalkyl group is substituted or unsubstituted. In some such embodiments, theC1-fi alkyl or C3-6 cycloalkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,. In others, the heterocyclyl group is a pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, or 3,8-diazabicyclo[3.2.1 ]octanyl group. In still others, the heterocyclylalkyl group is a (CH2)1-3-pyrrolidinyl, (CH2)1-3-piperidinyl, (CH2)1-3-piperazinyl, (CH2) 1-3-ruranyl, (CH2)1-3-oxazolyl, or (CH2)1-3-isoxazolyl group. In some such embodiments, the C1-6 alkyl, C3-6 cycloalkyl, heterocyclyl, and heterocyclylalkyl group is substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, neopentyl, (CH2)0.3-cyclopropyl, (CH2)0-3-cyclobutyl, (CH2)0-3-cyclopentyl, (CH2)0-3-cyclohexyl, (CH2)^3-OH, (CH2)0-3NH(C1-3 alkyl), (CH2)0-3N(C1-3 alkyl)2, or (CH2)1-3-pyrrolidinyl. In some such embodiments, R3 is a substituted or unsubstituted C1-4 alkyl or O(CM alkyl) group, or is a partially or fully halogenated 0(C1-2 alkyl) group.
[0020] Where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group. By way of illustration and not limitation, Table 1 sets forth various combinations of substituents of Formula 1 as described herein. Thus, e.g., combination 1006 describes those embodiments in which G is phenyl and L-Q is O-(Cμ alkyl)- N(C M alkyl-OR)2.
Table 1 : Exemplary combinations of G and L-Q for Formula I.
Figure imgf000010_0001
Figure imgf000011_0001
[0021 ] Table 2 sets forth various combinations of substituents X and Y of Formula I.
Thus, e.g., combination 2000 describes those embodiments in which X is C(O) and Y is C(O). Further, those skilled in the art will understand that a combination of substituents is permissible only if such a combination results in a chemically stable compound, and that any combination from Table 1, describing G and L-Q, may be combined with any combination from Table 2, describing X and Y. For example, combination 1006 from Table 1 and combination 2000 from Table 2 describe those embodiments of Formula I in which G is phenyl, L-Q is O-(C,_4 alkyl)- N(C1-4 alkyl-OR)2, X is C(O) and Y is C(O). Each G and L-Q in the tables is understood to be optionally substituted as described herein. Moreover, each value of R1 ( F, Cl, Br, I, NR2, CN, or a substituted or unsubstituted alkyl, alkcnyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heterocyclylalkyl group) may be combined with any combination from Table 1 or Table 2 or any pair of combinations from the two tables. Thus, e.g., it will be understood that combination 2000 describes those embodiments in which R1 is F, X is C(O) and Y is C(O), as well as those where R1 is -NR2, X is C(O) and Y is C(O), etc.
Table 2: Exemplary combinations of X and Y for Formula I.
Figure imgf000012_0001
[0022] In another embodiment, the cytokine inhibitor is selected from List I.
List I.
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(hydroxyimino)-2-(4-(2- (pyrrolidin-l -yl)pyrimidin-4-ylamino)naphthalen-l-yl)acetamide; N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-hydroxy-2-(4-(2-(pyrrolidin-l- yl)pyrimidin-4-ylamino)naphthalen- 1 -yl)acetamide; N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(3-cyanopropoxy)naphthalen-
1 -yl)-2-oxoacetamide; N-(5-tert-butyl-2-methoxy-3-(propylsulfonamido)phenyl)-2-(4-(3-cyanopropoxy)naphthalen-
1 -yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(2-(2- mcthoxycthoxy)ethoxy)naphthalen-l-yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(propylsulfonamido)phenyl)-2-(4-(2-(2- methoxyethoxy)ethoxy)naphthalen-l -yl)-2-oxoacetamidc;
2-(4-bromonaphthalen-l-yl)-N-(3-tert-butyl-5-cyanophenyl)-2-oxoacetamide;
N-(3-tert-butyl-5-cyanophenyl)-2-oxo-2-(4-(2-(pyrrolidin-l-yl)pyrimidin-4- ylamino)naphthalen- 1 -yl)acetamide:
N-(3-tluoro-5-morpholinophenyl)-2-oxo-2-(4-(2-(pyrrolidin-l-yl)pyrimidin-4- ylamino)naphthalen-l -yl)acetamidc:
N-(3-tert-butyi-5-cyanophenyl)-2-(4-(2-morpholinoethoxy)naphthalcn-l-yl)-2-oxoacetamide; N-(3-fluoro-5-morpholmophenyl)-2-(4-(2-morpholinoethoxy)naphthalen-l-yl)-2- oxoacetamide;
N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-(4-(2-morpholinoethoxy)naphthalen- l-yl)-2- oxoacetamide;
N-(3-tert-butyl-l-p-tolyl-lH-pyrazol-5-yl)-2-oxo-2-(4-(2-(pyrrolidin-l -yi)p>Timidin-4- ylamino)naphthalen-l-yl)acetamide;
N-(3-tert-butyl-l-m-tolyl-lH-pyrazol-5-yl)-2-oxo-2-(4-(2-(pyrrolidin-l -yl)pyrimidin-4- ylamino)naphthalen-l-yl)acetamide;
N-(3-cyano-5-morpholinophenyl)-2-(4-(2-morpholinoethoxy)naphthalen- l-yl)-2- oxoacetamide;
N-(3-morpholino-5-(trifluoromethyl)phenyl)-2-(4-(2-morpholinoethoxy)naphthalen-l-yl)-2- oxoacetamide;
2-(4-(2-morpholmoethoxy)naphthalen-l-yl)-2-oxo-N-(3-(piperidin-l -yl)-5-
(tri fl uoromethyl)phenyl) acetami d e;
2-(4-(2-morpholinoethυxy)naphthalen-l-yl)-2-oxo-N-(3-(pyrrolidin-l-yl)-5-
(trifluoromethyl)phenyl)acetamide;
N-(3-bromo-5-tert-butyl-2-methoxyphenyl)-2-(4-(2-morpholinoethoxy)naphthalen-l-yl)-2- oxoacetamide;
N-(5-tert-butyl-2-methoxyphenyl)-2-oxo-2-(4-(2-(pyrrolidin-l-yl)pyrimidin-4- ylamino)naphthalen-l-yl)acetamide;
5-tert-butyl-2-methoxy-3-(2-(4-(2-morpholinoethoxy)naphthalcn-l -yl)-2-oxoacetamido)-N-
(oxazol-2-ylmethyl)benzamide;
5-tcrt-butyl-2-methoxy-N-((5-methylfuran-2-yl)methyl)-3-(2-(4-(2- morpholinoethoxy)naphthalen- 1 -yl)-2-oxoacetamido)benzamide;
N-(3-cyano-5-(piperidin-l-yl)phcnyl)-2-(4-(2-morpholinoethoxy)naphthalen-l-yl)-2- oxoacetamide:
N-(3-cyano-5-(pyrrolidin-l-yl)phenyl)-2-(4-(2-morpholinoethoxy)naphthalen-l-yl)-2- oxoacetamide;
N-(5-tcrt-butyl-3-cyano-2-methoxyphenyl)-2-oxo-2-(4-(2-(2,2.6,6- tetramethylmorpholino)cthoxy)naphthalen-l-yl)acetamide;
2-(4-(2-(8-oxa-3-a7a-bicyclo[3.2.1Joctan-3-yl)ethoxy)naphthalen-l-yl)-N-(5-tert-butyl-2- methoxy-3-(methylsulfonamido)phenyl)-2-oxoacetamidc; 2-(4-(2-(8-oxa-3-aza-bicyclo[3.2.1 ]octan-3-yl)ethoxy)naphthalen-l-yl)-N-(5-tert-butyl-3- cyano-2-methoxyphenyl)-2-oxoacetamidc;
N-(5-tert-butyl-2-methoxy-3-(l H-tetrazol-5-yl)pheny])-2-(4-(2- morpholinoethoxy)naphthalen-l -yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(2-(4-methylpiperazin-l - yl)pyπmidin-4-ylamino)naphthalen-l -yl)-2-oxoacetamide;
2-(3-tcrt-butyl- l -methyl- lH-pyrazol-5-yl)-2-oxo-N-(4-(2-(2,2,6)6- tetramcthylmorpholino)ethoxy)naphthalcn- 1 -yl)acctamidc;
N-(4-(2-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)ethoxy)naphthalen-l-yl)-2-(3-tert-butyl-l - methyl- 1 H-pyrazol-5-yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(2-(2,2,6,6- tetramethylmoφholino)pyτimidin-4-ylamino)naphthalen-l-yl)acetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(2-(piperazin-l- yl)pyrimidin-4-ylamino)naphthalen- 1 -yl)acetamidc;
N-(5-tert-butyl-2-methoxy-3-(methylsulfbnamido)phenyl)-2-oxo-2-(4-(4-(piperazin-l - yl)pyrimidin-2-ylamino)naphthalen-l-yl)acetamide;
N-(5-terl-butyl-3-cyano-2-methoxyphenyl)-2-oxo-2-(4-(2-(2,2,6,6- tetramethylmorpholino)pyrimidin-4-ylamino)naphthalen-l-yl)acetamide;
2-(4-(2-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)pyrimidin-4-ylamino)naphthalen-l-yl)-N-(5- tert-butyl-3-cyano-2-mcthoxyphcnyl)-2-oxoacctamidc;
N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-(4-(2-(3,3-dimethylbutylamino)pyridin-4- ylamino)naphthalen-l -yl)-2-oxoacetamide;
N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-(4-(2-(2-(2,6-dimethylpiperidin-l - yl)ethylamino)pyridin-4-ylamino)naphthalen-l-yl)-2-oxoacetamide;
N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-oxo-2-(4-(pyridin-4-ylamino)naphthalen-l- yl)acctamidc;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(2-(3,5-dimethylpiperazin-l- yl)pyrimidin-4-ylamino)naphthalen-l-yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(4-(3,5-dimethylpiperazin-l - yl)pyrimidin-2-ylamino)naphthalen-l-yl)-2-oxoacetamide:
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-{4-[2-(10-oxa-4-aza- tπcyclo[5.2.1.02.6]dec-4-yl)-ethoxy]-naphthalen-l-yl}-2-oxo-acctamide: N-(.5-tert-Butyl-3-cyano-2-mcthoxy-phcnyl)-2- {4-[2-(10-oxa-4-aza-tricyclo[5.2.1.02,6]dec-4- yl)-ethoxy]-naphthalen-l -yl}-2-oxo-acetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(2-(3,3- dimeth)lbutylamino)pyridin-4-ylamino)naphthalen-l -yl)-2-oxoacetamide;
2-(4-(2-(bis(2-hydroxycthyl)amino)ethoxy)-naphthalen-l-yl)-N-(5-tert-butyl-2-methoxy-3-
(methylsulfonamido)phenyl)-2-oxoacetamide;
4-(2-(4-(2-(5-tert-butyl-2-mcthoxy-3-(methylsulfonamido)-phenylammo)-2- oxoacctyl)naphthalen-l-yloxy)ethyl)morpholine 4-oxide;
N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-(4-(2-methylpyridin-4-yl)naphthalen-l -yl)-2- oxoacetamide;
N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-oxo-2-(4-(pyridin-4-yl)naphthalen-l - yl)acetamide;
N-(5-tert-butyl-3-cyano-2-methoxyphcnyl)-2-oxo-2-(4-(pyridin-3-yl)naphthalen-l - yl)acctamidc
N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-(4-(6-methoxypyridin-3-yl)naphlhalen-l -yl)-2- oxoacetamide;
N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-(4-(6-fluoropyridin-3-yl)naphthalen-l-yl)-2- oxoacetamide;
N-(5-tert-butyl-3-cyano-2-mcthoxyphenyl)-2-(4-(2-(4-methylpiperazin-l-yl)pyridin-4- yl)naphthalen-l-yl)-2-oxoacetamide;
2-(4-(2-(bis(2-methoxyethyl)amino)ethoxy)naphthalen-l -yl)-N-(5-tert-butyl-2-methoxy-3-
(methylsulfonamido)phenyl)-2-oxoacetaraide;
N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-(4-(6-(methylamino)pyridin-3-yl)naphthalen-l - yl)-2-oxoacetamide;
N-(5-tert-butyl-3-cyano-2-mcthoxyphcnyl)-2-(4-(6-(3,3-dimethylbutylamino)pyridin-3- yl)naphthalen-l-yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(4-methylpiperazine-l-sulfunamido)phenyl)-2-(4-(2- morpholinoethoxy)naphthalen-l-yl)-2-oxoacetamide;
N-(3-tert-butyl-5-((4-methylpiperazin-l -yl)methyl)phcnyl)-2-oxo-2-(4-(pyridin-3- yl)naphthalen- 1 -yl)acetamide;
N-(5-tert-butyl-3-cyano-2-mcthoxyphcnyl)-2-oxo-2-(4-(2-(pyrrolidin-l -yl)pyrimidin-4- ylammo)naphthalen-l-yl)acetamide; (Z)-2-(4-(2-(8-oxa-3-aza-bicyclo[3.2.1 ]octan-3-yl)ethoxy)naphthalen-l-yl)-N-(5-tert-butyl-3- cyano-2-methoxyphenyl)-2-(hydroxyimino)acetamide;
(Z)-2-(4-(2-(8-oxa-3-aza-bicyclo[3.2.1 ]octan-3-yl)pyi"imidin-4-ylamino)naphthalen-l -yl)-N-
(5-tert-butyl-3-cyano-2-methϋxyphenyl)-2-(hydroxyimino)acetamide;
N-(3-tert-butyl-5-((4-methylpiperazin-l -yl)methyl)phenyl)-2-(4-(6-(methylamino)pyridin-3- yl)naphthalen- 1 -yl)-2-oxoacetamide;
N-(3-tcrt-butyl-5-((4-methylpiperazin-l-yl)methyl)phenyl)-2-(4-(2-methylpyridin-4- yl)naphthalen- 1 -yl)-2-oxoacetamidc;
2-(4-(2-(l ,4'-bipiperidin-l '-yl)pyrimidin-4-ylamino)naphthalen-l -yl)-N-(5-tert-butyl-2- methoxy-3-(methylsulfonamido)phenyl)-2-oxoacetamide;
(S)-N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(2-(2-(pyrrolidin- l -ylmethyI)pyrrolidin-l-yl)pyrimidin-4-ylamino)naphthalen-l -yl)acetamide;
(R)-N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(2-(3-
(dimethylamino)pyrrolidin-l-yl)pyrimidin-4-ylamino)naphthalcn-l-yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonaniido)phenyl)-2-(4-(2-(4-isopropylpiperazin-l- yl)pyπmidin-4-ylamino)naphthalen-l -yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(2-(4-methyl-l ,4-diazepan-l- yl)pyτimidin-4-ylamino)naphthalen-l -yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3 -(methylsulfonamido)phenyl)-2-(4-(2-(4-morpholinopiperidin- 1 - yl)pyrimidin-4-ylamino)naphthalen-l-yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(2-(4-
(cyclϋpropylmethyl)piperazin-l-yl)pyrimidin-4-ylamino)naphthalen-l -yl)-2-oxoacetamide;
N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-(4-(2-(4-(cyclopropylmethyl)piperazin-l- yl)pyrimidin-4-ylamino)naphthalen-l-yl)-2-oxoacetamide;
2-(4-(2-(l ,4'-bipiperidin-r-yl)pyrimidin-4-ylamino)naphthalen-l-yl)-N-(5-tert-butyl-3- cyano-2-methoxyphenyl)-2-oxoacetamide;
(S)-N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-oxo-2-(4-(2-(2-(pyrrolidin-l - ylmethyl)pyrrolidin-l-yl)pyτimidin-4-ylamino)naphthalen-l-yl)auetamide;
(R)-N-(5-tert-butyI-3-cyano-2-methoxyphenyl)-2-(4-(2-(3-(dimethylamino)pyrrolidin- l - yl)pyrimidin-4-ylamino)naphthalen- 1 -yl)-2-oxoacetamide;
N-(5-tcrt-butyl-3-cyano-2-methoxyphenyl)-2-(4-(2-(4-isopropylpiperazin-l-yl)pyrimidin-4- y]amino)naphthalen-l -yl)-2-oxoacetamide; N-(5-tert-butyl-3-cyano-2-methoxyphcnyl)-2-(4-(2-(4-methyl-l ,4-diazepan-l-yl)pyrimidin-4- ylamino)naphthalen-l-yl)-2-oxoacetamide;
N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-(4-(2-(4-moφholinopiperidin-l-yl)pyrimidin-4- ylaminυ)naphthalen-l -yl)-2-υxoacetamide;
(E)-2-(4-(2-(8-oxa-3-aza-bicyclo[3.2.1 ]octan-3-yl)ethoxy)naphthalen-l -yl)-N-(5-tert-butyl-3- cyano-2-methoxyphenyl)-2-(hydroxyimino)acetamide;
(E)-2-(4-(2-(8-oxa-3-aza-bicyclo[3.2.1 ]octan-3-yl)pyrimidin-4-ylamino)naphthalen-l -yl)-N-
(5-tert-butyl-3-cyano-2-methox>'phenyl)-2-(hydiOxyimino)acetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(2-(2,2,6,6- tetramethylmorpholino)ethoxy)naphthalen-l-yl)acetamide;
N-(5-tert-butyl-2-methoxyphenyl)-2-(4-(2-(cyclopropylamino)pyridin-4-ylamino)naphthalen-
1 -yl)-2~oxoacetamide;
N-(5-tert-butyl-2-methoxyphenyl)-2-(4-(2-(3,3-dimethylbutylamino)pyridin-4- ylamino)naphthalen-l-yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxyphenyl)-2-(4-(2-(2-(2,6-dimethylpiperidin-l- yl)ethylamino)pyridin-4-ylamino)naphthalen-l-yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxyphenyl)-2-(4-(2-methylpyridin-4-ylamino)naphthalen-l-yl)-2- oxoacetamide;
N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-(4-(2-methylpyridin-4-ylamino)naphthalen-l - yl)-2-oxoacetamide;
2-(4-(2-(benzylamino)pyridin-4-ylamino)naphthalen-l-y])-N-(5-tert-butyl-2- methoxyphenyl)-2-oxoacetamide;
(S)-N-(5-tert-butyl-2-methoxyphenyl)-2-oxo-2-(4-(2-(l-phenylethylamino)pyridin-4- ylamino)naphthalen- 1 -yl)acetamide;
2-(4-(2-(benzylamino)pyridin-4-ylamino)naphthalen-l-yl)-N-(5-tert-butyl-3-cyano-2- methoxyphenyl)-2-oxoacetamide;
(S)-N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-oxo-2-(4-(2-(l-phenylethylamino)pyridin-
4-ylamino)naphthalen- 1 -yl)acetamide;
N-(5-tert-butyl-2-methoxy-3-(piperazine-l-carbonyl)phenyl)-2-(4-(2- moφholinoethoxy)naphthalen-l-yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(4-methylpiperazine-l-carbonyl)phenyl)-2-(4-(2- moφholinoethoxy)naphthalen-l-yl)-2-oxoacetamide; N-(5-tert-butyl-3-(4-isopropylpiperazine-l-carbonyl)-2-methoxyphenyl)-2-(4-(2- morpholinoethoxy)naphthalen-l-yl)-2-oxoacetamide:
N-(5-tert-butyl-3-(4-(cyclopropylmethyl)piperazine-l -carbonyl)-2-methoxypheny])-2-(4-(2- morphϋlinυethoxy)naphthalen- 1 -yl)-2-oxoacetamide;
N-(5-tert-butyl-3-(4-(2-hydroxyethyl)piperazine-l -carbonyl)-2-methoxyphenyl)-2-(4-(2- morpholinoethoxy)naphthalen-l -yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(4-methyl-l ,4-diazepane-l-carbonyl)phenyl)-2-(4-(2- moφholinoethoxy)naphthalen- 1 -yl)-2-oxoacctamidc;
(R)-N-(5-tert-butyl-3-(3-(dimethylamino)pyrrolidine-l -carbonyl)-2-methoxyiihenyl)-2-(4-(2- moφholinoethoxy)naphthalen- 1 -yl)-2-oxoacetamide;
5-tert-butyl-2-methoxy-N-(l-methylpiperidin-4-yl)-3-(2-(4-(2-moφholinoethoxy)naphthalen- l-yl)-2-oxoacetamido)benzamide;
(S)-N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-oxo-2-(4-(2-(l - phcnylcthylamino)pyrimidin-4-ylamino)naphthalcn-l -yl)acctamide;
N-(3-(3,8-diaza-bicyclo[3.2.1 ]octane-3-carbonyl)-5-tert-butyl-2-methoxyphenyl)-2-(4-(2- morphϋlinoethoxy)naphthalen-l-yl)-2-oxoacetamide;
N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-(4-(2-(cyclopropylamino)pyrimidin-4- ylamino)naphthalen-l-yl)-2-oxoacetamide;
5-tert-butyl-2-methoxy-3-(2-(4-(2-moφholinoethoxy)naphthalen-l -yl)-2-oxoacetamido)-N-
(piperidin-4-yl)benzamide;
5-tert-butyl-2-methoxy-3-(2-(4-(2-moφholinoethoxy)naphthalen-l -yl)-2-oxoacetamido)-K-
(piperidin-3-yl)benzamide;
N-(5-tert-butyl-2-methoxyphenyl)-2-(4-(2-(cyclopropylamino)pyrimidin-4- ylamino)naphthalen-l-yl)-2-oxoacetamide;
5-tert-butyl-N-((l -ethylpyrrolidin-2-yl)methyl)-2-methoxy-3-(2-(4-(2- moφholinoethoxy)naphthalen- 1 -yl)-2-oxoacetamido)benzamide;
5-tert-butyl-2-methoxy-N-((l -methylpiperidin-4-yl)methyl)-3-(2-(4-(2- mϋφholinoethoxy)naphthaleπ- 1 -yl)-2-oxoacetamido)benzamide;
(S)-N-(5-tert-butyl-2-methoxy-3-(2-(pyrrolidin-l-ylmethyl)pyrrolidine-l-carbonyl)phenyl)-2-
(4-(2-moφholinoethoxy)naphthalen-l-yl)-2-oxoacetamide;
N-(5-tert-butyl-3-(2-((dimethylamino)methyl)piperidine-l-carbonyl)-2-methoxyphcnyl)-2-(4-
(2-moφho]inoethoxy)naphthalen-l-yl)-2-oxoacetamide; 5-tert-butyl-2-methoxy-3-(2-(4-(2-morphohnocthoxy)naphthalen-l-yl)-2-oxoacetamido)-N-
(2-(pyrroIIdIn-I -yl)cthyl)benzamide;
5-tert-butyl-2-methoxy-N-((l-methylpiperidin-2-yl)methyl)-3-(2-(4-(2- morpholmoethoxy)naphthalen-l-yl)-2-oxoacetamido)benzamide;
3-tert-butyl-5-(2-(4-(2-morpholinoethoxy)naphthalen-l -yl)-2-oxoacetamido)-N-(piperidin-3- yl)benzamide;
3-tert-butyl-5-(2-(4-(2-morpholinoethoxy)naphthalcn-l -yl)-2-oxoacetamido)-N-(2-
(pyrrohdm-2-yl)ethyl)benzamidc;
3-tert-butyl-N-(2-(methylamino)ethyl)-5-(2-(4-(2-morpholinoethoxy)naphthalen-l -yl)-2- oxoacetamido)benzamide;
3-tert-butyl-N-(2-(diethylamino)ethyl)-5-(2-(4-(2-moφholinoethoxy)naphthalen-l -yl)-2- oxoacetamido)benzamide;
N-(5-tert-butyl-3-(l H-imidazol-l-yl)-2-methoxyphenyl)-2-(4-(2- moφholinoethoxy)naphthalen-l -yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(4-methyl-lH-imidazol-l-yl)phenyl)-2-(4-(2- morpholinoethoxy)naphthalen-l-yl)-2-oxoacetamide;
2-(4-(2-(8-oxa-3-aza-bicyclo[3.2.1 ]octan-3-yl)pyτimidin-4-ylamino)naphthalen-l-yl)-N-(5- tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxoacetamide;
N-(3-azido-5-tert-butyl-2-methoxyphenyl)-2-(4-(2-morpholinocthoxy)naphthalen-l -yl)-2- oxoacetamide;
N-(5-tcrt-butyl-2-methoxy-3-( l H-l ,2,3-triazol-l-yl)phenyl)-2-(4-(2- morpholinoethoxy)naphthalen- 1 -yl)-2-oxoacetamide;
N-(5-tert-butyl-3-(4-(hydroxymethyl)-lH-l ,2.3-triazol-l-yl)-2-methoxyphenyl)-2-(4-(2- moφholinoethoxy)naphthalen- 1 -yl)-2-oxoacetamide;
N-(5-tcrt-butyl-2-methoxy-3-(4-(tπmethylsilyl)-lH-l,2,3-triazol-l-yl)phenyl)-2-(4-(2- morpholinoethoxy)naphthalen-l-yl)-2 -oxoacetamide;
N-(5-tert-butyl-3-(N,N-dimethylsulfamoyl)-2-methoxyphenyl)-2-(4-(2- morpholinoethoxy)naphthalen-l -yl)-2-oxoacetamide;
N-(3-tert-butyl-5-(methylsulfonamido)phenyl)-2-(4-(2-morpholinoethoxy)naphthalen-l-yl)-
2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonyl)phenyl)-2-(4-(2-morphohnoethoxy)naphthalen-
1 -yl)-2-oxoacetamidc; N-(4-(2-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)cthoxy)naphthalen-l-yl)-2-(5-tert-butyl-2- methylfuran-3-yl)-2-oxoacctamide;
(H)-N-(4-(2-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)ethoxy)naphthalen-l-yl)-2-(5-tert-butyl-2- methylfuran-3-yl)-2-(hydroxyimino)acetamide;
(Z)-N-(4-(2-(8-oxa-3-aza-bicyclor3.2.1 ]octan-3-yl)ethoxy)naphthalen-l-yl)-2-(5-tert-butyl-2- methylfuran-3-yl)-2-(hydroxyimino)acetamide;
(Z)-N-(4-(2-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)ethoxy)naphthalen-l-yl)-2-(3-tert-butyl-l- m ethyl- 1 H-pyrazol-5-yl)-2-(hydroxyimino)acetamide;
(E)-N-(4-(2-(8-oxa-3-aza-bicyclo[3.2.1 ]octan-3-yl)ethoxy)naphthalen-l-yl)-2-(3-tert-butyl-l- m ethyl- 1 H-pyrazol-5-yl)-2-(hydroxyimino)acetamide
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(2-(piperidin-l - yl)ethoxy)naphthalen-l-yl)acetamide;
2-(4-(2-morpholinoethoxy)naphthalen-l-yl)-N-(naphthalcn-2-yl)-2-oxoacetamide;
N-(5-isopropyl-2-methoxyphenyl)-2-(4-(2-morpholinoethoxy)naphthalen-l-yl)-2- oxoacctamide;
2-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-N-(4-(2-morpholinoethoxy)- naphthalen-l-yl)-2-oxoacetamide; and tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof.
[0023] In some embodiments, the compounds of the invention at a concentration of
10 μM inhibit induced TNFa-release from a cell by about 50% or greater than 50%.
[0024J In another aspect, there are provided compounds of Formula II:
Figure imgf000020_0001
Formula II wherein X is CN, CF3, or a halogen (such as F, Br or Cl); and PN is H or an amine protecting group, such as a Boc group. Compounds of Formula II are useful intermediates in the synthesis of various cytokine inhibitors described herein (see Examples). [0025] In another aspect, the invention provides compositions comprising a compound as described herein and a pharmaceutically acceptable carrier.
[0026] In yet another aspect, the invention provides methods of treating disorders mediated by cytokines, including but not limited to inflammatory disorders, autoimmune disorders, cardiovascular disorders, cancer and pain. The methods include administering to a subject in need of such treatment a therapeutically effective amount of a compound as described herein. In some such embodiments, the cytokine-mcdiated disorder is a p38 MAPK-mcdiatcd disorder. In other embodiments, the cytokine is selected from TNFa, IL-I , IL-6, IL-S, GM-CSF, and IFN-gamma, or a combination of any two or more thereof. In others, the cytokine is TNFa or IL-I . In some embodiments, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A), as described herein.
[0027] Cytokine-mediated disorders include rheumatoid arthritis, osteoarthritis,
Crohn's disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejections, pancreatitis, insulinitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, leprosy, acute synovitis, Reiter's syndrome, gouty arthritis, Behcet's disease, spondylitis, endometriosis, non-articular inflammatory conditions, such as intervertebral disk syndrome conditions, bursitis, tendonitis, tenosynovitis or fibromyalgic syndrome; and acute or chronic pain, including but not limited to neurological pain, neuropathies, polyneuropathies, diabetes-related polyneuropathies, trauma, migraine, tension and cluster headache, Horton's disease, varicose ulcers, neuralgias, musculoskeletal pain, osteo-traumatic pain, fractures, algodystrophy, spondylarthritis, fibromyalgia, phantom limb pain, back pain, vertebral pain, post-surgery pain, herniated intervertebral disc-induced sciatica, cancer-related pain, vascular pain, visceral pain, childbirth-related pain, or HIV- related pain.
[0028] Other cytokine-mediated disorders are stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, coronary heart disease, coronary artery disease, acute coronary syndrome, 1 akayasu arteritis, cardiac failure such as heart failure, cardiomyopathy, myocaiditis. \ ascuhtis, vascular restenosis, valvular disease or coronary artery bypass, hypercholesteremia, diseases or conditions related to blood coagulation or fibrinolysis, such as for example, acute venous thrombosis, pulmonary embolism, thrombosis during pregnancy, hemorrhagic skin necrosis, acute or chronic disseminated intravascular coagulation (DIC), clot formation from surgery, long bed rest or long periods of immobilization, venous thrombosis, fulminant menmgococccmia, acute thrombotic strokes, acute coronary occlusion, acute peripheral arterial occlusion, massive pulmonary embolism, axillary vein thiombosis, massive iliofemoral vein thrombosis, occluded arterial or venous cdnnulae. cardiomyopathy, venoocclusive disease of the liver, hypotension, decreased cardiac output, decreased vascular resistance, pulmonary hypertension, diminished lung compliance, leucopenia or thrombocytopenia, or atherosclerosis Yet others are allergic conjunctivitis, uveitis, glaucoma, optic ncuπtis, retinal ischemia, diabetic retinopathy, laser induced optic damage, or surgery or trauma-induced proliferative vitreoretinopathy Cytokine-mediated disorders further include allergic lhimtis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, obhterative bronchiolitis, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection and respiratory tract inflammation Also included are psoπasis, pemphigus, eczema, atopic dermatitis, contact dermatitis, or acne Yet other cytokinc-mcdiatcd disorders arc Guillam-Barrc syndrome, Parkinson's disease, Huntmgton's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and other demyehnating diseases, viral and bacterial meningitis, CNS trauma, spinal cord injury, seizures, convulsions, olivopontocerebellar atroph}, AIDS dementia complex, MERRF and MELAS syndromes, Leber's disease, Wernicke's encephalopathy, Rett syndrome, homocystemuπa. hyperprohnemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyπc aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett's syndiome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety, schizophrenia, aneurism, or epilepsy In another aspect of the invention, the cytokine-mediated disorders include bone resorption diseases such as osteopetrosis, osteoporosis, or osteoarthritis Also included are diabetes, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), obesity, anorexia or bulimia nervosa Additionally, the cytokine-mediated disease can be sepsis, HIV infection, HCV infection, malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer, including but not limited to breast cancer, colon cancer, lung cancer, prostatic cancer, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, osteosarcoma or follicular lymphoma, Castleman's disease, or drug resistance In some embodiments, the cytokine-mediated disorder is rheumatoid arthritis, osteoarthritis, Crohn's Disease, ulcerative colitis, inflammatory bowel disease, diabetes, psoriatic arthritis, psoriasis, pemphigus, chronic obstructive pulmonary disease, pain, atherosclerosis, ischemia reperfusion, restenosis, acute coronary syndrome, heart failure, multiple myeloma, follicular lymphoma or osteosarcoma.
[0029] In some embodiments of the invention, the cytokine mediated disorder is a neutrophil-mediated disorder, such as, for example, bronchial asthma, rhinitis, influenza, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis, hemodialysis, lcukopheresis, granulocyte transfusion associated syndromes, 01 necrotizing enterocolitis
[0030] In some embodiments of the invention, the cytokine mediated disorder is or results from abnormal bleeding, an abscess, actinic reticuloid syndrome, acute confusional migraine, acute confusional senile dementia, acute hepatocellular injury, acute tubular necrosis, adenohypophyseal diseases, adenovirus infections, adhesions, adhesive capsulitis, adnexitis, agammaglobulinemia, allergy, alopecia, fibrosing alveolitis, amyloidosis, angioplasty, angor pectoris, antiphosphohpid syndrome, arteriosclerotic dementia, arteritis temporal, arthropod-borne encephalitis, asphyxia, atopic hypersensitivity, atrial fibrillation, beaver fever, biliary cirrhosis, bone loss, bronchiolitis, cancer of endocrine gland, cancer of larynx, candidiasis, small cell lung carcinoma, cardiac hypertrophy, cardiac surgery, cardiomcgaly, carditis, carotid angioplasty, carotid endarterectomy, carotid stents, carotid ulcer, celiac disease, cirrhosis, colitis, colitis granulomatous, coronary artery bypass giaft, coronary artery bypass surgery, cortical cataracts, corticosteroid-resistant asthma, degenerative joint disease, dermatitis, diarrhea, erectile neuropathy, erectile vasculopathy, (particularly diabetic erectile neuropathy and vasculopathy) dry eye, dyshpidemia (including hyperhpidemia (increased lipids), hypercholesterolemia (increased cholesterol), hypcrglyccndcmia (increased glyceridcs), hypertriglyceridemia (increased triglycerides), hyperlipoproteinemia (increased lipoproteins), hypcrchylomicroncmia (increased chylomicrons) combined hyperhpidemia (increased I DI and triglycerides), familial hypercholesterolemia (hypercholesterolemia due to a defect on chromosome 19 ( 19pl 3 1- 13 3)), hypohpoproteinemid (decreased lipoproteins), hypoeholesterolemia (decreased cholesterol), abetahpoproteinemia (decreased beta lipoproteins), and Tangier disease (decreased high density lipoprotein)), dyspnea, edema, end-stage renal disease, epstein-barr λ irus infections, fever, follicular thyroid carcinoma, gastrocntcπtis, heart attack, heart bypass surgery, heart surgery, heart transplantation, hepatitis A, hepatitis B, hepatitis C, chrome hepatitis, insulin resistance, kidney failure kidney transplantation, adult chronic leukemia, liver cirrhosis, liver transplantation, meningitis, bacteπal meningitis, myeloproliferative disorders, myopathies, myositis, neonatal-onset multisystem inflammatory disease, nephritis, neuromuscular disorders, neuropathy, obhterative bronchiolitis, oral cancer, percutaneous coronary intervention, periodontal bone loss, peripheral nerve disorders, neuropathy, peritoneal dialysis, pleural disease, pneumonitis, polymyositis, posterior capsular opafication, pruritus (including ocular, skin and general pruritus) pulmonary fibrosis, renal cancer, ienal dialysis, scleroderma, septic arthritis, Sjogren's syndrome, ankylosing spondylitis, Still's disease, sympathetic opthalmia, toxemia, tuberculosis, urticaria, viral hepatitis, or Wegener's granulomatosis
[0031 J In another aspect of the invention, there are provided methods of reducing levels of a cytokine in a subject The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein or a steieoisomer, tautomer, soK ate, prodrug, or pharmaceutically acceptable salt thereof, effective to reduce a level of a cytokine relative to the level pπor to administration of the compound In some embodiments, the reduction in cytokine levels is at least 10%, at least 30%, at least 50%, or at least 90% In some embodiments the subject suffers from or is at risk for a cytokine mediated disorder, as described herein In some embodiments, the cytokine is selected from TNFa, IL-I , IL-6, IL-8, GM-CSF, IFN-gamma, or a combination of an> two or more thereof In others, the cytokine is TNFa or IL-I In some embodiments, the cytokine level is measured in the subject or samples from the subject, e g , tissue or bodily fluids such as the subject s blood In others, cytokine level is measured in the subject's synovium In still others, the cytokine level is measured in the subject's skin In some embodiments ot the invention, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A), as described herein.
[0032] In yet another aspect of the invention, there are provided methods of reducing the level of a cytokine released from a cell in response to a pro-inflammatory stimulus. The methods comprise exposing a cell to an amount of a compound as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to reduce the level of cytokine released from the cell in response to a proinflammatory stimulus relative to the level of released cytokine prior to contacting the cell with the compound. In some embodiments, the reduction in cytokine levels is at least 10%, at least 30%, at least 50%, or at least 90%. In some embodiments, the pro-inflammatory stimulus results from the presence of TNFa, IL-I, IL-6, IL-8, GM-CSF, IFN-gamma, LPS, or a combination of any two or more thereof. In other embodiments, the cytokine level is the level of TNFa, IL-I, IL-6, IL-8, GM-CSF, IFN-gamma, or a combination of any two or more thereof. In some embodiments of the invention, the method further includes exposing the cell to additional therapeutic ingredients (hereafter referred to as ingredient A), as described herein.
[0033] In yet another aspect of the invention, there are provided methods of inhibiting p38 activity. The methods comprise contacting p38 with an amount of a compound as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof effective to inhibit p38 activity, the phosphorylation of p38, or both. In some embodiments, the inhibition of p38 activity or phosphorylation of p38 is at least 10%, at least 30%, at least 50%, or at least 90%. The p38 may be isolated such as in a cell-free in vitro system, a cellular preparation or it may be in a cell. In some other embodiments, the p38 is in a subject. In some embodiments, the subject suffers from, or is at risk for, a cytokine mediated disorder as described herein. In some embodiments of the invention wherein the p38 is in a subject, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A) to the subject, as described herein.
[0034] In another aspect of the invention, there are provided methods of reducing the activity of a pro-inflammatory mediator. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein or a stereoisomer tautomer, soh atc, prodrug, or pharmaceutically acceptable salt thereof effective to reduce the activity of a pro-inflammatory mediator telatrve to the activity prior to the administration of the compound In some embodiments the reduction in pro-inflammatory mediator activity is at least 10%, at least 30%, at least 50%, or at least 90% In certain embodiments, the subject suffers from or is at πsk for a cytokine mediated disorder as described heiein In some embodiments, the reduction in activity results from a decrease in circulating levels of a pro-inflammatory mediator relative to the circulating levels pπor to administration of the compound as described herein In some such embodiments, the decrease in circulating pro-inflammatory mediator level is at least 10%, at least 30%, at least 50%. or at least 90% In some such embodiments, the pro-inflammatory mediator is a prostaglandin or a leukotπene, or a combination of two or more thereof In some other embodiments, the reduction in activity results from an inhibition of the production of a proinflammatory mediator In some such embodiments, the inhibition of pro-inflammatory mediator production is at least 10%, at least 30% at least 50%, or at least 90% In some such embodiments, the pro-inflammatory mediator is a prostaglandin, leukotπene, COX-2, NO- synthdse, or a combination of any two or more thereof In some embodiments of the inv ention, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient Λ), as described herein
[0035] In another aspect of the invention, there are provided methods of reducing the circulating levels of C-Reactive Protein or Rheumatoid Factor, or both The methods comprise administering to a subject, such as a subject m need thereof, an amount of compound as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof effective to reduce the circulating levels of C- Reactive Protein or Rheumatoid Factoi, or both, in the subject's blood relative to the level pπor to the administration of the compound In some embodiments, the circulating C- Reactπ e Protein levels before administration are higher than about 2 87 mg/1 In some embodiments, the reduction m circulating level is at least 10%, at least 30%, at least 50%, or at least 90% In some embodiments, the subject suffers from, or is at πsk for, a cytokine mediated disorder as described herein In certain embodiments of the invention, the method furthei includes administration of additional therapeutic ingredients (hereafter referred to as ingredient Λ). as descπbed herein, for example, the method further includes administration of methotrexate
[0036] In yet another aspect of the invention, there are provided methods of reducing at least one indicium of rheumatoid arthritis The methods comprise administering to a subject exhibiting one or more indicia of iheumatoid arthπtis, an amount of a compound as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to reduce at least one of the indicia to a level below that which exists pπor to the administration of the compound, wherein the indicia are selected from erythrocyte sedimentation rate (FSR), number of painful and tender joints, level of joint pain, joint tenderness, Ritchie articular index, duration of morning stiffness, joint immobility, joint swelling, and/or circulating C-reactive protein level In some embodiments of the invention, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A), as descπbed herein
[0037J Also provided arc methods of reducing the number or severity of clinical signs of psoiiasis The methods comprise administering to a subject exhibiting one or more clinical signs of psoriasis an amount of a compound as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to reduce the number or severity of clinical signs of psoriasis relative to those present in the subject pπor to the administration of the compound, wherein the clinical signs of psoiiasis are the percentage of total body surface area (BSA) affected by psoriasis, psoπasis plaque thickness, level of lymphocytes within psoπatic lesions, epidermal thickness, T-cell infiltration, pathological epidermal hyperplasia, cell-mediated immunity reactions, tetanus antibody response, lymphocyte subpopulations, or any two or more thereof In some embodiments, one or more of the clinical signs of psoπasis, especially BSA. is reduced by at least 10%, by at least 30%, by at least 50%, by at least 70% or by at least 90% In some embodiments of the invention, the method further includes administration of additional therapeutic ingredients (heieaftei referred to as mgiedient A), as descπbed herein
[0038] Combination therapy employing cytokine inhibitors of the im ention in combination with additional ιngredient(s) (hereinafter referred to as "ingredient A") provides a beneficial therapeutic effect, particularly an additive or over-additive effect or an ov erall reduction of side effects of therapy Such a beneficial therapeutic effect is desirable in the treatment of cytokine-mediated disorders as descπbed herein, and in particular in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis, and in the other methods described herein Thus, in one aspect, the invention provides methods that further include administering to a subject one or more, typically one, of the ingredients Λ described herein together with one or more, typically one, compound of the invention In some embodiments, the methods are for treating cytokine-mediated disorders or conditions In some embodiments, a combination of any two or more ingredients A are administered with a compound as descπbed herein An additive or over-additive (e g synergistic) effect of the pharmaceutical combinations according to the invention provides for dose reduction, side- cffcct reduction and/or interval extension when compared to the individual compounds of the invention alone, or ingredient A alone 1 he effects mentioned above are observed both when the two substances are admimsteied simultaneously in a single formulation and when they arc administered successively in separate formulations In the case of ingredient A being an injectable, especially a biological agent, other benefits of adding the compound of the invention may be seen, such as, for example, cost reduction by way of interval and/or dose reduction
[0019] A vaπety ot ingredients A arc contemplated for use in the combinations of the invention For example, non-steroidal anti-inflammatory drugs (NSAIDs), which are widely used for the treatment of inflammation, pain and fever may be used Such NSAIDs include acetaminophen, aspiπn, lbuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac. fenoprofen calcium, flurbiprofen, lndomethacin, ketoprofen, carprofen, indoprofen, ketorolac tromethamme, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulmdac, tolmetin, meloxicam, rofecoxib, celecoxib, etoπcoxib, valdecoxib, nabumetone, naproxen, lomoxicam, nimesulide. indoprofen, remifenzone, salsalate, tiaprofenic acid, flosuhde, and the like, or a combination of two or more thereof
[0040] Λngiogenesis inhibitors may serve as ingredient A, such as VEGF inhibitors, taxol, pentoxyfyllinc and/or thalidomide [0041 J Biological agents shall be understood to mean any natural or artificial /synthetic biological molecule or fragment thereof as known in the art, such as antibodies, proteins, fusion proteins, receptors, nucleic acids, lipids, carbohydrates, and the like Therefore, ingredient A includes biological agents, such as etanercept, infliximab, alefacept adahmumab, efahzumab, anakmra, IL-IRA, alpha-interferon, interferon beta 1 -B CTLA-4, and other antibodies or receptor constructs directed against TNFa. IL1-6, LFA-I , or C 5
[0042] Also within the scope of the invention for ingredient A are steroids, such as glucocorticoids, and vitamin D3 and analogs thereof (cholccalciferols), alone (the latter being used mostly for psoriasis) or in combination Steroids include budesonidc, dcxamethasone, fluocmomde, hydrocortisone, betamethasone, halobetasol (ulobetasol), methylprednisolone, prednisolone, prednisone, clobetasone, deflazacort, fluocmolone acetonide, fluticasone, triamcinolone acetonide, mometasone and diflucortolone Among vitamin D3 derivatives are calcipotnol, tacalcitol, maxacalcitol, and tacalitol, the calciotropic hormones, l α,2,5- dihydroxyvitamm D^, and parathyroid hormone-related peptide
[0043] Many types of immunomodulatory immunosuppressive or cytostatic drugs can be used in combination with the compounds as described herein Exemplary agents include hydroxychloroquine, D-penicillamme, sulfasalazine, auranofin, gold sodium thiomalatc, minocycline, dapsone, chlorambucil, mercaptopuπne, tacrolimus, sirohmus, pimecrolimus, mycophcnolate mofetil, cyclospoπne, leflunomide, methotrexate, azathioprme, cyclophosphamide, macrolides, ascomycin, hydroxyurea, 6-thioguanine, (Orfanos C E , 1999, Cutis 64 (5) 347), alefacept, leflunomide, infliximab, etanercept, etahzumab, anti-CD4, anti- CD25. peptide T, LFA3TIP, ahcaforsen, DAB389, CTLA-4Ig, anti-CD80, for example IDFC- 1 14 or ABX-IL8, DAB-IL-2, IL-10, anti-TAC, basihximab and dach/umab In addition, agents or therapies which act on other targets or immune mediated pioducts are suitable as the ingredient A These include, for example, inhibitors of protein tyrosine kinases (PTKs) such as epidermal growth factor receptor (FGFR), E-selectm inhibitors, and therapies widely used for psoπasis such as anthrahn, coal tar, phototherapies including ultraviolet B (UVB) or psoialens ultraviolet A (PUVA), photodynamic therapy and laser theiapy [0044] Retinoid therapy can also be used as ingredient A Thus, for example bcxarotcne, acitretm, etretinate, tazarotene, hydroxyurea, 6 thioguanine and phototherapies are suitable additional ingredients (Ortanos C E , 1999 Cutis 64(5) 347-53, see also Saurat J H , 1999 J Am Acad Derm 41(3 Pt 2) S2-6)
[0045] Ingredients A useiul in the invention further include small molecule inhibitors directed against enzymes involved in signal transduction pathways or to cell adhesion molecules like LFA-I or ICAM 1
[0046] Statins and HMG-CoA. reductase inhibitors may also be employed as ingredients A including, e g , atorvastatin (LIPI I OR, I ORV AS I ), flm astatin (LESCOL), lovastatin (MEVACOR, ALTOCOR), mevastatin, pravastatin (LIVALO, PITAVA), pravastatin (PRA VACHOL, SELEKTINE, LIPOSTAT), losuvastatin (CRESTOR) or sim\ astatin (ZOCOR, LIPEX) Other ingredients A contemplated for use in methods ot the invention include fibrates, such as bezafibrate (e g , BEZALIP), ciprofibrate (e g , MODALIM), clofibrate, chnofibrate, gemfibrozil (e g , LOPID) or fenofibrate, cholesterol absorption inhibitors, such as, ezetimibe (e g , ZE I IA), nicotinic acid, bile acid sequestrants, such as cholestyramine (QUESTRAN) and colestipol (COLFSTID), and/or plant sterol- containmg products and ω 3 -fatty acids Also contemplated aie the combination of two oi more of the above, for example the combination of ezetimibe/simvastahn (W TORIN or INEGY) Combination therapy with the abo\ e ingredients A is contemplated for use in any method of the invention including treatment of the cytokine-mediated disorders and conditions as well as in the methods described in the related applications U S Application No 10 939,324, International Application PCT/US2006/042679 International Application PCT/US2006 048803, and Internationol Application No PCT US2006/006682, each of which is herein incorporated by reference in its entirety
[0047] In another aspect, there are provided the above-mentioned combinations comprising ingredient A and one or more compounds as described herein, typically in therapeutically effective amounts, for use as pharmaceutical compositions with anti-cytokine activ ity Moreo\ ei, combinations comprising ingiedient A and a compound as descπbed herein can be used for preparing a pharmaceutical composition for the treatment and or prevention of a cytokme-mediated disorder or condition The pharmaceutical preparations, containing as the active substance one or more compound combinations comprising ιngredient(s) A and the compound as described herein may further include the phaimaceutically acceptable deπvatives theieot, and may be optionally combined with a conventional eκcipient, carrier, or combination thereof
[0048] In psoriasis, known combination treatments have been effective and are used as rotation therapy for maintenance of remission or if the subject is refractory to usual systemic products Most of the combinations are with different modes of action either to impro\ e efficacy or to reduce side effects by reduction of the dosage See Van de Kerkhof, P 1997 Clinics in Dermatology, 15 831 , which show ed the effect of topical steroids or vitamin D with systemic agents Two combinations which aie widely accepted include ultraviolet B (UVB) or psoralens ultraviolet A (PUVA), each optionally administered with retinoids, methotrexate, or the combination of cyclospoπne and retinoids
[0049] A typical combination for treating psoriasis is the compound as described herein compound in combination with immunotherapy drugs which include cyclospoπne, pimeciohmus, tacrolimus, ascomycine, anti-CD4, anti-CD25, peptide T, LhA3TlP, DAB3S9, Cl LA-4Ig, E-selectm inhibitors, alefacept, infliximab etaneicept, efalizumab, and those disclosed in Griffiths, Christopher E M , 1998 Hospital Medicine, VoI 59 No 7, and the obvious variants thereof Another typical combination for treating psoriasis is the compound as described herein as described herein with methotrexate (MTX) It is expected this combination will be effective because of the good tolerability of MTX in the short term and because of the acceptability if maintenance of remission is obtained with good quality of life Another typical combination for treating psoriasis is the compound as described herein with cyclospoπne, especially because of cycloφonne's efficiency for induction of remission Another embodiment of the invention comprises administration in the following sequence induction w ith the compound as described herein and cyclospoπne, followed by continuation with alter decrease of dosing and discontinuation of cyclospoπne Another typical combination for ti eating psoπasis is the compound as descπbed herein in combination with retinoids Retinoids provide minimal efficacv with potential Cyt P450 interactions and iisk of teratogenicity, and this would be alleviated by continuation of therapv with the compound as described herein Yet another typical combination for treating psoriasis is the compound as described herein, in combination with ingredients A selected from steroids, such as glucocorticostcroids, vitamin D analogs retinoids and dithranol In some such combination treatments, the steroids and retinoids can be administered topically A more typical combination for treating psoriasis is a compound as described herein with vitamin D derivatives, most typically calcipotπol or tacalcitol Another typical combination for treating psoriasis is the compound as described herein in combination with macrohdes, most typically with ascomycin analogues, administered topically, and even more typically with those available orally such as pimecrolimus Another typical combination for treating psoriasis is the compound as descπbed herein in combination with cell adhesion molecule inhibitors, such as anti-LFA3, and-Or anti-LFAl This includes adhesion molecule blockage by recombinant fusion proteins like alefacept, anti-LFA3-IgCl, or by anti-CDl 1 monoclonal antibodies, efahzumab, and the obvious variants thereof Cell adhesion molecule inhibitors appear to provide an acceptable response rate with limited tolerability problems Combination with a compound as descπbed herein could avoid the disadvantage ot their injectable form, with CAM inhibitors being used intermittently Another embodiment of the invention comprises administration in the following sequence induction with a compound as descπbed herein and CAM inhibitors, followed by maintenance treatment with the compound as described herein alone and retreatment with CAM inhibitors in case of significant relapse
[0050] Another typical combination for treating psoriasis is the compound as described herein with another anti- 1 NFa ingredient A typical embodiment is one wherein the other anti- I NFa ingredient is selected from infliximab oi etanercept, typically infliximab Infliximab is believed to have a higher rate of response for induction of remission, which recently was suggested to be maintained on the long term Within the scope of the invention is the use of topical or general antisense inhibitors of TNFa, such as ahcaforsen, in combination with a compound as described herein Another typical combination lor treating psoriasis is the compound as descπbed herein with anti-CD4, anti-CD80 (IDEC-1 14 or ABX-1L8), DAB 1L-2, DAB389 IL-2, CTLA4-Ig, IL-I O, the IL2 receptor inhibitors such as dach/umab (anti-TAC), or basihximab (See Tutrone, "Biologic Therapy for Psoπasis, A Brief History, I, " Biologic Therapy for Psoπasis, 2001, 68, 331 , Ben-Bassat, "Biological activity of tyrosine kinase inhibitors Novel agents for psoπasis therapy," Current Opinion in Inv estigational Drugs, 2001 , 2 (1 1), 1539 Sahm. ct al , "Targeting interleukin-2 as a treatment for psoriasis," Current Opinion in Investigational Drugs, 2001 , 2(1 1), 1546) [0051] The combinations described above can also be used to reduce the number or severity of the clinical indicia of psoriasis.
[0052] Any of the above mentioned combinations within the scope of the invention may be tested by animal models known in the art. Reference in this regard may be made to: Schon, Michael P. 1999 Animal models of Psoriasis-- What can we learn from them, The Society for Investigative Dermatology-Reviews, 12. No. 4, 405-410.
[0053] In rheumatoid arthritis, combination of immunosuppressive or immunomodulatory agents is a long and well established therapeutic paradigm. Combination partners may be selected from various therapeutic entities. Their identification is either based on empirical data supported by evolving knowledge about the underlying mechanisms or based on a well defined mode of action. These agents are generally referred to as Disease Modifying Antirheumatic Drugs (DMARDs) or Slow Acting Antirheumatic Drugs (SAARDs). Apart from the combinations listed below, combination of the compound as described herein, with one or more agents classified as DMARD/SAARD or NSAID and/or steroids, are contemplated in this invention.
[0054] A typical combination for treating rheumatoid arthritis is the compound as described herein combined with one or more of the following immunosuppressive, immunomodulatory, or cytostatic drugs, such as, for example, hydroxychloroquine, D-penicillaminc, sulfasalazine, auranofm, gold sodium thiomalatc, minocycline, dapsonc, chlorambucil, mercaptopurine, tacrolimus, sirolimus, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate, azathioprine or cyclophosphamide. Another typical combination for treating rheumatoid arthritis is the compound as described herein combined with angiogenesis inhibitors, such as compounds directed against VEGF, taxol, pentoxyfylline, thalidomide, interferon beta- IB and alpha-interferon. Yet another typical combination for treating rheumatoid arthritis is the compound as described herein in combination with inhibitors of cell adhesion, such as inhibitors of LFA-I or inhibitors of ICAM-I .
[0055] Another typical combination for treating rheumatoid arthritis is the compound as described herein combined with anti-TNFa antibodies or TNFa-receptor antagonists such as etanercept, infliximab, adalimumab (D2E7), or biological agents such as CTLA-4, or biological agents directed against targets such as CD-4, LFA- 1 , IL-6, ICAM- 1 , C5, or IL-I receptor In another embodiment the compound as descπbed herein is combined with infliximab alone or infliximab and methotrexate Another typical combination for treating rheumatoid arthritis is the compound as descπbed herein in combination with IL-I receptor antagonists, such as anakmra (KINERET) Yet another typical combination for treating rheumatoid arthritis is the compound as described herein combined with NSAIDs, including acetaminophen, aspiπn, lbuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, mdomefhacm, ketoprofen, carprofen, mdoprofen, ketorolac tromefharmne, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozm, piroxicam, sodium salicylate, sulindac, tolmetm, meloxicam, rofecoxib, celecoxib, etoπcoxib, valdecoxib, nabumetone, naproxen, lomoxicam nimesuhde, mdoprofen, remifenzone, salsalate, tiaprofenic acid, flosuhde, and the like Another typical combination for treating rheumatoid arthritis is the compound as described herein combined with steroids, such as glucocorticosteroids, for example, betamethasone, dexamethasone methylpredmsolone, prednisolone, and deflazacort
[0056] The combinations descπbed above can also be used to reduce at least one of the indicia of rheumatoid arthritis
[0057] Any of the above mentioned combinations within the scope of the invention may be tested by animal models known in the art (See Wooley, P H 1998, Animal models of arthritis in Klippel J H , Dieppe, P A , (eds ) Rheumatology, second edition, 5 8 1-5 8 6 Mosby, London, Philadelphia, St I ouis, Sydney, l okyo)
[0058] In Crohn's disease, the follow ing groups of drugs combined with the compound as descπbed herein may be effective steroids such as budesomde, 5-ASA drugs like mesalamme, immunosuppressants, biological agents and adhesion molecule inhibitors A typical combination for treating Crohn's disease is the compound as described herein with one or more of the following steroids including all those listed herein, 5-ASA, methotrexate and a/athioprme Anothei typical combination for treating Crohn's disease is the compound as described herein combined with IL-I receptor antagonists, such as anakmra (K1NERET) Yet another typical combination for treating Crohn's disease is the compound as described herein with anti-TNFa antibodies or TNFa-receptor antagonists, such as etanercept, infliximab, adalimumab (D2E7), or biological agents such as CTLA -4, or biological agents directed against targets such as CD-4, LFA- I , IL-6, ICAM-I , or C5. In another embodiment the compound as described herein is combined with infliximab and methotrexate. More typically, the compound as described herein is combined with infliximab. Another typical combination for treating Crohn's disease is the compound as described herein combined with IL-IO, alicaforsen (anti ICAM 1), or antegren (VCAM receptor antagonist).
[0059] In another aspect of the invention, there are provided methods of increasing the HDL-lcvels of a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to increase the HDL-level of the subject relative to the level prior to the administration of the compound. In some embodiments, the compound is a p38 inhibitor. In certain embodiments, the subject suffers from or is at risk for a cytokine mediated disorder as described herein. In some embodiments, the HDL level prior to administration is less than about 70 mg/dl, less than about 65 mg/ml, less than about 60 mg/dl, less than about 55 mg/dl, less than about 50 mg/dl, less than about 45 mg/dl or less than about 40 mg/dl. For example, the HDL level prior to administration is less than about 55 mg/dl. In some embodiments, the HDL is HDL2, while in others it is HDL3. In other embodiments, the subject has an LDL level less than about 150 mg/ml.
[0060] In some embodiments of methods for increasing HDL levels in a subject, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound as described herein. In still other embodiments, the subject is suffering from or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome.
[0061 ] In some embodiments, the methods of increasing HDL-levels in a subject additionally comprise administration of statins or HMG-CoA reductase inhibitors, such as, atorvastatin (LIPITOR. TORVAST), fluvastatin (LESCOL), lovastatin (MEVACOR, ALTOCOR), mcvastatin, pravastatin (LIVALO, PITAVA), pravastatin (PRAVACHOL, SELEKTINE, LIPOSTAT), rosuvastatm (CRESTOR), or simvastatin (ZOCOR, LIPEX); fibrates, such as, gemfibrozil, fenofibrate, bezafibrate, ciprotϊbrate, clofibrate, or clinofibrate; bile acid sequestrants, such as, cholestyramine (QUESTRAN); cholesterol absorption inhibitors, such as colestipol (COLESTID), or ezetimibe (ZETIA); niacin; plant sterol- containing products; ω 3 -fatty acids ; or combinations of two or more thereof, for example czctimibc/ simvastatin (VYTORIN or INEGY). In some embodiments, the HDL level of the subject is increased by at least about 5%, by at least about 7%, by at least about 10%, or by at least about 15%. For example, the HDL level of the subject is increased by at least about 12%. In other embodiments the HDL level of the subject may be increased by about 5% to about 20%.
[0062] In another aspect, there are provided methods of increasing Apo-Al -levels of a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to increase the Apo-A l -level of the subject relative to the level prior to the administration of the compound. In some embodiments, the Apo-Al -level is increased by at least about 5% or by at least about 10%. In some other embodiments, the subject's HDL level prior to administration is less than about 70 mg/dl, less than about 65 mg/dl, less than about 60 mg/dl, less than about 55 mg/dl, less than about 50 mg/dl, less than about 45 mg/dl or less than about 40 mg/dl. In other embodiments, the HDL level prior to administration is less than about 55 mg/dl; or the subject's LDL level prior to administration is less than about 150 mg/ml. In some embodiments, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. For example, the vascular event can be a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound as described herein. In other embodiments, the subject is suffering from or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome. In some embodiments, the HDL level of the subject is increased by at least about 5%, by at least about 7%, by at least about 1 0%, or by at least about 15%. For example, the HDL level of the subject is increased by at least about 12%. In other embodiments the HDL level of the subject may be increased by about 5% to about 20%.
[0063] In another aspect, there are provided methods of decreasing or preventing from increasing the systolic or diastolic blood pressure of a subject in need thereof. The methods comprise administering to a subject an amount of a compound effective to decrease or to prevent from increasing the systolic or diastolic blood pressure of the subject relative to the blood pressure prior to the administration of the compound, wherein the compound is as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the blood pressure is the systolic blood pressure. In others, the blood pressure is the diastolic blood pressure. In some embodiments, the subject's systolic blood pressure prior to administration is above 140 mm Hg, and the diastolic blood pressure prior to administration of the compound is above 90 mm Hg. In others, the diastolic blood pressure prior to administration of the compound is higher than 85 mm Hg. In some embodiments, the decrease in systolic or diastolic blood pressure, or both, is at least about 5 mm Hg, at least about 3 mm Hg or at least about 2 mm Hg. In some other embodiments, the subject's HDL level prior to administration is less than about 70 mg/dl, less than about 65 mg/dl, less than about 60 mg/dl, less than about 55 mg/dl, less than about 50 mg/dl, less than about 45 mg/dl or less than about 40 mg/dl. In other embodiments, the HDL level prior to administration is less than about 55 mg/dl; or the subject's LDL level prior to administration is less than about 150 mg/ml. In some embodiments, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. For example, the vascular event may be a cardiovascular event or a cerebrovascular event. In some embodiments, the present methods produce a reduction of the occurrence or severity of the vascular event in the subject, relative to a subject who is at risk of a vascular event who has not been administered a compound described herein. In other embodiments, the subject is suffering from or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome. In some embodiments, the HDL level of the subject may be increased by at least about 5%, by at least about 7%, by at least about 10%, or by at least about 15% For example the HDL level of the subject is increased by at least about 12% In other embodiments the HDL level of the subject may be increased by about 5% to about 20%
[0064] Compounds disclosed herein, such as cytokine inhibitors, may be used in combination therapv with one or more anti-hypertensive agents, for example, ACE inhibitors, calcium channel blockers, aldosterone antagonists, angiotensin Il antagonists, diuretics, benzodiazepine dcπvativcs, beta blocking agents, dihydropyridine derivatives, potassium- sparing agents, urologicals, sulfonamides, or thiazides Examples include benazepril, enalapπl, hsinopril, quinapril, captopnl, ramipπl, spironolactone, olmesartan, valsartan, telmisartan, valsartan, losartan, lrbesartan, diltiazem, verapamil, trandolapπl, atenolol, bisoprolol, metoprolol, toprol, tenoretic, amlodipine, nifedipine, felodipine, msoldipine, triamterene, furosemide, lasix, prazosin, propanolol, hydrochlorothiazide, or combinations of two or more thereof
[0065] In another aspect, there are provided methods of decreasing or preventing an elevation in PAI-I levels The methods comprise administering to a subject at risk for increased PAI-I levels (for example in a subject suffeπng from, or at risk of obesity, metabolic syndrome or inflammatory conditions) an amount of a compound effective to decrease or prevent an elevation in the PAI-1-level of the subject relative to the level in the untreated subject, wherein the compound is as descπbed herein, or a stereoisomer, tautomer, soh ate prodrug, or pharmaceutically acceptable salt thereof
[0066] In yet another aspect of the invention, there are provided methods of decreasing the tπglvceride-level of a subject The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound as descπbed herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to decrease the tπglyccπdc-lcvel of the subject relative to the level prior to the administration of the compound as described herein In some embodiments, the tπglyccπde- level pπor to administration is abov e 500 mg/dl, above 200 mg/dl, or above 150 mg/dl For example, the tπglyceπde-level pπor to administration is above 200 mg/dl In certain embodiments, the subject suffers from or is at risk for a cytokine mediated disorder as described heiein In other embodiments, the subject is at πsk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic ie-occlusion subsequent to a coronary interv ention procedure and a disorder m which at least one major coronary artery exhibits gt eater than 50° o stenosis In some such embodiments, the vascular event is a cardiov ascular event or a ceiebrovascular event In some embodiments, a reduction of the occurrence or seventy of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound as described herein In some embodiments of the invention, the method additionally comprises administration of statins or HMG-CoA reductase inhibitors, such as, atorvastatm (LIPITOR, TORVAST), fluvastatin (LESCOL), lovastatin (MEVACOR, ALTOCOR), mevastatin, pravastatin (LIVALO, PITAVA), pravastatin (PRAVACHOI , SELEKTINE, LIPOSTAT), rosuvastatm (CRESTOR), or simvastatin (ZOCOR, LIPEX), librates, such as, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate, clofibrate, or chnofibrate, bile acid sequestrants, such as, cholestyramine (QUESTRAN), cholesterol absorption inhibitors, such as colestipol (COLESTID), or ezetimibc (ZETIA), niacin, plant sterol- containmg products, ω3 -fatty acids , or combinations of two or more thereof, tor example ezetimibe/ simvastatin (VYTORIN or INEGY) In other embodiments, the subject is suffering from, or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome In some embodiments, the subject is a primate, particularly a human In some embodiments of the invention, the triglyceride level of the subject is reduced by at least about 10% In others, the triglyceride level of the subject is reduced by at least about 20%
[0067] In yet another aspect of the invention, there are provided methods of decreasing the fasting glucose-level in a subject The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein, or a stereoisomer, tautomcr, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to decrease the fasting glucose-level in a subject relative to the level prior to the administration of the compound In some embodiments, the glucose level pπor to the administration is above about 130 mg/dl In others, the glucose level is decreased by about 5%, about 10%, about 20% or about 30% In certain embodiments, the subject suffers from, or is at πsk for, a cytokine mediated disorder as described herein In others, the subject suffers from, or is at πsk of suffering from diabetes, insulin resistance, or metabolic syndrome In some embodiments, the method further comprises administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glybuπdc, glimcpiπde, gliclazidc, rcpaglinide, nateglinide, metformin, miglitol, acarbose, exendin, pramlintide, insulin, or combinations of two or more thereof. In some embodiments of the invention, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound as described herein.
[0068] In another aspect of the invention, there are provided methods of decreasing the HbAIc value in a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to decrease the HbAI c value in the subject relative to the level prior to the administration of the compound. In some such embodiments, the subject has a HbAI c value above about 8%, above about 7.5%, or above about 7%. In others, the HbAI c level is decreased to between about 4% and about 6.5%. In certain embodiments, the subject suffers from, or is at risk for, a cytokine mediated disorder as described herein. In other embodiments, the subject suffers from, or is at risk of suffering from, or is at risk for, diabetes, insulin resistance or metabolic syndrome. In some embodiments, the method further comprises administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, repaglinide, nateglinide, metformin, miglitol, acarbose, exendin, pramlintide, insulin, or combinations of two or more thereof. In some embodiments of the invention, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound as described herein. [0069] In yet another aspect of the invention, there are provided methods for decreasing the insulin level in a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to decrease the insulin-level in the subject relative to the level prior to the administration of the compound, In some such embodiments, the subject has a fasting insulin level prior to administration of above about 100 pmol/1, above about 150 pmol/1, above about 200 pmol/1, above about 250 pmol/1, above about 300 pmol/1, above about 350 pmol/1, above about 400 pmol/1, or above about 500 pmol/1. In others, the subject has a postprandial insulin level of above about 400 pmol/1, above about 500 pmol/1, above about 600 pmol/1, above about 700 pmol/1, or above about 800 pmol/1. In some embodiments, the insulin level is reduced by about 10%, about 20%, about 30%, or about 40%. In certain embodiments, the subject suffers from or is at risk for a cytokine mediated disorder as described herein. In yet other embodiments, the subject suffers from, or is at risk of suffering from diabetes, insulin resistance or metabolic syndrome. In some embodiments of the invention, the method further comprises administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, repaglinide, nateglinide, metformin, miglitol, acarbose, exendin, pramlintide, insulin, or a combination of two or more thereof. In some embodiments of the invention, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound as descπbed herein.
[0070] In another aspect of the invention, there arc provided methods for decreasing the HOMA Insulin Resistance Index in a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, effective to decrease the HOMA Insulin Resistance Index in the subject relative to the Index prior to the administration of the compound. In some such embodiments, the Insulin Resistance Index is reduced to below about 2 5, below about 2 0 or below about 1 8 In some embodiments, the Insulin Resistance Index, is reduced by about 10%, about 20% or about 30% In certain embodiments, the subject is in need of a decreased HOMA Insulin Resistance Index because, e g , the subject suffeis from, or is at risk tor a cytokine mediated disorder as descπbed herein In others the subject buffers from or is at πsk of suffering from diabetes, insulin resistance or metabolic syndrome In some embodiments of the in\ ention the method further compπses administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glybuπde, ghmepinde, gliclazide, repaghnide, nateglinide metformin, miglitol, acaibose, exendm, pramhntide, insulin, or a combination of two or more thereof In some embodiments of the invention, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention piocedure and or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event In some embodiments, a reduction of the occurrence or se\ eπty of the \ ascular event occurs, relative to a subject who is at πsk of a vascular event who has not been administered the compound as described herein
[0071 ] In yet another aspect of the invention, there are provided methods of increasing the indirect bihrubm-le\el in a subject The methods compose administering to a subject such as a subject in need thereof, an amount of a compound as descπbed herein, or a stereoisomer, tautomei, solvate prodrug, or pharmaceutically acceptable salt thereof, effective to increase the indirect bilirubin level in the subject relative to the le\el pπor to the administration of the compound In some embodiments, the indirect bilirubin level is increased to about 0 4 mg/dl, to about 0 5 mg/dl, to about 0 6 mg/dl, or to about 0 7 mg/dl In others, the indirect bilirubin level is increased by about 10%, about 20%, or about 30% In other embodiments, the bilirubin level is increased w ithout causing jaundice In certain embodiments, the subject is in need of increased indirect bilirubin level because, e g the subject suffers from, or is at πsk for, a cytokine mediated disorder as described herein In some embodiments of this aspect of the invention, the subject is at πsk of a vasculai event, foi example, the vascular event is one or more of thrombotic disorder, m>ocardial infarction, angina, stroke transient ischemic attack, thrombotic re-occlusion subsequent to a coronar> intei\ ention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In other embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound as described herein.
[0072] In some embodiments, compounds as described herein possess inhibitory effects on the procoagulant and pro fibrinolytic responses during human endotoxemia. In another aspect, the invention therefore also provides a method of anticoagulant and fibrinolytic therapy for a disease or condition relating to blood coagulation or fibrinolysis, comprising administering to a subject in need thereof a pharmaceutically effective amount of the compound as described herein. This administration may be of benefit given either prophylactically to subjects at risk or therapeutically to subjects who have developed complications related to these pathways.
[0073] Compounds disclosed herein may be used in combination therapy with one or more other anticoagulant or fibrinolytic agents. These include recombinant tissue plasminogen activator (rtPA), streptokinase (SK), urokinase (UK), proUK, heparin, enoxoparin, dalteparin, coumarin anticoagulants, aspirin, dipyrimidamole, aggrennox, ticlopidine, clopidogrel (Plavix), abciximab, RheoPro, integrilin, aggrestat, and the like. Particular dosages, formulations and methods of administration of the anticoagulant and fibrinolytic agents are known in the art. In view of the present disclosure it is within the skill in the art to determine appropriate dosages, formulations and methods of administration for the combinations of the compounds of the invention and the anti-coagulant or fibrinolytic agents for particular applications.
[0074] In another aspect of the invention, there is provided a method comprising administering to a subject a combination of a compound as described herein and one or more ingredients A, in an amount effective to control, treat or prevent obesity or obesity-related conditions or disorders in a subject in need thereof, wherein ingredient A is selected from agents useful in the treatment of obesity or an obesity-related condition or disorder. In some such embodiments, the obesity-related disorder is selected from overeating, binge eating, bulimia, diabetes, elevated plasma insulin concentrations, insulin resistance, metabolic syndrome, dyslipidemias, hyperlipidemia, lipodystrophy, osteoarthritis, arthritis deformans, lumbodyma, emmeniopathy. obstructive sleep apnea, cholelithiasis, gallstones, nonalcoholic steatohepatitis, heart disease, abnormal heart rhythms and abnormal heart arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, coronary artery disease, angina pectoris, hypertension, sudden death, stroke, cerebral infarction, cerebral thrombosis, transient ischemic attack, polycystic ovary disease, craniopharyngioma, Pickwickian syndrome, fatty liver. Prader-Willi Syndrome, Frohhch's syndrome, GH-deficiency, normal variant short stature, Turner's syndrome, pediatπc acute lymphoblastic leukemia, infertility, hypogonadism in males, hirsutism in females, gastrointestinal motility disorders, respiratory disorders, cardiovascular disorders, inflammation, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, endometrial cancer, breast cancer, piostate cancer, colon cancer or kidney cancer In other embodiments of the invention, the subject desires to lose body weight relati\e to the subject's body weight prior to administration of the combination In some embodiments, the method additionally compπses treatment of the subject with hpoplasty, gastπc bypass, laparoscopic adjustable gastπc binding, biliopancreatic diversion or vertical banded gastroplasty.
[0075] In some embodiments, both the compound as described herein and ingredient
A are administered orally In others, both the compound as described herein and ingredient A are administered intravenously, subcutaneously or by inhalation In still others, the compound as described herein is administered orally and the ingredient A is administered mtra\ enously, subcutaneously, or by inhalation Alternatively, the cytokine inhibitor may be administered intravenously, subcutaneously, or by inhalation and the ιngredient(s) A may be administered orally
[0076] Examples of agents useful in the treatment of obesity or an obesity-related condition or disorder as ingredients A include an insulin sensitizer, an insulin or insulin mimetic, a sulfonylurea, an oglucosidase inhibitor, a cholesterol lowering agent, a PPARδ agonist, a CB receptor hgand, a serotonergic agent, an adrenoceptor agonist, a pancreatic lipase inhibitor, an ApoB/MTP inhibitor, a MCH receptor antagonist, an amylin and'or calcitonin receptor agonist, an NPY antagonist, an orexin antagonist, a GLP-I agonist, an MC agonist a ghrehn antagonist, a leptm agonist, a CCK agonist, a PYY agonist, a CNTF, a GII secretagogue a GH secretagogue receptor modulator, a DP-IV inhibitor, a H3 antagonist or inverse agonist, a 5HT agonist, a serotonin transport or reuptake inhibitor, a dopamine agonist, a NE transport inhibitor, a DAG inhibitor, a glucose transporter inhibitor, a 0-HSD-1 inhibitor, a CETP inhibitor, a squalene synthase inhibitor, a glucocorticoid antagonist, a PDE inhibitor, an anti-platelet agent, an ACE inhibitor, an All receptor antagonist, a UCP-I , -2, or -3 activator, a thyroid hormone β agonist, a COX-2 inhibitor, a monoamine reuptake inhibitor, a mGlu5 receptor antagonist, an acyl-estrogen, a FAS inhibitor, an ACC2 inhibitor, a corticotropin-rclcasing hormone agonist, a galanin antagonist, a BRS3 agonist, a PTP-I B inhibitor, a fatty acid transporter inhibitor, a dicarboxylate transporter inhibitor, a phosphate transporter inhibitor, a urocortin binding protein antagonist, a urocortin hgand, a human agouti-related protein, a neuromedin U receptor agonist, topiramate, oxyntomodulin, tagatose, CP741952, zonisamide, IDI l Ol , BDC03, S2367, AOD9604, fluasterone, GT389255, QCBT16, MK0916, MK0493, MK0364, PD6735, c2735 adiponectin, or a combination of two or more thereof In some such embodiments, ingredient A is an insulin sensitizer, an insulin or insulin mimetic, a sulfonylurea, an oglucosidase inhibitor, or a glucose transporter inhibitor In others, ingredient A is a cholesterol lowering agent, or a PPARδ agonist In still others, ingredient A is a CB receptor hgand. a serotonergic agent, an adrenoceptor agonist, a pancreatic lipase inhibitor, an ApoB/MTP inhibitor, a DP-IV inhibitor, a H3 antagonist or inverse agonist, a 5HT agonist, a serotonin transport or reuptake inhibitor, a dopamine agonist, a NE transport inhibitor, a CETP inhibitor, a squalene synthase inhibitoi, a PDE inhibitor, or an acyl-cstiogen In other embodiments, ingredient A is a MCH receptor antagonist, an NPY antagonist, an orexm antagonist, a GLP-I agonist, an MC agonist, a ghrehn antagonist, a leptm agonist, a CCK agonist a PYY agonist, a CNTF, a GH secretagogue, or a GH secretagogue receptor modulator In some embodiments, ingredient A is πmonabant, sibutramine, fluoxetine, phentermine, bupropion, radafaxine, orhstat, cetihstat, oxyntomoduhn, or olcoyl-estrone
[0077] Typical examples of ingredients A, and combinations of any two or more thereof, that may be combined with the compounds as descπbcd herein, for the treatment or pievention of obesity, diabetes and/or obesity-related disorders, either administered separately or in the same pharmaceutical compositions, include, but are not limited to
[0078] (a) insulin sensitizers including (i) peroxisome prohlerator activated receptors
(PPAR) γ agonists, such as ghtazones (e g isaglitazone, pioghtazone. rosightazone, rivoglitazone, netoglitazone), naveglitazar, farglitazar, metaglidasen, GW6779542, CSO38, MBX2044, AZD6610, PLX204, LBM642, AMG131 , AVE0847, AVE5376, ONO5129, TAK654, CLX0921 , and the like); (ii) biguanides such as metformin and phenformin;
[0079] (b) insulin or insulin mimetics, such as insulin aspart, insulin glulisine, insulin glargine, insulin lispro, insulin detemir, NN5401 , NN9101, NN344, AT1391 , DTYOOl , betaRx, insulin zinc suspension (lente and ultralente); insulintropin (by "insulin" is meant a polypeptide or its equivalent useful in regulation of blood glucose levels. A general description of such insulins is provided in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th Rd., Pergamon Press (1990). Such insulins can be fast acting, intermediate acting, or long acting. Various derivatives of insulin exist and arc useful in this invention. Such compositions can be administered by any standard route, including oral, nasal, pulmonary, or transdermal administration.);
[0080] (c) sulfonylureas, such as acetohexamide; chlorpropamide; glibenclamide; glipizide; glyburidc; glimepiride; gliclazide; glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide;
[0081 ] (d) oglucosidase inhibitors, such as alglucosidase alfa, voglibosc, cclgosivir, miglitol, acarbose, and the like;
[0082] (e) cholesterol lowering agents such as (i) 3-hydroxy-3-methylglutaryl-
Cocnzyme A (HMG-CoA) reductase inhibitors (atorvastatin, pravastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, lovastatin and other statins); (ii) bile acid absorbers/sequestrants, such as colesevelam, colestipol, cholestyramine, dialkylaminoalcyl derivatives of a cross-inked dextran, and the like; (ii) nicotinyl alcohol, nicotinic acid or a salt thereof; (iii) PPARα agonists such as fenυfibric acid derivatives (ciprofibrate, gemfibrozil, clofibrate, fenofibrate and benzafibrate), GW677954, CSO38, ABT335, LY674, GFT14, PLX204, Kl 1 1 , naveglitazar, LBM642, GW590735, NS220, AVE5376, AVE8134, DRF10945, ONO5 I29, KRPlOl , GW641597, and DRF4832: (iv) inhibitors of cholesterol absorption such as stanol esters, beta-sitosterol, sterol glycosides such as tiqucside; and azetidinones such as ezetimibe, and the like, and acyl CoA cholesterol acyltransferase (ACAT) inhibitors such as SMP797, K604, and SR-45023A, (v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii) thyromimetics; [0083] (t) PPARδ agonists, such as GW677954, CS068, RWJ800025, GW501516, and CKD501 ; and
[0084] (g) other therapeutic agents, including anti-obesity and anti-diabetic agents, such as
[0085] (1) cannabinoid (CB) receptor ligands, such as CB-I receptor antagonists or inverse agonists, for example rimonabant, surinabant, AVE 1625, CP945598, and SLV-319, and those disclosed in U.S. Pat. Nos. 6,344,474, 6,028,084, 5,747,524, 5,596,106, 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,1 12,820, 5,292,736, 5,624,941 , PCT Application Nos. WO 96/33159, WO 98/33765, WO98/43636, WO98/43635, WO 01/09120, WO 98/31227, WO 98/41519, WO 98/37061 , WO 00/10967, WO 00/10968, WO 97/29079, WO 99/02499, WO 01/58869, WO 01/64632, WO 01/64633, WO 01/64634, WO 02/076949, and WO 03/007887, WO 02/076949; and EPO Application No. EP-658546, EP-656354, EP-576357;
[0086] (2) anti-obesity serotonergic agents, such as fenfluramine, dexfenfluramine, phentermine, DOVl 02677, zimeldine, and sibutramine;
[0087] (3) adrenoceptor agonists, including /53-adrenoreceptor agonists, such as solabregon, YM 178, amibregon, tesofensince, fenfluramine, amphetamine, phenmetrazine, phentermine, and N5984;
[0088] (4) pancreatic lipase inhibitors, such as orlistat, cetilistat, and GT389255;
[0089] (5) apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-
B/MTP) inhibitors, such as ISIS301012, ISIS301012, JTT130, and SLx4090;
[0090] (6) melanin-concentrating hormone (MCH) receptor antagonists, including
MCH l R and MCH2R antagonists, for example, 856464, and AMG076, and those described in U.S. Patent Application Publication Nos. 2005/0009815, 2005/0026915, 2004/0152742, 2004/0209865; PCT Patent Application Publication Nos. WO 01/82925, WO 01/87834, WO 02/06245, WO 02/04433, and WO 02/51809; and Japanese Patent Application No. JP 13226269; [0091 ] (7) neuropeptide Y (NPY) antagonists, such as NPYl antagonists, for example, BIBP3226, Jl 15814, B1BO3304, LY357897, CP671906, GI264879A, and those disclosed in U.S. Pat, No. 6,001,836 and PCT Application Nos. WO 96/14307, WO 01/23387. WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; NPY5 antagonists, for example, S2367, FMS586, GW569180A, GWr594884A, GW587081, GW5481 18.. FR226928. FR240662, FR252384, 1229U91 , GI264879A, CGP71683A, LY377S97, PD160170, SR120562A, SR120819A and JCF104, and those disclosed in U.S. Pat. Nos. 6, 124,331, 6,140,354, 6, 191,160, 6,214,853, 6,258,837, 6,313,298, 6,337,332, 6,329.395, 6,326,375, 6,335,345, and 6,340,683, European Patent Nos. EP-01010691 , and EP-01044970, and PCT Application Nos. WO 97/ 19682, WO 97/20820, WO 97/20821 , WO 97/20822, WO 97/20823, WO 98/27063, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01 /07409. WO 01/02379, WO 01 /23388, WO 01/23389, WO 01/44201 , WO 01/62737, WO 01 /62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648;
[0092] (8) peptide YY (PYY) agonists, such as PYY, PYY 3-36, peptide YY analogs, and PYY agonists, for example, AC162352, N-Acetyl [Leu(28,31)]NPY 24-36, and PYY(3-36)NH2, cyclo-(28/32)-Λc-[Lys28- Glu32]-(25-36)-pNPY, TASP-V, pancreatic peptide (PP), 122U91, and those disclosed in U.S. Pat. Publication No. 2002/0141985 and PCT Application Publication No. WO 2005/077094, WO 03/026591 , WO 03/057235, and WO 03/027637;
[0093] (9) orexin antagonists, such as υrexin-1 receptor antagonists, for example
SB334867-A, and those disclosed in PCT Application Nos. WO 01/96302. WO 01/68609, WO 02 '51232, and WO 02/51838;
L0094J (10) glucagon-like peptide (GLP)-I agonists, including GLP-I , GLP- I analogs and derivatives, such as exenatide, exenatide-LAR, liraglutide, CJCl 134PC, LY548806, 716155, and AVEOOlO;
[0095] (1 1) melanocortin (MC) agonists, including MC4 agonists and MC4R agonists, such as Melanotan II, PT15, BL3020, AP1030, or those described in PCT Application Nos. WO 99/64002, WO 00/74679, WO 01/991752, WO 01/74844,
WO 02/12166, WO 02/1 1715, WO 02/12178, WO 03/007949, WO 02/068388, WO 02 '068387, WO 02/067869, WO 03/0401 17, WO 03/066587, WO 03/068738. WO 03/094918, and WO 03/031410;
[0096] (12) ghrelin receptor antagonists, such as NOXBl 1, CYT009GhrQb,
TZP300, EP01492, and those disclosed in PCT Application Nos. WO 01/87335, and WO 02/08250;
[0097] (13) leptin agonists, including recombinant human leptin and recombinant methionyl human leptin, and leptin derivatives, such as OB3, and those disclosed in U.S. Pat. Nos. 5,552,524, 5,552,523, 5,552,522, 5,521 ,283, 6,777,388 and 6,936,439, and PCT Application Nos. WO 96/23513, WO 96/23514, WO 96/23515, VVO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519, WO 96/23520, WO 96/05309, VVO 96/40912; WO 97/06816, WO 00/20872, WO 97/18833. WO 97/38014, WO 98/08512, WO 98/284427, U.S. patent publications 2004/0072219, 2003/049693, 2003/0166847, and 2003/0092126;
[0098] (14) cholccystokinin (CCK) agonists, such as ARRl 5849, GIl 81771 ,
JMV180, A71378, A71623, SR146131, UCL2000, and A71378, and those described in U.S. Pat. No. 5,739,106;
[0099] ( 15) ciliary neurotrophic factors (CNTF), including CNTF, CNTF modulators, and CNTF derivatives, such as Axokine and NT501, and those disclosed in U.S. Pat. Nos. 6,680,291 and 6,767,894 and in PCT Application Nos. WO 94/09134, WO 98/22128, and WO 99/43813;
[00100] (16) growth hormone (GH) secretagogues, growth hormone secretagogue receptor modulators, such as SUNl 1031 , RC1291, tesamorelin, scrmorelin, examorelin, NN703, hexarelin, MK677, SM-130686, CP-424,391 , L-692,429 and L-163,255:
[00101] (17) dipeptidyl peptidase IV (DP-IV or DPP-IV) inhibitors, such as denaghptm, sitagliptin, SYR322, RO0730699, TS021 , ALS20426, vidagliptin. GRC8200, MP513. PHXl 149, PSN9301, TA6666, saxagliptin, SSR162369, R1438, KRP104, 825964, and the compounds disclosed in PCT Application Nos. WO 03/004498; WO 03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250: WO 03/002530; WO 03/002531 ; WO 03/002553; WO 03/002593; WO 03/000180; and WO 03/000181 ; [00102] (1 8) histamine receptor-3 (H3) antagonists/inverse agonists, such as
GSK189254A, A331440, ABT239, ABT834, BP294, thioperamide, 3-(lH-imidazol-4- yl)propyl N-(4-pentenyl)carbamate. clobenpropit. iodophenpropit, imυproxifan. GT2394, and those described and disclosed in PCT Application Nos. WO 02/15905;
[00103] (19) 5-hydroxytryptamine (5HT) agonists, for example 5HT2C (serotonin receptor 2C) agonists, such as lorcaserin, vabicaserin, APD356, and those disclosed in U.S. Pat. No. 3,914,250, and PCT Application Nos. WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457; and 5HT6 agonists, such as PRX07034;
[00104] (20) serotonin transport or serotonin reuptake inhibitors such as nefazodone, citalopram, dapoxetine, duloxetine, desvenlafaxine, fluvoxamine, escitalopram, sibutramine, venlafaxine, vilazodone, DOV21947, LUAA21004, BGC201259, NS2359, UK416244, DOV102677. SEP225289, OPC14523, SLV314, WLl OI l , WL1017, zimeldinc, fluoxetine, paroxetine, fenfluramine, imipramine and sertraline, and those disclosed in U.S. Pat. No. 6,365,633, and PCT Application Nos. WO 01/27060 and WO 01/162341 ;
[00105] (21) dopamine agonists, for example dopamine D2 agonists, such as, ropinirole, bifeprunox, aripiprazole, pergolide, talipexole, ACP 104, quinagolide, nolomirole, NHOO l , SLV3O8, piribedil, lisuride, bromocriptine, aplindore, tesofensine, and preclamol;
[00106 J (22) norepinephrine (NE) transport inhibitors, such as lisdexamfctaminc, atomoxetine, duloxetine, SLE381 , desvenlafaxine, amfebutamone, sibutramine, venlafaxine, DOC21947, radafaxine, bupropion, DOV216303, reboxetine, AD337, NS2359, DOVl 02677, SEP225289, Xen2174, indeloxazine, protriptyline, and S33005;
[00107] (23) diacyl glycerol acyltransferase (DAG) inhibitors, such as BAY7441 13;
[00108] (24) glucose transporter inhibitors, for example, sodium glucose cotransporter
(SGLT) inhibitors, such as, KGTl 251 , 189075, AVE2268, and SGLOOl O;
[00109] (25) 1 1/3-hydroxy steroid dehydrogenase- 1 (/3-HSD-I) inhibitors, such as
INCB 13739, and AMG221 ; [00110] (26) cholesterol ester transfer protein (CETP) inhibitors, such as torcetrapib,
CETi I . JTT705, BAY605521 ,and JTT302;
[00111] (27) squalene synthase inhibitors, for example, lapaquistat;
[001 12] (28) glucocorticoid antagonists, for example, mifepristone, Org34517, and
Org34850;
[001 13] (29) phosphodiesterase (PDE) inhibitors, including phosphodiestcrasc-3B
(PDE3B) inhibitors, for example, tetomilast, tadalafil, atopik, vardenatϊl, tipelikast, HT0712, QADl 71 A, SK3530, oglemilast, acanafil, cilostazol, roflumilast, parogrelil, udenafil, EHT0202, dasantafil, MEM1414, SLx2101, CC10004, 256066, cilomilast, vinpocetine, ibudilast. pimobendan, ND7001 , LAS37779, Kl 23, UK357903, NDl 251 , tofimilast, UK169003, senazodan, trapidil, arofylline, theophylline, doxofylline. olprinone. pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast;
[001 14] (30) antiplatelet agents, such as, limaprost, clopidogrel, felbinac, eptifibatide,
NCX4016, ticagrelor, tirofiban, abcixmab, sarpogrelade, DA697B, argatroban, SCH530348, cilostazol, YSPSL, parogrelil, asasantin, DG041 , prasugrel, ramatroban. cangrelor, epoprostenol, beraprost, aspirin. Kl 34, triflusal, YY280, xemilofiban, ozagrel, alprostadil alfadex. TP9201 , procainamide, AT1015, Z335. BGC728, glyrofam, EF5077, SH529, and ME3229;
[001 15] (31 ) angiotensin converting enzyme (ACE) inhibitors, such as peridopril, enalapril, ramipril, fosinopril, quinapril, lisinopril, imidapril, benazepril, ilepatril, captopril, trandolapril, temcapil, cilazapril, MC4232, CHFl 521 , omapatrilat, spirapril, moexipril, zofcnopril, delapril, alacepril, S5590, and fasidotril;
[001 16] (32) angiotensin II (All) receptor antagonists, for example, losartan, candcsartan, tcmisartan, coaprovel, imidapril, azilsartan, valsartan, irbesartan, olmesartan, CYT006AngQb, TAK491. eprosartan, VNP489, CGP63170, fimesartan, pratosailan, and saralasin; [001 17] (33) uncoupling protein (UCP)-I , 2, or 3 activators, such as phytanic acid,
4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8.8-tetramethyl-2-napthalenyl)-l-propenyl]benzoic acid (TTNPB), retinoic acid, and those disclosed in PCT Patent Application No. WO 99/00123;
[001 18] (34) thyroid hormone β agonists, such as thyroid hormone, levo thyroxine,
KB21 15, 3,5-diiodothyropropionic acid, liothyronine, methimazole, and those disclosed in PCT Patent Application No. WO 02/15845, and Japanese Patent Application No. JP 2000256190;
[001 19] (35) cyclo-oxygcnase (COX)-2 inhibitors such as etoricoxib, GW406381 , meloxicam, lumiracoxib, diclofenac, valdecoxib, parecoxib, PMIOOl , 6444784, SVT2016, nimesulfide, CS706, cimicoxib, LR3001 , LAS34475, P54, rofecoxib, celecoxib, and arcoxia;
[00120] (36) monoamine reuptake inhibitors, such as those disclosed in PCT
Application No. WO 01 /27068, and WO 01/62341;
[00121 ] (37) metabotropic glutamate 5 (mGlu5) receptor antagonists, such as
ADXl 0059, AFQ-056, 2-mcthyl-6-(phenylethynyl)-pyridine (MPEP), (3-[(2-methy]-l,3- thiazol-4-yl)ethynyl]pyridine) (MTEP) and those compounds described in Anderson et al. (2003) J. Eur. J. Pharmacol. 473:35-40; Cosford et al. (2003) Bioorg. Med. Chcm. Lett. 13(3):351 -4; and Anderson et al. (2002) J. Pharmacol. Exp. Ther. 303: 1044-1051 :
[00122] (38) acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001);
[00123] (39) fatty acid synthase (FAS) inhibitors, such as Cerulenin, and C75;
[00124] (40) acetyl-CoA carboxylase-2 (ACC2) inhibitors;
[00125] (41 ) corticotropin-releasing hormone agonists;
[00126] (42) galanin antagonists;
[00127] (43) bombesin receptor subtype 3 (BRS3) agonists;
[00128] (44) protein tyrosine phosphatase- IB (PTP-IB) inhibitors; [00129] (45) fatty acid transporter inhibitors;
[00130] (46) dicarboxylate transporter inhibitors;
[00131 ] (47) phosphate transporter inhibitors;
[00132] (48) urocortin binding protein antagonists and urocortin ligands, such as urocortin II;
[00133] (49) human agouti -related proteins (AGRP);
[00134] (50) neuromedin U receptor agonists;
[00135] (51) topiramate, oxyntomodulin, tagatosc, CP741952, zonisamide, IDl 101,
BDC03, S2367, AOD9604, fluasterone, GT389255, QCBTl 6, MK0916, MK0493, MK0364, PD6735, c2735, and adiponectin.
[00136] Examples of other anti-obesity agents that can be employed in combination with the compounds as described herein are disclosed in "Patent focus on new anti-obesity agents," Exp. Opin. Ther. Patents, 10: 819-831 (2000); "Novel anti-obesity drugs," Exp. Opin. Invest. Drugs, 9: 1317-1326 (2000); and "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity, Exp. Opin. Ther. Patents, 11: 1677-1692 (2001). The role of neuropeptide Y in obesity is discussed in Exp. Opin. Invest. Drugs, 9: 1327-1346 (2000). Cannabinoid receptor ligands are discussed in Exp. Opin. Invest. Drugs, 9: 1553-1571 (2000).
[00137] Obesity and weight loss treatments also include surgery. Typically the weight loss surgical procedure is liposuction or lipoplasty. Surgical obesity treatments include gastric bypass, laparoscopic adjustable gastric binding, biliopancreatic diversion or vertical banded gastroplasty.
[00138] In another aspect, there is provided a method comprising administering a compound as described herein, or is a mixture of any two or more thereof and/or a stereoisomer, tautomcr, solvate, prodrug, or pharmaceutically acceptable salt thereof, and one or more ingredients A to a subject in need thereof, in an amount effective to increase or enhance the effectiveness of the ingredient A when used alone, wherein ingredient A is selected fiom agents useful in the treatment of obesity or an obesity-related condition or disorder In some embodiments, the effectiveness enhancement is obtained by allowing administration of lower dosages of one or more of the ingredient A used in combination as relatn e to the use of either agent alone
[00139] In another aspect of the invention, there is provided a method comprising administering to a subject a compound as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, and an ingredient A, in an amount effective to ieduce the risk ol metabolic disorders in a sub|ect m need thereof relative to the subject's risk pπor to administration of the compound and mgiedient A, wherein ingredient A is selected from agents useful in the treatment ot obesity or an obesity-related condition or disorder In some embodiments, the reduction in risk of metabolic disorders is obtained by reducing the body weight of the subject, relative to the subject's body weight prior to administration of the combination of the compound as described herein and ιngredient(s) A
[00140] For therapeutic use, the pharmaceutical combinations of ingredient A and the compound(s) as described herein may be administered in any conventional dosage form in any conventional manner, including any of the routes described herein Accordingly, routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intiasynovial, by infusion, sublingual, transdermal, oral, topical and by inhalation Typical modes of administiation aie oial, topical or intrav enous
[00141] The pharmaceutical combinations of ingredient A and the compound(s) as described herein may be administered separately, or in a combination formulation with other ingiedients or adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutical compositions containing them, provide increased dissolution or dispersion, muease inhibitory activity, provide adjunct therapy, or provide like advantages Such combination therapies typically utilize lowei dosages of the conventional therapeutics, and av oid the possible toxicity and adverse side effects incurred when those agents aie used as monotherapies Pharmaceutical combinations of ingredient A and the compound as described herein may therefore be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition The ingredient A and 'or the compound as described herein may be used in the combination as a salt, solvate, tautomer and/or prodrug and as a single stereoisomer or mixtures of stereoisomers, including racemates.
[00142] The proportions in which the two components, ingredient A and the compound as described herein, may be used in the combinations according to the invention are variable. Ingredient A and the compound as described herein are optionally present in the form of their solvates or hydrates. Depending on the choice of the ingredient A and the compound of the invention, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various compounds and their different potencies. Determination of ratios by weight is dependent on the particular ingredient A and the compound as described herein, and are within the skill in the art.
[00143] In yet another aspect of the invention, there is provided a method of treating a cancer, which comprises administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
[00144] In some embodiments of the invention, the method of treating cancer further comprises treating the subject with surgery, radiation, cryotherapy, or one or more antiproliferative agents or a combination thereof. In some such embodiments, the antiproliferative agent is an alkylating agent, platinum agent, antimetabolite, topoisomerase inhibitor, antitumor antibiotic, antimitotic agent, aromatase inhibitor, thymidylate synthase inhibitor, DNA antagonist, farnesyltransferase inhibitor, pump inhibitor, histone acetyltransferase inhibitor, metalloproteinase inhibitor, ribonucleoside reductase inhibitor, endothelin A receptor antagonist, retinoic acid receptor agonist, immunomodulator, hormonal or antihormonal agent, photodynamic agent, angiogenesis inhibitor, or a tyrosine kinase inhibitor. In some of these embodiments, the alkylating agent is busulfan, procarbazine, ifosfamide, altretamine, hexamethylmclaminc, estramustine phosphate, thiotepa, mechlorethamine, dacarbazine, streptozocin, lomustine, temozolomidc, cyclophosphamide, semustine, or chlorambucil. Examples of platinum agents include spiroplatin, lobaplatin (Aeterna), tetraplatin, satraplatin (Johnson Matthey), ormaplatin, iproplatin, miriplatin (Sumitomo), nexplatin (AnorMED), polymer platinate (Access), oxaliplatin, or carboplatin. In some embodiments, the antimetabolite is azacytidine, trimetrexate. floxuπdme, deox>cofomiycin, 2-chlorodeoxyadenosine, pentostatm, 6-mercaptopuπne, hydroxyurea. 6-thioguanine, decitabine (SuperGen), cytarabme, clυfarabine (Bioenvision), 2-fluorodeoxy cytidine, irofulven (MGI Pharma), methotrexate, tomudex. ethynylcytidine (Taiho), fludarabine, gemcitabine, raltitrexed, or capecitabine In others, the topoisomerase inhibitor is amsacπne, exatecan mesylate (Daiichi), epirubicm, qumamed (ChemGenex), etoposide, gimatccan (Sigma-Tau), tcniposidc, mitoxantrone, diflomotecan (Beaufour-Ipscn), 7-cthyl- 10-hydroxy-camptothecin, dexrazoxanet (TopoTarget), elsamitrucm (Spectrum), pixantrone (NOΛ uspharma), edotecarin (Merck & Co), becatecaπn (Exehxis), karenitecm (BioNumeπk), BBR-3576 (Novuspharma), belotecan (Chong Kun Dang), rubitecan (SupeiGen), irinotecan (CPT- 1 1), or topotecan In yet others, the antitumor antibiotic is dactmomycin (actinomycin D), a/onafide, valrubicin, anthrapyrazole. daunorubicin (daunomycin), oxantrazole, thcrarubicin, losoxantronc, ldarubicin, blcomycimc acid, rubidazonc, sabarubicin (Menarini), phcamycinp, 13-deoxydoxorubicin hydrochloride (Gem Pharmaceuticals), porfϊromycm, epirubicm, mitoxantrone (novantrone) or amonafide Examples of antimitotic agents are colchicines, ABT-751 (Abbott), vinblastine, xyotax (Cell Therapeutics), vindesine, IDN 5109 (Bayer), dolastatin 10 (NCI), A 105972 (Abbott), rhizoxm (Fujisawa), A 204197 (Abbott), mivobuhn (Warner-Lambert), synthadotin (BASF), cemadotm (BASF), mdibuhn (AS I A.Mcdica), RPR 10988 IA ( Avcntis), IXD 258 (Avcntis), combretastatm A4 (BMS), epothilone B (Novartis), isohomohahchondπn-B (PharmaMar), T 900607 (Tulaπk), ZD 6126 (AstraZeneca), batabuhn(Tulank), cryptophycin 52 (Eh Lilly), vinflunine (Fabre), hydravin (Prescient NeuroPharma), auπstatin PE (Teikoku Hormone), azaepothilone B (BMS), lxabepilone (BMS), tavocept (BioNumenk), BMS 184476 (BMS), combrestatm A4 disodium phosphate (OXiGENE), BMS 188797 (BMS), dolastatin-10 (NIH), taxoprexm (Protarga), cantuzumab mcrtansinc (GlaxoSmithKlinc), docctaxel, vinorelbinc, or vincristine In some embodiments, the aromatase inhibitor is aminoglutethimide, atamestane (BioMedicines), formestane, fadrozole, letrozole, exemestane, or anastrazole In others, the thymidylate synthase inhibitor is pemetrexed (Eh Lilly), nolatrexed (Eximias), ZD-9331 (BTG). doxifl undine (Nippon Roche), or 5,10-methylenetetrahydrofolate (BioKeys) In yet others, the DNA antagonist is trabectedin (PharmaMar), edotreotide (Novartis), glufosfamide (Baxter International), mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals), or thymectacin (NewBiotics) In still others, the farnesyltransferase inhibitor is arglabin (NuOncology Labs), tipifarnib (Johnson & Johnson), lonafarnib (Schcring-Plough), perillyl alcohol (DOR BioPharma), or sorafenib (Bayer). Examples of pump inhibitors are zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova). biricodar dicitrate (Vertex), or MS-209 (Schering AG). Examples of histone acetyltransferase inhibitors include tacedinaline (Pfizer), pivaloyloxymethyl butyrate (Titan), AP-CANC-03 and AP-CANC-04 (Aton Pharma). depsipeptide (Fujisawa), or MS-275 (Schering AG). In some embodiments, the metalloproteinase inhibitor is neovastat (Aeterna Laboratories), rnetastat (CollaGcncx), or marimastat (British Biotech). In others, the ribonucleoside reductase inhibitor is gallium maltolate (Titan), tezacitabine (Aventis), triapine (Vion), or didox (Molecules for Health). In yet others, the endothelin A receptor antagonist is atrasentan (Abbott), bosentan (Roche), ambrisentan (BASF), sitaxsentan (Encysive), clazosentan (Roche), darusentan (Knoll), and ZD-4054 (AstraZeneca). In still others, the retinoic acid receptor agonist is fenretinide (Johnson & Johnson), alitretinoin (Ligand), tazarotenc (Allcrgan), tctrinoin (Roche), isotretinoin (Roche), I3-cis-rctinoic acid (UCSD), or LGD- 1550 (Ligand). In some embodiments, the immuno-modulator is interferon, Roferon-A (Roche), dexυsome therapy (Anosys), oncυphage (Antigenics), pentrix (Australian Cancer Technology), GMK vaccine (Progenies), CDl 54 cell therapy (Tragen), adenocarcinoma vaccine (Biomira), transvax (Intercell), avicine (AVI BioPharma), norelin (Biostar), IRX-2 (lmmuno-Rx), BLP-25 liposome vaccine (Biomira), PEP-005 (Peplin Biotech), multiganglioside vaccine (Progenies), synchrovax vaccine (CTL Immuno), β-alethine (Dovetail), melanoma vaccine (CTL Immuno), vasocare (Vasogen), rituximab (Genentech/Biogen Idee), or p21 RAS vaccine (GemVax). In others, the hormonal agent is an estrogen, dexamethasone, a conjugated estrogen, prednisone, ethinyl estradiol, methylprednisolone, chlortrianisen. prednisolone, idenestrol, aminoglutcthimide, hydroxyprogesterone caproate, leuprolide, medroxyprogesterone, octreotide, testosterone, mitυtane, testosterone propionate, fluoxymesterone, methyltestosterone, 2-methoxyestradiol (EntreMed), diethylstilbestrol, arzoxifene (Eli Lilly), megestrol, tamoxifen, bicalutamide, toremofine, flutamide, goserelin, nilutamide, or leuporelin. In yet others, the photodynamic agent is talaporfϊn (Light Sciences), Pd-bacteriophcophorbidc (Yeda), thcralux (Theratechnologies), lutetium texaphyrin (Pharmacyclics), motexafin, gadolinium (Pharmacyclics), or hypericin. In still others, the angiogenesis inhibitor is neovastat (AEterna Zentaris), ATN-224 (Attenuon), sorafenib (Bayer), thalidomide, bevacizumab (Genentech), ranibizumab (Genentech), benefin (Lane Labs), L-651582 (Merck & Co), vatalanib (Novartis), or sutent (Pfizer). Examples of tyrosine kinase inhibitors include imatinib (Novartis), leflunomide (Aventis), kahalide F (PharmaMar) iressa (AstraZeneca), lestaurtinib (Cephalon), erlotinib (Oncogene Science), canertinib (Pfizer), tandutinib (Millenium), squalamine (Genaera), midostaurin (Novartis), phenoxodiol, SLJ6668 (Pharmacia), cetuximab (ImClone), rhu-Mab (Genentech), ZD6474 (AstraZeneca), MDX-H210 (Mcdarcx), vatalanib (Novartis), omnitarg (Genentech), lapatimb (GlaxoSmithKline), panitumumab (Abgenix), IMC-I Cl 1 (ImClone), sorafenib (Bayer) or trastuzumab (Genentech). In some embodiments, the anti -proliferative agent is melphalan, carmustine, cisplatin, 5-fluorouracil, mitomycin C, adriamycin (doxorubicin), bleomycin, or paclitaxel (Taxol*).
[00145] In some embodiments of the invention, the cancer is osteosarcoma, Kaposi's sarcoma, colorectal cancer, brain cancer, epithelial cell-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, gastric cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamus cell cancer, basal cell cancer, prostate cancer, renal cell carcinoma; leukemia, lymphoma, erythroblastoma, glioblastoma, glioma, meningioma, astrocytoma, myoblastoma, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, or follicular lymphoma. In some such embodiments, the cancer is acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadcnoma, endodeπnal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumors, glioblastoma, glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intaepithelial neoplasia, interepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo maligna melanomas, malignant melanoma, malignant mesothelial tumors, mcdulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucocpidcrmoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma nodular melanoma, oat cell carcinoma, oligodendroghal. osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pineal cell, pituitary tumor, plasmacytoma, pseudosarcoma. pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatm-secreting tumor, squamous carcinoma, squamous cell carcinoma, submesothehal, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, \ipoma, well differentiated carcinoma, or Wilm's tumor
[00146] In some embodiments, the cancer is leukemia, erythroblastoma, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-hodgkm's lymphoma or follicular lymphoma In some embodiments, the cancer is follicular lymphoma, acute myelogenous leukemia, multiple myeloma or non-hodgkin's lymphoma
[00147] In other embodiments, the cancer is bram cancer, glioblastoma, meningioma, astocytoma, medulloblastoma, neuroblastoma or retinoblastoma In some such embodiments, the cancer is glioma or glioblastoma
[00148] In yet other embodiments, the cancer is osteosarcoma, Kaposi's sarcoma, chondosarcoma, Ewing's sarcoma or myoblastoma. In some such embodiments, the cancer is osteosarcoma bone cancer
[00149] In some embodiments, the cancer is breast, lung, kidney or prostate cancer metastasis In some such embodiments, the neoplasm is bone metastasis
[00150] In yet another aspect of the invention, there is provided a method ol treating, modifying or managing pain, which compπses administering to a patient in need of such treatment, modification or management, a composition compπsing a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof In some embodiments, the composition further compπses an antidepressant, antihypertensive, anxiolytic, calcium channel blocker, α-adrenergic receptor agonist, α-adrenergic receptor antagonist, ketamme, anesthetic, muscle relaxant, non-narcotic analgesic opioid analgesic, NSAID, immunomodulatory agent, immunosuppressive agent, corticosteroid, anticonvulsant, hyperbaric oxygen, α.2δ hgand, NMDA receptor antagonist, or a combination of any two or more thereof In some such embodiments, the antidepressant is nortriptyline, amitπptyline, lmipramine, doxepm, clomipramine, fluoxetine, sertraline, nefd/odone, venlafaxine, trazodone, or bupropion In others, the anti-hypertensive is nifedipine terazosin, prazosin, losartan. \ erapamil, telmisartan, fosinopπl, bosentan, or olmesartan In yet others, the anxiolytic is fluoxetine, paroxetine, sertraline, or venlafaxine Examples of calcium channel blockers include nifedipine, verapamil and clomdme In other embodiments, the α-adrenergic receptor agonist is clomdme or midodπne In yet others, the α-adrenergic receptor antagonist is terazosin, prazosin, or doxasozm In some embodiments, the anesthetic is procaine, hdocame, mepivacame, articame, pπlocaine, etidocaine, bupu acaine, or ropivacame Examples of opioid analgesic include hydromorphone, oxycodone, morphine sulfate, meperidine, and tentanyl transdermal patch In some embodiments, the NSAID is a COX-2 inhibitor, salicylic acid acetate, ibuprofen, ketoprofen, naproxen sodium, ketorolac, diclofenac, lndometacm, or acetaminophen In some such embodiments, the COX-2 inhibitor is rofecoxib, celecoxib, or valdecoxib In yet others, the corticosteroid is prednisone, dexamethasone or hydrocortisone In others, the anticonvulsant is carbamazepine, oxcarbazepme, gabapcntin, pregabahn, phenytom, sodium valproate, clonazepam, topiramate, lamotπgine, zonisamide, tiagabine, famotodinc, phenobarbital, diphenylhydantoin. mephenytoin, ethotoin, mephobarbital, pπmidone, ethosuximide, methsuximide, phensuximide, tπmethadione, benzodiazepine, phenacemide, acetazolamide, progabide, divalproex sodium, magnesium sulfate injection, metharbital, paramethadione, clobazam, sulthiame, dilantm, diphenylan, or L-5-hydroxytryptophan In some embodiments, the NMDA receptor antagonist is dextromethorphan, dextrorphan, ketamine, memantme, amantadine, agmatine, aptiganel, gavestinel, selfotel, 7-chlorokynuratc, rcmacemide, riluzole, pyrroloquinolme qumone or cis-4-(phosphonomethyl)-2-pipeπdmecarboxylic acid In others, the α2δ hgand is gabapentm, pregabahn, [(lR,5R,6S)-6-(Ammomethyl)bicyclo[3 2 0]hept-6- yljacetic acid, 3-(l -Aminomethyl-cyclohcxylmcthyl)-4H-[l ,2,4]-oxadiazol-5-one and C-[I-( I H-Tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3 S,4S)-( 1 -Ammomcthyl-3 ,4- dimethyl-cyclopentyl)-acetic acid, (l α,3α,5α)(3-ammo-methyl-bicyclo[3 2 0]hept-3-vl)- acetic acid, (3S,5R)-3-Aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl- heptanoic acid, (3S,5R)-3-ammo-5-methyl-nonanoic acid and (3S,5R)-3-Amino-5-methyl- octanoic acid In yet other embodiments, the composition further comprises acetyl salicylic acid, diclofenac, ibuprofen, mdυmetdcin, flufenamic acid, mefenamic acid, morphine, pethidine, methadone, fentanyl, buprenorphme, tramadol, gabapentin, pregabahn. carbamazepine, lamotπgin. topiramate, phenylom. levitiracetam, procaine, hdocaine, mepn acame articame, pπlocaine, etidocaine, bupivacaine, roprvacaine, amitryptilmc, paioxetine, citalopram, bupiopione duxoletine, ketamine. memantine, 2,3-beti7odia7epincs, or a combination of any two 01 more thereof
[00151 ] In some embodiments of the invention, the pain is acute pam, chrome pain, pain resulting from soft tissue and peripheral damage from acute trauma, neuropathic pain. post-stroke pam, postherpetic neuralgia, occipital neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgias, pain associated w ith osteoarthritis and rheumatoid arthritis, musculoskeletal pain, spinal pain, central nervous system pain, lower back pain, sciatica, dental pam, myofascial pain syndiomes, episiotomy pam, gout pam, and pain resulting from burns, deep and visceral pain, muscle pain, eye pain, inflammatory pain, orofacial pain, abdominal pain, and gynecological pain, somatogenic pain, pain associated with nerve and root damage, pain associated with hmb amputation, tic douloureux, neuroma, or vasculitis, diabetic neuropathy, chcmothcrapy-induced-neuropathy, acute herpetic and postherpetic neui algia, atypical facial pam, neuropathic lower back pain, and arachnoiditis, trigeminal neuralgia, segmental or intercostal neuialgia, HIV ielated neuralgias, AIDS related neuralgias and other neuralgias, allod>nia, hyperalgesia, burn pain, idiopathic pam, pam caused by chemotherapy, occipital neuralgia, psychogenic pain, brachial plexus avulsion, pain associated with restless leg syndrome, pain associated with gallstones, pam caused by chronic alcoholism or hypothyroidism or uremia or vitamin deficiencies, neuropathic and non-neuiopathic pam associated with carcinoma, cancer pain, phantom limb pam, functional abdominal pam, headache, temperomandibular pain and maxillary sinus pam, pain resulting from ankylosing spondylitis, pam caused by increased bladder contractions, complex regional pain syndrome, sympathetic maintained pain syndrome, reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, chronic fatigue syndrome, radiculopathy, luetic neuropathy, oi painful neuiopathic condition induced from a drug post operative pain, scar pam, or chronic non-neuropathic pam
[00152] In some such embodiments, the musculoskeletal pam is pain associated with strains, sprains or broken bones In others, the central nervous system pam is pain due to spinal cord or brain stem damage. In yet others, the deep and visceral pain is heart pain. In others, the orofacial pain is odontalgia. In some embodiments, the gynecological pain is dysmenorrhoea, labour pain and pain associated with endometriosis. In others, the pain associated with nerve and root damage, is pain associated with peripheral nerve disorders. In some such embodiments, the peripheral nerve disorder is nerve entrapment or brachial plexus avulsions. In some other embodiments, the headache is migraine with aura, migraine without aura, vascular headaches, acute or chronic tension headache, sinus headache or cluster headache. In yet other embodiments, the chronic non-neuropathic pain is pain associated with HIV, anthralgia, vasculitis or fibromyalgia. In some embodiments, the complex regional pain syndrome is type I or type II.
[00153] In some other embodiments, the pain is nociceptive pain or neuropathic pain.
In some such embodiments, the nociceptive pain is associated with chemical or thermal burn, cut of the skin, contusion of the skin, osteoarthritis, rheumatoid arthritis, systemic lupus erthrematosis (SLE), tendonitis, or myofascial pain. In others, the neuropathic pain is diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, post-stroke pain, complex regional pain syndrome, sympathetic maintained pain syndrome, reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, spinal cord injury pain, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, pain related to cancer or metastases, phantom limb pain, fibromyalgia, chronic fatigue syndrome, radiculopathy, luetic neuropathy, or painful neuropathic condition induced by a drug. In embodiments where the pain is related to cancer or metastases, the cancer is osteosarcoma, colorectal cancer, brain cancer, epithelial call-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamus cell and/or basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body; leukemia; lymphoma; or angiogenesis including neoplasia. In other embodiments, the metastases are breast, lung, kidney or prostate cancer metastases.
[00154] In yet another aspect of the invention, there is provided a method of treating pemphigus, which comprises administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of a compound as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments of methods of treating pemphigus, the pemphigus is pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus, bullous pemphigoid, paraneoplastic pemphigus, cicatricial pemphigoid, bullous impetigo, or staphylococcal scalded-skin syndrome.
[00155] In another aspect, there are provided methods comprising administering to a subject in need thereof a combination of (i) an effective amount of a compound of the invention and (ii) an effective amount of one or more therapeutic Ingredients A useful in the treatment of pemphigus as described herein, wherein the effective amount of Ingredients A is less than the effective amount of Ingredient A when used alone.
[00156] Also provided are methods comprising administering to a subject exhibiting one or more clinical indicia of pemphigus an amount of a compound as described herein effective to reduce the number and/or severity of clinical indicia of pemphigus relative to those present in the subject prior to the administration of the compound as described herein, wherein the clinical indicia of pemphigus include the percentage of total body surface area (BSA) affected by pemphigus, pemphigus lesion thickness, the number of new pemphigus lesions, the number of active pemphigus lesions (including blisters and erosions), the healing time of active lesions (for example, time to 80% healing), serum anti-desmoglein-1 (DSGl) antibody levels, serum anti-DSG3 antibody levels, serum TNFa-levels, serum IL6 levels, skin TNFa-mRNA levels, skin IL6 mRNA levels, or any two or more thereof. In some embodiments of the invention, the methods additionally comprise administering to the subject an effective amount of one or more Ingredients A, useful in the treatment of pemphigus, as described herein. In some such embodiments, the effective amount of Ingredients A is less than the effective amount of Ingredient A when used alone.
[00157] In some embodiments of the methods of the invention, the methods further comprise administering to the subject an Ingredient A, wherein the Ingredient A is an antiinflammatory agent, an immunosuppressant, an anti-infective, an antibiotic, a gold salt, an alkylating agent, an immunoglobulin, or a combination of two or more thereof. [001 58] In some embodiments in which Ingredient Λ is an anti-inflammatory agent, the anti-inflammatoiy may be a corticosteroid, a COX-2 inhibitor, a non-steroidal antiinflammatory drug (NSAID), a TNFa antagonist, or an IL-I antagonist For example, the corticosteroid can be prednisone, prednisolone, or methylprednisolone Corticosteroids such as these may also be administered with either chlorambusil 01 mycophenylate mofetil In some embodiments, the TNFa antagonist is infliximab, etanercept, or adalimumab In others, the IL- I antagonist is anakinra
[00159] In other embodiments, the immunosuppressant is mycophenylate mofetil, cyclosporin, azathiυpnne, methotrexate, alefacept, πtuximab, anti-interferon gamma, or cyclophosphamide In some other embodiments, the anti-mfective is dapsonc, or hydroxychloroquine In some embodiments, the gold salt is myochrysme, oi solganal In some embodiments, the alkylating agent is lukeran In some embodiments, the antibiotic is tetiacychne, minocycline, or doxycychne In some such embodiments, the method further comprises administration of nicotinamide, or niacinamide In other embodiments of the methods of the inv ention, the methods of the invention further comprise administering plasmapheπsis therapy or photophoresis therapy to the subject
[00160] In some embodiments of the methods of the invention, the dosage of
Ingredient A is reduced by from about 10% to about 90% in comparison to the dosage used to achieve the same therapeutic effect with Ingredient A alone In some embodiments, the dosage is reduced by at least about 10%, about 20%, about 30%, about 40%, about 50%. or about 60% In some embodiments, Ingiedient A is a corticosteroid, for example, prednisone or prednisolone In some other embodiments, Ingredient A comprises a corticosteroid and cither chlorambusil or mycophenylate mofetil In some embodiments, the dosage of prednisone is reduced to less than about 70 mg/day, less than about 50 mg/day, less than about 30 mg/day, less than about 20 mg/day, less than about 15 mg/ day, or less than about 10 mg/day
[00161 ] In yet other embodiments, the compound as described herein is administered orally or topically In some embodiments, Ingredient A is a corticosteroid or antibiotic and is administered orally, topically, in a mouthwash or in a mouth spray DETAILED DESCRIPTION OF THE INVENTION
[00162] The following terms are used throughout as defined below.
[00163] Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Hence, isotopically labeled compounds are within the scope of the invention.
[00164] In general, '"substituted" refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to atoms other than hydrogen or unsubstituted carbon. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom arc replaced by one or more bonds, including double or triple bonds, to a heteroatom. Thus, a substituted group will be substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group is substituted with 1 , 2, 3, 4, 5, or 6 substituents. Examples of substituent groups include halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclyl alkoxy groups; carbonyls (oxo); carboxyls; esters; urethanes; oximes; hydroxyl amines; alkoxyamines; aralkoxyamincs; thiols; sulfides: sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides: isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitriles (i.e. CN); and the like.
[00165] Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.
[00166] Alkyl groups include straight chain and branched alkyl groups having from
1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Alkyl groups further include cycloalkyl groups as defined below. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tcrt-butyl, ncopcntyl, isopentyl, and 2,2-dimethylpropyl groups. Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above,
[00167] Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl. cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 10 or 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include mono-, bicyclic and polycyclic ring systems, such as, for example bridged cycloalkyl groups as described below, and fused rings, such as, but not limited to, decalinyl, and the like. In some embodiments, polycyclic cycloalkyl groups have three rings. Substituted cycloalkyl groups may be substituted one or more times with non- hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that arc substituted with straight or branched chain alkyl, alkenyl or alkynyl groups as defined above. Representative substituted cycloalkyl groups may be mono- substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents such as those listed above.
[00168] Bridged cycloalkyl groups are cycloalkyl groups in which two or more hydrogen atoms arc replaced by an alkylcnc bridge, wherein the bridge can contain 2 to 6 carbon atoms if two hydrogen atoms are located on the same carbon atom, or 1 to 5 carbon atoms if the two hydrogen atoms are located on adjacent carbon atoms, or 2 to 4 carbon atoms if the two hydrogen atoms are located on carbon atoms separated by 1 or 2 carbon atoms. Bridged cycloalkyl groups can be bicyclic, such as, for example bicyclo[2.1.1]hexane, or tricyclic, such as. for example, adamantyl. Representative bridged cycloalkyl groups include bicyclo[2.1.1]hexyl. bicyclo[2.2.1 ]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1 ]nonyl, bicyclo[3.3.2]decanyl, adamantyl, noradamantyl, bornyl, or nυrbornyl groups. Substituted bridged cycloalkyl groups may be substituted one or more times with substituents as defined above, including straight or branched chain alkyl, alkenyl, or alkynyl groups. Representative substituted bridged cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono- di- or tri-substitutcd adamantyl groups, which may be substituted with substituents such as those listed abo\ e
[00169] Cycloalkylalkyl groups are alkyl groups as defined abo\ e m which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cvcloalkyl group as defined above In some embodiments, cy cloalkylalkyl groups have from 4 to 20 carbon atoms, 4 to 16 carbon atoms, and typically 4 to 10 carbon atoms Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl or both the alkyl and cycloalkyl portions of the group Representative substituted cycloalkylalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tii-substituted with substituents such as those listed above
[00170] Alkenyl groups include straight and branched chain and cycloalkyl groups as defined above, except that at least one double bond exists between two carbon atoms Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments from 2 to 8, 2 to 6, or 2 to 4 caibon atoms In some embodiments, alkenyl groups include cycloalkenyl groups having from 4 to 20 carbon atoms, 5 to 20 carbon atoms. 5 to 10 carbon atoms, or e\en 5, 6 7 or 8 carbon atoms Examples include but are not limited to vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hcxadicnyl, among others Representative substituted alkenyl groups may be mono- substituted oi substituted more than once, such as, but not limited to, mono-, di- or tri- substituted with substituents such as those listed above
[00171 ] Cycloalkenylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above Substituted cycloalkenylalkyl groups may be substituted at the alkyl, the cvcloalkenyl or both the alkyl and cycloalkenyl portions of the group Representative substituted cycloalkenylalkyl groups mav be substituted one or more times with substituents such as those listed above
[001 72] Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms Thus, alkynyl groups have from
2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Examples include, but arc not limited to -C≡CH, -CsC(CH3), -CsC(CH2CH3), -CH2C≡CH, -CH2CsC(CH3). and -CH2CsC(CH7CH3), among others. Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above.
[00173] Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
Aryl groups include monocyclic, bicyclic and polycyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenylenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms in the ring portions of the groups. Although the phrase "aryl groups" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups. Representative substituted aryl groups may be mono-substituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.
[00174] Aralkyl groups arc alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. In some embodiments, aralkyl groups contain 7 to 20 carbon atoms, 7 to 14 carbon atoms or 7 to 10 carbon atoms. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above.
[00175] Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non- aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. In some embodiments, heterocyclyl groups include 3 to 20 πng membeis, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 15 πng members Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, lmidazolyl, lmidazolinyl and lmidazolidinyl groups The phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups, such as, for example, bcnzotnazolyl, 2,3-dihydrobenzo[l ,4]dioxinyl, and benzo[1.3]dioxolyl The phrase also includes bridged polycyclic πng systems containing a heteroatom such as, but not limited to. quinudidyl However, the phrase does not include heterocyclyl groups that have other groups, such as dlkyl, oxo or halo groups, bonded to one of the πng members Rather, these are referred to as "substituted heterocyclyl groups" Heterocyclyl groups include, but are not limited to, aziπdinyl, azetidinyl, pyrrolidinyl, lmidazolidinyl, pyrazolidinyl, thiazohdmyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrohnyl, imida7olyl, imidazohnyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazohnyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pipeπdyl, piper azinyl, morpholinyl, thiomoφholmyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyπdyl, pyπmidinyl, pyπdazinyl, pyrazinyl, triazinyl, dihydropyπdyl, dihydrodithnnyl, dihydrodithionyl, homopiperazinyl, qumuclidyl, mdolyl, lndohnyl, isoindolyl,azamdolyl (pyrrolopyπdyl). indazolyl, mdohzinyl, benzotnazolyl, benzimidazolyl, ben7ofuranyl, benzo thiophenyl, benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithπnyl, benzoxathnnyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, ben/othiadiazolyl, benzo[l,3"]dioxolyl, pyrazolopyπdyl, lmidazopyridyl (azabenzimidazolyl), triazolopyπdyl, lsoxazolopyπdyl, puπnyl, xanthmyl, adeninyl, guaninyl, quinohnyl, lsoquinohnyl, quinohzmyl, quinoxahnyl, quinazolinyl, cinnohnyl, phthalazinyl, naphthyπdinyl, ptcπdinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydromdolyl, dihydrobenzodioxmyl, tetrahydroindolyl, tetrahydromdazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyπdyl, tetrahydropyrazolopyπdyl, tetrahydroimidazopyπdyl, tetrahydrotriazolopyπdyl, and tetrahydroquinolinyl groups. Representative substituted heterocyclyl groups may be mono- substituted or substituted more than once, such as, but not limited to, pyπdyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents suLh as those listed above [00176] Heteroaryl groups are aromatic ring compounds containing 5 or more πng membeis, of which, one or more is a heteroatom such as, but not limited to, N. O, and S Heteroaryl groups include but aie not limited to, groups such as pyrrolyl, pvrazolyl, lmidazυlyl, triazυlyl, tetrazolyl, oxazolvl, lsoxazolyl, thiazolyl. pynd>l, pyiidazmyl, pyπmidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanvl, benzofuranyl, indolyl, azaindolyl (pyrrolopyπdyl), indazolyl, benzimidazolyl. lmidazopvπdyl (azabenzimidazolyl), pyra/olopyπdyl, triazolopyndyl, benzotnazolyl, benzoxazolyl, benzothiazolyl, ben/othiadia7oly] imidazopyridyl, lsoxazolopyπdyl, thianaphthalenyl, puπnyl, xanthinyl, adeninyl, guaninyl, quinohnyl, lsoqumolmyl tetrah^droqumohnyl, qumoxahnyl, and quina/olinyl groups Although the phrase "heteroaryl groups" includes fused img compounds such as indolyl and 2,3-dihydro indolyl, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups Rather, heteroaryl groups with such substitution are referred to as "substituted heteroaryl groups" Representative substituted heteroaryl groups may be substituted one or more times with vatious substituents such as those listed above
[00177] Heterυcyclylalkyl groups are alkyl groups as defined above in which a hydiogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above Substituted heterocyclylalkyl groups may be substituted at the alkvl, the heterocyclyl or both the alkyl and heterocyclyl portions of the group Representative heterocyclyl alkyl groups include, but arc not limited to, 4-ethyl-morpholinyl, 4-ptopylmorphohnyl, furan-2-yl methyl furan-3-yl methvl, pyπdine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indoI-2-yl propyl Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those listed above
[00178] Heteroaralkyl groups are alkyl groups as defined abo\ e in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined abov e Substituted heteroaralkyl groups may be substituted at the alkyl, the heteroaryl, or both the alkyl and heteroaryl portions of the group Representative substituted heteioaialkyl groups may be substituted one or more times with substituents such as those listed above [00179] Alkoxy groups arc hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy. propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groups include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.
[00180] The terms "aryloxy" and "arylalkoxy" refer to, respectively, a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those listed above.
[00181 ] Alkyl, alkenyl, and alkynyl groups may be divalent as well as monovalent.
The valency of an alkyl, alkenyl, or alkynyl group will be readily apparent from the context to those of skill in the art. For example, the alkyl group in an aralkyl group is divalent. In some embodiments, divalency is expressly indicated by appending the suffix "ene" or "ylene" to terms defined herein. Thus, for example, "alkylene" refers to divalent alkyl groups and alkcnylcnc refers to divalent alkcnc groups.
[00182] The term "carboxylate" as used herein refers to a -COOH group.
[00183] The term "carboxylic ester" as used herein refers to -COOR30 groups. R30 is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
[00184] The term "amide" (or "amido") includes C- and N-amide groups, i.e.,
-C(O)Ml31R32, and -NR31C(O)R32 groups, respectively. R31 and R32 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH2) and formamide groups (-NHC(O)H). [00185] Urethane groups include N- and O-urethane groups, i.e., -NR33C(O)OR34 and
-OC(O)NR33R34 groups, respectively. R33 and Rj4 arc independently hydrogen, or a substituted or un substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
[00186] The term "amine" (or "amino") as used herein refers to -NHR35 and -NR36R37 groups, wherein R35, R36 and R37 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. In some embodiments, the amine is NHi, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.
[00187] The term "sulfonamido" includes S- and N-sulfonamide groups, i.e.,
-SO2NR38R39 and -NR38SO2R31* groups, respectively. R38 and R19 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-SO2NH2).
[00188] The term "thiol" refers to -SH groups, while sulfides include -SR40 groups, sulfoxides include -S(O)R41 groups, sulfones include -SO2R42 groups, and sulfonyls include -SO2OR43. R40, R41, R42, and R43 are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
[00189] The term "urea" refers to -NR44-C(O)-NR45R46 groups. R44, R45, and R46 groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.
[00190] The term "amidine" refers to -C(NR47)NR4SR49 and -NR47C(NR4S)R49, wherein R47, R4\ and R49 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. [00191] The term "guanidine" refers to -NR50C(KR51)NR52R53, wherein R50, R51, R52 and R33 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl. alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
[001921 The term "enamine" refers to -C(R54)=C(R55)NRSbR57 and
-NR54C(R55)=C(R56)R57, wherein R54, R55, R56 and R57 are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
[00193] The teπn "imide" refers to -C(O)NR58C(O)R59, wherein R58 and R59 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
[00194J The term "imine" refers to -CR6(J(NR61) and -N(CR60R61) groups, wherein R60 and R61 are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R60 and R61 are not both simultaneously hydrogen.
[00195] The term "protected" with respect to hydroxyl groups, amine groups, carboxy groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction by means of protecting groups. Protecting groups are known to those skilled in the art and can be added or removed using well-known procedures, such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methyfhiom ethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyefhoxymethyl ether, tetrahydropyranyl ethers, 1 -ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoyl formate, foπnate, acetate, trichloroacetate, and trifluoroacetate.
[00196] N-Protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butyl acetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloro acetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl. and the like; carbamate forming groups such as benzyl oxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2- - nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3, 5-dimethoxybenzyl oxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybcnzyloxycarbonyl, l-(p-biphenylyl)-l -methyl ethoxycarbonyl, (αα-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohcxyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymcthyl, and the like; and silyl groups such as trimethylsilyl, and the like. Typical N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl. phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
[00197] Examples of protected sulfhydryl groups include, but are not limited to, thioethcrs such as S-benzyl thioether, S-t-butylthioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
[00198] Representative carboxy protecting groups arc C1 to C8 alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cyclopentyl, and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cyclopentylmethyl, and the like; arylalkyl, for example, phcncthyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups, and the like; arylalkcnyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g.. dimethylaminoethyl. and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valerytoxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1 -(propionyloxy)- 1 -ethyl, 1 -(pivaloyloxyl)-l -ethyl, 1 -methyl- 1 -(propionyloxy)- 1 -ethyl, pivaloyloxymethyl, propionyloxymethyl, and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymcthyl, and the like; aroyloxyalkyl. such as benzoyloxymethyl, benzoyloxyethyl, and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl, and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-l -ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1-ethoxycarbonyloxy-l -ethyl, 1-cyclohexyloxycarbonyloxy-l - ethyl, and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl, and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl, and the like; alkanuylaminoalkyl, such as acetylaminomethyl, and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl, and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl, and the like; (5-(alkyl)-2-oxo-l,3-dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-l ,3-dioxolcn-4-yl)methyl, and the like; and (5-phenyl-2-oxo-l ,3-dioxolen-4- yl)alkyl, such as (5-phenyl-2-oxo-l ,3-dioxolen-4-yl)methyl, and the like.
[00199] Those of skill in the art will appreciate that compounds of the invention may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or optical isomerism. As the formula drawings within the specification and claims can represent only one of the possible tautomeric, conformational isomeric, optical isomeric or geometric isomeric forms, it should be understood that the invention encompasses any tautomeric, conformational isomeric, optical isomeric and/or geometric isomeric forms of the compounds having one or more of the utilities described herein, as well as mixtures of these various different forms.
[00200] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, triazυles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
Figure imgf000076_0001
[00201] As readily understood by one skilled in the art. a wid groups and other stiuctuies may exhibit tautomensm and all tautom descπbed herein are withm the scope of the present invention
[00202] Stereoisomers of compounds (also known as optical chiral. diastereomeπc, and racemic forms of a structure unless the s expiessly indicated Thus, compounds used m the present invention resolved optical isomers at any or all asymmetπc atoms as are appar p Both racemic and diasteieomeπc mixtures, as well as the indiv idual optical isomers can be isolated or synthesized so as to be substantially free of then enantiomeric or diastereomeπc partners, and these are all within the scope of the invention
[00203] As used herein, a solvate is an aggregation of a molecule and one or moie molecules of solvent Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the solid state The solvent molecules may interact with the non-solvent molecule by dipole-dipole interactions, ion-dipole interactions, coordinate bonds, and the like When the solvent is w ater, the solvate is a hydrate Many oiganic solvents can also form solvates, including, e g , ethers, such as diethyl ether and tetrahydrofuran, alcohols, such as methanol and ethanol ketones such as acetone, DMF, DMSO and others Solvates may be identified by various methods known in the art For example, solvates in which the solvent molecules contain hydrogen may be observable by 1H NMR Additional methods useful in identifying solvates include theiτnogra\imetπc analysis, differential scanning caloπmetry, X-ray analysis and elemental analysis Solvates are readily formed simply by dissolving a compound in a solvent and remo\ing the untrapped solvent b> evaporation, freeze-drymg oi crystallization techniques It is therefore well withm the skill in the art to produce such soh ates Indeed, it is often the case that careful drying of a compound is necessary to remove the i esidual solvent that is part of a solvate Compounds described herein may form soh ates and all such soh ates are within the scope of the invention [00204] Certain compounds within the scope of the invention are derivatives referred to as "prodrugs". The expression "prodrug'" denotes a derivative of a known direct acting drug, e.g.. esters and amides, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process; see Notari, R. E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology /72:309-323 (1985); Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future 6: 165-182 (1981); and Bundgaard, H., "Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, New York (1985), Goodman and Gilmans, The Pharmacological Basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992. The preceding references and all references listed herein are hereby incorporated in their entirety by reference.
[00205 J Pharmaceutically acceptable salts of the invention compounds are considered within the scope of the present invention. When the compound of the invention has a basic group, such as, for example, an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., formic acid, acetic acid, trifluoroacctic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methancsulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compound of the invention has an acidic group, such as for example, a carboxyhc acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g., Naτ, Li+, K+, Ca +, Mg"+, Zn2'), ammonia, organic amines (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolaminc, dicthanolamine, triethanolamine), or basic amino acids (e.g., arginine, lysine and ornithine).
[00206] Compounds of the invention may be readily synthesized by techniques well known to those of skill in the art. Examples of synthesis approaches can be found in, for example, U.S. Application No.10/939,324 and International Application No. PCT/US2006/006682.
[00207] C-reactive protein (CRP) is a plasma protein, and an acute phase protein produced by the liver. CRP is a member of the class of acute phase reactants as its levels rise dramatically during inflammatory processes occurring in the body. CRP is used mainly as a marker of inflammation. Measuring and charting C-reactive protein values can prove useful in determining disease progress or the effectiveness of treatments. Blood, usually collected in a serum-separating tube, is analyzed in a medical laboratory or at the point of testing. Various analytical methods are available for CRP determination, such as ELISA, immunoturbidimetry. rapid immunodiffusion and visual agglutination. Research suggests that patients with elevated basal levels of CRP are at an increased risk for diabetes, hypertension and cardiovascular disease. It is thought that CRP levels <lmg/l represent low cardiovascular risk, while levels >3mg/l represent high risk.
[00208] Lipoproteins are complexes which contain both a lipid and protein. Most of the lipids in plasma are present as lipoproteins and are transported as such. Lipoproteins are characterized by their flotation constants (e.g., densities). Various classes of lipoproteins exist and include high density lipoproteins (HDL) and low density lipoproteins (LDL). The HDL fraction comprises two major fractions, namely HDL2 (large, buoyant HDL, density 1.063 - 1 , 125 g/ml) and HDL3 (small, dense HDL, density 1.125-1.21 g/ml). LDLs are particularly rich in cholesterol esters. Traditionally, high levels of LDL and/or low levels of HDL are associated with coronary artery disease. Epidemiological studies have shown that high concentrations of HDL (over 60 mg/dl) have protective value against cardiovascular diseases. Low concentrations of HDL (below 40 mg/dl for men, below 50 mg/dl for women) are a positive risk factor for atherosclerotic diseases. A near optimal level of LDL is considered to be between 100 to 129 mg/dl, with levels below 100 mg/dl considered optimal, while very high LDL levels (above 190 mg/dl) correspond to the highest increased risk of heart disease.
[00209] Assessment of these levels is associated with assessing the risk of cardiovascular and/or cerebrovascular disease. Lipoprotein levels and triglyceride levels are measured and assessed using routine methods known in the art. Commercially available kits and assays may be used to evaluate the level of HDL-C, LDL-C and the level of triglycerides in a subject. Typically, cholesterol analysis is performed by two methods, namely an NMR based method and an ultracentrifugation method. The first method is based on NMR analysis of the lipid environment to determine the size classes and utilizes deconvolution to determine the number of particles in each class. The second method, based on density gradient ultracentrifugation, measures the amount of cholesterol across a range of densities and utilizes deconvolution to determine the amount of cholesterol in each traction (HDL, including HDL2 and HDL3, LDL, IDL, VLDL)
[00210] Apohpoprotein A-I (ApoA-I) is the major protein component of HDL in plasma The protein promotes cholesterol efflux from tissues to the liver tor excretion and helps to clear cholesterol from arteries
[0021 1] Glucose, or "blood sugar", is normally present in humans at concentrations of about 80- 120 mgvdl and is the principal source of carbohydrate energy for man and many other organisms Excess glucose is stored in the body (especially in the liver and muscles) as glycogen, a starch-like substance which is, essentially, polymerized glucose Glycogen is metabolized into glucose as needed to meet bodily requirements
[00212] Glucose normally stimulates both the secretion and biosynthesis of insulin In addition to this glucose-stimulated insulin secretion, however, there exists a basal insulin secretion, namely the biological process by which insulin is released into the circulation in the absence of stimulation by levels of glucose, or other agents that promote insulin secretion, that are elevated above their "fasting" or non-fed levels The values for fasting and postprandial (after a meal) insulin are about 14 to 145 pmol/1, and 100 to 300 pmol/1 respectively in healthy people, with perhaps 3 -to 4-fold higher levels in insulin-resistant people
[00213] Glycosylated (or glycated) hemoglobin (hemoglobin AIc, Hb Ie, HbAI c or
HgA Ic) is a form of hemoglobin used primarily to identify the plasma glucose concentration over time The normal range (that found in healthy subjects) is 4% to 5 9% People with diabetes melhtus often have higher levels of HbA 1 c While diabetic subject treatment goals vary, many include a target range of HbAI c values A diabetic with good glucose control has a HbAIc level that is close to or within the reference range The International Diabetes Federation and Ameπcan College of Endocπnology recommends HbAI c values below 6 5%, while the range recommended by the Ameπcan Diabetes Association extends to 7% A very high HbAIc represents poor glucose control
[00214] Insulin resistance is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells Insulin resistance in fat cells results m hydrolysis of stored triglycerides, which elevates free fatty acids in the blood plasma Insulin resistance in muscle reduces glucose uptake whereas insulin resistance in liver reduces glucose storage, with both effects serving to ele\ ate blood glucose High plasma levels of insulin and glucose due to insulin resistance often leads to metabolic syndrome and type 2 diabetes Metabolic syndrome, also known as Syndrome X, metabolic syndrome X, insulin resistance syndrome, is a combination of medical disorders, having at least three of the following symptoms and features fasting hyperglycemia (including diabetes melhtus type 2 or impaired fasting glucose, impaired glucose tolerance or insulin resistance), high blood pressure, central obesity (also known as visceral adiposity), decreased HDL cholesterol, and elevated triglycerides
[00215] Insulin resistance can be detected by the follow ing indications as an increased le\ el of blood insulin, increased blood level of glucose in response to oral glucose tolerance test (OGTT), decreased level of phosphorylated protein kinase B (AKT) in response to insulin administration, and the like Insulin resistance may be caused by decreased sensitivity of the insulin receptor-related signaling system in cells and/or by loss of beta cells in the pancreas through apoptosis There is also evidence that insulin resistance can be characterized as having an underlying inflammatory component
[00216] Bilirubin is formed when red blood cells die and their hemoglobin is broken down within the macrophages to heme and globins The heme is further degraded to Fe"+, carbon monoxide and bilirubin via the intermediate compound bihverdin Since bilirubin is poorly soluble in water, it is carried to the liver and bound to albumin Bilirubin is made water-soluble in the liver bv conjugation with glucuronic acid Conjugated bilirubin, or bihrubinglucuronide, moves into the bile canahculi of the liver and then to the gall bladder Bilirubin is found in blood either in the conjugated form (also called direct bilirubin), or in the unconjugated form (also called indirect bilirubin) The reference range for total bilirubin is 0 3 - 1 0 mg/dl For direct bilirubin, it is 0 1 - 0 3 mg/dl, while for indirect bilirubin it is 0 2 - 0 7 mg/dl In diseases where too much hemoglobin is broken down or the removal of bilirubin does not function properly, the accumulating bilirubin in the body causes jaundice Lsually the concentration of total bilirubin in the blood must exceed 2-3 mg/dl for the coloration to be easilv visible [00217] Λ "cytokine inhibitor" within the context of this invention is a compound which at a concentration of 10 μM inhibits induced cytokine release from a cell by about 50% or greater than 50%. For example, induction of TNFa release can be achieved by, but not limited to, treatment of a cell or cell line with lipopolysaccharide (LPS) or IL-Ib and is inhibited by compounds described herein.
[00218] The association of disorders with imbalances in specific cytokine levels is well known in the art, as documented by the references in List II.
LIST II. References describing cytokine-mediated processes and disorders.
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
[00219] "Treating" within the context of the instant invention, means an alleviation, in whole or in part, of symptoms associated with a disorder or disease, or slowing, or halting of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder in a subject at risk for developing the disease or disorder. As used herein, a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with a disorder or disease, or slows or halts further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disease or disorder in a subject at risk for developing the disease or disorder. As will be apparent to those of skill in the art, it is to be expected that the therapeutically effective amount of a compound disclosed herein may vary depending on the indication being treated, e.g., the therapeutically effective amount of a compound described herein would likely be different for treating subjects suffering from, or at risk for, cytokine- mediated disorders relative to the therapeutically effective amount of the compound for treating subjects suffering from, or at risk of, a different disorder, e.g., vascular event(s), diabetes, insulin resistance, or metabolic syndrome. Similarly, it is also to be expected that, for example, the therapeutically effective amount of a compound for decreasing CRP-levels in a subject would likely be different from the therapeutically effective amount for raising
HDL-levels in a subject. However, determining a therapeutically effective amount of a compound described herein for treating a particular disorder or disease is well within the skill in the art in view of the present disclosure.
[00220] A subject is any animal that can benefit from the administration of a compound as described herein. In some embodiments, the subject is a mammal, for example, a human, a primate, a dog, a cat, a horse, a cow, a pig, a rodent, such as for example a rat or mouse. Typically, the subject is a human.
[00221 ] Subjects who are at risk for a cardiovascular and/or cerebrovascular event are also subjects who manifest at least one symptom indicative of a vascular disorder/event. Symptoms that are indicative of a coronary-related vascular event, for example, include chest pain, abnormal electrocardiograms, elevated levels of ischemic markers, necrosis markers, or thrombin/fibrin generation markers. Such markers include, but are not limited to, Creatine Kinase with Muscle and/or Brain subunits (CKMB), D-Dimer, F 1.2, thrombin anti-thrombin (TAT), soluble fibrin monomer (SFM), fibrin peptide A (FPA), myoglobin, thrombin precursor protein ( TPP), platelet monocyte aggregate (PMA) and troponin (cTn). Subjects who are at risk also include subjects having a history of a thrombotic event (e.g., disorder), including coronary heart disease (CHD), stroke, or transient ischemic attacks (TIA). A history of CHD can include, for example, a history of MI, coronary revascularization procedure, angina with ischemic changes, or a positive coronary angiogram (e.g., showing greater than about 50% stenosis of at least one major coronary artery).
[00222] The term "cancer" refers to any of various malignant neoplasms characterized by the proliferation of cells that can invade surrounding tissue and metastasize to new body sites. Both benign and malignant tumors are classified according to the type of tissue in which they are found. For example, fibromas are neoplasms of fibrous connective tissue, and melanomas are abnormal growths of pigment (melanin) cells. Malignant tumors originating from epithelial tissue, e.g., in skin, bronchi, and stomach, are termed carcinomas. Malignancies of epithelial glandular tissue such as are found in the breast, prostate, and colon, are known as adenocarcinomas. Malignant growths of connective tissue, e.g., muscle, cartilage, lymph tissue, and bone, are called sarcomas. Lymphomas and leukemias are malignancies arising among the white blood cells. [00223] In the context of neoplasm, cancer, tumor growth or tumor cell growth, inhibition may be assessed by delayed appearance ot primary or secondary tumors, slowed development of primary or secondary tumors, decreased occuiience of primary or secondary tumors, slowed or decreased seventy of secondary effects of disease, arrested tumor growth and regression of tumors, among others In the extreme, complete inhibition, is referred to herein as prevention or chemoprev ention In this context, the term "prevention" includes either preventing the onset of clinically evident neoplasia altogether or preventing the onset ot a prcclinically evident stage of neoplasia in individuals at risk Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or to arrest or reverse the progression of premahgnant cells to malignant cells This includes prophylactic treatment of those at risk of developing the neoplasia
[00224] The term "nociceptive pain" includes, but is not limited to, pain associated with chemical or thermal burns, cuts of the skin, contusions of the skin, osteoarthritis, rheumatoid arthritis, tendonitis, and myofascial pain
[00225] The term "neuropathic pain" includes, but is not limited to, CRPS (Complex
Regional Pain Syndrome) type I. CRPS type II, reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy, reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, sympathetically maintained pam syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia, post herpetic neuralgia, cancer and metastases related pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, spinal cord injury pam, central post-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pam, luetic neuropathy, and other painful neuropathic conditions such as those induced by drugs such as vincristine, velcade and thalidomide The neuropathic pain can result from a mononeuropathy, polyneuropathy, complex regional pain syndromes or dcaffcrcntation.
[00226] The term "neuropathy" includes, but is not limited to, a functional distuibaiice oi pathological change in the nervous system, especially in the peripheral nervous system, and is characteπzed clinically by sensory or motor neuron abnormalities The term mononeuropathy indicates that a single nerve is affected, while the term polyneuropathy indicates that several nerves are affected. Deafferentation indicates a loss of the sensory input from a portion ol the body, and can be caused by interruption of either penphei al sensory fibers or nerv es from the central nervous s> stem I he etiology of a neuropathy can be known or unknown Known etiologies include complications of a disease or toxic state such as diabetes, which is the most common metabolic disorder causing neuropathy, or irradiation, ischemia or \ asculitis It is understood that the methods of the invention can be used to treat chronic pain of these or other chronic neuropathies of known or unknown etiology
[00227] A therapeutically effective amount of a compound as described herein used in the present invention may λ ary depending upon the ioute of administration and dosage form Effective amounts of invention compounds typically fall in the range of about 0 001 up to 100 mg/kg/day, and more typically in the range of about 0 05 up to 10 mg/kg/day Typically the compound or compounds used in the instant invention are selected to provide a formulation that exhibits a high therapeutic index The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD5O and ED50 The LD50 is the dose lethal to 50% of the population and the EDso is the dose therapeutically effective in 50% of the population The LD50 and ED50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals
[00228] Treatment ma> also include administering the compounds or pharmaceutical formulations of the present invention in combination with other therapies Combinations of the invention may be administered simultaneously, separately or sequentially For example, the compounds and pharmaceutical formulations of the piesent invention ma\ be administered before, during, or after surgical procedure and'Or radiation therapy Alternatively, the compounds of the invention can also be administered in conjunction with other anti-inflammatory agents, anticancer agents and other agents described herein In the context of inflammation, many types of immunomodulatory, immunosuppressive or c>tostatic drugs as described heiein, can be used in combination with the compounds as described heiein
[00229] The specific amount of the additional active agent will depend on the specific agent used, the type of condition being tieated or managed, the severity and stage of the condition, and the amount(s) of compounds and any optional additional active agents concurrently administered to the subject.
[00230] In some embodiments of the invention, one or more compounds of the invention and an additional active agent are administered to a subject, more typically a human, in a sequence and within a time interval such that the compound can act together with the other agent to provide an enhanced benefit relative to the benefits obtained if they were administered otherwise. For example, the additional active agents can be coadminstered by coformulation, administered at the same time or administered sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect. In some embodiments, the compound and the additional active agents exert their effects at times which overlap. Each additional active agent can be administered separately, in any appropriate form and by any suitable route. In other embodiments, the compound is administered before, concurrently or after administration of the additional active agents.
[00231 ] In various examples, the compound and the additional active agents are administered less than about 1 hour apart, at about 1 hour apart, at about 1 hour to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 1 1 hours apart, at about 1 1 hours to about 12 hours apart, no more than 24 hours apart or no more than 48 hours apart. In other examples, the compound and the additional active agents are administered concurrently. In yet other examples, the compound and the additional active agents are administered concurrently by coformulation.
[00232] In other examples, the compound and the additional active agents are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.
[00233] In certain examples, the inventive compound and optionally the additional active agents are cyclically administered to a subject. Cycling therapy involves the administration of a first agent for a period of time, followed by the administration of a second agent and-Or third agent for a period of time and repeating this sequential administration. Cycling therapy can provide a variety of benefits, e.g., reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one or more of the therapies, and/or improve the efficacy of the treatment.
[00234] In other examples, the inventive compound and optionally the additional active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week. One cycle can comprise the administration of an inventive compound and optionally the second active agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle, about 30 minutes every cycle or about 15 minutes every cycle. Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest. The number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.
[00235] Courses of treatment can be administered concurrently to a subject, i.e., individual doses of the additional active agents are administered separately yet within a time interval such that the inventive compound can work together with the additional active agents. For example, one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks. In other words, the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.
[00236] The additional active agents can act additively or, more typically, synergistically with the inventive compound. In one example, the inventive compound is administered concurrently with one or more second active agents in the same pharmaceutical composition. In another example, the inventive compound is administered concurrently with one or more second active agents in separate pharmaceutical compositions. In still another example, the inventive compound is administered prior to or subsequent to administration of a second active agent. The invention contemplates administration of an inventive compound and a second active agent by the same or different routes of administration, e.g., oral and parenteral. In certain embodiments, when the inventive compound is administered concurrently with a second active agent that potentially produces adverse side effects including, but not limited to, toxicity, the second active agent can ad\ antageously be administered at a dose that falls below the threshold that the adverse side effect is elicited
[00237] The instant invention also provides for pharmaceutical compositions and medicaments which may be prepaied by mixing one or more compounds of the invention, prodrugs thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to prevent and treat disorders associated with excess cytokine production The compounds and compositions of the invention may be used to prepare formulations and medicaments that prevent or treat a variety of disorders associated with excess cytokine production as disclosed herein, e g , diseases and pathological conditions involving inflammation, pain, cancer, etc Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions The instant compositions can be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, oi v ia implanted reservoir Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, lntrapeπtoneally, intramuscular, mtia-articular, mtrasynovial, mtrasternal, intrathecal, mtralesional and intracranial injections The following dosage forms are given by way of example and should not be construed as limiting the instant invention
[00238] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms These can be prepared, for example, by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitms, chitosans, pectins, tragacanth gum, gum arable, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glyceπdes Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, oi preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteneis, flavoring agents or perfuming agents Tablets and pills may be further treated with suitable coating materials known in the art [00239] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteial administration
[00240] As noted abo\e, suspensions may include oils Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olrv e oil Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopiopyl myπstate fatty acid glyceπdes and acetylated fatty acid glyceπdes Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol Ethers, such as but not limited to. poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum, and water may also be used in suspension formulations
[00241] Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent Acceptable solv ents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution Alternatively, steπle oils may be employed as solvents or suspending agents Typically, the oil or fatty acid is nonvolatile, including natural or synthetic oils, fatty acids, mono-, di- or tπ-glyceπdes
[00242] For injection, the pharmaceutical formulation and/or medicament may be a pow der suitable for rcconstitution with an appropπate solution as descπbed above Examples of these include but are not limited to, freeze dried, rotary dπed or spray dπed powders, amorphous powders, granules precipitates, or particulates For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these
[00243] For rectal administration, the pharmaceutical formulations and medicaments may be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum. Rectal suppositories are prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils may also be employed in the preparation of formulations of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and related sugar solutions, and glycerols may be employed in the preparation of suspension formulations which may also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.
[00244] Compounds of the invention may be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. Formulations for inhalation administration contain as excipients, for example, lactose, polyoxyethylcne-9- lauryl ether, glycocholate and deoxycholate. Aqueous and nonaquous aerosols are typically used for delivery of inventive compounds by inhalation.
[00245] Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of the compound together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens. Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions. A nonaqueous suspension (e.g., in a fluorocarbon propellant) can also be used to deliver compounds of the invention.
[00246] Aerosols containing compounds for use according to the present invention are conveniently delivered using an inhaler, atomizer, pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, pressurized dichlorodifluoromethane, trichlorotluoromcthane, dichlorotetrafluoroethane, nitrogen, air, or carbon dioxide. In the case of a pressuπzed aerosol the dosage unit may be controlled by pro\ idmg a vah e to deliv er a metered amount Capsules and cartridges of for example, gelatin tor use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch Delivery of aerosols of the present invention using sonic nebulizers is advantageous because nebulizers minimize exposure of the agent to shear, which can result in degradation of the compound
[00247] For nasal administration, the pharmaceutical formulations and medicaments ma\ be a spray, nasal drops or aerosol containing an appropπatc solvcnt(s) and optionally other compounds such as, but not limited to stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these For administration in the form of nasal drops, the compounds may be formulated in oily solutions or as a gel For administration of nasal aerosol, any suitable propellant may be used including compressed air, nitrogen carbon dioxide, or a hydrocarbon based low boiling solvent
[00248] Dosage forms for the topical (including buccal and sublingual) or transdermal administration of compounds of the invention include powders, sprays, ointments, pastes ci earns, lotions, gels, solutions, and patches The active component may be mixed undei sterile conditions with a pharmaceutical ly-acceptable earner or excipient, and with any preservatives, or buffers, which may be required Powders and sprays can be prepared, for example, with excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances The ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils waxes paraffins, staich, tragacanth, cellulose derivatives, polyethylene glycols silicones, bentomtes, silicic acid talc and zinc oxide, or mixtures thereof
[00249] Transdermal patches have the added advantage of providing controlled delivery of a compound of the inv ention to the body Such dosage forms can be made by dissolving or dispersing the agent in the proper medium Absorption enhancers can also be used to increase the flux of the inventive compound across the skin The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel [00250] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. The compounds of this invention can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant). The compounds are typically incorporated into topical ophthalmic formulations for delivery to the eye. The compounds may be combined with one or more ophthalmologically acceptable preservatives, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound. Furthermore, the ophthalmic solution may contain an agent to increase viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylccllulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac. Gelling agents can also be used, including, but not limited to, gellan and xanthan gum. In order to prepare sterile ophthalmic ointment formulations, the compound of the invention is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the invention compound in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic preparations. Preservatives and tonicity agents can be optionally incorporated.
[00251] Intrathecal administration, via bolus dosage or constant infusion, allows the local administration of a compound to a region of the spinal cord, such as the dorsal horn regions, delivering the compound directly to the subarachnoid space containing the CSF (cerebrospinal fluid).
[00252] Central delivery to the spinal cord regions can also be performed by epidural injection to a region of the spinal cord exterior to the arachnoid membrane. Enhancing permeation of the active compound through meningeal membranes may be achieved by using hypertonic dosing solutions that increase permeability of meningeal membranes, or by addition of permeation enhancers, such as, but not limited to, liposomal encapsulation, surfactants, or ion-pairing agents. [00253] Besides those representative dosage forms descπbed above pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant in\ ention Such excipients and carriers are descnbed for example in "Remingtons Pharmaceutical Sciences" Mack Pub Co , New Jersey (1991 ), which is incorporated herein b> reference
[00254J The formulations of the invention may be designed to be short-acting, fast- releasing long-acting, and sustained-releasing as descπbed below Thus the pharmaceutical lormulations may also be formulated for controlled release or for slow release
[00255] The instant compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect Therefore, the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents Such implants may employ known inert materials such as silicones and biodegradable polymers
[00256] The present disclosure also provides medical devices mcorpoiatmg the compounds as descπbed herein A. representative device includes a vascular stent coated or impregnated w ith the compounds as described herein The device can be configured to be inserted into a blood vessel where it can release the compounds as descπbed herein to help reduce or prevent vascular inflammation, for example vascular inflammation
[00257] Other embodiments disclose medical devices that include compounds as described herein, or a combination of the compounds with additional ingredients A, as described herein The compounds as described herein can be coated on the surface of the medical device or the device can be saturated with the compounds such that the compounds are released from the device, for example over a peπod of time Exemplary medical devices including the compounds as disclosed herein include but are not limited to, vascular medical devices such as vascular stents
[00258] Stents and methods for making and using stents coated or impregnated with therapeutic agents are well-known in the art see, e g , U S Application No US20050181977 and U S Application No US20050129729 [00259] Specific dosages may be adjusted depending on conditions of disease, the age, bod} weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention.
[00260] A therapeutically effective amount of a compound of the present invention may Λ ary depending upon the route of administration and dosage form. Effective amounts of invention compounds typically fall in the range of about 0 001 up to 100 mg/kg/day, and more typically in the range of about 0.05 up to 10 mg/kg/day Typically, the compound or compounds of the instant invention are selected to provide a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic eifccts which can be expressed as the ratio between LD^o and ED50 The LDs0 is the dose lethal to 50% of the population and the ED50 is the dose therapeutically effective in 50% of the population. The LD50 and ED50 are determined by standard pharmaceutical procedures in animal cell cultures or expeπmental animals.
[00261 ] In the context of cancer, the compounds as descπbed herein can be used in the methods and compositions of the invention either alone or together with additional treatments or active ingredients or a combination thereof. Additional treatments comprise treatment by smgery, radiation, or cryotherapy, while treatment with additional active ingiedients comprises the use of antiproliferative agents Combinations of drugs are administered in an attempt to obtain a synergistic cytotoxic effect on most cancers, e g , carcinomas, melanomas, lymphomas and sarcomas, and to reduce or eliminate emergence of drug- resistant cells and to reduce side effects to each drug. The specific amount of the additional active agent will depend on the specific agent used, the type of cancer being treated or managed, the seventy and stage of the cancer, and the amount(s) of compounds as described herein and any optional additional active agents concurrently administered to the subject Typically, the additional active ingredients that can be used in combination with the compounds as descπbed herein are used at dosages well known in the art. [00262] In general, surgery and radiation therapy are employed as potentially curative therapies foi humans under 70 years of age who present with clinically localized disease and are expected to live at least 10 years
[00263] The phrase "antiproliferativ e agents" includes agents that prevent the development, maturation, or spread of cells, by acting directly on the cell, e g , by cytostatic or cytocidal effects, and not indirectly through mechanisms such as biological response modification There are large numbers of antiproliferative agents available in commercial use, in clinical evaluation and in pre-clmical development, which could be included in the present invention for treatment of cancel by combination drug chemotherapy
[00264] Typical antiproliferative agents can be categorized as alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltiansterase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, πbonucleoside reductase inhibitors, endofhehn A receptor antagonists, retinoic acid receptor agonists, lmmunomodulators, hormonal or antihormonal agents, photodynamic agents, angiogenesis inhibitors, tyiosme kinase inhibitors, and the like Some antiproliferative agents operate through multiple or unknown mechanisms and can thus be classified into more than one category
[00265] A family of antiproliferative agents which may be used in combination with the present invention includes alkylatmg-type agents The alkylating agents are believed to act by alkylating and cross-linking guanine and possibly other bases in DNA, arresting cell division Typical alkylating agents include nitrogen mustards, ethyl eneimine compounds, alkyl sulfates, cisplatin, and various nitrosoureas A disadvantage with these compounds is that they not only attack malignant cells, but also other cells which are naturally dividing, such as those of bone marrow, skm, gastro-mtestinal mucosa, and fetal tissue Suitable alkylating-type agents that may be used in the present invention include, but are not limited to, busulfan, procarbazine, lfosfamide, altretamine, hexamethylmelamine, estramustme phosphate, thiotepa, mechlorethamme, dacarbazme, streptozocin, lomustine, temozolomide, cyclophosphamide, semustine, and chlorambucil [00266] A family of antiproliferative agents which may be used in combination with the present invention includes platinum agents Suitable platinum agents that may be used in the present invention include, but are not limited to spiroplatin, lobaplatin ( Aeterna), tetrapldtm, satraplatin (Johnson Matthey) ormaplatm, iproplatin, miπplatin (Sumitomo), nexplatin (AnorMED), polymer platinate (Access), oxahplatin, or carbopldtm
[00267] An additional family of antiproliferative agents which may be used in combination with the present invention includes antimetabohte-type agents Antimetabolites are typically reversible or irreversible enzyme inhibitors, or compounds that otherwise interfeie with the replication, translation or transcription of nucleic acids Suitable antimetabolite agents that may be used in the present invention include, but are not limited to azacvtidine tπmetrexate, floxuπdine, deoxycoformvcin, 2-chlorodeoxyddenosine, pentostatin, 6-mercaptopuπne, hydroxyurea, 6-thioguamne, decitabine (SuperGen), cytarabine, clofarabine (Bioenvision), 2-fluorodeoxy cytidine, irofulven (MGI Pharma), methotrexate, tomudex, ethynylcytidinc ( 1 aiho), fludarabine gemcitabine, raltitrexed or tapecitabine
[00268] Another family of antiproliferative agents whiϋi may be used in combination with the present invention includes topoisomerase inhibitors Suitable topoisomerase agents that may be used in the present invention include, but are not limited to amsacπne, exatecan mesylate (Daiichi), cpirubicm, quinamed (ChemGenex), etoposide, gimatecan (Sigma-Tau) temposide, mitoxantrone, diflomotecan (Bcaufour-Ipscn), 7-ethyl-l O-hydroxy-camptothecin, dexrazoxanet (TopoTarget), elsamitrucin (Spectium), pixantrone (Novuspharma), edotecaπn (Merck & Co), becatecaπn (Exehxis), karemtecin (BioNumeπk), BBR-1576 (Novuspharma), belotecan (Chong Kun Dang), rubitecan (SuperGen), irinotecan (CPT-1 1), or topotecan
[00269] Another family of antiproliferative agents which may be used in combination with the present invention includes antibiotic-type antiproliferative agents Suitable antibiotic-type antiproliferatn e agents that may be used in the present invention include, but are not limited to dactmomycm (actinomycin D), azonafide, valrubicin, anthrapyrazole, daunorubicin (daunomycin), oxantrazole, therarubicin, losoxantrone, idarubicin, bleomycinic acid, rubidazone, sabarubicin (Menaπni), plicamycinp, 13-deoxydoxorubicin hydrochloπde (Gem Pharmaceuticals), porfiromycin, epirubicin, mitoxantrone (novantrone) or amonafide [00270] Another family ot antiproliferative agents which may be used in combination with the present invention includes antimitotic agents Suitable antimitotic antiproliferative agents that may be used in the present invention include, but are not limited to colchicines, ABT-751 (Abbott), vinblastine, xyotax (Cell Therapeutics), vindesme, IDN 5109 (Bayei), dolastatin 10 (NCI), A 105972 (Abbott), rhizoxin (Fujisawa), A 204197 (Abbott), mivobuhn (Warner-Lambert), synthadotin (BASF), cemadotin (BASF), mdibuhn (ASTAMedica), RPR 109881 A (Aventis), TXD 258 (Aventis), combrctastatin A4 (BMS), epothilone B (Novartis). isohomohahchondrm-B (PharmaMar), T 900607 (Tulaπk), ZD 6126 (AstraZcncca), batabuhn(Tulaπk), cryptophycin 52 (Eh Lilly), vinflunine (Fabre), hydravin (Prescient NeuroPharma), auπstatin PE (Teikoku Hormone), azaepothilone B (BMS), lxabepilone (BMS), tavocept (BioNumeπk), BMS 184476 (BMS), combrestattn A4 disodium phosphate (OXiGENE), BMS 188797 (BMS), dolastatm-10 (NIH), taxoprexin (Protarga), cantuzumab mertansine (GlaxoSmithKhne), docetaxcl, vinorclbinc, or vincristine
[00271 ] Another family of antiproliferative agents which may be used in combination with the present invention includes aromatase inhibitors Suitable aromatase inhibitors that may be used in the present invention include, but are not limited to ammoglutethimide, atamestane (BioMedicmes), formestane, fadrozole, letrozole, exemestane, or anastra/ole
[00272] An additional family of antiproliferative agents which may be used in combination with the present invention includes the thymidylate synthase inhibitors Suitable thymidylate synthase inhibitors that may be used in the present invention include, but are not limited to, pemetrexed (Eh Lilly), nolatrexed (Eximias), ZD-9331 (BTG), doxifluπdme (Nippon Roche), or 5,10-methylenetetrahydrofolate (BioKeys)
[00273] Yet another family of antiproliferative agents which may be used in combination with the present invention includes DNA antagonists Suitable DNA antagonists that may be used in the present invention include, but arc not limited to trabectedm (PharmaMar). edotreotide
Figure imgf000105_0001
glufosfamide (Baxter International), mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals), or thymectacin (IsewBiotics)
[00274] Another family of antiproliferative agents which may be used in combination with the present invention includes farnesyltransferase inhibitors Suitable farnesyltransfcrasc inhibitors that may be used in the present invention include, but are not limited to arglabin (NuOncology Labs), tipif'arnib (Johnson & Johnson), lonafarnib (Schering-Plough), perillyl alcohol (DOR BioPharma), or sorafenib (Bayer).
[00275] An additional family of antiproliferative agents which may be used in combination with the present invention includes pump inhibitors. Suitable pump inhibitors that may be used in the present invention include, but are not limited to zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova), biricodar dicitrate (Vertex), or MS-209 (Schering AG).
[00276] An alternative family of antiproliferative agents which may be used in combination with the present invention includes histone acetyltransferase inhibitors. Suitable histone acetyltransferase inhibitors that may be used in the present invention include, but are not limited to tacedinaline (Pfizer), pivaloyloxymethyl butyrate (Titan), AP-CANC-03 and AP-CANC-04 (Aton Pharma), depsipeptide (Fujisawa), or MS-275 (Schering AG).
[00277] Another family of antiproliferative agents which may be used in combination with the present invention includes metalloproteinase inhibitors. Suitable metalloproteinase inhibitors that may be used in the present invention include, but are not limited to neovastat (Aeterna Laboratories), metastat (CollaGenex), or marimastat (British Biotech).
[00278] Also, the family of antiproliferative agents which may be used in combination with the present invention includes ribonucleoside reductase inhibitors. Suitable the DNA antagonists that may be used in the present invention include, but are not limited to gallium maltolate (Titan), tezacitabine (A vends), triapine (Vion), or didox (Molecules for Health).
[00279] Another family of antiproliferative agents which may be used in combination with the present invention includes endothelin A receptor antagonists. Suitable endothelin A receptor antagonists that may be used in the present invention include, but arc not limited to atrasentan (Abbott), bosentan (Roche), ambrisentan (BASF), sitaxsentan (Encysive), clazυsentan (Roche), darusentan (Knoll), and ZD-4054 (AstraZeneca).
[00280] Yet another family of antiproliferative agents which may be used in combination with the present invention includes retinoic acid receptor agonists. The family of retinoic acid receptor agonists includes compounds which are natural and synthetic analogues of retinol (Vitamin A). The retinoids bind to one or more retinoic acid receptors to initiate diverse processes such as reproduction, development bone formation, cellular proliferation and differentiation, apoptosis, hematopoiesis, immune function and vision. Retinoids are required to maintain normal differentiation and proliferation of almost all cells and have been shown to reverse/suppress carcinogenesis in a variety of in vitro and in vivo experimental models of cancer, see (Moon et al., Ch. 14 Retinoids and cancer. In The Retinoids, Vol. 2. Academic Press, Inc. 1984). Suitable retinoic acid receptor agonists that may be used in the present invention include, but are not limited to fenretinide (Johnson & Johnson), alitretinoin (Ligand), tazarotene (Allergan), tetrinoin (Roche), isotretinoin (Roche), 13-cis-retinoic acid (UCSD), or LGD- 1550 (Ligand).
[00281] Another family of antiproliferative agents which may be used in combination with the present invention includes immunomodulators. Suitable immunomodulators that may be used in the present invention include, but are not limited to interferon, Roferon-A (Roche), dexosome therapy (Anosys), oncophage (Antigenics), pentπx (Australian Cancer Technology), GMK vaccine (Progenies), CDl 54 cell therapy (Tragen), adenocarcinoma vaccine (Biomira). transvax (Intercell), avicine (AVI BioPharma), norelin (Biostar), IRX-2 (Immuno-Rx), BLP-25 liposome vaccine (Biomira), PEP-005 (Peplin Biotech), multiganglioside vaccine (Progenies), synchrovax vaccine (CTL Immuno), β-alethine (Dovetail), melanoma vaccine (CTL Immuno), vasocare (Vasogen), rituximab (Genentech/Biogen Idee), or p21 RAS vaccine (GemVax).
[00282] An additional family of antiproliferative agents which may be used in combination with the present invention includes hormonal agents. Suitable hormonal agents that may be used in the present invention include, but are not limited to an estrogen, dexamethasone, a conjugated estrogen, prednisone, ethinyl estradiol, methylprednisolonc, chlortrianisen, prednisolone, idenestrol, aminoglutethimide, hydroxyprogesterone caproate, leuprolide, medroxyprogesterone, octreotide, testosterone, mitotane, testosterone propionate, fluoxymesterone, methyltestosterone, 2-methoxyestradiol (EntreMed), diethylstilbestrol, arzoxifene (Eli Lilly), megcstrol, tamoxifen, bicalutamide, toremofme, flutamide, goserelin, nilutamide, or leuporelin. [00283] Yet another family of antiproliferative agents which ma) be used in combination with the piesent invention includes photodynamic agents Suitable photodynamic agents that may be used in the present inv ention include, but are not limited to talaporfm (Light Sciences), Pd-bacteπopheophorbide (Yeda), theralux (Theratechnologies), lutetium texaphyim (Pharmacychcs), motexafln, gadolinium (Pharmacychcs). or hypeπcm
[0U284J Yet another family of antiproliferative agents which may be used in combination with the present invention includes angiogenesis inhibitors Suitable angiogenesis inhibitois that may be used in the present invention include, but are not limited to neovastat (AEterna Zentaπs), ATN-224 (Attention), sorafemb (Bayer) thalidomide, bevdcizumab (Genentech). ranibizumab (Genentech), benefm (Lane Labs), L-651582 (Merck & Co), vatalanib (Novartis), or sutent (Pfizer)
[00285] Another family of antiproliferative agents which may be used in combination with the present invention includes 1 yrosine Kinase Inhibitors Suitable Tyrosine Kinase Inhibitors that may be used in the present invention include, but are not limited to imatinib (Novartis), leflunomide (Aventis), kahahde F (PharmaMar) iressa (AstraZeneca), lestaurtmib (Cephalon), erlotinib (Oncogene Science), canertmib (Pfizer), tandutinib (Millenium) squalamine (Genaera), midostauπn (Novartis), phenoxodiol, SU6668 (Pharmacia), cetuximab (ImClone), rhu-Mab (Genentech), ZD6474 (AstraZeneca), MDX-H210 (Medarex), vatalanib (Novartis), omnitarg (Genentech), lapatinib (GlaxoSmithKlinc), panitumumab (Abgemx), IMC-I Cl 1 (ImClone), sorafemb (Bayer) oi trastuzumab (Genentech)
[00286] Additional antiproliferative agents which may be used in combination with the present invention include melphalan, carmustme, cisplatin, 5-fluorouracil, mitomycin C, adπamycin (doxorubicin), bleomycin, paclitaxel (Taxol ), and the like
[00287] In the context of pain treatment, the comopounds of the invention can be used in methods and compositions together with additional active ingredients or agents Typically, the additional active agents are capable of relieving pain, inhibiting inflammatory reactions, prov iding a sedative effect or an antineuralgic effect, or ensuring patient comfort Examples of the additional active agents include, but are not limited to. opioid analgesics, non-narcotic analgesics, anti-inflammatones, COX-2 inhibitors, α-adrcnergic receptor agonists or antagonists, ketamine, anesthetic agents, NMDA antagonists, u2δ hgands, immunomodulatory agents, immunosuppressive agents, antidepiessants, anticonvulsants, antihypertensives, anxiolytics, calcium channel hlockers, muscle relaxants, corticosteroids, hyperbaric oxygen other therapeutics known to relieve pain, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, prodrugs and pharmacologically active metabolites thereof
[00288J Opioids can be used to treat severe pam Examples of opioid analgesics include, but are not limited to, oxycodone (OxyContin™), morphine sulfate (MS Contin™, Duramorph™, Astramorph™), meperidine (Demerol rM), and fcntanyl transdermal patch (Duragesic™) and other known conventional medications [See, e g , Physicians' Desk Reference, 594-595, 2851 and 2991 (57th ed . 2003)] Oxycodone (Ox>Contm™) is a long- dcting form of an opioid and may be used usually in initial and later stages of CRPS Morphine sulfate ma> be used for analgesia due to reliable and predictable effects, safety profile, and ease of reversibility with naloxone Morphine sulfate is sold in the United States under the trade name MS Contin™, Duramorph™ or Astramorph™ [See, e g , Physicians' Desk Reference, 594-595 (57th ed , 2003)] Fentanyl transdermal patch (Duragesic™) is a potent narcotic analgesic with much shorter half-life than morphine sulfate Meperidine (Demerol ™) and hydromorphone (Dilaudid™) may also be used for pain management [See, e g , Ph>sicians' Desk Reference, 2991 (57th ed , 2003)]
[00289] Non-narcotic analgesics and antiinflammatories are preferably used foi treatment of pam duπng pregnancy and breastfeeding Antiinflammatories such as nonsteroidal anti-inflammatory drugs (NSAIDs) and cox-2 inhibitors typically inhibit inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis NSAIDs may proude pam relief in the early stage of pam syndrome Fxamples of antiinflammatories include, but are not limited to, salicylic acid acetate (Aspirin™) ibuprofen (Motrin™, Advil™), ketoprofcn (Oruvail™), rofecoxib (Vioxx'M), naproxen sodium (Anaprυx™, Naprelan™, Naprosyn™), ketorolac (Acularr 1), and other known conventional medications A specific cox-2 inhibitor is celecoxib (Celebrex™) [See, e g , Physicians' Desk Reference, 1990. 1910-1914 and 2891 (57th ed 2003) Physicians' Desk Reference for Nonprescription Drugs and Dietary Supplements, 51 1, 667 and 773 (23rd ed , 2002)] [00290] Antidepressants increase the synaptic concentration of serotonin and/or norepinephrine in the CNS by inhibiting their reuptake by presynaptic neuronal membrane. Some antidepressants also have sodium channel blocking ability to reduce the firing rate of injured peripheral afferent fibers. Examples of antidepressants include, but are not limited to, nortriptyline (Pamelor™), amitriptyline (Elavil™), imipramine (Tofranill), doxepin (Sinequan™), clomipramine (Λnafranil™), fluoxetine (Prozac'M), sertraline (ZoloftI M), nefazodone (Serzone™), venlafaxine (Effexor % ), trazodone (Desyrel™), bupropion (Wellbutrin™) and other known conventional medications [See. e.g., Physicians' Desk Reference, 329, 1417, 1831 and 3270 (57th ed., 2003)].
[00291] Anticonvulsant drugs may also be used in embodiments of the invention.
Examples of anticonvulsants include, but are not limited to, carbamazepine, oxcarbazepine, gabapentin (Neurontin™), phenytoin, sodium valproate, clonazepam, topiramate, lamotrigine, zonisamide, and tiagabine [Sec, e.g., Physicians' Desk Reference, 2563 (57th ed., 2003)].
[00292] Corticosteroids (e.g., prednisone, dexamethasone or hydrocortisone), orally active class Ib anti-arrhythmic agents (e.g.. mexiletine), calcium channel blockers (e.g., nifedipine), beta-blockers (e.g., propranolol), α-blockers (e.g., phenoxybenzamine). and α2- adrenergic agonists (e.g., clonidine) can also be used in combination with a compound as described herein [See, e.g., Physicians' Desk Reference, 1979, 2006 and 2190 (57th ed., 2003)].
[00293] The specific amount of the additional active agent will depend on the specific agent used, the type of pain being treated or managed, the severity and stage of pain, and the amount(s) of compounds as described herein and any optional additional active agents concurrently administered to the patient.
[00294] Hydromorphone (Dilaudid ) is typically administered in an initial dose of about 2 mg orally, or about 1 mg intravenously to manage moderate to severe pain [See, e.g., Physicians' Desk Reference, 2991 (57* ed., 2003)]. Morphine sulfate (Duramorph™, Astramorph™, MS Contin™) is typically administered in an initial dose of about 2 mg 1V/SC/1M, depending on whether a patient has already taken narcotic analgesics [Sec, e.g.,
Physicians' Desk Reference, 594-595 (57th ed., 2003)]. No intrinsic limit to the amount that can be given exists, as long as a patient is observed for signs of adverse effects, especially respiratory depression. Various IV doses may be used, commonly titrated until a desired effect is obtained. For patients not using long-term agents, as little as 2 mg IWSC may be sufficient. Larger doses are typically required for patients taking long-term narcotic analgesics. Morphine sulfate is also available in oral form in immediate-release and timed- release preparations. The long-acting oral form may be administered twice per day. An immediate-release form may be needed for periods of pain break-through, with the dose dependent on previous use. Oxycodone (OxyContin™) is a long-acting form of an opioid and may be used in initial and later stages of pain syndrome. Oxycodone (OxyContin7' ) is usually administered in an amount of about 10-160 mg twice a day [See, e.g., Physicians' Desk Reference, 2851 (57th ed., 2003)]. Meperidine (Demerol™) is typically administered in an amount of about 50-150 mg PO/IWIM/SC every 3-4 hours. A typical pediatric dose of meperidine (Demerol™) is 1-1.8 mg/kg (0.5-0.8 mg/lb) PO/IV/IM/SC every 3-4 hours [See, e.g.. Physicians' Desk Reference, 2991 (57l1 cd., 2003)]. Fentanyl transdermal patch (Duragesic™) is available as a transdermal dosage form. Most patients are administered the drug in 72 hour dosing intervals; however, some patients may require dosing intervals of about 48 hours. A typical adult dose is about 25 mcg/h (10 cm2), 50 mcg/h (20 cm2), 75 mcg/h (75 cm2), or 100 mcg/h (100 cm2) [See, e.g., Physicians' Desk Reference, 1775 (57lh ed., 2003)].
[00295] Non-narcotic analgesics and anti-inflammatories such as NSAIDs and cox-2 inhibitors may be used to treat patients suffering from mild to moderate pain. Ibuprofen (Motrin™, Advil™) is orally administered in an amount of 400-800 mg three times a day [See, e.g., Physicians' Desk Reference, 1900-1904 (57th ed., 2003); Physicians' Desk Reference for Nonprescription Drugs and Dietary Supplements, 51 1 , 667 and 773 (23rd ed., 2002)]. Naproxen sodium (Anaprox™. Naprclan™, Naprosyn™) may also be used for relief of mild to moderate pain in an amount of about 275 mg thrice a day or about 550 mg twice a day [See, e.g., Physicians' Desk Reference, 1417,2193 and 2891 (57th ed., 2003)].
[00296] Antidepressants, e.g., nortriptyline (Pamelor™), may also be used in the invention to treat patients suffering from chronic and/or neuropathic pain. The oral adult dose is typically in an amount of about 25-100 mg, and usually does not exceed 200 mg/d. A typical pediatric dose is about 0.1 mg/kg PO as initial dose, increasing, as tolerated, up to about 0 5-2 mg'd Amitπptyline (Etraton M) is typically used tor neuropathic pain m an adult dose of about 25-100 mg PO [See, e g , Physicians' Desk Reference, 1417 and 2193 (57lh ed , 2003)]
[00297] Anticonvulsants such as gabapentm (Neurontin™) may also be used to treat patients suffeπng from chronic and neuropathic pain Typically, gabapentm is orally administered in an amount of about 100-1 ,200 mg three times a day [See, e g , Physicians' Desk Reference, 2563 (571 ed , 2003)J Carbamazepine (Tegretol™) is used to treat pain associated with true trigeminal neuralgia The oral adult dose is typically in an amount of about 100 mg twice a day as initial dose, increasing, as tolerated, up to about 2,400 mg/d [See. e g , Physicians' Desk Reference, 2323-25 (57th ed , 2003)]
[00298] For the treatment of pemphigus, other agents which may be used in combination with the novel compounds of the invention include, but are not limited to, antiinflammatory agents, immunosuppressants, anti-infectives, antibiotics, gold salts, alkylating agents, immunoglobulins, or a combination of two or more thereof Examples of antiinflammatory agents include corticosteroids, COX-2 inhibitors, non-steroidal antiinflammatory drugs (NSAID), TNFa antagonists, and IL-I antagonists For example, the corticosteroid can be prednisone, prednisolone, or mefhylprednisolone Corticosteroids such as these may also be administered with either chlorambusil or mycophenylate mofetil Examples of TNFa antagonists are infliximab, etanercept, and adalimumab An example of an IL-I antagonist is anakinra Examples of immunosuppiessants are mycophenylate mofetil, cyclosporin, azathiopπne, methotrexate, alefacept, πtuximab, anti-mterferon gamma, and cyclophosphamide, while anti-infectives include dapsone and hydioxychloroqume In some instances, the gold salt can be myochrysine, or solganal An example of an alkylating agent is lukcran Antibiotics useful in combinations are tetracycline, minocycline, and doxycycline, sometimes in combination with nicotinamide, or niacinamide
[00299] Treatment of pemphigus can also include plasmapheiisis therapy or photophoresis therapy to the subject
[00300] The present invention, thus generally descπbed, will be understood more readily by reference to the following examples, which are provided by way of illustration and arc not intended to be limiting of the present invention EXAMPLES The following abbreuations are used throughout the application with respectrminology
AcN: Acetonitπle
AcOH or HOAc: Acetic acid aq Aqueous
Bu Butyl
BINAP: 2,2'-Bis(diphenylphosphmo)- 1 , 1 '-binaphthyl
Boc: N-tert-Butoxycarbonyl
BOP: (Benzotriazol- 1 -y loxy)tns-
(dimcthylamino)phosphonium hexafluorophosphate dba. Dibenzylideneacetone
DIEA: N,N-Dhsopropylethylamine
DCM: Dichloromethane
DME Dimethoxyethane
DMF: /V,/V-Dimethylformamide
DMSO Dimcthylsulfoxide
DPPA Diphenyl phosphorazidatc
EDC or EDCI. l-(3-Dimethylammopropy])-3-ethylcarbodiimide hydrochloride eq : Equivalent
EtOAc: Ethyl acetate
FtOH' Ethanol
Hex Hexanes
HPLC. High Pressure Liquid Chromatography hr: Hour
IC1o value: The concentration of an inhibitor that causes a 50 % reduction in a measured activity.
LC-MS Liquid chromatography- mass spectroscopy
MeOH Methanol mm.. Minute(s) NMM: N-Methylmorphohne
PE: Petroleum ether
Ph: Phenyl
PyBOP: Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
RP: Reverse phase r.t.: Room temperature
TFA: Trifluoroacetic acid
THF: Tetrahy drυ furan
TLC: Thin layer chromatography
TMS: Trimethylsilyl
[00302] Compounds are named using the automatic naming application Autonom
2000 (MDL Information Systems, San Leandro, CA), or the automatic name generating tool provided in Chcmdraw Ultra (CambridgeSoft, Cambridge, MA), which generates systematic names for chemical structures according to IUPAC rules, with support for the Cahn-lngold- Prelog rules for stereochemistry.
Synthesis of aniline-intermediates.
Figure imgf000114_0001
A
[00303] Intermediate A. 3-Amino-5-tert-butylbenzonitrile. Step 1. tert-Butyl 3- tert-butyl-5-cyanophenylcarbamate. To a solution of 3-tert-butyl-5-cyanobenzoic acid (1.0 g, 4.9 mmol, prepared as in U.S. application No. 60/842,051) in t-BuOH, DPPA (1.4 ml, 6.4 mmol) and NMM (slight excess) were added. The mixture was stirred at reflux overnight, extracted with DCM, the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel (gradient: 5 to 100% EtOAc in Hex). (Calculated mass: 274.4, observed mass: 275.1 ). [00304] Step 2. To a solution of the compound obtained above in DCM (10 ml), TFA
(1.5 ml) was added and the mixture was stirred at r.t. overnight. The solvent was evaporated and the residue used in the next step without further purifieation. (Calculated mass: 174.2, observed mass: 215.8 (M+AcN)+).
Figure imgf000115_0001
[00305] Intermediate B. 3-Amino-5-morpholinobenzonitrile. 3-Fluoro-5- nitrobenzonitrilc (350 mg, 2.1 1 mmol) was treated with morpholine (1 ml) in a 40 ml vial. The reaction was capped and stirred at 700C overnight. The solvent was evaporated and the residue triturated twice with MeOH. The residue was suspended in DMF (0.5 ml), treated with tin chloride dihydrate (2.38 g, 10.5 mmol) and heated at 75"C for 40 min. The reaction was quenched with saturated Na2CO3 (7 ml) and solid Na2CO3 (3 g). The organic layer was diluted with DCM, filtered, washed with saturated Na2CO3 and dried over solid anhydrous Na2SO^ The solvents were removed and the residue was purified on silica gel to afford the target compound (282 mg, 65%). 1H NMR (acetonc-d6) δ (ppm) 6.53 (s, I H), 6.52 (s, I H), 6.45 (s, IH), 3.75 (t, J = 5.0 Hz, 4H), 3.123 (t, J = 5.0 Hz, 4H), 2.73 (s, 2H).
[00306] Intermediate C. 3-Amino-5-(piperidin-l-yl)benzonitrile was prepared under the same conditions as above, using pipcridinc as the amine component. H NMR (10% CD3OD/CDCI3) δ (ppm) 6.47 (dd, J = 2.5 and 1.0 Hz, I II), 6.34 (t, J = 2.0 Hz, IH), 6.30 (t, J = 1.5 Hz, IH), 3.40 (bs, 2H), 3.05 (t, 7 =1 1 Hz, 4H), 1.58 (q, J = 6.0 Hz, 4H), 1.50 (m, 211).
[00307] Intermediate D. 3-Amino-5-(pyrrolidin-l-yl)benzamide. The same conditions as above starting from pyrrolidine as the amine component resulted in formation of the corresponding pyrrolidine benzamide derivative. 1H NMR (CD3OD/CDCI3) δ (ppm) 6.37 (t, J = 1.5 Hz, I H), 6.34 (t, J = 1.5 Hz, I H), 3.5 (bs, 4H), 3.19 (q, J = 3.5Hz, 4H), 1.91 (q, J = 3.5 Hz, 4H).
Figure imgf000116_0001
[00308] Intermediate E. 3-amino-5-tert-butyl-2-methoxy-N-(oxazoI-2- yl)benzamide. Step 1. 5-tert-Butyl-2-methoxy-3-nitro-N-(oxazol-2-ylmethyl)benzamide.
To a solution of 5-tert-butyl-2-methoxybenzoic acid (253 mg, 1 rnmol, prepared as in WO2005023761 ) in DCM/DMF (5 ml, 1 : 1 ), oxazol-2-ylmethanamine hydrochloride (135 mg, 1 mmol), PyBOP (1.04 g, 2 mmol) and DIEA (0.87 ml, 5 mmol) were added. The resulting mixture was stirred at r.t. overnight. The DCM was evaporated and the resulting DMF solution was subjected to RP-HPLC (gradient: 40 to 99% AcN in H2O) to give the TFA-salt of the title compound (78 mg, 17%) as a yellow solid. (Calculated mass: 333.3, observed mass: 334.1 ).
[00309] Step 2. To a solution of the compound obtained above (75 mg, 0.17 mmol) in
MeOH (2 ml), a spatula of Raney nickel was added and the suspension was stirred at r.t. under H2 atmosphere for 4 hr. The mixture was filtered (celite), the solid was washed with MeOH and the filtrate was evaporated to give the target compound (65 mg, 95% yield, >95% pure by LC-MS) as a yellow oil, which was used in the next step without further purification. (Calculated mass: 303.4, observed mass: 304.1).
[00310] Intermediate F. 3-Amino-5-tert-butyl-2-methoxy-jV-((5-mcthylfuran-2- yl)methyl)benzamide. Step 1. 5-tert-Butyl-2-methoxy-N-((5-methylfuran-2-yl)methyl)- 3-nitrobenzamide. The intermediate compound was prepared as above from (5- methylfuran-2-yl)methanamine (1 1 1 mg, 1 mmol). The target compound (224 mg, 65%) was obtained after RP-HPLC (gradient: 40 to 99% AcN in H2O) as a brown thick oil that solidified upon standing. (Calculated mass: 346.4, observed mass: 347.2).
[0031 1 ] Step 2. The target compound was prepared as above the compound obtained above (220 mg, 0.64 mmol). The target compound (181 mg, 90% yield, >90% pure by LC- MS) was obtained as a thick yellow oil, which was used in the next step without further purification. (Calculated mass: 316.4, observed mass: 317.1 ). pyrrolidiπ-1-yl
Figure imgf000117_0001
[003 12] Intermediate G. 3-Morpholino-5-(trifluoromethyl)aniline. Step 1. tert-
Butyl 3-morpholino-5-(trifluoromethyl)phenylcarbaniate. To a 2 dram vial containing 3- morpb.olino-5-(trifluoromethyl)benzoic acid (100 mg, 360 μmol) (prepared as in International Application No. PCT/US06/042679) was added a 1.3 M solution diphenylphosphorylazide in DMF (360 μl, 468 μmol), and a 2.6 M solution of NMM in tert-butanol (360 μl, 0.94 mmol). Additional tert-butanol (1 ml) was added and the reaction was capped and heated at 70°C for 16 hr. The solvent was removed and the residue was purified on silica gel, eluting with 0- 40% ErOAc/Hex to afford 61 mg (49% yield) of the tert-butyl 3-morpholino-5- (trifluorornethyl)phenylcarbamate. 1H NMR (CDCl3) δ (ppm) 7.316 (s, I H), 6.953 (s, I H), 6.775 (s, I H), 6.593 (s, IH), 3.848 (t, J=4.5 Hz, 4H), 3.199 (t, J-4.5Hz, 4H), 1.517 (s, 9H).
[00313] Step 2. The compound obtained above (61 mg, 176 μmol), was treated with
1 : 1 TFA/DCM for 30 min. The solvent was removed and the residue was treated with solid Na2CO3 in DCM. Removal of the solvent afforded 46 mg (106% yield) of 3-morpholino-5- (trifluoromethyl)aniline, which was used without further characterization.
[003 14] Intermediate H. 3-Piperidino-5-(trifluoromethyl)aniline. Step 1. tert-
Butyl 3-(piperidin-l-yl)-5-(trifluoromethyl)phenylcarbamate. Using the same procedure as above, starting from 3-piperidino-5-(trifluoromethyl)benzoic acid (100 mg, 360 μmol) afforded 42 mg (34%) of the target compound. 1H NMR (CDCl3) δ (ppm) 7.203 (s, IH), 6.955 (s, I II), 6.802 (s, I H), 6.51 1 (s, IH), 3.200 (t, J=5.5Hz, 4H), 1.691 (q, J=5.0Hz, 4H), 1.589 (m, 2H), 1.516 (s, 9H).
[003 15] Step 2. Using the same procedure as above, starting from tert-butyl 3- piperidino-5-(trifluoromethyl)phenylcarbamatc (42 mg, 122μmol) afforded 36 mg (120% yield) of 3-piperidino-5-(trifluoromethyl)aniline.
[00316] Intermediate I. Pyrrolidino-5-(trifluoromethyl)aniline. Step 1. tert-Butyl
3-(pyrrolidin-l-yl)-5-(trifluoromethyl)phenylcarbamate. Using the same procedure as above, starting from 3-pyrrolidino -5-(trifluoromcthyl)benzoic acid (94 mg, 360 μmol) afforded 52 mg (44%) of tert -butyl 3-pyrrolidinϋ-5-(trifluoromethyl)phenylcarbamate. 1H NMR (CDCl3) δ (ppm) 6,824 (s, 2H), 6.526 (s, IH), 6.432 (s, I H), 3.295 (t, J=6.5Hz, 4H), 2.005 (q, J=3.5Hz, 4H), 1.519 (s, 9H).
[00317] Step 2. Using the same procedure as above, starting from tert-butyl 3- pyrrolidino -5-(trifluoromethyl)phenyl-carbamate (52 mg. 157 μmol), afforded 36 mg (105% yield) of 3- pyrrolidino-5-(trifluoromethyl)aniline.
H ^
Figure imgf000118_0001
[00318] Intermediate J. 5-tcrt-Butvl-2-mcthoxv-3-cvanobenzoic acid. Step 1. 3-
Bromo-5-tert-butyl-2-methoxybenzoic acid. NBS (1.71 g, 9.6 mmol) was added to a solution of 5-tert-butyl-2-methoxybenzoic acid (1.0 g, 4.8 mmol) in glacial acetic acid (15 ml) and the mixture was heated to 1000C for 16 hr. The reaction was allowed to cool and was diluted with 10 ml water and then extracted with DCM. The combined organic layers were washed with water, dried over MgSO4 and concentrated to give 5-tert-butyl-2-methoxy-3- bromobenzoic acid (1.2 g, 87%) as a pale yellow solid in > 90% purity. 1H-NMR (CDCl3) δ (ppm) 8.01 (s, IH), 7.78 (s, I H), 4.00 (s, 3H), 1.33 (s, 9H).
[003 19] Step 2. Methyl 3-bromo-5-tert-butyl-2-methoxybenzoate. To a solution of the compound obtained above (0.63 g, 2.2 mmol) in DCM (18 ml), oxalyl chloride (1.0 ml, 1 1.5 mmol) and six drops of DMF were added. The mixture was stirred at r.t. for 1 hr, concentrated, the residue was dissolved in MeOH (10 ml) and further stirred at r.t. for 15 minutes. The solvent was evaporated to give a viscous yellow oil (quantitative) in >90% purity. 1H-NMR (CDCl3) δ (ppm) 7.75 (s, IH), 7.73 (s, IH), 3.95 (s, 3H), 3.92 (s, 3H), 1.33 (s, 9H).
[00320] Step 3. Methyl 5-tert-butyl-3-cyano-2-methoxybenzoate. To a solution of
5-tert-butyl-2-methoxy-3-bromobenzoic acid methyl ester (0.15 g, 0.5 mmol) in a 1 : 1 DMF/dioxane (5 ml) mixture, KCN (65 mg, 1 mmol), Pd(OAc)2 ( 12 mg, 10 mol%), CsCO3 (0.49 g, 1.5 mmol) and BlNAP (62 mg, 20 mol%) were added. The mixture was stirred at 1500C for 40 min. in the microwave, filtered over Celite, and the solids were washed with DCM. The filtrate was concentrated and the residue purified on reverse phase using 50-99% AcN in water to give the intermediate cyano ester (49 mg, 40%) as a pale yellow solid. 1H- NMR (CDCl3) S (ppm) 8.00 (s, IH), 7.72 (s, IH), 4.04 (s, 3H), 3.94 (s, 3H), 1.32 (s, 9H).
[00321 ] Step 4. To a solution of 5-tert-butyl-2-methoxy-3-cyanobenzoic acid methyl ester (40 mg, 0.16 mmol) in 1 : 1 THF/MeOH (1 ml) mixture, 2N NaOH (0.35 ml) was added. The mixture was stirred at room temperature for 1 hr. neutralized with IN HCl and extracted with approx. 20 ml of EtOAc. The organic layer was dried over MgSθ4 and concentrated to give intermediate J (quantitative) as a white solid which was used in the next step without further purification. 1H-NMR (CDCl3) δ (ppm) 7.81 (d, J= 2.43 Hz, I H), 7.64 (d, J= 2.44 Hz, I H), 7.02 (br s, I H), 3.97 (s, 3H), 3.89 (s, 3H), 3.03 (s, 3H), 1.35 (s, 9H).
Figure imgf000119_0001
[00322] Intermediate K. 3-tert-Butyl-5-((4-methylpiperazin-l-yl)methyl)aniline.
Step 1. Methyl 3-tert-butyl-S-formylbenzoate. Methyl 3-tert-butyl-5- (hydroxymethyl)benzoate (444 mg, 2 mmol), dissolved in DCM (4 ml), was treated with pyridinium chlorochromate (1.72 g, 8 mmol) at r.t. for 2.5 hr. Completion of the reaction was monitored by TLC. Upon completion, the mixture was filtered through silica gel, using DCM as the eluent. Concentration of the filtrate afforded 440 mg of the target compound as a colorless oil, which was used in the next step without purification.
[00323] Step 2. Methyl 3-tert-butyl-5-((4-methylpiperazin-l-yl)methyl)benzoate.
The compound obtained in the previous reaction (ca. 1 mmol) and 1-methylpiperazine (200 mg, 2 mmol) were dissolved in DCM (5 ml) and AcOH (0.5 ml). The reaction mixture was stirred at r.t. for 1 hr, followed by addition OfNaBH(OAc)3 (633 mg, 31 mmol). The resulting mixture was stirred overnight at r t., diluted with DCM and washed with aq. NaHCO3. The DCM layer was dried over NaISO4 and concentrated to give the target compound as a yellow oil in 268 mg yield.
[00324] Step 3. 3-tert-Butyl-5-((4-methylpiperazin-l-yl)methyl)benzoic acid. The compound obtained above (268 mg, ca. 0.88 mmol) was dissolved in EtOH (2 ml), THF (1.6 ml), and water (0.4 ml), and was treated with 2 N NaOH (1.6 ml) at r.t. for 2 hr and 500C for 30 min. The reaction mixture was neutralized with aq. HCl, evaporated to dryness and used as such in the next step.
[00325] Step 4. tert-Butyl 3-tert-butyl-5-((4-niethylpiperazin-l- yl)πicthyl)phcnylcarbamate. The compound obtained above was dissolved in t-BuOH (10 ml) and DPPA (379 μl, 1.8 mmol) and NMM ( 143 μl, 1.8 mmol) were added. The mixture was stirred at 8O0C overnight. The reaction mixture was diluted with EtOAc, and the organic layer was washed with aq. NaHCθ3, dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to afforded 258 mg of a orange oil. (Calculated mass: 362, observed mass: 3262.1).
[00326] Step 5. The compound obtained above was treated with TFA/DCM/H2O
(6/3/1 , 5 ml) for 2 hr at r.t. The solvents were evaporated and the residue was used as such in the next step.
Figure imgf000120_0001
[00327] Intermediate L. 3-Amino-5-tcrt-butyl-2-methoxy-N,N- dimethylbenzenesulfonamide. Step 1. 5-tert-Butyl-2-methoxybenzene~l-sulfonyl chloride. l -tert-Buty]-4-methoxybenzene (3.79 g, 23.08 mmol) was dissolved in DCM (70 ml) and was cooled to O0C. Chlorosulphonic acid (5 ml, 75.22 mmol) in DCM (40 ml) was added dropwise over 10 min and the reaction was stirred at 00C for 35 min., after which it was allowed to warm to r.t. over 10 min. The reaction mixture was poured into a mixture of ice (150 ml) and water (150 ml) and the DCM layer was separated. The DCM layer was washed with aq. saturated NaHCO3, dried over MgSO4, filtered and evaporated. H NMR (CDCU) δ (ppm) 7,94 (d, I H), 7.70 (dd, I H), 7.07 (d, I H), 4.05 (s, 3H), 1.34 (s. 9H)
[00328] Step 2. 5-tert-Butyl-2-methoxy-3-nitrobenzene-l-sulfonyl chloride. The compound obtained above (21.45 g, 82 mmol) was dissolved in nitric acid (85 ml, 1.34 mol). Sulfuric acid (50 ml, 0.9 mol) was added dropwise over 40 min to control the exothermic reaction. The reaction mixture was heated to 90 - 1 100C for 85 min, then stirred overnight at r.t. The yellow precipitate was filtered, washed with water and dried in vacuo, yielding 19.3 g of the target product. 1H NMR (CDCl3) δ (ppm) 8.21 (d, I H), 8.20 (d, IH), 4.12 (s, 3H), 1 .41 (s, 9H).
[00329] Step 3. 5-tert-Butyl-2-methoxy-N,N-dimethyl-3-nitrobenzenesulfonamide.
The compound obtained above (296 mg, 0.962 mmol) was dissolved in 2 M dimethylamine/THF solution (5 ml, 10 mmol). The solution was evaporated and the resulting residue was taken up in diethyl ether. The organic solution was washed with aq. NaHCO3, water and dried over MgSO4. After filtration, the solvent was evaporated to yield the target compound in 296 mg yield. 1H NMR (CDCl3) δ (ppm) 8.18 (d, IH), 8.02 (d, I H), 4.04 (s, 3H), 2.87 (s, 6H), 1.38 (s, 9H).
[00330] Step 4. The compound obtained above (0.96 mmol) was dissolved in MeOH and Raney nickel (catalytic amount) was added. The reaction was stirred under hydrogen atmosphere for 17 hr at r.t.. The catalyst was removed by filtration and the solvent was evaporated. The residue was obtained in 257 mg yield and was used as such in the next reaction. 1H NMR (DMSO-d6) δ (ppm) 7.03 (d, I H), 6.85 (d, 1H),5.26 (s, 2H), 3.68 (s, 3H), 2.66 (s, 6H), 1.23 (s, 9H). (Calculated mass: 286, observed mass: 287).
Figure imgf000121_0001
[00331 ] Intermediate M. N-(3-Amino-5-tert-butyl-2~methoxyphenyl)-4- methylpipcrazinc-1-sulfonamide. Step 1. Sodium 5-tert-butyl-2-methoxy-3- nitrophenylsulfamate. In a 250 ml round-bottomed flask containing pyridine (20 ml) and pyridine-sulfur trioxide (4.09 g, 25.7 mmol) was added 5-tert-butyl-2-rnethoxy-3-nitroaniline
(1.15 g, 5.13 mmol) in pyridine (5 ml). The vial containing the aniline was rinsed with 5 ml pyridine twice and the suspension was heated at 50°C for 4 hr. The solvent was evaporated and the residue was dried in high vacuum. The residue was treated with saturated aq. Na2CO3 until a basic pH was maintained. The solution was concentrated, diluted to ~20 ml with water, filtered and evaporated to afford 2.73 g of sodium 5-tert -butyl -2-methυxy-3- nitrophenylsulfamate (containing NaICO3) as a yellow powder. 1H NMR (500 MHz, DMSO- d6) δ ppm 7.89 (d, J = 2.36 Hz, IH), 7.21 (d, J = 2.36 Hz, I H), 6.85 (s, I H), 3.72 (s, 3H), 1.24 (s, 9H).
[00332] Step 2. N-(5-tert-ButyI-2-methoxy-3-nitrophenyI)-4-methyIpiperazine-l- sulfonamide. The compound obtained above (1 14 mg, 213 μmol) was place in a 50 ml round-bottomed flask and suspended in DCM (5 ml). To this mixture was added PCI5 (222 mg, 1.07 mmol) and the flask was fitted with a condenser and a CaSO4 drying tube and heated at reflux for 3hr. The reaction was treated with 1 drop of brine and the solution was stirred for 15 min. The suspension was diluted with DCM and filtered. The solvent was evaporated to afford 82 mg of 5-tert-butyl-2-methoxy-3-nitrophenylsulfamoyl chloride which was used without further purification. This compound was placed in a 50 ml round-bottomed flask and diluted with DCM (5 ml). To this stirred mixture in an ice bath was added 1 -methylpiperazine (32 mg, 0.32 mmol) in DCM (2 ml), followed by TEA (29 μl, 0.21 mmol). After 1 hr the solvent was evaporated and the residue was purified on silica gel, eluting with 0 - 20% MeOH/DCM to afford 22 mg (27% yield) of the target compound. 1H NMR (500 MHz, CDCl3) δ ppm 7.74 (d, J = 2.15 Hz, IH), 7.62 (d, J = 2.34 Hz, IH), 3.93 (s, 3H), 3.65-3.51 (bs, 4H), 2.95-2.65 (bs, 4H), 2.54 (bs, 3H), 1.32 (s, 9H).
[00333] Step 3. The compound obtained above (22 mg, 57 μmol) was dissolved in
MeOH (5 ml) in a 50 ml round-bottomed flask. Raney nickel (50 mg) was added and the solution was stirred under hydrogen atmosphere for 2.5 hr, after which time the mixture was filtered and the solvent evaporated. Intermediate M was used as such in the next step.
Figure imgf000122_0001
[00334] Intermediate N. Methyl 3-amino-5-tert-butyl-2-methoxybeiizoate. In a
100 ml round-bottomed flask were placed 5-tert-butyl-2-methoxy-3-nitrobenzoic acid (594 mg, 2.35 mmol) (prepared as described in WO2005/023761 ), DCM (20 ml) and DMF (2 drops), Oxalyl chloride (0.41 ml, 4.69 mmol) was added and the reaction was stirred for 1.5 hr. The solvent was evaporated and the residue was treated with MeOH (10 ml) and evaporated. The residue was diluted with MeOH (20 ml), Raney nickel (200 mg) was added and the resulting mixture was stirred under hydrogen atmosphere overnight. The reaction was filtered and the solvent evaporated to afford 551 mg (99% yield) of Intermediate N. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.23 (d, J= 2.14 Hz, I H), 6.99 (d, J = 2.12 Hz, IH), 3.84 (s, 3H), 1.28 (s, 9H).
Figure imgf000123_0001
[00335] Intermediate O. 5-tert-Butyl-3-(lH-imidazol-l-yl)-2-methoxyaniline. In a
50 ml round-bottomed flask were placed tert-butyl 3-ammo-5-tert-butyl-2- methoxyphenylcarbamate (264 mg, 0.90 mmol) (prepared from 5-tert-butyl-2- methoxybenzene-l ,3-diamine via standard Boc protection), glyoxal (40% w/w in water, 280 μl. 1.79 mmol), formaldehyde (37% w/w in water, 146 μl, 1.79 mmol) and ammonium hydroxide (28% w/w in water, 109 μl, 1.79 mmol). The flask was capped and heated at 6O0C overnight. Glyoxal (560 μl), formaldehyde (290 μl) and ammonium hydroxide (600 μl) were added and the reaction was heated for 1 hr. The solvents were evaporated and the residue was purified on silica gel, eluting with 0 - 100% EtOAc/Hex. 1H NMR (500MHz, CDCl3) δ (ppm) 8.24 (s, I H), 7.91 (s, I H), 7.28-7.26 (m, 2H), 7.12 (s, I H), 6.93 (d, I H), 3.80 (s, 3H), 1.56 (s, 9H), 1.35(s, 9H).
[00336] The Boc group was removed using TFA/DCM and the product was partitioned between DCM and aq. Na2CO3 solution. The DCM layer was dried over NaτSθ4, filtered and evaporated to afford the target compound, which was used as such in the next step.
Figure imgf000124_0001
[00337] Intermediate P. N-(3-Amino-5-tert-butylphenyl)methanesuIfonamide.
Step 1. 4-tert-Butyl-2,6-dinitrophenoI. 4-tert-Butylphenol (30 g, 0.2 mol) in glacial acetic acid (50 ml) was added dropwise to a stirred solution of 90% nitric acid (48 ml) and glacial acetic acid (100 ml) at -15°C to -100C over one hr. After the addition was complete, the mixture was stirred at r.t. for 1 hr and then poured into cracked ice. The mixture was diluted with water, cooled and extracted with DCM. The combined organic layers were dried and concentrated. The residue was purified by column chromatography (PE:EtOAc = 50: 1) to give the target compound (28g, 58% yield). 1H NMR (300MHz, CDCl3) δ (ppm) 1 1.3 (s, IH), 8.3 (s, 2H), 1.38 (s, 9H).
[00338] Step 2. 5-tert-Butyl-2-chloro-l,3-dinitrobenzene. The compound obtained above (15 g, 62.5 mmol) was added to a mixture of thionyl chloride (22.3 g, 187 mmol), DMF (8.6 g) and dry toluene (200 ml). The mixture was stirred under reflux for 8 hr. The mixture was evaporated under vacuum and the residue was purified by column chromatography (PE: EtOAc = 10:1) to provide the target compound (12.6 g, 78% yield). 1H NMR (300MHz, CDCl3) δ (ppm) 7.9 (s, 2H), 1.38 (s, 9H).
[00339] Step 3. 5-tert-Butylbenzene-l,3-diamine. The compound obtained above (3 g, 1 1.6 mmol), methanol (300 ml) and 10% Pd/C (1 g) were placed in an autoclave. The mixture was hydrogenated under 3 MPa for 1 hr. Solid K2CO3 (4 g, 29 mmol) and 10% Pd/C ( 1 g) were added to the above reactor. The mixture was again hydrogenated under 1.5 MPa overnight, filtered and evaporated to provide the target compound (1.5 g, 79% yield). 1H NMR (300 MHz. CDCl3) δ (ppm) 6.2 (m, 2H), 5.9 (d, IH), 3.5 (s, 4H), 1.2(s, 9H).
[00340] Step 4. To a solution of the compound above (2 g, 12.2 mmol) in DCM
(20 ml) was added TEA (2.5 ml) and methylsulfonyl chloride (1.6 g, 14.6 mmol) dropwise at 00C. After the addition was complete, the mixture was stirred at r.t. overnight, and washed with saturated brine. The aqueous phase was extracted with DCM and the combined organic layers were dried and evaporated. The residue was purified by column chromatography (PErHtOAc = 4: 1) to provide the target compound (1.0 g, 34% yield). (Calculated mass: 242.3. observed mass: 243.1).
Figure imgf000125_0001
[00341] Intermediate Q. 5-tert-butyl-2-methoxy-3-(methylsulfinyl)aniline. Step 1.
5-tert-Butyl-2-methoxy-3-nitrobenzenesulfInic acid. A solution OfNa2SO3 (580 mg, 4.6 mmol) and NaHCO3 (420 mg, 5.0 mmol) in water (2.5 ml) was heated at 800C. Solid 5-tert- butyl-2-methoxy-3-nitrobenzene-l-sulfonyl chloride (539 mg, 1.751 mmol) (obtained as described above) was added over 2 min, with evolution of gas. After 80 mm, the solution was allowed to cool to r.t. and stirring was continued overnight, resulting in a very viscous mixture.
[00342] Step 2. 5-tert-Butyl-2-methoxy-l-(methylsulfinyl)-3-nitrobenzene. To this reaction mixture was added NaHCO3 (400 mg, 4.76 mmol) and water (2.5 ml) and the mixture was heated to 800C. Dimethylsulfate (0.5 ml, 5.3 mmol) was added, resulting in gas evolution. More dimethylsulfate was added in 2 portions (0.2 ml) each at 3 and 4 hr. After 6 hr, the reaction was allowed to cool to r.t. and stirred overnight. The crystalline product was filtered, washed with water and dried. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.25 (d, IH), 8.14 (d, I H), 4.08 (s, 3H), 3.31 (s, 3H), 1.40 (s, 9H).
[00343] Step 3. The compound obtained above (155 mg, 0.539 mmol) was dissolved in 12M HCl (1.5 ml) and treated with SnCl2.2H2O (400 mg, 1.77 mmol) for 40 min. The precipitated was filtered, washed with IM aq. HCl and dried. The residue was triturated with DCM and the solution was evaporated. The combined HCl washes were neutralized with 45% NaOH and the product was extracted into DCM. The organic layer was dried over MgSO4, filtered, and evaporated to yield the target compound. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.82 (bs, IH), 7.68 (bs, IH). 4.14 (s, 3H), 3.25 (s, 3H), 1.35 (s, 9H). Synthesis of heteroaryl amine intermediates.
c
Figure imgf000126_0001
[00344] Intermediates I - V. Intermediates IA and IB. A mixture of 2-chloro- pyrimidin-4-amine and 4-chloro-pyrimidin-2-amine (100 mg, 0.77 mmol, prepared as in WO2005023761) was derivatized with 2,2,6,6-tetramethylmorpholine hydrochloride (277 mg, 1.54 mmol, prepared as in WO2006066174), by the procedure described in WO2005023761. Briefly, the aminopyrimidine mixture was dissolved in THF (5 ml) and treated with 2 eq. of the amine component in the presence of 3 eq. of DIEA. The mixture was stirred at 800C overnight, after which the solvent was evaporated. The residue was taken up in EtOAc, the solution was filtered and chromato graphed on silica gel (gradient: 0 to 50% EtOAc in Hex) to give the product(s) (59.7 mg, 33%) as a pale yellow solid. (Calculated mass: 236.3, observed mass: 236.0).
[00345] Regioisomers were separated at this stage or after subsequent reactions. The following intermediates were obtained.
[00346] Intermediate I-A: 2-(2,2,6,6-Tetramethylmorpholino)pyrimidin-4-amine.
(Calculated mass: 236.3, observed mass: 236.0).
[00347] Intermediate H-A. 2-(8-Oxa-3-azabicyclo [3.2.1 ]octan-3-yl)pyrimidin-4- amine . The same procedure as above was carried out with 8-oxa-3-azabicyclo[3.2.1 ]octane hydrochloride (prepared as in WO2004009589) (23.4 mg, 15%), (Calculated mass: 206.3, observed mass: 206.1).
[00348] Intermediate III-A. 2-(4-Methylpiperazin-l-yl)pyrimidin-4-amine was similarly prepared from N-methylpiperazine. (Calculated mass: 193.1 , observed mass: 193.3).
(See also JP50058082). [00349] Intermediates IV-A and IV-B. tert-Butyl 4-(4-aminopyrimidin-2- yl)piperazine-l-carboxylate (IV-A) was prepared as above from tert-butyl piperazine-1 - carboxylate, (Calculated mass: 279.2, observed mass: 279,9).
[00350] Intermediate IV-B. tert-Butyl 4-(2-aminopyrimidin-4-yl)piperazine-l- carboxylate (Calculated mass: 279.2, observed mass: 279.9). (See also WO9R25617)
[00351 ] Intermediates V-A and V-B. 2-(3,5-Dimethylpiperazin-l-yl)pyrimidin-4- amine (V-B) was prepared as above from 2,6-dimethylpiperazine. (Calculated mass: 207.2, observed mass: 207.2).
[00352] Intermediate V-B. 4-(3,5-Dimethylpiperazin-l-yl)pyrimidin-2-amine
(Calculated mass: 207.2, observed mass: 207.2).
Figure imgf000127_0001
[00353] Intermediate VI. N2-(3,3-Dimethylbutyl)pyridine-2,4-diamine was prepared using the procedure described in WO2006091862. 2-Chloro-4-nitropyridine 1 - oxidc was dissolved in EtOH and treated with the amine component (2.2 eq) at 800C overnight. After evaporation of the EtOH, the residue was dissolved in DCM and purified. Purification of the intermediate 2-(3,3-dimethylbutylamino)-4-mtropyridine 1 -oxide was carried out using silica gel (gradient: 0 to 100% (EtOAc/DCM 1 : 1 ) in DCM). (Calculated mass: 241 .2, observed mass: 281.0 (M+AcN)+). 1H-NMR (500 MHz, CDCl3) δ (ppm) 8.30 (d, I H), 7.42 (d, I H), 7.40 (s, I H), 6.92 (bs, IH), 3.38 (m, 2H), 1 .66 (t, 2H), 1.02 (s, 9H). Subsequent reduction with Raney nickel and 1 atm hydrogen in MeOH, at r.t. for 3 hr provided the title compound which was used in the next step without further purification.
[00354] Intermediate VII. N2-(2-(2,6-Dimethylpiperidin-l-yl)ethyl)pyridine-2,4- diamine was prepared using a similar procedure to above. Purification of the intermediate 2-(2-(2,6-dimethylpiperidin-l-yl)ethylamino)-4-nitropyridine 1-oxide was carried out using silica gel (gradient: 0 to 100% (MeOH/DCM 1 :9) in DCM). 1H-NMR (500 MHz, DMSO-d6) δ (ppm) 8.34 (d, I H), 7.70 (bt, I H), 7.56 (s, I H), 6.38 (d, I H), 3.34 (m, 2H), 2.74 (t, 211). 2.42 (bs, 2H), 1.58 (d, I H), 1.46 (d, 2H), 1.25 (m, I H), 1.12 (m, 2H), 1.06 (s, 6H). Subsequent reduction as above again provided the title compound which was used in the next step without further purification.
Figure imgf000128_0001
[00355] Intermediate VIII. N-Methyl-5-(tributylstannyl)pyridin-2-amine. Step 1.
5-Bromo-N-methyIpyridin-2-amine. Intermediate VIII was prepared using similar methods described in WO2005/023761. 2,5-Dibromopyridinc (2.5 g, 10.6 mmol) was treated with a 33% MeNH2ZEtOH (13.2 ml, 106 mmol) at 800C for several days. The solvent was evaporated, the residue was dissolved in 1 M HCl and the aqueous solution was washed with DCM. The acidic layer was basified with 1 M NaOH to pH ~1 1 and the milky suspension was extracted with DCM. The organic layer was dried over MgSO.* and evaporated to give the target product as a brown solid in quantitative yield. (Calculated mass: 187.0, observed mass: 188.3).
[00356] Step 2. To a solution of the compound obtained above (561 mg, 3 mmol) in heptane/THF (30 ml) cooled to -78°C under N2 atmosphere, a solution of t-BuLi 1.7 M (3.4 ml, 6.6 mmol) was added. After 30 minutes ClSnBu3 (1.8 g, 6.6 mmol) in THF (3 ml) was added and the reaction mixture was stirred for 2 hr at -78 C. Then a solution of 5% AcOH/THF (20 ml) was added and the mixture was allowed to warm up to room temperature. The solvents were evaporated and the residue was dissolved in EtOAcZH2O. The compound was extracted into EtOAc and the organic layer was washed with aq. NaHCO3 and dried over Na2SO4. After filtration the solvent was evaporated and the residue was purified by silica gel chromatography, using a gradient of 0-100% 50%EtOAcZHex, to give the target compound in 380 mg yield. (Calculated mass = 397.2, observed mass = 399.0).
Synthesis of naphthalenyl intermediates.
Figure imgf000128_0002
[00357] Intermediate a. 2-(4-(3-Cyanopropoxy)naphthalen-l-yl)-2-oxoacetic acid.
(X = CH2CN). Step 1. 4-(Naphthalen-l-yloxy)butanenitrile. A mixture of 1 -naphthol (144 mg, 1 mmol), t-BuOK (224 mg, 2 mmol) and 4-chlorobutyronitrile (0.13 ml, 1.5 mmol) in DMF was stirred at 60°C overnight. The mixture was filtered and the solvent was removed under vacuum. The residue was taken up in DCM, the organic layer was washed with saturated aq. NaHCO3, dried (MgSO4), and evaporated. The residue was purified by chromatography on silica gel using Hex/EtOAc as eluents.
[00358] Step 2. Methyl 2-(4-(3-cyanopropoxy)naphthalen-l-yl)-2-oxoacetate. The title compound was prepared from the compound above (106 mg, 0.5 mmol) using the procedure described in WO2005023761. Briefly, AlCh (1.5 eq.) was mixed with methyl 2- chloro-2-oxoacetate (1.4 eq. an stirred for 5 min. and then added to the starting material, which was suspended in DCM and cooled. The mixture was stirred for 2 hr and then quenched with H2O. The organic layer was washed with NaHCO^, dried and evaporated. The residue was purified over silica gel using EtOAc/Hex.
[00359] Step 3. Intermediate a was prepared from the compound obtained in the previous step, using the procedure described in WO2005023761, by suspending the material in THF, and treating with LiOH (3-4 eq.) for 2 hr. The compound was extracted into DCM, which was dried, evaporated and used as such in the next step.
[00360] Intermediate b. 2-(4-(2-(2-Methoxyethoxy)ethoxy)naphthalcn-l-yl)-2- oxoacetic acid (X = O(CH2)2θMe) was similarly prepared.
Figure imgf000129_0001
[00361] Intermediate c. 2-Oxo-2-(4-(2-(2,2,6,6-tetramethylmorpholino)ethoxy)- naphthalen-l-yl)acctic acid. Step 1. 2,2,6,6-Tetramethyl-4-(2-(naphthalen-l- yloxy)ethyl)morpholine. To a solution of l-(2-chloroethoxy)naphthalene (200 mg, 0.97 mmol, see J. Med. Chem. 2004, 47, 3823) in DMF (5 ml), was added 2,2,6,6-tetramethylmorpholine hydrochloride (172 mg, 0.96 mmol, prepared as in WO2006066174) and K2CO3 (664 mg, 4.80 mmol) and the suspension was stirred at 10O0C overnight. The mixture was filtered and the DMF solution subjected to RP-HPLC (gradient: 10 to 95% AcN in H2O) to give the TFA-salt of the product (173 mg, 42%) as a brown crystalline solid. (Calculated mass: 313.4, observed mass: 314.2).
[00362] Step 2. Methyl 2-oxo-2-(4-(2-(2,2,6,6- tetramethylniorphulino)ethoxy)naphthalen-l-yl)acetate. Methyl 2-oxo-2-(4-(2-(2,2,6,6- tetramethylmorpholino)ethoxy)-naphthalen-l -yl)acetate was prepared from the compound obtained above using a similar procedure to that described to above and in WO2005023761. The crude yellow oil (69 mg, 87% yield, >95% pure by LC-MS) was of sufficient purity to be used in the next step. (Calculated mass: 399.5, observed mass: 400.3).
[00363] Step 3. The target compound was prepared from the compound obtained above using a similar procedure to described in WO2005023761. Specifically, a solution of the compound obtained above was dissolved in THF^McOH (1/ 1 , 2 ml) and 2 N NaOH (2 eq.) was added. The reaction mixture was stirred at r.t. for 30 min, neutralized with 1 N HCl, and evaporated. The pale brown solid obtained was used in next step without further purification. (Calculated mass: 385.5, observed mass: 386.2).
[00364] Intermediate d. 2-(4-(2-(8-Oxa-3-azabicyclo[3.2.1]octan-3- yl)ethoxy)naphthalen-l-yl)-2-oxoacetic acid. Step 1. 3-(2-(Naphthalen-l-yloxy)ethyl)-8- oxa-3-azabicyclo[3.2.1]octane. The compound was obtained using the same procedure as above with 8-oxa-3-azabicyclo[3.2.1 ]octane hydrochloride (72 mg, 0.48 mmol, prepared as in WO2004009589), to afford the TFA-salt of the target product (66 mg, 34%) as a pale yellow solid. (Calculated mass: 283.4, observed mass: 284.0).
[00365] Step 2. Methyl 2-(4-(2-(8-oxa-3-azabicyclo[3.2.11octan-3- yl)ethoxy)naphthalen-l-yl)-2-oxoacetatc. Methyl 2-(4-(2-(8-oxa-3-azabicyclo[3.2.1]octan- 3-yl)ethoxy)naphthalen-1 -yl)-2-oxoacetate, prepared as above from 3-(2-(naphthalen-l - yloxy)ethyl)-8-oxa-3-azabicyclo[3.2.1]octane, was obtained as a yellow oil (44 mg, 72% yield, >95% pure by LC-MS). (Calculated mass: 369.4, observed mass: 370.2).
[00366] Step 3. The target compound was prepared as above from methyl 2-(4-(2-(8- oxa-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)naphthalen-l-yl)-2-oxoacetate and was obtained as a pale brown solid, which was used in next step without further purification. (Calculated mass: 355.4. observed mass: 356.1). [00367] Intermediate e was similarly prepared using 10-Oxa-4-aza- tricyclo[5.2.1.0 Λ2-,6°]' decane (see WO2004009589).
Figure imgf000131_0001
[00368] Intermediate f. 4-(2-(2,2,6,6-Tetramethylmorpholino)ethoxy)naphthalen-
1-amine. Step 1. tert-Butyl 4-(2-(2,2,6,6-tetramethylmorpholino)ethoxy)naphthalen-l- ylcarbamate. To a solution of tert-butyl 4-(2-chloroethoxy)naphthalen-l-ylcarbamate (50 mg, 0.16 mmol, prepared as in WO2006010082) in DMF (2 ml), was added 2,2,6,6-tetramethylmorpholine hydrochloride (29 mg, 0.16 mmol, prepared as in WO2006066174) and K2CO3 (107 mg, 0.78 mmol), and the suspension was stirred at 1000C overnight. The mixture was filtered and the DMF solution was subjected to RP-HPLC (gradient: 25 to 80% AcN in H2O) to give the TFA-salt of the product ( <70% pure by LC-MS). (Calculated mass: 428.6, observed mass: 429.4).
[00369] Step 2. The title compound was prepared by treating the compound obtained above with a 1 :1 mixture of DCM:TFA and was used in the next step without further purification.
[00370] Intermediate g. 4-(2-(8-Oxa-3-azabicyclo[3.2.1]octan-3- yl)ethoxy)naphthalen-l-amine. Step 1. tert-Butyl 4-(2-(8-oxa-3-azabkyclo[3.2.1]octan- 3-yl)ethoxy)naphthalen-l- ylcarbamate. The same procedure as above was used, starting with 8-oxa-3-azabicyclo[3.2.1 ]octane hydrochloride (24 mg, 0.16 mmol, prepared as in WO2004009589), yielding the TFA-salt of the above product ( <70% pure by LC-MS) after RP-HPLC (gradient: 10-95% AcN in H2O). (Calculated mass: 398.5, observed mass: 399.3).
[00371 ] Step 2. The target compound was prepared as above, from tert-butyl 4-(2-(8- oxa-3-azabicyclo[3.2. l]octan-3-yl)ethoxy)naphthalen-l -ylcarbamate, and was used in the next step without further purification.
[00372] The intermediates are used in the reactions exemplified in the following examples. Example 1: Formation of target compounds via coupling reaction with naphthalenyl oxoacetic acid compounds.
Figure imgf000132_0001
[00373] Method A. PyBOP Coupling. N-(5-tert-buryl-2-methoxy-3-
(methylsulfonamido)phenyl)-2-(4-(3-cyanopropoxy)naphthalen-l-yl)-2-oxoacetamide
(X=CH2CN, R= Me). To a solution of 2-(4-(3-cyanopropoxy)naphthalen-l-yl)-2-oxoacetic acid (Intermediate a) in DCM, N-(3-amino-5-re/-r-butyl-2-methoxyphenyl)methanesulfon- amide (1.1 eq., prepared as in WO2005023761), PyBOP (2 eq.) and DIEA (5 eq.) were added. The resulting mixture was stirred at r.t. overnight, concentrated and purified via preparative LC-MS to yield 8 mg of target product. (Calculated mass: 537.6, observed mass: 560.5 (M + Na)+).
[00374] N-(5-tert-butyl-2-methoxy-3-(propylsulfonamido)phcnyl)-2-(4-(3- cyanopropoxy)naphthalen-l-yl)-2-oxoacetamide (X=CII2CN, R= Pr). Prepared as above from N-(3-arnino-5-tert-butyl-2-methoxyphenyl)propane-l -sulfonamide (prepared as in WO2005023761 ). (Calculated mass: 565.7, observed mass: 566.6 (M + H)+, 588.6 (M + Na)+).
[00375] N-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(2-(2- mcthoxyethoxy)naphthalen-l-yl)-2-oxoacetamide (X= O(CH2)2OMe, R= Me). To a solution of 2-(4-(2-(2-methoxyethoxy)ethoxy)naphthalen-l -yl)-2-oxoacetic acid (Intermediate b) in DMF, N-(3-amino-5-tert-butyl-2-methoxyphenyl)methanesulfonamide (1.1 eq., prepared as in WO2005023761 ), PyBOP (1.5 cq.) and DIEA (5 eq,) were added. The resulting mixture was stirred at r.t. overnight, concentrated and purified via LC-MS to yield 3 mg of target product. (Calculated mass: 572.7, observed mass: 595.6 (M + Na)' ).
[00376] N-(5-tert-Butyl-2-methoxy-3-(propylsulfonarnido)phenyl)-2-(4-(2-(2- methoxyethoxy)naphthalen-l-yl)-2-oxoacetamide (X= O(CH2)2OMe, R= Pr). Prepared as above from N-(3-amino-5-tert-butyl-2-methoxyphenyl)propane-l -sulfonamide (prepared as in WO2005023761 ). (Calculated mass: 600.7, observed mass: 623.7 (M + Na)+).
Figure imgf000133_0001
[00377] Method B. EDC coupling. N-(3-Cyano-5-morpholinophenyl)-2-(4-(2- morpholinoethoxy)naphthalen-l-yl)-2-oxoacetamide (R1= morpholinyl, R2= CN, R3= H).
In an 18 mm test tube containing 2-(4-(2-morpholinoethoxy)naphthalen-l-yl)-2-oxoacetic acid ( 255 mg, 0.70 mmol, Y = OH, prepared as in WO2005023761) and 3-amino-5- morpholinobenzonitrile (150 mg, 0.74 mmol) was added DMF (1 ml) followed by EDC (170 mg, 0.89 mmol) dissolved in DCM (2 ml). NMM (81 μl, 0.74 mmol) was added followed by DCM ( 1 ml) and the reaction was allowed to sit at r.t. for 40 min after which time the solvent was removed. The residue was purified on silica gel, eluting with 0-50% EtOAc/Hex to afford the title compound (250 mg, 70%) as a pale yellow solid. (Calculated mass: 514.2, observed mass: 515.6).
[00378] N-(3-tert-But>l-5-cyanophenyl)-2-(4-(2-morpholinoethoxy)naphthalen-l- yl)-2-oxoacetamide (R1= t-Bu, R2= CN, R3= H). The procedure above with 3-amino-5-t- butylbenzomtrile (Intermediate A) (21 mg, 0.12 mmol) gave the target compound (19.0 mg, 31 %) after preparative LC-MS as the TFA-salt. (Calculated mass: 485.2, observed mass: 486.5).
[00379] N-(3-Fluoro-5-morpholinophenyl)-2-(4-(2-morpholinoethoxy)naphthalen- l-yl)-2-oxoacetamide (R1= morpholinyl, R2= F, R3= H). Using the procedure above with 3-ΩuoiO-5-morpholinoaniline (24 mg, 0.12 mmol, prepared as in WO20030909) gave the target compound (25 mg, 34%) after preparative LC-MS as the bis-TFA-salt. (Calculated mass: 507.2, observed mass: 508.5).
[00380] N-(5-tert-Butyl-3-cyano-2-methoxyphcnyl)-2-(4-(2- morpholinoethoxy)iiaphthalen-l-yl)-2-oxoacetamide (R1= t-Bu, R2= CN, R3= OMe).
Using a similar procedure to above with 3-amino-5-tert-butyl-2-mcthoxybenzonitrile (21 mg, 0.12 mmol, prepared as in International Application No. PCT/US06/042679) gave the target compound (6.6 mg, 10%) after preparative LC-MS as the TFA-salt. (Calculated mass: 515,2, observed mass: 516.5).
[ 00381] N-(3-Morpholino-5-(trifluorornethyl)phenyl)-2-(4-(2- morpholinoethoxy)naphthalen-l-yl)-2-oxoacetamide (R1= morpholinyl, R2= CF1,
R-= H). The procedure above with 3-moφholino-5-(trifluoromethyl)aniline (24 mg, 0.12 mmol, see WO2004005281) afforded the target compound (22.8 mg, 82%) after chromatography on silica gel eluting with 0-100% EtOAc/Hex followed by 0-100% (20% MeOH'DCM)/EtOΛc, as the bis-TFA-salt. (Calculated mass: 557.2, observed mass: 558.6).
[00382] 2-(4-(2-Morpholinoethoxy)naphthalen-l-yl)-2-oxo-N-(3-(piperidin-l-yl)-5-
(trifluoromethyl)phenyl)acetamide (R1= piperidinyl, R2= CF3, R3= H). Using the procedure above with 3-(piperidin-l-yl)-5-(trifluoromethyl)aniline (12 mg, 0.05 mmol) (prepared as in International Application No. PCT/US06/042679) gave the target compound (9.3 mg, 33%) after chromatography on silica gel eluting with 0-100% EtOAc/Hex followed by 0-100% (20% MeOH/DCM)/EtOAc. (Calculated mass: 555.2, observed mass: 556.6).
[00383] 2-(4-(2-Morpholinoethoxy)naphthalen-l-yl)-2-oxo-N-(3-(pyrrolidin-l-yl)-
5-(trifluoromethyl)phenyl)acetamide (R1= pyrrolidinyl, R2= CF3, R3= H). Using a similar procedure to above with 3-(pyrrolidin-l -yl)-5-(trifluoromcthyl)aniline (12 mg, 0.05 mmol, see WO2001051456) gave the target compound (8.8 mg, 33%) after chromatography on silica gel eluting with 0-100% EtOAc/Hex followed 0-100% (20% MeOH/DCM)/EtOAc. (Calculated mass: 541.2, observed mass: 542.6).
[00384] N-(3-Bromo-5-tert-butyl-2-methoxyphenyl)-2-(4-(2- morpholinocthoxy)naphthalen-l-yl)-2-oxoacetamide (R1= t-Bu, R2= Br, R3= OMe).
Using a similar procedure to above with 3-bromo-5-tert-butyl-2-methoxyaniline (0.23 mmol, prepared as in International Application No. PCT/US06/042679) gave the target compound (28.9 mg, 76%) after chromatography on silica gel eluting with 0-100% EtOAc/Hex followed 0- 100% (20% MeOH/DCM)/EtOAc. (Calculated mass: 568.2, observed mass: 569.5).
[00385] N-(5-tert-Butyl~2-methoxy-3-(4-mcthylpiperazine-l-sulfonamido)phenyl)-
2-(4-(2-morpholinoethoxy)naphthalen-l-yl)-2-oxoacetamide (R1= t-Bu, R2=NHSO2- 4-methylpiperazinyl, R = OMe). Using a similar procedure to above with Intermediate M (57 μmol) afforded the target compound (22 mg, 60%) after preparative HPLC, eluting with
10-70% AcN/water. (Calculated mass: 667.3, observed mass: 668.0), 1H NMR (500 MHz, CDCl3ZCD3OU, 9: 1 ) δ (ppm) 8.78 (d, J - 8.52 Hz, I H), 8.45 (d, J = 8.32 Hz, I H), 8,20 (d. J= 8.48, I H), 8.14 (d, J= 2.26, IH), 7.64 (ddd, J = 1.5, 7.0, 8.5, I H), 7.53 (ddd, J = 1.0. 7.0, 8.0, I H), 7.23 (d, J - 2.26, IH), 6.88 (d, J= 8.43, I II), 4.65 (t, J = 4.0, 2H), 3.96-3.93 (m, 4H), 3.83 (s, 3H). 3.66 (t, J= 4.5, 2H), 3.54 (bs, 8H), 2.74 (s, 3H), 1.26 (s. 9H).
[00386] Method C. Acid Chloride coupling. 5-tert-ButyI-2-methoxy-3-(2-(4-(2- morpholinoethoxy)naphthalen-l-yl)-2-oxoacetamido)-N-(oxazol-2-ylmcthyl)benzamide (R1= t-Bu, R = CONHCH2-OXaZoIyI, R = OMe). The target compound was prepared from 2-(4-(2-moipholinoethoxy)naphthalen-l-yl)-2-oxoacetyl chloride (Y = Cl) (66 nig. 0.19 mmol, prepared as in WO2005023761) and Intermediate E (65 mg, TFA-salt, 0.15 mmol) using a similar procedure to that described in WO2005023761. Briefly, to a suspension of 2-(4-(2-rnorpholinoethoxy)naphthalen-l -yl)-2-oxoacetic acid (0.19 mmol) in DCM (3 ml) containing a few drops of DMF. was added oxalyl chloride (5 eq.). The mixture was stirred at r.t. for 1 hr, after which the solvent was evaporated. The residue was dissolved in DCM (3 ml) and the amine (1 eq.) and DIEA (5 eq.) were added. The resulting mixture was stirred at r.t. overnight and then washed with H2O, dried, and evaporated. The residue was purified by RP-HPLC (gradient: 10 to 95% AcN in H2O), followed by chromatography over silica gel with EtOAc as eluent, to yield the final product (7.8 mg, 8.5% ) as a thick yellow oil. (Calculated mass: 614.7, observed mass: 615.7).
[00387] 5-tert-Butyl-2-methoxy-N-((5-methylfuran-2-yl)methyl)-3-(2-(4-(2- morpholinoethoxy)naphthaIen-l-yl)-2-oxoacetamido)benzamide (R1= t-Bu, R2= CONHCH2-5-methylfuranyl, R3= OMe). The target compound was prepared as above from Intermediate F (175 mg, 0.55 mmol). The TFA-salt of the final product (58 mg, 14%) was obtained after RP-HPLC (gradient; 10 to 95% AcN in H2O), followed by a second RP-HPLC purification (gradient; 40 to 99% AcN in H2O) as a thick brown oil. (Calculated mass: 627.7, observed mass: 628.7).
[00388] N-(3-Cyano~5-piperidinophenyl)-2-(4-(2-morpholinoethoxy)naphthaIen-l- yl)-2-oxoacetamide (R1= pipcridinyl, R2= CN, R3= H). Using a similar procedure to above with Intermediate C (35 mg, 0.14 mmol) the target compound (7.3 mg, 20%) was obtained, after chromatography on silica gel, eluting with 0-100% EtOAc/Hex followed by 0-100% (20% MeOH/DCM)/EtOAc, as a pale yellow solid. (Calculated mass: 512.2, observed mass: 513.6). [00389] N-(3-Cyano-5-(pyrrolidin-l-yI)phenyI)-2 (4-(2- morphoIinoethoxy)naphthaIen-l-yI)-2-oxoacetamide (R1= pyrrolidinyl, R2= CN, R3= H). Step 1. Using the procedure above with Intermediate D (35 mg, 0.14 mmol) yielded 3-(2-(4- (2-morpholinoethoxy)naphthalen-l-yl)-2-oxoacetamido)-5-(pyrrolidin-l-yl)bcnzamide (15,9 mg, 44%) after chromatography on silica gel, eluting with 0-100% EtOAc/Hex followed by 0-100% (20% MeOH/DCM)/EtOAc, as a pale yellow solid. (Calculated mass: 516.2, observed mass: 517.6).
[00390] Step 2. To a solution of this compound in DCM (3 ml), TEA (22 μl,
154 μmol) was added, followed by triflic anhydride (26 μl, 154 μmυl). The resulting mixture was stirred at r.t. overnight after which additional TEA (75 μl, 0.47 mmol) and triflic anhydride (75 μl, 0.46 mmol) were added. After stirring for 1 hr, the reaction was diluted with DCM and quenched with water. The organic layer was dried over NaZSO4 and the solvent was removed in vacuo. The residue was purified on silica gel, eluting with 0-100% EtOAc/Hex followed by 0-100% (20% MeOH/DCM)/EtOAc to afford the title compound (3.2 mg) which contained triethylamine hydrochloride. The residue was triturated with water and the solid was dried to afford 2.8 mg (18% yield) of the pure product. (Calculated mass: 498.2, observed mass: 499.6).
[00391 ] Methyl 5-tcrt-butyI-2-methoxy-3-(2-(4-(2-morpholinoethoxy)naphthalen- l-y[)-2-oxoacetamido)benzoate (R1= t-Bu, R2= COOMe, R3= OMe). Using the acid chloride procedure above with Intermediate N (551 mg, 2.32 mmol) the target compound was obtained in 859 mg (67%) yield) after purification on silica gel, eluting with 0 - 100% EtOAc/Hex. 1H NMR (500 MHz, CDCl3) δ (ppm) 9.81 (s, III), 8.85 (d, J = 8.47 Hz, I H), 8.82 (d, J =- 2.48 Hz, I H), 8.64 (d, J= 8.36 Hz, IH), 8.34 (d, J = 7.98 Hz, IH), 7.69 (ddd, J = 8.46, 6.86, 1.41 Hz, I H), 7.65 (d, J = 2.47 Hz, IH), 7.57 (ddd, J= 8.16, 6.85, 1.13 Hz, I H), 6.89 (d, J = 8.44 Hz, III), 4.46 (s, 2H), 3.97 (s, 3H), 3.96 (s, 3H), 3.79 (bs, 4H), 3.07 (bs, 2H), 2.74 (bs. 4H), 1.37 (s, 9H).
[00392] N-(5-tert-ButyI-3-(lH-imidazoI-l-yl)-2-methoxyphenyI)-2-(4-(2- morphoIinoethoxy)naphthaIen-l-yI)-2-oxoacetamidc (R1= t-Bu, R2= lH-imidazoI-l-yl, R3= OMe). Intermediate O (60 mg, 0.25 mmol) was coupled using the acid chloride method to afford 7.4 mg (5% yield) of the target molecule. (Calculated mass: 556.3, observed mass:
557.1). [00393] N-(5-tert-Butj'l-2-methoxy-3-(4-methyl-lH-imidazol-l-yl)phenyl)-2-(4-(2- morphoIinoethoxy)naphthalen-l-yl)-2-oxoacetamide (R1= t-Bu, R2= 4-methyl-lH- imidazol-1-yl, R3= OMe). Using essentially the same acid chloride method starting from 5- tert-butyl-2-methoxy-3-(4-m ethyl- l H-imidazol-l-yl)aniline (9 mg, 0.03 mmol) (prepared as described for Intermediate O), the target compound was obtained (17 mg, 71% yield). (Calculated mass: 570.3, observed mass: 571.1).
[00394] tert-Butyl 5-tert-butyl-2-methoxy-3-(2-(4-(2- morpholinoethoxy)naphthaIen-l-yl)-2-oxoacetamido)phenylcarbamate oxoacetamide (R1= t-Bu, R = NH-Boc, R3= OMc). Using essentially the same method starting from tert- butyl 3-amino-5-tert-butyl-2-methoxyphenylcarbamate (217 mg, 0.74 mmol) (prepared from 5-tert-butyl-2-methoxybenzene-l,3-di amine via standard Boc protection), the target compound was obtained (232 mg, 57% yield). 1H NMR CDCl3O (ppm) 9.52 (s, I H), 8.82 (d, J = 8.5Hz, I H), 8.64 (d, J= 8.0 Hz, I H), 8.27 (bs, I H), 8.21(d, J = 2.5 Hz, I II), 7.95 (bs, I H), 7.70 (td, J - 7.0, 1.5 Hz, I H), 7.59 (td, J=7.0, 1.0 Hz, IH), 7.93 (d, J= 8.5Hz, I H), 6.89 (bs. I H), 4.84 (bs, 2H), 3.96 (bs, 4H), 3.87 (s, 3H), 3.54 (bs, 4H), 3.09 (bs, 2H), 1.56 (s, 9H), 1.36 (s, 9H).
Figure imgf000137_0001
[00395] N-(5-tert-Butyl-3-cyano-2-methoxyphcnyl)-2-oxo-2-(4-(2,2,6,6- tetramethylmorpholino)ethoxy)naphthalen-l-yl)acetaniide (R1= CN,
R= 2,2,6,6-tetramethylmorpholino). The title compound was prepared from Intermediate c and 3-amino-5-tert-butyl-2-methoxybenzonitrile (prepared as in International application No. PCT/US06/042679) using the acid chloride procedure described above (see also WO2005023761). The TFA-salt of the product (28.3 mg, 46%) was obtained as a yellow solid after RP-HPLC (gradient: 35 to 80% AcN in H2O). (Calculated mass: 571.7, observed mass: 572.7).
[00396] 2-(4-(2-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)naphthaIen-l-yl)-iV-
(5-?ert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxoacetamide (R1= NHSO2Me, R- 8-oxa-3-azabicyclo[3.2.1]octanyl). The target compound was prepared using the acid chloride method above from Intermediate d and N-(3-amino-5-re/-/-butyl-2- methoxyphenyl)methanesulfonamide (prepared as in WO2005023761). The TFA-salt of the product (6.0 mg, 14%) was obtained as a yellow solid after RP-HPLC (gradient: 10 to 70% AcN in H2O). (Calculated mass: 609.7. observed mass: 610.7).
[00397] 2-(4-(2-(8-Oxa-3-azabicycloI3.2.1]octan-3-yl)ethoxy)naphthalen-l-yl)-Λ-
(5-tørf-butyl-3-cyano-2-methoxyphenyl)-2-oxoacetamide (R1= CN, R= 8-oxa-3- azabicyclo [3.2.1 Joctanyl). The target compound was prepared as above from Intermediate d and 3-amino-5-tert-butyl-2-methoxybenzonitrile (prepared as in International Application No. PCT/US06/042679). The TFA-salt of the product (15.1 mg, 38%) was obtained as a yellow solid after RP-HPLC (gradient: 10 to 65% AcN in H2O). (Calculated mass: 541.7, observed mass: 542.5).
Example 2: Formation of target compounds via crosscoupling reaction with bromonaphthalenyl compounds.
Figure imgf000138_0001
[00398] Step 1. 2-(4-Bromonaphthalen-l-yl)-Λ-(3-terf-butyl-5-cyanophenyl)-2- oxoacetamide (R1= t-Bu, R2= CN, R3= H). The intermediate product was prepared from 2-(4-bromonaphthalen-l -yl)-2-oxoacetyl chloride (41 mg, 0.14 mmol, prepared as in WO2006091862) and Intermediate A (24 mg, 0.14 mmol) via an acid chloride coupling reaction similar to described above, using TEA as a base. The residue was purified by chromatography over silica gel (gradient: 0-100% EtOAc/Hex) to give the final product (4.8 mg, 7.9%) as a pale yellow solid. 1H-NMR (500 MHz, CDCl3) δ (ppm) 9.22 (br s, IH). 8.58 (m, I H), 8.43 (m, IH), 8.25 (d, J = 7.91 Hz, I H), 8.07 (m, I H), 7.96 (d, J = 7.89 Hz, IH), 7.90 (t, J = 1.91 Hz, I H), 7.73 (m, 2H), 7.55 (X, J= 1.55 Hz, IH), 1.39 (s, 9H).
[00399] 2-(4-Bromonaphthalen-l-yl)-N-(3-fluoro-5-morpholinophenyl)-2- oxoacetamide (R1= morpholino, R2= F, R3= H). Prepared using the acid chloride procedure described above using 3-fluoro-5-morpholinoaniline (prepared as in WO20030909). [00400] 2-(4-Bromonaphthalen-l-yl)-Λ45-tert-buryl-3-cyano-2-methoxyphenyl)-2- oxoacetamide (R1= t-Bu, R2= CN, R3= OMe). The acid chloride procedure described above was used with 3-amino-5-tert-butyl-2-methoxybenzonitrile (prepared as in International Application No. PCT/US06/042679) to afford the title compound (72,5 mg, 1 1 %) after RP- HPLC (gradient: 25 to 100% AcN in H2O) as a pale yellow solid. 1H-NMR (500 MHz, CDCl3) δ (ppm) 9.73 (br s, IH), 8.85 (d, J= 2.38 Hz, IH), 8.58-8.56 (m, IH), 8.41 -8.39 (m. I H), 8.22 (d, J = 7.91 Hz, IH), 7.93 (d, J = 7.88 Hz, IH), 7.72-7.70 (m, 2H), 7.38 (d, ./ = 2.37 Hz, I H), 4.24 (s, 3H), 1.35 (s, 9H).
[00401 ] Step 2. N-(5-tert-Butyl-5-cyanophenyl)-2-oxo-2-(4-(2-(pyrrolidin-l- yl)pyrimidin-4-ylamino)naphthalen-l-yl)acetamide (R1= t-Bu, R2= CN, R3= H, NR2= pyrrolidinyl). The title compound was prepared from 2-(4-bromonaphthalen-l-yl)-N- (3-/erf-butyl-5-cyanophcnyl)-2-oxoacetamide (73 mg, 0.17 mmol) (as obtained in step 1 above) and 2-(pyrrolidin-l -yl)p>τimidin-4-amino (30 mg, 0.19 mmol, prepared as in WO200609186), using the procedure described in W 02006091862. Briefly, the compound obtained above was dissolved in toluene/dioxane 1/1 and BINAP (0.2 eq.), Cs2CO3 (2 eq.) and Pd(II)OAc2 (0.1 eq.) were added. The reaction was heated to 8O0C overnight. The residue was purified by RP-HPLC (gradient: 5 to 90% AcN in H2O) to yield the TFA-salt of the final product (43 mg, 40%) as a yellow solid. (Calculated mass: 518.6, observed mass: 519.5).
[00402J N-(3-Fluoro-5-rnorpholinophenyl)-2-oxo-2-(4-(2-(pyrrolidin-l- yl)pyrimidin-4-ylamino)naphthalen-l-yl)acetamide (R1= morpholinyl, R2= F, R3= H, NR2= pyrrolidinyl). The title compound was prepared using the palladium-mediated coupling described above using 2-(4-bromonaphthalen- l -yl)-N-(3-fluoro-5- morpholinophenyl)-2-oxoacetamide. (Calculated mass: 540.6, observed mass: 541.6).
[00403] N-(5-tert-Butyl-2-methoxyphenyl)-2-oxo-2-(4-(2-(pyrrolidin-l- yl)pyrimidin-4-ylamino)naphthalen-l-yi)acetamide (R1= t-Bu, R2= H, R3= OMe, NR2= pyrrolidinyl). The target compound was similarly prepared using 2-(4- bromonaphthalen- 1 -yl)-N-(5-tert-butyl-2-methoxyphenyl)-2-oxoacetamide and 2-(pyrrolidin- 1 -yl)pyrimidin-4-amine (prepared as in WO2006091862). (Calculated mass: 523.6, observed mass: 524.6). [00404J N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(2-
(2,2,6,6-tetramethylmorpholino)pyrimidin-4-ylamino)naphthalen-1-yl)acetamide (R1= t-Bu, R2= NHSO2Me, R3= OMe, NR2= 2,2,6,6-tetraniethylmorpholino). The target compound was prepared via the palladium-mediated coupling above using 2 -(4- bromonaphthalen-l-yl)-N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2- oxoacetamide (23,3 mg, 44 μmol, see WO2006091862) and Intermediate I-A (1 1.3 mg, 48 44 μmol). 1 he TFA-salt of the title compound (2.4 mg, 7%) was obtained after RP-HPLC (gradient: 10 to 95% AcN in HoO) as a yellow solid. (Calculated mass: 688.8, observed mass: 689.1 ).
[00405] N-(5-tert-Butyl-3-cyano-2-methoxyphenyl)-2-oxo-2-(4-(2-(2,2,6,6- tetramethylniorpholino)pyrimidin-4-ylamino)naphthalen-l-yl)acetamide (R1= t-Bu, R =
CN, R3= OMe, NR2= 2,2,6, 6-tetramethylmorpholino). The compound was prepared similarly using 2-(4-bromonaphthalen-l-yl)-N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2- oxoacetamide and Intermediate I-A. The TFA-salt of the title compound (10.1 mg, 24%) was obtained after RP-HPLC (gradient: 10 to 95% AcN in H2O) as a yellow solid. (Calculated mass: 620.7, observed mass: 621.1).
[00406] 2-(4-(2-(8-Oxa-3-azabicyclo|3.2.1]octan-3-yl)pyrimidin-4- ylamino)naphthalcn-l-yl)-iY-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-oxoacetamide (R1= t-Bu, R2= CN, R3= OMe, NR2= 8-oxa-3-azabicyclo [3.2.1 ]octan-3-yl). The title compound was similarly prepared from Intermediate H-A. The TFA-salt of the title compound (16.4 mg, 37%) was obtained after RP-HPLC (gradient: 10 to 100% AcN in H2O) as a yellow solid. (Calculated mass: 590.7, observed mass: 591.1).
[00407] N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(2-(4- methylpiperazin-l-yl)pyrimidin-4-ylamino)naphthalen-l-yl)-2-oxoacetamide (R = t-Bu,
R2= NHSO2Me, R3= OMe, NR2= 4-methylpiperazinyl). Prepared using the palladium- mediated coupling described above from 2-(4-bromonaphthalen-l -yl)-N-(5-tert-butyl-2- mcthoxy-3-(mcthylsulfonamido)phenyl)-2-oxoacetamide (26 mg, 49 μmol, see WO2006091862 A2) and Intermediate IH-A (49 μmol). The pure compound (8.1 mg, 25%) was obtained after RP-HPLC and silica gel purification. (Calculated mass: 645.3, observed mass: 646.3). [00408] N-(5-tert-ButyI-2-methoxy-3-(methyIsulfonamido)phenyI)-2-oxo-2-(4-(2- piperazin-l-yI)pyrimidin-4-ylamino)naphthalen-1-yI)acetamide (R1= t-Bu, R2= NHSO2Me, R3= OMe, NR2= piperazinyl). The compound was prepared similarly using Intermediate IV-A and subsequent deprotection by treatment with 95% TFA/H2O (3 ml). (Calculated mass: 631 ,3, observed mass: 632.1 ).
[00409] N-(5-tert-ButyI-2-methoxy-3-(methylsulfonamido)phenyl)-2~(4-(2-(3,5- dimethylpiperazin-l-yl)pyrimidin-4-ylamino)naphthalen-l-yl)-2-oxoacetamide (R1= t-Bu, R2= NHSO2Me, R3= OMe, NR2= 3,5-dimethyIpiperazinyI). The compound was prepared as above using Intermediate V-A. (Calculated mass: 659.3, observed mass: 660.1).
Figure imgf000141_0001
[00410] N-(5-tert-butyI-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(4-
(piperazin-l-yl)pyrimidin-2-ylamino)naphthalen-l-yl)acetamide (NR2= piperazinyl).
The target compound was prepared using 2-(4-bromonaphthalen-l-yl)-N-(5-tert-butyl-2- mcthoxy-3-(methylsulfonamido)phenyl)-2-oxoacetamide (prepared as in WO2006091862) and Intermediate IV-B using a similar procedure to that described in WO2006091862. followed by Boc-deprotection as above. (Calculated mass: 631.3, observed mass: 632.1 ).
[00411] N-(5-tert-buty]-2-mcthoxy-3-(methyIsulfonamido)pheny])-2-(4-(4-(3,5- dimethyIpiperazin-l-yI)pyrimidin-2-yIamino)naphthalen-l-yI)-2-oxoacetamide (NR2- 3,5-dimethylpiperazinyI). The target compound was prepared using the palladium mediated coupling described above using Intermediate V-B. (Calculated mass: 659.3, observed mass: 660.1).
Figure imgf000141_0002
[00412] N-(5-tert-Butyl-3-cyano-2-methoxyphenyl)-2-(4(2-(3,3- dimethylbutylamino)pyridine-4-ylamino)naphthalene-l-yl)-2-oxoacetamide (R=
NH(CH2)2-t-Bu). The target compound was prepared from Intermediate Vl (0.1 mmol) and 2-(4-bromonaphthalen-l-yl)-Λr-(5-tcrt-butyl-3-cyano-2-methoxyphenyl)-2-oxoacetamide (32 mg, 0.07 mmol), using a palladium-mediated coupling procedure similar to above (see also WO2006091862). The TFA-salt of the title compound (25.5 mg. 53%) was obtained after preparative LC-MS (gradient: 40 to 100% AcN in H2O) as an orange-red solid. (Calculated mass: 577.7, observed mass: 578.2).
L00413J N-(5-tert-Butyl-3-cyano-2-methoxyphenyl)-2-(4-(2-(2-(2,6- dimethylpiperidin-l-yl)ethylamino)pyridine-4-ylamino)naphthalene-l-yl)-2- oxoacetamide (R= 2-(2,6-dimethylpiperidin-l-yl)ethylamino) was prepared using a similar palladium-mediated-coupling procedure as above, using Intermediate IX. (Calculated mass: 632.8. observed mass: 633.2).
[00414] N-(5-tert-Butyl-3-cyano-2-methoxyphenyl)-2-oxo-2(4-pyridin-4- ylamino)naphthalene-l-yl)acetamide (R=H) was prepared using a similar procedure as above, using pyridin-4-amine. (Calculated mass: 478.5, observed mass: 479.1 ).
Figure imgf000142_0001
[00415] N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-(4-(6-(methylamino)pyridin-
3-yl)naphthalen-l-yl)-2-oxoacetamide. 2-(4-Bromonaphthalen-l -yl)-Λr-(5-tert-butyl-3- cyano-2-methoxyphenyl)-2-oxoacetamide (28 mg, 0.06 mmol), prepared using a procedure similar to above (see also WO2006091862), and Intermediate VIII (26 mg, 0.06 mmol) were dissolved in toluene (0.5 ml) and dioxane (1 ml). The reaction mixture was placed under a nitrogen atmosphere and Pd2(dba)3.CHCl3 (9.3 mg, 15 mol%) was added. The reaction was stirred at 300C for 3 hr. After removal of the solvents, the residue was dissolved in DCM and purified by silica gel chromatography (gradient: 0 to 100% 50% EtOAc/Hcx). The target compound was obtained as an orange-red solid. (Calculated mass: 492.6, observed mass: 493.0).
Figure imgf000143_0001
[00416] N-(3-tert-ButyI-5-((4-methylpiperazin-l-yl)methyl)phenyl)-2-oxo-2-(4-
(pyridin-3~yl)naphthalen-l-yl)acetamide. 2-(4-Bromonaphthalen-l-yl)-N-(3-tert-butyl-5- ((4-methylpiperazin-l-yl)mcthyl)phenyl)-2-oxoacetamide (52 mg, 0.1 mmol) (prepared using a procedure similar to above) and pyridin-3-ylboronic acid (24 mg, 0.2 mmol) were dissolved in DME (1.3 ml) and (PPh3)2PdCl2 (7 mg, 10 mo.%), Pd2(dba)3CHCl3 (10 mg, 10 mol%) and Cs2CO3 (97 mg, 0.3 mmol) were added. The reaction was placed under N2 atmosphere and was heated to 1000C for 3 hr. The mixture was filtered through a silica gel column, which was washed with DMF. The resulting solution was purified via preparative LC-MS (gradient: 10-60% AcN/H2O over 8.5 min), yielding the target product in 17.1 mg yield. (Calculated mass: 520.7, observed mass: 521.1).
Figure imgf000143_0002
[00417] Step 1. 2-(4-Bromonaphthalen-1-yl)-N-(3-tert-butyl-l-p-tolyI-lH-pyrazol-
5-yl)-2-oxoacetamide (R= p-Me). The target compound was prepared from 2-(4- bromonaphthalen-l-yl)-2-oxoacetyl chloride (1 12 mg, 0.38 mmol, prepared as in WO2006091862) and 3-tert-butyl-l -p-tolyl-lH-pyrazol-5-amine (87 mg, 0.38 mmol, prepared as in WO2005023761 ) using the acid chloride procedure described above (see also WO2006091862). The residue was chromatographcd over silica gel (gradient: 0 to 50% EtOAc'Hex) to give the final product (72 mg, 39%). 1H-NMR (500 MIIz, CDCl3) δ (ppm) 9.45 (br s, I H), 8.55 (m, IH), 8.38 (m, I H), 8.26 (d, J= 7.95 Hz, IH), 7.90 (d, J- 7.94 Hz, I H), 7,68 (m, 2H), 7.44 (d, J = 8.39 Hz, 2H), 7.38 (d, J= 7.09 Hz, 2H), 6.85 (s, IH), 2.45 (s, 3H), 1.41 (s, 9H). [00418] 2-(4-Bromonaphthalen-l-yl)-N-(3-tert-butyI-l-m-tolyI-lH-pyrazol-5-yl)-2- oxoacetamide (R= m-Me) was similarly prepared using 3-tert-butyl-l-m-tolyl-l H-pyrazol-5- amine (87 mg, 0.38 mmol, prepared as in WO2005023761 ).
[00419] Step 2. N-(3-tert-Butyl-l-p-tolyl-lH-pyrazoI-5-yl)-2-oxo=2-(4-(2-
(pyrrolidin-l-yl)pyrimidin-4-ylamino)naphthaIen-l-yl)acetamide (R= p-Me). The title compound was prepared from 2-(4-bromonaphthalen-l -yl)-N-(3-tert-butyl- l-p-tolyl-l H- pyrazol-5-yl)-2-oxoacetamide (72 mg, 0.15 mmol) and 2-(pyrrolidin-l -yl)pyτimidin-4-amino (25 mg, 0.15 mmol, prepared as in WO2006091862), using a palladium-mediated coupling procedure similar to the one described above and in WO2006091862. The residue was purified over silica gel (gradient: 0 to 100% EtOAc/Hex, then 10% MeOH/Hex) to yield the final product (8.2 mg, 9.5%) as an orange solid. (Calculated mass: 573.7, observed mass: 574.7).
[00420] N-(3-tert-Butyl-l-m-toIyl-lH-pyrazol-5-yl)-2-oxo=2-(4-(2-(pyrrolidin-l- yI)pyrimidin-4-ylamino)naphthalen-l-yI)acetamide (R= m-Me). The compound was prepared similarly, starting from 2-(4-bromonaphthalen-l-yl)-N-(3-tert-butyl-l-m-tolyl-lH- pyrazol-5-yl)-2-oxoacetamide (36 mg, 0.073 mmol). The residue was purified over silica gel (gradient: 0 to 100% Et O Ac/Hex, then 10% MeOH/Hex) followed by RP-HPLC (gradient: 35 to 70% AcN in H2O) to yield the TFA-salt of the final product (4.0 mg. 8.0%) as a yellow solid. (Calculated mass: 573.7, observed mass: 574.6).
Example 3: Formation of N-(naphthalen-l-yI)-2-oxo-2-(lH-pyrazol-5-yI)acetamide compounds.
Figure imgf000144_0001
[00421] 2-(3-tert-Butyl-l-methyl-lH-pyrazol-5-yI)-2-oxo-N-(4-(2-(2,2,6,6- tetramethylrnorpholino)ethoxy)naphthalen-l-yl)acetamide (R= 2,2,6,6- tetramethylmorpholino). To a solution of the TFA-salt of Intermediate f (8.8 mg, 0.02 mmol) in DCM (2 ml), was added 2-(3-tert-butyl-l-methyl-lH-pyrazol-5-yl)-2-oxoacetic acid (X - OH) (4.6 mg, 0.022 mmol, prepared as in WO2005023761 or US20050107399), BOP (excess) and DIEA (excess). The mixture was stirred at r.t. overnight, evaporated and the residue was subjected to RP-HPLC (gradient: 20 to 80% AcN in H2O) to give the TFA- salt of the final product (2.8 mg, 22%) as a yellow solid. (Calculated mass: 520.7. observed mass: 521.3).
[00422] N-(4-(2-(8-Oxa-3-azabicycloI3.2.1]octan-3-yl)ethoxy)naphthalen-l-yl)-2-
(3-tert-butyl-l-methyl-lH-pyrazol-5-yl)-2-oxoacetamide (R= 8-Oxa-3- azabicyclo|3.2.1|octan-3-yl). Using the same procedure as above, starting with the TFA- salt of Intermediate g (20.6 mg, 0.05 mmol) gave the TFA-salt of the final product (3.0 mg, 9.9%) as a yellow solid after repeated RP-HPLC (gradient: 20 to 80%, followed by 10 to 60% AcN in H2O). (Calculated mass: 490.6, observed mass: 491.2).
Example 4: Additional derivatization reactions.
Figure imgf000145_0001
[00423] N-(5-tcrt-Butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-
(hydroxyimino)-2-(4-(2-(pyrrolidin-l-yl)pyrimidin-4-ylamino)naphthalen-l- yl)acetamide. The title compound was prepared from N-(5-tert-butyl-2-methoxy-3- (methylsulfonamido)phenyl)-2-oxo-2-(4-(2-(pyrrolidin-l -yl)pyrimidin-4- ylamino)naphthalen-l-yl)acetamide (prepared as in WO2006091862) using the procedure described in WO2005023761, namely the starting material was treated with hydroxylamine hydrochloride in EtOH containing catalytic pyridine. (Calculated mass: 631.7, observed mass: 632.6).
Figure imgf000145_0002
[00424] N-(4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)naphthalen-l-yl)-2-(5- tert-butyl-2-methylfuran-3-yl)-2-(hydroxyimino)acetamide. The title compound was prepared from N-(4-(2-(8-oxa-3-azabicyclo[3.2.1 ]octan-3-yl)ethoxy)naphthalen-l-yl)-2-(5- tert-butyl-2-methylfuran-3-yl)-2-oxoacetamide (itself prepared from 2-(5-tert-butyl-2- methylfuran-3-yl)-2-oxoacetic acid, synthesized as described in WO2006091862, and intermediate g via BOP coupling as described above) using the procedure described in WO2005023761 : namely the starting material was treated with hydroxylamine hydrochloride in EtOH containing catalytic pyridine. The two oxime isomers were separated by RP-HPLC, affording 10.6 mg of the E-isomer and 5.0 mg of the Z-isomer. E-isomer: 1H-NMR (500 MHz, MeOD) δ (ppm) 8.34 - 8.32 (m, I H), 8.24 - 8.22 (m, 111), 7.60 - 7.58 (m, 2 H), 7.55 (d, J = 8.16 Hz, 1 H), 7.01 (d, J - 8.23 Hz, IH), 6.24 (s, IH), 4.62 - 4.61 (m, 2H), 4.56 (m, 2H), 3.78 - 3.77 (m, 2H), 3.58 - 3.55 (m, 2H), 3.50 - 3.47 (m, 2H), 2.45 (s, 3H), 2.17 - 2.08 (m, 4H), 1.30 (s, 9H); Z-isomer: 1H-NMR (500 MHz, MeOD) δ (ppm) 8.34 (d, J = 8.0 Hz, IH), 7.98 (d, J = 8.21 Hz, I H), 7.63 - 7.58 (m, 3H), 7.01 (d, J = 8.17 Hz, IH), 6.26 (s, IH), 4.62- 4.60 (m, 211), 4.57 - 4.56 (m, 2H), 3.78 - 3.77 (m, 2H), 3.57 - 3.55 (m, 2H), 3.50 - 3.47 (m, 2H). 2.30 (s, I H), 2.19 - 2.07 (m, 4H), 1.29 (s, 9H).
Figure imgf000146_0001
[00425] N-(5-tert-Butyl-2-methoxy-3-(methyIsulfonamido)phenyl)-2-hydroxy-2H^-
(2-(pyrrolidin-l-yl)pyrimidin-4-yIamino)naphthalen-l-yl)acetamide. To a solution of N- (5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(2-(pyrrolidin-l- yl)pyrimidin-4-ylamino)naphthalen-l -yl)acetamide (prepared as in WO2006091862) in DCM/MeOH, NaBH3 (excess) was added and the mixture was stirred at r.t. overnight, to afford 18 mg of product. (Calculated mass: 618.7, observed mass: 619.5).
Figure imgf000146_0002
[00426] 4-(2-(4-(2-(5-te>t-ButyI-2-methoxy-3-(methylsulfonamido)phenyIamino)-
2-oxoacetyl)naphthalen-l-yloxy)ethyl)morpholine 4-oxide. To a solution of Λλ-(5-tert- butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(2-moφholinoethoxy)naphthalen-l -yl)- 2-oxoacctamide (100 mg, 0.17 mmol) (obtained as described in WO2005/023761) in MeOH'ΑcN (3 ml, 2: 1 ), H2U2 (1 ml, 30% aq. solution) was added and the mixture was stirred at r.t. for several days. The solvent was evaporated and the residue was subjected to RP- HPLC (gradient of 10-90% AeN in H2O) to give the product as a brown film (14,0 mg, 14%), (Calculated mass: 599.7, observed mass: 599.9).
Figure imgf000147_0001
[00427] 5-tert-Butyl-2-methoxy-3-(2-(4-(2-morphoIinocthoxy)naphthaIen-l-yl)-2- oxoacetamido)-N-(2-(pyrrolidin-l-yl)ethyl)benzamide. In a 50 ml round-bottomed flask were placed MeOH (3 ml), THF (2 ml), methyl 5-tert-butyl-2-methoxy-3-(2-(4-(2- moφholinocthoxy)naphthalen-l-yl)-2-oxoacetamido)benzoate (795 mg, 1.45 mmol) (prepared as described above) and NaOH (182 mg, 4.55 mmol). The reaction was heated overnight, then evaporated. The residue was suspended in THF (10 ml), treated with 2N HCl (2.27 ml, 4.55 mmol) and evaporated. The residue was lyophilized from dioxane. The compound obtained (50 mg, 0.094 mmol) was suspended in DCM (3 ml), treated with DMF (1 drop) followed by oxalyl chloride (1 10 μl, 0.54 mmol). After 0.5 hr the solvent was evaporated and the residue was stripped from THF. To half of this residue was added 2-(pyrrolidin-l -yl)ethanaminc (24 μl, 0.19 mmol). The reaction mixture was loaded onto silica gel, eluting with 0 - 10% MeOH/DCM to afford 2.2 mg of the target compound. Calculated mass: 630.3, observed mass: 631.1.
Figure imgf000147_0002
[00428J N-(5-tert-Butyl-2-methoxy-3-(lH-tetrazol-5-yl)phenyl)-2-(4-(2- morpholinoethoxy)naphthalen-l~yl)-2-oxoacetamide. To a solution of N-(5-tert-butyl-3- cyano-2-methoxyphenyl)-2-(4-(2-morpholinoethoxy)naphthalen-l-yl)-2-oxoacetamide (51 mg, 91 μmol) in DMF (0.5 ml), triethylamme hydrochloride (25 mg, 180 μmol) and sodium azide (14 mg, 215 μmol) were added. The mixture was stirred at 8O0C overnight, after which the mixture was purified via preparative LC-MS to afford the target compound (35.2 mg, 57% ) as the TFA-salt. (Calculated 558.2, observed 559.4).
Figure imgf000148_0001
[00429] N-(3-amino-5-tert-butyl-2-methoxyphenyI)-2-(4-(2- morpholinoethoxy)naphthaIen-l-yl)-2-oxoacetamide. tert-Butyl 5-tert-butyl-2-methoxy-3- (2-(4-(2-morpholinoethoxy)naphthalen- 1 -yl)-2-oxoacetamido)phenylcarbamate (232 mg, 0.38 mmol) was dissolved in DCM (5 ml) and treated with TFA (5 ml). After 5 min the solvent was evaporated and the residue (245 mg, 100% yield) was used as the TFA salt without further purification.
Figure imgf000148_0002
[00430] N-(3-Azido-5-tert-butyl-2-methoxyphenyl)-2-(4-(2- morpholinocthoxy)naphthalen-l-yl)-2-oxoacetaniide. In a 250 ml round-bottomed flask containing the compound obtained above (245 mg, 0.38 mmol), dissolved in 10% H2SO4 (10 ml) in an ice bath, was added sodium nitrite (35 mg, 0.51 mmol). After 10 min stirring, sodium nitrite (50 mg, 0.76 mmol) was added and the reaction was allowed to warm to r.t. The reaction was quenched with solid Na2CO3 and extracted with DCM and dried over Na2SO4. The solvent was removed to afford 188 mg (103% yield) of the target compound. (Calculated mass: 531.2, observed mass: 532.1).
Figure imgf000148_0003
[00431] N-(5-tert-Butyl-2-methoxy-3-(lH-l,2,3-triazol-l-yI)phenyl)-2-(4-(2- morpholinoethoxy)naphthaIen-l-yl)-2-oxoacetamide. To the compound obtained above (24 mg. 0.038 mmol) in AcN (4 ml) and water (400 μl) was added TMS-acetylene (700 μl) and copper wire. After heating at 5U0C for seven days, the solvent was evaporated and the reaction was treated with 2M HCl in dioxane (4 ml) and THF (2 ml) for 2 days. The solvents were evaporated and the residue was purified on preparative HPLC to afford N-(5-tcrt-butyl- 2-methoxy-3-(l H-l ,2,3-triazol-l -yl)phenyl)-2-(4-(2-moφholinoethoxy)naphthalen-l -yl)-2- oxoacetamide (7.8 mg, 31%yield) (Calculated mass: 557.3, observed mass: 558.1), and N-(5- tert-butyl-2-methoxy-3-(4-(trimethylsilyl)-l H-1.2,3-triazol-l-yl)phenyl)-2-(4-(2- morpholinoethoxy)naphthalen-l -yl)-2-oxoacetamide (8.7 mg, 31 % yield) (Calculated mass: 629.3, observed mass: 630.1).
Figure imgf000149_0001
[00432J N-(5-tert-Butyl-3-(4-(hydroxymethyl)-lH-l,2,3-triazol-l-yl)-2- methoxyphenyI)-2-(4-(2-morpholinocthoxy)naphthalen-l-yl)-2-oxoacetamide. The target compound was prepared using an analogous procedure ( 1 1 mg, 41 % yield) starting from propargyl alcohol (26 mg, 0.45 mmol) and the compound obtained above (24 mg, 0.038 mmol), heating at 1000C overnight. (Calculated mass: 587.3, observed mass: 588.1).
Biological Testing. Example 5: Inhibition of TNFa production in THP cells
[00433 J The inhibition of cytokine production can be observed by measuring inhibition of TNFa in lipopolysaccharide-stimulated THP-I cells (see Prichett et al. J. Inflammation, 1995, 45, 97). THP-I cells (ATCC TIB 202, American Type Culture Collection, Rockville, MD) were maintained at 37°C, 5% CO2 in RPMI 1640 media with 10% fetal bovine serum, 10 mM Hepes, 1 mM sodium pyruvate, 4.5 g/1 glucose and 0.05 mM 2-mercaptoethanol as suggested by ATCC. For the assay, the cells and compounds were diluted in the media above except with 1% fetal bovine serum (assay media). Test compound stocks in DMSO were diluted into assay media to 6x the final assay concentration, with a final DMSO concentration of less than 0.3% in the assay. THP-I cells were plated at lxl O7well in 96 well tissue culture plates. Diluted compounds (or DMSO control) were added and allowed to preincubate with the cells at 37°C, 5% CO2 for 30 minutes prior to the addition of LPS (Sigma) to a final concentration of 1 μg/ml. Cells were then incubated 1 8-20 hours at 37°C/5% CO2. The assay was terminated by centrifuging the plates for 10 min at r.t. Supernatants were removed to clean culture plates and aliquots were removed for analysis for TNFa by a commercially available ELlSA kit (R&D Systems #DY210, Minneapolis. MN). Data was analyzed by nonlinear regression using PRISM 4 software from Graphpad Software (San Diego, CA). The calculated IC50 is the concentration of the test compound that caused a 50% decrease in the maximal TNFa production.
[00434] Each of the compounds in List 1 was tested in the TNFa ELISA assay and was found to have activity therein, with most compounds having IC50S below 10 μM in this assay.
Example 6: Inflammation models
[00435] Methods for the testing of systemic lupus erythematosus (SLE) in susceptible mice are known in the art (Knight et al., J. Exp. Med., 1978, 147, 1653; Reinersten et al.. New Eng. J. Med., 1978, 299, 515). Myasthenia Gravis (MG) is tested in SJL/J female mice by inducing the disease with soluble AchR protein from another species (Lindstrυm et al., Adv. Immunol., 1988, 42, 233). Arthritis is induced in a susceptible strain of mice by injection of Type II collagen (Stuart et al., Ann. Rev. Immunol., 1984, 42, 233). A model by which adjuvant arthritis is induced in susceptible rats by injection of mycobacterial heat shock protein has been described (Van Eden et al., Nature, 1988, 331, 171 ). Thyroiditis is induced in mice by administration of thyro globulin as described (Maron et al., J. Fxp. Med., 1980, 152, 1115). Insulin dependent diabetes mellitus (IDDM) occurs naturally or can be induced in certain strains of mice such as those described by Kanasawa et al., Diabetologia, 1984, 27, 1 13. Experimental autoimmune encephalomyelitis (EAE) in mouse and rat serves as a model for MS in human. In this model, the demyelinating disease is induced by administration of myelin basic protein (see Paterson, Textbook of lmmuopathology, Mischer et al., eds., Grune and Stratton, New York, 1986, pp. 179-213; McFarlin et al., Science, 1973, 179, 478: and Satoh et al., J. Immunol., 1987, 138, 179). Examples are described in more detail below.
[00436] Collagen Induced Arthritis model in mice. Immunization of for example,
DBA/1 mice with murine type II collagen induces a chronic relapsing polyarthritis that provides a strong model for human autoimmune arthritis. The model is described, for example, by Courtenay et al., Nature, 1980, 282, 666; Kato ct al., Ann. Rheum. Dis., 1996, 55, 535; and Myers et al., Life Sci., 1997, 61, 1861-1878, each of which is incorporated herein by reference. Briefly, mice are quarantined for at least three days. On day 0, the mice are weighed and separated into treatment groups. The non-diseased control group animals receive no adjuvant (10 mice), in contrast to diseased mice (20 mice/treatment group). The mice are anesthetized, shaved at the base of tail, and injected (id) with adjuvant (50 μl/mouse; 100 μg/mouse collagen; lOOμg/mouse M. tuberculosis H37Ra), using a 1 ml syringe fitted with a 26 G needle. On day 21 , the adjuvant is prepared by emulsifying (in an homogenizer) a 1 : 1 combination of collagen and M. tuberculosis H37Ra. The adjuvant is injected (id) (50 μl/mouse; 100 μg/mouse collagen; 100μg/mouse M. tuberculosis H37Ra) using 1 ml syringe fitted with a 26 G needle. On days 22-27 the macroscopic signs of arthritis are scored daily. Each paw receives a score: 0 = no visible effects of arthritis; 1 = edema and/or erythema of one digit; 2 = edema and/or erythema of two joints; 3 = edema and/or erythema of more than two joints; or 4 = severe arthritis of the entire paw and digits. The Arthritic Index is calculated by addition of all the individual pawr scores, and recorded (maximum arthritic index = 16). On day 28 the mouse weights arc recorded and the macroscopic signs of arthritis are scored. The mice are sorted into treatment groups ( 10 mice/group) based upon their arthritic index, Each treatment group is designed to have a similar average Arthritic Index and a similar range of arthritic indices. The dosing regimen by oral route is initiated. On day 29-42 the mice are dosed and any adverse effects of test agent administration are recorded. The macroscopic signs of arthritis for each paw are scored daily. On day 43 the macroscopic signs of arthritis are scored, the mice are exsanguinated and their blood is collected in heparinized tubes. The hindlimbs and/or forelimbs are removed and immersed in four volumes of 10% buffered formalin. The paws are evaluated for decalcification and histology. Livers are removed and their weights are recorded.
[00437] Collagen Induced Arthritis model in rats. Female Lewis rats, (Charles
River ref #7218419), weighing 125-150 g on arrival (8/group for arthritis, 4/group for normal control), are housed 4/cage, and are acclimated for 4-8 days after arrival. Acclimated animals are anesthetized with Isoflurane and given collagen injections (DO). On day 6 they are anesthetized again for the second collagen injection, Collagen is prepared by making a 4 mg/ml solution in 0.01 N acetic acid. Equal volumes of collagen and Freund's incomplete adjuvant are emulsified by hand mixing until a bead of this material holds its form when placed in water. Each animal receives 300 μl of the mixture each time spread over 3 subcutaneous sites on its back. Caliper measurements of normal (pre-disease) right and left ankle joints arc collected on day 9 On da>s 10-1 1, the onset of arthritis occurs and the rats are i andomi/ed into treatment groups Animals to be gi\en vehicle or compound doses are enrolled and qd (24 hr interv als) dosing is initiated tor days 1-6 using a volume of 5 ml kg for oral solutions The rats are weighed on days 1-7 of arthritis, caliper measurements or ankles are taken ev erv dav The final body w eights are collected on day 7 of arthritis On dav 7, the animals are anesthetized for whole blood draw to exsanguinate (serum can be used for clinical chemistry) and then euthanized Both hind paws and knees are removed, the hind paws are weighed and then (with knees) placed in formalin and piocessed for microscopy Following 1-2 days in fixative and 4-5 days in decalcifier, the ankle joints are cut in half longitudinally, the knees are cut in hall in the frontal plane, processed, embedded, sectioned and stained with toluidine blue The arthritic ankles and knees are given scores of 0 (normal) -5 (severe effects) for inflammation, pannus formation and bone i esorption Percent inhibition of paw weight and AUC is calculated using the following formula
% Inhibition A - B/A x 100
with A = (Mean Disease Control - Mean Normal) and B = (Mean Tieated - Mean Normal)
[00438] Inflammatory Bowel and Crohn's Disease Models. To evaluate the effectiveness of test compounds in Crohn's disease, the TNFΔ MU transgenic mouse model of C1ohn's disease (oπginally descπbed by Kontoyiannis et al , Immunity, 1999, 10, 3 S"7) is used (the DSS (dextran sodium sulfate) model can also be used m a similar fashion) The animals develop an IBD phenotype with similarity to Crohn's disease starting between 4 and 8 weeks of age I cst compounds are administered at either 3 weeks of age (to test prevention of disease) or 6 weeks of age (to test stabilization, prevention of progression or reversal of disease symptoms), and animals are scored by weight and histologically as described herein Test compositions are administered eithei weekly or twice w eekly, or can be administered continuously, for example, using an osmotic pump Alternatively oral delivery formulations can also be applied The studies are continued for up to 7 weeks or more once initiated Animals can be monitored for bowel disease according to a standard scale as described in Kontoyiannis et al , 2002, supra Paiaffin-embedded intestinal tissue sections of ileum are histologically ev aluated in a blinded fashion according to the following scale Acute and chronic inflammation are assessed separately in a minimum ot 8 high power fields (hpf) as follows --acute inflammatory score: O=(O-I ) polymorphonuclear (PMN) cells per hpf (PMN/hpf); 1-(2-1O) PMN/hpf within mucosa; 2=(l l-20) P MN/hpf within mucosa; 3=(21- 30) PMN/hpf within mucosa or (1 1 -20) PMN/hpf with extension below muscularis mucosae; and 4=>30 PMN/hpf within mucosa or >20 PMN/hpf with extension below muscularis mucosae. Chronic inflammatory score: O=(O-I O) mononuclear leukocytes (ML) per hpf (ML/hpf) within mucosa; I=(1 1-20) ML/hpf within mucosa; 2-(21-3O) ML/hpf within mucosa or (1 1-20) ML/hpf with extension below muscularis mucosae; 3=(31-40) ML/hpf within mucosa or (21-30) ML/hpf with extension below muscularis mucosae or follicular hyperplasia; and Ψ=>40 ML/hpf within mucosa or >30 ML/hpf with extension below muscularis mucosae or follicular hyperplasia. Total disease score per mouse is calculated by summation of the acute inflammatory or chronic inflammatory scores for each mouse.
[00439] Efficacy in the TNF A : model of Crohn's disease is shown by any of: i) a failure to develop disease symptoms when administered to animals beginning at 3 weeks of age; ii) lessened severity of disease symptoms appearing when administered starting at 3 weeks of age, relative to control animals; iii) failure to progress to more severe disease or progression at a lower rate relative to control animals when administered beginning at 6 weeks of age; iv) reversal of symptoms at any of 7, 8, 9, 10, 1 1 , 12, or 14 weeks when administered to an animal beginning at 6 weeks of age. In particular, treatment is considered effective if the average histopathological disease score is lower in treated animals (by a statistically significant amount) than that of a vehicle control group. Treatment is also considered effective if the average histopathological score is lower by at least 0.5 units, at least 1.0 units, at least 1.5 units, at least 2.0 units, at least 2.5 units, at least 3.0 units, or by at least 3.5 units relative to the vehicle-only control group. Alternatively, the treatment is effective if the average histopatholigical score remains at or is lowered to 0 to 0.5 throughout the course of the therapeutic regimen.
[00440] Other models of IBD include, for example, the DSS model of chronic colitis in
BALB/c mice. The DSS model was originally described by Okayasu et al.. Gastroenterology, 1990, 98, 694 and was modified by Kojouharoff et al., Clin Exp. Immunol. 1997, 107, 353 (sec also WO 2004/041 862, incorporated herein by reference). BALB/c mice weighing 21 -22 g are treated to induce chronic colitis by the administration of DSS in their drinking water at 5% w/v in cycles of 7 days of treatment and 12 days recovery interval without DSS.
The 4th recovery period can be extended from 12 to 21 days to represent a chronic inflammation status, rather than the acute status modeled by shorter recovery. After the last recovery period, treatment with a compound of the invention, optionally with one or more ingredient(s) A, is initiated. Weekly administration is recommended initially, but can be adjusted by one of skill in the art as necessary. At intervals during treatment, animals are killed, the intestine is dissected and histopathological scores are assessed as described herein or as described in Kojouharoff et al., 1997, supra. Other animal models of inflammatory bowel disease include the chronic intestinal inflammation induced by rectal instillation of 2,4,6-Trinitrobenzene sulfonic acid (TNBS; method described by Neurath et al., J. Exp. Med.. 1995, 182, 1281 ; see also U.S. Patent No. 6,764,838, incorporated herein by reference). Histopathological scoring can be performed using the same standard described above.
Example 7: Clinical Inflammatory Disease Assessments
[00441 ] Ex-vivo LPS challenge endotoxemia model. Ex- vivo treatment of blood from patients treated with anti-inflammatory compounds with endotoxin represents a safe, well-defined model of acute inflammation in humans. It is also an excellent tool to study the mechanisms contributing to inflammatory responses in man in vivo. Given the importance of the balance of inflammatory and anti-inflammatory cytokines and other factors in the etiology of inflammatory diseases such as rheumatoid arthritis and Crohn's disease, evaluation of compounds as described herein in a human LPS model could prove beneficial in elucidating potential effects of anti-inflammatory compounds in human inflammatory processes.
[00442] Compounds described herein are administered orally at different doses to human volunteers. After 1 to 24 hours, blood samples are collected via venepuncture into vacutainer tubes and heparinized. Prior to the stimulation assay, a monocyte count is performed for each individual's undiluted heparinized whole blood sample (Cell Dyn 3500 SL). For this purpose a small volume (100-200 μl) is aspirated directly form the whole blood sample into the analyzer. For each sample and for each subject the following stimulation assays are performed: a. Unstimulated control (only vehicle) and b. Stimulated: 10 ng/ml LPS (final concentration). The stimulation assays are performed within one hour after withdrawal of the whole blood samples. The stimulation assay procedure is as follows.
1. Dilute the whole blood sample 1 + 1 with RPMI- 1640 medium; mix gently by inversion. 2. Pipette the diluted whole blood into each of the two separate sterile tubes (one for each condition).
3. Add to each tube 200 μl of the appropriate LPS stock (or blank) to yield the above-listed final LPS concentrations. Mix gently by inversion.
4. From each tube, add gently 0.5 ml per well into multiple (e.g., eight) master block wells.
5. Any empty wells should be filled with 0.5 ml of PBS buffer.
6. Cover the master blocks with their specific covers.
7. Incubate for 24 hours at 37°C and 5% CO2.
8. At the end of the incubation period, centrifuge the blocks at 1000 x g for 10 minutes at r.t.
9. Collect the supernatants and pool the appropriate wells into their appropriate polypropylene tubes (expected yield at 1 + 1 whole blood dilution: 40-60% of volume).
10. Mix and aliquot into separate tubes; one for each cytokine to be analyzed (target supernatant volume per aliquot: 0.5 ml).
11. Store samples at -700C until analysis.
[00443] TNF-α, IL-1/3, IL-6 or other cytokines arc analyzed using validated ELISA methods.
[00444] Rheumatoid Arhritis disease assessment. Rheumatoid arthritis is clinically scored on the basis of several clinically accepted scales, such as those described in U.S. Patent No. 5,698, 195, which is incorporated herein by reference, and Alctaha et al., Clin. Exp. Rheumatol. 2005, 23 (suppl. 39), S 100. Disease activity and change effected with treatment can be evaluated using the disease activity score (DAS) and/or the chronic arthritis systemic index (CASI), see Carotti et al., 2002, Ann. Rheum. Dis. 61:877-882, and Salaffi et al., 2000, Rheumatology 39: 90-96. Briefly, clinical response studies can assess the following parameters: A. Number of tender joints ; B. Number of swollen joints (Both tenderness and swelling are evaluated for each joint separately); and C. Visual analog pain scale (0-10 cm). Clinical response is assessed using a subjective reporting system as follows: Without any difficulty, With some difficulty, With much difficulty, or Unable to do. The visual analog scale for pain is a straight line with the left end of the line representing no pain and the right end of the line representing the worst pain. Patients are asked to mark on the line where they think their pain is.
[00445] Additionally, blood chemistry analysis determines levels of CRP, Rheumatoid
Factor, cytokines and other biomarkers.
[00446] Crohn's Disease assessment: Crohn's Disease Activity Index. The CDAl is a patient assessment form incorporating both objective and subjective information. Using established criteria the physician calculates the CDAI score. CDAI scores > 150 indicate active disease with a poorer prognosis than scores < 150. (See Best WR, Becktel JM, Singleton JVV, Kern F Jr. Development of a Crohn's disease activity index., National Cooperative Crohn's Disease Study. Gastroenterology 1976: 70: 439-444; Winship DH. Summers RW, Singleton JW, et al. National Cooperative Crohn's Disease Study: study design and conduct of the study. Gastroenterology 1979; 77; 829-842).
[00447] Psoriasis disease assessment. Efficacy of psoriasis treatment can be monitored by changes in clinical signs and symptoms of the disease, including Psoriasis Area and Severity Index (PASI) scores, physician's global assessment (PGA) of the patient compared with the baseline condition. A decrease in PASI score indicates a therapeutic effect. Psoriatic disease activity can also be determined based on Overall Lesion Severity (OLS) scale, percentage of total body surface area (BSA) affected by psoriasis, and psoriasis plaque thickness. Skin biopsies are studied for the effects of the drug on lymphocytes within psoriatic lesions. Histological analysis of skin biopsies can be performed to look for reduction in epidermal thickness and T-cell infiltration and reversal of pathological epidermal hyperplasia. Immunological activity can be monitored by testing for the effects of treatment on cell-mediated immunity reactions (delayed hypersensitivity), tetanus antibody responses, and lymphocyte subpopulations (flow cytometry).
Example 8: Cardiovascular and metabolic disease models
[00448] Lipid determinations. The anti -atherosclerotic activity of compounds may be demonstrated by determining the amount of agent required to alter plasma lipid levels, for example HDL cholesterol levels, LDL cholesterol levels, VLDL cholesterol levels or triglycerides, in the plasma of certain animals, for example marmosets (Crook et al. Arteriosclerosis 10, 625, 1990) or Golden Syrian Hamsters (Goulinet et al., J. Lipid Res., 34, 943, 1993). and others, that possess a plasma lipoprotein profile similar to that of humans. [00449] Blood chemistry evaluation in Marmosets. Adult marmosets are assigned to treatment groups so that each group has a similar τnean.+/-SD for total, HDL, and/or LDL plasma cholesterol concentrations. After group assignment, the marmosets are dosed daily with compound as a dietary admix or by intragastric intubation for from one to eight days. Control marmosets receive only the dosing vehicle. Plasma total, LDL VLDL and HDL cholesterol values may be determined at any point during the study by obtaining blood from an antecubital vein and separating plasma lipoproteins into their individual subclasses by density gradient centrifugation, and by measuring cholesterol concentration as previously described (Crook et al. Arteriosclerosis 10, 625, 1990).
[00450] Blood chemistry evaluation in cynomolgous monkeys. Sixteen male and
16 female cynomolgous monkeys are assigned to four dose groups. A compound is formulated in a suitable vehicle at low, medium, and high concentrations. The three dosages of the compound and vehicle alone are administered once daily by oral gavagc for 90 consecutive days to all male and female monkeys in the corresponding dose group. Blood samples (4 to 6 ml) are collected from the femoral vein at days 0, 28, and 90. The blood samples are processed for serum, and clinical chemistry values, including, for example, HDL cholesterol, triglyceride and total bilirubin levels, which are determined by standard methods.
[00451] Blood chemistry evaluation in Wistar rats. Eighty male and 80 female
Wistar rats are assigned to four dose groups. A compound is formulated in a suitable vehicle at low, medium, and high concentrations. The three dosages of the compound and vehicle alone are administered once daily by oral gavage for 90 consecutive days to all male and female rats in the corresponding dose group. Blood samples (2 to 3 ml) arc collected via the orbital sinus at days 0, 28, and 90. The blood samples are processed for serum, and clinical chemistry values, including, for example, HDL cholesterol levels, which are determined by standard methods.
[00452] Blood chemistry evaluation in Golden Syrian Hamsters. Female Golden
Syrian Hamsters (6-8 weeks old) were quarantined for 72 hours and then assigned to treatment groups. A sample bleed was taken by retro-orbital bleed on day 0, prior to dosing, and processed to 1 ml serum in pre-chilled EDTA-treatcd tubes. Each serum sample was aliquoted to 0.5 ml and 0.3 ml volumes and stored at -2O0C until shipment. Subsequently the test compound or vehicle was administered orally (typically 5 ml/kg, for a dose of 30 mg/kg). Once daily dosing at those doses was continued on days 1 -13. On day 2, day 6 or 13, terminal bleeds were taken several hours after the final oral dose, and the sera were processed, aliquoted and stored as before. Lipid analysis and clinical chemistry panel analysis was performed on all bloodsamples.
[00453] Rabbit Atherosclerosis Assay. Anti-atherosclerotic effects of the compounds may be determined by the amount of compound required to reduce the lipid deposition in rabbit aorta. Male New Zealand White rabbits are fed a diet containing 0.2% cholesterol and 10% coconut oil for 4 days (meal-fed once per day). Rabbits are bled from the marginal ear vein and total plasma cholesterol values are determined from these samples. The rabbits are then assigned to treatment groups so that each group has a similar mean. +/-SD for total plasma cholesterol concentration, HDL cholesterol concentration, triglyceride concentration and/or cholesteryl ester transfer protein activity After group assignment, rabbits are dosed daily with compound given as a dietary admix or on a small piece of gelatin based confection. Control rabbits receive only the dosing vehicle, be it the food or the gelatin confection. The cholesterol/coconut oil diet is continued along with the compound administration throughout the study. Plasma cholesterol values may be determined at any point during the study by obtaining blood trom the marginal ear vein. After 3-5 months, the rabbits are sacrificed and the aortae are removed from the thoracic arch to the branch of the iliac arteries. The aortae are cleaned of adventitia, opened longitudinally and then analyzed unstained or stained with Sudan IV as described by Holman et. al. (Lab. Invest. 1958, 7, 42- 47). The percent of the lesioned surface area is quantitated by densitometry using an Optimas Image Analyzing System (Image Processing Systems). Reduced lipid deposition is indicated by a reduction in the percent of lesioned surface area in the compound-receiving group in comparison with the control rabbits.
[00454] Cuff induced accelerated atherosclerosis. The compounds are tested in a mouse model for restenosis and accelerated atherosclerosis based on cuff placement around the femoral artery in ApoE3 Leiden mice (Lardenoye et al. Circ Res. 2000, 87(3):248-53). fhe model is highly regulated by inflammatory factors (Pires et al. Cardiovasc Res, 68 (2005) 415 ^ 424) including TNFa (Monraats et al. FASEB J 2005;19: 1998-2004) and MCP-I, as has been demonstrated by Egashira et al (Circ Res 2002; 90: 1 167-72). Cuff placement in ApoE3 Leiden mice receiving a mild hypcrcholesterolemic diet results in a rapid adhesion and infiltration of monocytes, followed by a rapid induction of neointima formation, and in the induction in foam cell accumulation within the cuffed vessel segment.
[00455] Briefly, male ApoE3 Leiden mice (age 12 weeks) are fed a mildly hypercholesterolemic diet for 3 weeks prior to surgical cuff placement. After 3 weeks mice are divided in 3 groups, matched for plasma cholesterol levels. The mice either receive daily (from day-1 on) a control gavage solution or a gavage solution containing test compound (typically at a concentration of 30 mg/kg). On day 0 surgery is performed, i.e. a non- constricting cuff (2-3 mm in length) is placed around both the femoral arteries of the mice. Mice are sacrificed after 2 days for analysis of monocyte adhesion and infiltration, and additional mice are sacrificed after 2 weeks for histomorphometric analysis to quantify the (inhibition of) accelerated atherosclerotic lesions and neointima formation.
Example 9: Clinical Cardiovascular and Metabolic Disease Assessments [00456] Anti-obesity assay. The ability of compounds to cause weight loss may be assessed in obese human subjects with body mass index (BMI) >30 kg/nT. Doses of inhibitor are administered sufficient to result in an increase of >15% in HDL cholesterol levels. BMI and body fat distribution, defined as waist (W) to hip (H) ratio (WHR), arc monitored during the course of the 3-6 month studies, and the results for treatment groups compared to those receiving placebo.
[00457] Diagnostic methods for glucose and insulin disorders. Oral glucose tolerance testing (OGTT). During a glucose tolerance test, wrhich may be used to diagnose diabetes mellitus, a fasted subject takes a 75 gram oral dose of glucose. Blood glucose levels are then measured over the following 2 hours. Interpretation is based on WHO guidelines, but glycemia greater than or equal to 1 1 . lmmol/1 at 2 hours or greater than or equal to 7.0mmol/L fasting is diagnostic for diabetes mellitus. OGTT can be normal or mildly abnormal in simple insulin resistance. Often, there are raised glucose levels in the early measurements, reflecting the loss of a postprandial (after the meal) peak in insulin production. Extension of the testing (for several more hours) may reveal a hypoglycemic "dip", which is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response.
[00458] Iiyperinsulinemic cuglycemic clamp. The standard for investigating and quantifying insulin resistance is the "hyperinsulinemic euglycemic clamp," so called because it measures the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia. The procedure takes about 2 hours. Through a peripheral vein, insulin is infused at 10-120 mU per m* per minute. In order to compensate for the insulin infusion, glucose 20% is infused to maintain blood sugar levels between 5 and 5.5 mmol, 1. The rate of glucose infusion is determined by checking the blood sugar levels every 5-10 minutes. Low dose insulin infusions are more useful for assessing the response of the liver whereas high dose insulin infusions are useful for assessing peripheral (i.e. muscle and fat) insulin action. The rate of glucose infusion during the last 30 minutes of the test determines insulin sensitivity. If high levels (7.5 mg/min or higher) are required, the subject is insulin-sensitive. Very low levels (4.0 mg/min or lower) indicate that the body is resistant to insulin action. Levels between 4.0 and 7.5 mg/min are not definitive and suggest "impaired glucose tolerance," an early sign of insulin resistance.
[00459] Given the complicated nature of the "clamp" technique (and the potential dangers of hypoglycemia in some subjects), alternatives have been sought to simplify the measurement of insulin resistance. The first was the Homeostatic Model Assessment (HOMA) [ Matthews DR. Hoskcr JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-9], and a more recent method is QUICKI (quantitative insulin sensitivity check index). Both employ fasting insulin and glucose levels to calculate insulin resistance, and both correlate reasonably with the results of clamping studies.
[00460] Using a fasting blood sample, insulin resistance (IR) is quantified using the following formula:
IR- Glucose (mg/dl)) x Insulin (μU/ml) / 405
[00461] In this equation, one should use the constant 22.5 instead of 405 if the glucose is reported in mmol/1. This model correlates well with estimates using the euglycemic clamp method.
[00462] HOMA IR values between 1.7 and 2.5 are seen in subjects with normal glucose tolerance [Tripathy D, Carlsson M, Almgren P, Isomaa Bo5 Taskinen MR, Tuomi T, Groop LC: Insulin secretion and insulin sensitivity in relation to glucose tolerance: lessons from the Botnia Study. Diabetes 49:975-980, 2000; Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Targher G, Albeπche M. Bonadonna RC, Muggeo M: Prevalence of insulin resistance in metabolic disorders: the Bruneck Study. Diabetes 47: 1643 - 1649, 1998; Juan F. Ascaso, MD, Susana Pardo, MD, Jose T. Real, MD, Rosario I. Lorentc, MD, Antonia Priego, MD and Rafael Carmena, MD Diagnosing Insulin Resistance by Simple Quantitative Methods in Subjects With Normal Glucose Metabolism, Diabetes Care 26: 3320-3325, 2003],
Example 10: Analysis of biomarkers in clinical samples.
[00463] Patients with low HDL-C and elevated TG levels, with or without concomitant lipid-lowering therapy (e.g., statins, bile acid sequestrants, or cholesterol absorption inhibitors), are treated with a compound as described herein, administered orally once daily for 6 weeks. A fasting lipid panel (total cholesterol, HDL-C, LDL-C, TG), CRP and general laboratory parameters (CBC, general chemistry panel) are assessed at baseline, every two weeks during dosing and 4 weeks after the end of dosing. At Week 1 , patients have a general chemistry panel assessed. Weight, and waist and hip circumference are assessed at each visit, other than Week 1. Lipid/metabolic, inflammatory, and prothrombotic biomarkers are assessed at Baseline, Week 2, Week 4, Week 6 and Follow-up. Urinalysis and coagulation parameters are assessed at baseline and at the end of dosing.
Example 11: Cancer models
[00464] Proliferation assay. Human non-small cell lung carcinoma cells A549
(ATCC# CCL-185), are grown at 37DC I /- 0.50C and 5% CO2 in DMEM supplemented with 10% FBS, 2 mM glutamine, 1 % penicillin, and 1 % streptomycin. Anti-proliferation assays are performed in 384-well plates. 6.6 μL of 10x stock compound solutions is added to 40 μL of culture media in assay wells. The tumor cells are liberated from the culture flask using a solution of 0.25% trypsin. Cells are diluted in culture media such that 3000 or 6000 cells are delivered in 20 μL of media into each assay well. Assay plates are incubated for 72-80 hours at 37°C +/-0.50C with 5% CO2. Twenty microliters of 20% Alamar Blue warmed to 37°C +/- 0.50C is added to each assay well following the incubation period. Alamar Blue metabolism is quantified by the amount of fluorescence intensity 3.5-5.0 hours after addition. Quantification, using an LJL Analyst AD reader (LJL Biosystems), is taken in the middle of the well with high attenuation, a 100 msec read time, an excitation filter at 530 nm, and an emission filter at 575 nm. For some experiments, quantification is performed using a Wallac
Victor reader. Measurements are taken at the top of the well with stabilized energy lamp control; a 100 msec read time, an excitation filter at 530 nm, and an emission filter at 590 nm. Ko significant differences between plate readers are measured.
[00465] The percent inhibition (% I) for each well is calculated using the following formula:
% I=|(avg. untreated wells-treated well)/(avg. untreated wells)] x 100
[00466] The average untreated well value (avg. untreated wells) is the arithmetic mean of 40 wells from the same assay plate treated with vehicle alone. Negative inhibition values result from local variations in treated wells as compared to untreated wells.
[00467] The anti-cancer effect that can be demonstrated with the tumor cell lines refered to herein can be similarly demonstrated using other cancer cell lines, such as, for example, NSC lung carcinoma, MCF7 mammary adenocarcinoma, PA-I ovarian tcratocarcinoma, HT29 colorectal adenocarcinoma, H 1299 large cell carcinoma, U -2 OS osteogenic sarcoma, U-373 MG glioblastoma, U-1 18 MG glioblastoma, U-138 MG glioblastoma, LN-229 glioma, Hep-3B hepatocellular carcinoma, BT-549 mammary carcinoma, T-24 bladder cancer, C-33A cervical carcinoma, HT- 3 metastatic cervical carcinoma, SiHa squamous cervical carcinoma, CaSki epidermoid cervical carcinoma, NCI- H292 mucoepidermoid lung carcinoma, NCI-2030, non small cell lung carcinoma, HeLa, epithelial cervical adenocarcinoma, KB epithelial mouth carcinoma, HT 1080 epithelial fibrosarcoma, Saos-2 epithelial osteogenic sarcoma, PC3 epithelial prostate adenocarcinoma, SW480 colorectal carcinoma, CCL-228, MS-751 epidermoid cervical carcinoma, LOX IMVI melanoma, MALME-3M melanoma, Ml 4 melanoma, SK-MEL-2 melanoma, SK-MEL-28 melanoma, SK-MEL-5 melanoma, UACC-257 melanoma, or UACC-62 melanoma cell lines. The specificity can be tested by using cells such as NHLF lung fibroblasts, NHDF dermal fibroblasts, HMEC mammary epithelial cells, PrEC prostate epithelial cells, HRE renal epithelial cells, NHBE bronchial epithelial cells, CoSmC Colon smooth muscle cells, CoEC colon endothelial cells, NHEK epidermal keratinocytcs, and bone marrow cells as control cells.
[00468] As will be rccogonized by those of skill in the art, many more cancer cell lines, such as those available from American Type Culture Collection (ATCC) (P.O. Box 1549 Manassas, VA 20108, USA), can be used similarly. Example 12
[00469] Table 3 lists compounds of the invention prepared using the methods of
Examples 1-5 or methods previously disclosed. Each compound was analyzed by LCMS and displayed the expected molecular ion. Each of the compounds in Table 3 was tested in the TNFa ELlSA assay (Example 5) and found to have activity therein, with some compounds having IC5øS below 10 μM in this assay.
TABLE 3
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
[00470] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as "up to," "at least," "greater than," "less than," and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 atoms refers to groups having 1 , 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to groups having 1 , 2, 3, 4, or 5 atoms, and so forth.
[00471 J All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.
[00472] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims.

Claims

CLAIMSWhat is claimed is:
1. A compound of Formula 1:
Figure imgf000186_0001
I stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is phenyl or pyrazolyl, wherein G is substituted by one or more R1, R2 or R3; X is C(O) or C(S); Ar is (Y)-naphthyl; Y is C(O) or C(NOR); L-Q is selected from:
1) O-(C,_4 alkyl)-Q, wherein Q is CN, 0-(C, A alkyl)-OR, N(CM alkyl-OR)2, or a heterocyclyl group selected from
Figure imgf000186_0002
4)
Figure imgf000187_0003
or
Figure imgf000187_0001
each R1 is independently F, Cl, Br, I, NR2, CN, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or hcterocyclylalkyl group; each R2 is independently F, Cl, Br, I, CN, NO2, a substituted or unsubstituted alkyl, heterocyclyl, or heterocyclylalkyl group, OR', C(O)R", C(O)OR', C(O)NR '2, NR'2, NRC(O)R", NR'C(0)0R", NR'SO2R", NR'C(O)NR'2, NR'C(S)NR'2, S(O)01R", or SO2NR'2; each R is independently a substituted or unsubstituted alkyl, alkenyl, or alkynyl group, or an 0(C1-4 alkyl) group, wherein each alkyl group is optionally partially or fully halogenated;
R4 is a substituted or unsubstituted Cμ alkyl, NH-(C1-8 alkyl), NH-aralkyl, or NH-heterocyclylalkyl group;
R5 is selected from substituted or unsubstituted NH-(C)-8 alkyl) group or a substituted or unsubstituted heterocyclyl selected from:
Figure imgf000187_0002
R is selected from a substituted or unsubstituted C) .4 alkyl, heterocyclyl, I I-(C1-4 alkyl), NH-alkylaryl, or NH-heterocyclylalkyl group; R is selected from F or Cl, or a substituted or unsubstituted NH-(C2-S alkyl) group;
each R is independently hydrogen or a substituted or unsubstituted C1-6 alkyl group; each R' is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclyl, aralkyl, or heterocyclylalkyl group; each R" is independently a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl group; and each m is independently 0, 1 or 2.
2. The compound of claim 1, wherein G is
Figure imgf000188_0001
The compound of claim 1, wherein Ar is
Figure imgf000188_0002
4. The compound of claim 1, wherein L-Q is O-(C?.τ alkyl)-Q, and Q is
-N(C2_3 alkyl-OR)2,
Figure imgf000188_0003
5, The compound of claim 4, wherein L-Q is
Figure imgf000188_0004
6. The compound of claim 1. wherein L-Q is
Figure imgf000189_0001
and R4 is a substituted or unsubstituted C1- 4 alky] or -NH-(C1-S alkyl) group.
7. The compound of claim 6, wherein R4 is
Figure imgf000189_0002
8. The compound of claim 1, wherein L-Q is
Figure imgf000189_0003
and R3 is selected from substituted or unsubstituted
Figure imgf000189_0004
9. The compound of claim 1 , wherein L-Q is
Figure imgf000189_0005
and R0 is
Figure imgf000189_0006
10. The compound of claim 1, wherein L-Q is
Figure imgf000190_0001
and R' is F, or a 3,3-dimethylbutan-l-amine-l -yl group.
1 1. The compound of claim 1, wherein R1 is a substituted or unsubstituted C1-6 alkyl, or heterocyclyl group.
12. The compound of claim 11 , wherein R1 is a substituted or unsubstituted methyl, isopropyl, tert-butyl, isobutyl, sec-butyl, neopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazepanyl, morpholinyl, or thiomorpholinyl group.
13. The compound of claim 1, wherein R~ is a substituted or unsubstituted (C1-6 alkyl), heterocyclyl, or heterocyclylalkyl group, F, Br, CN, C(O)NR'2, C(O)R", S(O)111R", NR'SO2R". or SO2NR" 2.
14. The compound of claim 13, wherein R" is F, Br, CN, CF3, imidazolyl, triazolyl, tetrazolyl, C(O)NH2, C(O)NH(C, _6 alkyl), C(O)NH(C3-6 cycloalkyl), C(O)NH(heterocyclyl), C(O)NH(heterocyclylalkyl), (CH2)i-3-heterocyclyl, C(O)-heterocyclyl, NHSO2(CL6 alkyl), NHSO2(C3-6 cycloalkyl), NHSO2(heterocyclyl), SO2NH(C1-6 alkyl). SO7N(C1 -6 alkyl)2, wherein each C1 -6 alkyl, C3-6 cycloalkyl. heterocyclyl, and heterocyclylalkyl group is substituted or unsubstituted.
15. The compound of claim 14, wherein the C1 -6 alkyl or C3-6 cycloalkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl. neopentyl, cyclopropyl. cyclobutyl, cyclopentyl, cyclohexyl, wherein the alkyl or cycloalkyl group is optionally substituted by OH or N(C 1 -3 alkyl)2 group.
16. The compound of claim 14, wherein the heterocyclyl group is a pyrrolidinyl, piperidinyl, piperazinyl, azepanyl. or 3,8-diazabicyclo[3.2.1 ]octanyl group.
17. The compound of claim 14, wherein the heterocyclylalkyl group is a (CH2)i_3-pyrrolidinyl, (CH2)1-3-piperidinyl, (CH2)i_3-piperazinyl, (CH2)|.3-furanyl, (CH2)) _3-oxazolyl, or (CH2)).3-isoxazolyl group.
18. The compound of claim 14, wherein the hctcrocyclyl and heterocyclylalkyl group is substituted with methyl, ethyl, n-propyl, isopropyl. n-butyl, tcrt- butyl, sec-butyl, isobutyl, neopentyl, (CH2)0-3-cyclopropyl, (CH2)0-3-cyclobutyl, (CH2)o-]- cyclopentyl, (CH2)0.-,-cyclohexyl) (CH2)2.3-OH, (CH2)0-3NH(C1-3 alkyl), (CH2)O^N(C3 alkyl>2, or (CH2)i-3-pyrrolidmyl.
19. The compound of claim 1 , wherein R3 is a substituted or unsubstituted C M alkyl or O(Cj-4 alkyl) group, or is a partially or fully halogenated O(C1-2 alkyl) group,
20. The compound of claim 1, wherein G is phenyl and R1 a substituted or unsubstituted methyl, isopropyl, tert-butyl, isobutyl, sec-butyl, neopentyl, cyclohexyl. pyrrolidinyl, piperidinyl, piperazinyl, oxazepanyl, morpholinyl, or thiomorpholinyl group.
21. The compound of claim 20, wherein R" is a substituted or unsubstituted (C1-6 alkyl) or heterocyclylalkyl group, F, Br, CN, C(O)NR'2, C(O)R", S(O)1nR", NR-SO2R", or SO2NR'2.
22. The compound of claim 20, wherein R2 is is F, Br,CN, CF3, imidazolyl, triazolyl, tetrazolyl, C(O)NH2, C(O)NH(C ,.6 alkyl), C(O)NH(C6 cycloalkyl), C(0)NH(hcterocyclyl), C(0)NH(heterocyclylalkyl), (CH2), _3-heterocyclyl, C(O)-heterocyclyl, NHSO2(C1-6 alkyl), NHSO2(Cv6 cycloalkyl), NHSO2(heterocyclyl), SO2NH(C, _6 alkyl), SO2N(C1 -6 alkyl)2, wherein each C1 -6 alkyl, C6 cycloalkyl, heterocyclyl, and heterocyclylalkyl group is substituted or unsubstituted.
23. The compound of claim 20, wherein R3 is a substituted or unsubstituted C1-4 alkyl or O(C1-4 alkyl) group, or is a partially or fully halogenated O(C]_2 alkyl) group.
24. A composition comprising a compound of any one of claims 1-23 and a pharmaceutically acceptable carrier.
25. A method of treating a disorder mediated by cytokines which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of any one of claims 1-23.
26. The method according to claim 25. wherein the cytokme-mediated disorder is rheumatoid arthritis, osteoarthritis Crohn's disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejection, pancreatitis, lnsulimtis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, leprosy, acute synovitis, Reiter's syndrome, gouty arthritis, Behcet's disease, spondylitis, endometriosis, non-articular inflammatory conditions, acute or chronic pam, stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, coronary heart disease, coronary artery disease, acute coronary syndrome, Takayasu arteritis, cardiac failure, hypercholesteremia, diseases or conditions related to blood coagulation or fibrinolysis, atherosclerosis, allergic conjunctivitis, uveitis, glaucoma, optic neuritis, retinal ischemia, diabetic retinopathy, laser induced optic damage, surgery or trauma-induced proliferative vitreoretinopathy, allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, obhterative bronchiolitis, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection, respiratory tract inflammation, psoriasis, pemphigus, eczema, atopic dermatitis, contact dermatitis, acne, Guillain-Barre syndrome, Parkinson's disease, Huntmgton's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyehnating diseases, viral meningitis, bacterial meningitis, CNS trauma, spinal cord injury, seizures, convulsions, olivopontocerebellar atrophy, AIDS dementia complex, MERRF syndrome, MELAS syndrome, Leber's disease. Wernicke's encephalopathy, Rett syndrome, homocystcinuπa, hyperprolinemia, hyperhomocystememia, nonketotic hyperglycinemia, hydroxybutyπc aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety, schizophrenia, aneuπsm, epilepsy, diabetes, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome, obesity, anorexia nervosa, bulimia nervosa, bone resorption diseases, osteopetrosis, osteoporosis, sepsis, HIV infection, HCV infection, malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer, Castleman's disease, or drug resistance
27 The method of claim 25, wherein the disorder is abnormal bleeding, an abscess, actinic reticuloid syndrome, acute confusional migraine, acute confusional senile dementia, acute hepatocellular injury, acute tubular necrosis, adenohypophyseal diseases, adenovirus infections, adhesions, adhesive capsulitis, adnexitis, agammaglobulinemia, allergy, alopecia, fibrosing alveolitis, amyloidosis, angioplasty, angor pectoris, antiphospholipid syndrome, arteriosclerotic dementia, arteritis temporal, arthropod-bome encephalitis, asphyxia, atopic hypersensitivity, beaver fever, biliary cirrhosis, bone loss, bronchiolitis, cancer of endocπne gland, cancer of larynx, candidiasis, small cell lung carcinoma, cardiac hypertrophy, cardiac surgery, cardiomegaly, carditis, carotid angioplasty, carotid endarterectomy, carotid stents, carotid ulcer, celiac disease, cirrhosis, colitis, colitis granulomatous, coronary artery bypass graft, coronary artery bypass surgery, degenerative joint disease, dermatitis, diarrhea, dry eye, dyslipidemia. dyspnea, edema, end-stage renal disease, epstein-barr virus infections, fever, gastroenteπtis, heart attack, heart bypass surgery, heart surgery, heart transplantation, hepatitis A, hepatitis B, hepatitis C, chronic hepatitis, insulin resistance, kidney failure, kidney transplantation, adult chronic leukemia, liver cirrhosis, liver transplantation, meningitis, bacterial meningitis, myeloproliferative disorders, myopathies, myositis, neonatal-onset multisystem inflammatory disease, nephritis, neuromuscular disorders, neuropathy, obliterative bronchiolitis, oral cancer, percutaneous coronary intervention, peripheral nerve disorders, neuropathy, peritoneal dialysis, pleural disease, pneumonitis, polymyositis, pulmonary fibrosis, renal cancer, renal dialysis, scleroderma, septic arthπtis, Sjogren's syndrome, ankylosing spondylitis, Still's disease, toxemia, tuberculosis, urticaria, viral hepatitis, or Wegener's gianulomatosis
28. A method comprising administeπng to a subject an amount of a compound of any one of claims 1-23 effective to reduce a level of a cytokine relative to the level pnor to administration of the compound
29 A method comprising exposing a cell to an amount of a compound of any one of claims 1-23 effective to reduce the level of cytokine released from the cell in response to a pro-inflammatory stimulus relative to the level of released cytokine prior to contacting the cell with the compound
30 A method comprising contacting p38 with an amount ot a compound ot an> one of claims 1-23 effective to inhibit p38 activity, the phosphorylation of p38, or both
31 A method comprising administering to a subject in need thereof, an amount of a compound of any one of claims 1-23 effective to reduce the activity of a proinflammatory mediator relatπ e to the activity prior to the administration of the compound
32 A method comprising administering to a subject an amount of a compound of any one of claims 1 -23 effective to reduce the circulating levels of C-Reactive Protein or Rheumatoid Factor, or both, in blood relative to the level prior to the administration of the compound
33 A method comprising administering to a subject exhibiting one or more indicia of rheumatoid arthritis, an amount of a compound of any one of claims 1-23 effective to reduce at least one of the indicia to a level below that which exists pπor to the administration of the compound, wherein the indicia are selected from erythrocyte sedimentation rate (ESR), joint redness, joint pain, ioint tenderness, Ritchie articular index, duration of morning stiffness, joint immobility, joint swelling, and/or circulating C-reactive protein level
34 A method comprising administering to a subject exhibiting one or more clinical signs of psoriasis an amount of a compound of any one of claims 1 -23 effective to reduce the number or severity of clinical signs of psoπasis relative to those present in the subject prior to the administration of the compound, wherein the clinical signs of psoriasis arc the percentage of total body surface area (BSA) affected by psoπasis, psoriasis plaque thickness, level of lymphocytes within psoriatic lesions, epidermal thickness, T-cell infiltration, pathological epidermal hyperplasia, cell-mediated immunity reactions, tetanus antibody response lymphocyte subpopulations, or any two or more thereof
35 A compound of Formula II
Figure imgf000195_0001
Formula II
wherein X is CN, CF3, or a halogen,; and PN is H, or an amine protecting group.
36. A compound selected from List I.
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