Heterocyclic cytokine inhibitors 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
WO2007075896 A2 2007-07-05 [WO200775896]WO2007075896 A3 2008-03-06 [WO200775896] / 2007-07-052008-03-06
申请号/申请日
2006WO-US48803 / 2006-12-20
发明人
BOMAN ERIK;MONTALBAN ANTONIO GARRIDO;PEI YAZHONG;LARSON CHRISTOPHER;WANG ZHIJUN;URBAN JAN;DELAET NANCY G L;SEBO LUBOMIR;LUM CHRISTOPHER;ERNST JUSTIN;
申请人
KEMIA;
主分类号
IPC分类号
A01N-043/40A61K-031/44
摘要
(WO200775896) 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, anti-pain or anti-cancer agents.  There are further provided methods for the preparation of such agents and their use in preventing or treating conditions mediated by cytokines.
机翻摘要
暂无翻译结果,您可以尝试点击头部的翻译按钮。
地址
代理人
代理机构
;
优先权号
2005US-60753634 2005-12-22 2006US-60787362 2006-03-30 2006US-60842051 2006-09-01
主权利要求
(WO200775896) CLAIMS What is claimed is: 1. A compound comprising: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the carbonyl of the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with a target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with a target protein; a linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety, L, wherein the anchoring moiety is capable of forming at least one hydrogen bond interaction with an ATP-binding pocket of the target protein; wherein the compound is a cytokine inhibitor. 2. The compound of claim 1 , wherein the targeting moiety is an amide group. 3. The compound claim 1 , wherein the pocket-expanding moiety comprises a 6 membered aryl or heteroaryl moiety, substituted by a substituted or unsubstituted C2-4 alkyl, C3.g cycloalkyl, or heterocyclyl group. 4. The compound of claim 3, wherein the C2-4alkyl group is a substituted or unsubstituted isopropyl, tert-butyl, isobutyl, or sec-butyl group. 5. The compound of claim 3, wherein the C3..9cycloalkyl group is a substituted or unsubstituted cyclohexyl or norbornyl group. 6. The compound of claim 3, wherein the heterocyclyl group is a substituted or unsubstituted morpholinyl, pyrrolidinyl, piperidyl, 8-oxa-3-aza- bicyclo[3.2.1]octan-3-yl, oxazepanyl, thiazolyl, or thiomorpholinyl group. 7. The compound of claim 1, wherein the orienting moiety comprises a phenyl, pyridyl, or pyridazinyl group, substituted by a halogen, methyl or trifluoromethyl group. 8. The compound of claim 1, wherein the linker moiety comprises an oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl group. 9. The compound of claim 1 , wherein the anchoring moiety comprises a substituted or unsubstituted amide, hydrazide or urethane group. 10. A compound of Formula I, stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof; wherein X and Y are each independently CH or N; A is F, Cl, Br, I, NR2, or a Cj-3alkyl or -0(Ci-3alkyl) group, wherein the alkyl group is optionally partially or fully halogenated; B, D and E are each independently N, NR, O, S or CR; wherein B7D, and E are selected such that the ring containing B, D3and E is aromatic; G is an aryl or heteroaryl group, wherein G is substituted by one or more R1, R2or R3; L1is -C(O)NH-;  -(CR'2)n-C(O)NR-(CR'2)p-, -(CR'2)n-C(O)NRNR-(CR'2)p-, or -(CR'2)n-O-C(O)NR-(CR'2)p-; Q is hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclyl group; each R1is independently F, Cl5Br, I, -NR2, -CN, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heterocyclylalkyl group; each R2is independently F, Cl, Br, I, -CN, -NO2, a substituted or unsubstituted alkyl or heterocyclylalkyl group, -OR', -C(O)R', -C(O)OR', -C(O)NR'2>-NR'2>-NRC(O)R", -NR5C(O)OR", -NR5SO2R", -NR'C(O)NR'2)-NR'C(S)NR'2, -S(O)mR'\ or -SO2NR'2; each R3is independently a substituted or unsubstituted alkyl, alkenyl, or alkynyl group, or an -0(Ci-4alkyl) group, wherein the alkyl group is optionally partially or fully halogenated; each R is independently hydrogen or a substituted or unsubstituted alkyl group; each R' is independently hydrogen, or a substituted or unsubstituted alkyl, aralkyl, heterocyclyl, or heterocyclylalkyl group; each R" is independently a substituted or unsubstituted alkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl group; each m is independently O, 1 or 2; and n and p are each independently O, 1, 2 or 3. 11. The compound of claim 10, wherein the compound is  Formula II. 12. The compound of claim 10, wherein the compound is  13. The compound of claim 10, wherein B is N. 14. The compound of claim 10, wherein D is NH, O or S. 15. The compound of claim 10, wherein E is CH or O. 16. The compound of claim 10, wherein A is F, -CH3, or -CF3. 17. The compound of claim 10, wherein G is a phenyl, pyrimidyl or pyridyl group. 18. The compound of claim 17, wherein G is  19. The compound of claim 10, wherein L2is -C(O)-(CR'2)p-, -(CH2)n-C(O)NR-(CH2)p- or -(CH2)n-C(O)NRNR-(CH2)p-. 20. The compound of claim 19, wherein L2is -C(O)-,-C(O)CH2-, -C(O)CH2CH2-, -C(O)CH2CH2CH2-, -C(O)NHNH-, -C(O)N(CH3)NH-, -C(O)N(CH3)NH-CH2-, -C(O)N(CH3)NH-CH2CH2-, -C(O)N(CH3)NH-CH2CH2CH2-, -C(O)NHNH-CH2-, -C(O)NHNH-CH2CH2- Or -C(O)NHNH-CH2CH2CH2-, -C(O)NH-, -C(O)N(CH3)-, -C(O)N(CHs)-CH2-, -C(O)N(CHa)-CH2CH2-, -C(O)N(CH3)-CH2CH2CH2-, -C(O)NH-CH2-, -C(O)NH-CH2CH2- Or-C(O)NH-CH2CH2CH2-. 21. The compound of claim 10, wherein the compound is  22. The compound of claim 10, wherein the compound is Q is a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclyl group; 23. The compound of claim 10, wherein Q is H, or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, pyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidyl, or piperazinyl group. 24. The compound of claim 23, wherein Q is a substituted or unsubstituted phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidyl, morpholinyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or neopentyl group. 25. The compound of claim 10, wherein R1is F, -CN, -NR2, or a substituted or unsubstituted Cj-4alkyl, C3.9cycloalkyl, aryl, heterocyclyl or heterocyclyl alkyl group. 26. The compound of claim 25, wherein R1is F, -CN, or -N(Ci-3alkyl)2wherein each C|.3alkyl group is independently substituted or unsubstituted, or R1is a substituted or unsubstituted isopropyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, phenyl, 8- oxa-3-aza-bicyclo[3.2.1]octan-3-yl, thiazolyl, CHb-thiazolyl, CH^CHa-thiazolyl, pyrrolidinyl, CH2-pyrrolidinyl, CH2CH2-pyrrolidinyl, piperidyl, CH2-piperidyl, CH2CH2-piperidyl, morpholinyl, CH2-morpholinyl, CH2CH2-morpholinyl, thiomorpholinyl, CH2-thiomorpholinyl, CH2CH2-thiomorpholinyl, piperazinyl, CH2-piperazinyl, CH2CH2-piperazinyl, oxazepanyl, CH2-oxazepanyl, or CH2CH2-oxazepanyl group. 27. The compound of claim 10, wherein R2is a substituted or unsubstituted Ci-4alkyl or heterocyclylalkyl group, F, Cl, -CN, -NO2, OR', -C(O)OR', -C(O)NR'2, -NRC(O)R", -NRC(O)OR", -NR'SO2R", -NR*C(0)NR'2, or -SO2NR'2. 28. The compound of claim 27, wherein the alkyl group is substituted with NRR. 29. The compound of claim 27, wherein the heterocyclylalkyl group is a substituted or unsubstituted -(Cj.3alkyl)-pyrrolidinyl, -(Ci-3alkyl)-piperidyl, -(Ci-3alkyl)-piρerazinyl, or -(Ci-3alkyl)-morpholinyl group. * 30. The compound of claim 27, wherein R2is F, CF3, -CN, -NO2, -O(C1-6alkyl), -C(O)O(C-6alkyl), -C(O)NH2, -C(O)NH(C1-6alkyl), -C(O)NH(aryl), -C(O)NH(aralkyl), -NHC(O)(C1-6alkyl), -NHC(O)(aryl), -NHC(O)(aralkyl), -NHSO2(CL6alkyl), -NHSO2(aryl), -NHSO2(aralkyl), -SO2NH(Ci-6alkyl), -SO2NH(aryl), or -Sθ2NH(aralkyl), wherein each Ci-6alkyl, aryl, or aralkyl group is substituted or unsubstituted. 31. The compound of claim 10, wherein R3is a substituted or unsubstituted Ci-4alkyl or -0(Ci-4alkyl) group, or is a partially or fully halogenated -0(Ci-2alkyl) group. 32. The compound of claims 10, 11 or 12, wherein G is phenyl and R1is F, Cl, -CN, -N(C]_3alkyl)2wherein each CL3alkyl group is independently substituted or unsubstituted, or a substituted or unsubstituted morpholinyl, thiomorpholinyl, 8-oxa-3-aza- bicyclo[3.2.1]octan-3-yl, pyrrolidinyl, piperidyl, oxazepanyl, isopropyl, tert-butyl, iso-butyl, sec-butyl, or cyclohexyl group. 33. The compound of claim 32, wherein R1is F, Cl, a substituted or unsubstituted morpholinyl, 8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl, pyrrolidinyl, piperidyl, oxazepanyl, tert-butyl, or cyclohexyl group. 34. The compound of claim 32, wherein R2is a substituted or unsubstituted Ci-4alkyl or heterocyclylalkyl group, F, -CN, -NO2, -0(C1-6alkyl), -C(O)O(Ci- 6 alkyl), -C(O)NH2, -C(O)NH(C)-6alkyl), -C(O)NH(aryl), -C(O)NH(aralkyl), -NHC(O)(CL6alkyl), -NHC(O)(aryl), -NHC(O)(aralkyl), -NHSO2(Ci-6alkyl), -NHSO2(aryl), -NHSO2(aralkyl), -SO2NH(CL6alkyl), -SO2NH(aryl) or -SO2NH(aralkyl), wherein each Ci-6alkyl, aryl, or aralkyl group is substituted or unsubstituted. 35. The compound of claim 34, wherein the alkyl group is substituted with NRR. 36. The compound of claim 34, wherein the heterocyclylalkyl group is a substituted or unsubstituted -(Ci_3alkyl)-pyrrolidinyl, -(Ci-3alkyl)-piperidyl, -(Ci-3alkyl)-piperazinyl, or -(Ci-3alkyl)-morpholinyl group. 37. The compound of claim 34, wherein R2is F, CF3, -CN, -C(O)NH2, -C(O)NH(Ci-6alkyl), -NHSO2(C1-6alkyl), or -SO2NH(C ,_6alkyl), wherein each C1-6alkyl group is substituted or unsubstituted. 38. The compound of claim 34, wherein R3is a substituted or unsubstituted C1-4alkyl or -0(CMalkyl) group, or is a partially or fully halogenated -0(Ci-2alkyl) group. 39. The compound of claim 10, 11 or 12, wherein I/ '-Q is  40. The compound of claim 39, wherein G is a phenyl or a pyridyl group. 41. The compound of claim 10, wherein the compound is  42. The compound of claim 10 wherein the compound at a concentration of 10 μM inhibits induced TNFa-release from a cell by about 50% or greater than 50%. 43. A composition comprising a compound of claim 10, 11 or 12 and a pharmaceutically acceptable carrier. 44. 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 claim 10. 45. The method of claim 44, wherein the cytokine-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, iπsulinitis, 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 pain, 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, obliterative 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, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelinating 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, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety, schizophrenia, aneurism, 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. 46. The method of claim 45, wherein the cancer is breast cancer, colon cancer, lung cancer, prostatic cancer, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, osteosarcoma, or follicular lymphoma. 47. The method of claim 45, wherein the non-articular inflammatory condition is intervertebral disk syndrome conditions, bursitis, tendonitis, tenosynovitis, or fϊbromyalgic syndrome. 48. The method of claim 45, wherein the cardiac failure is heart failure, cardiomyopathy, myocarditis, vasculitis, vascular restenosis, valvular disease or coronary artery bypass. 49. The method of claim 45, wherein the disorder related to fibrinolysis is acute venous thrombosis, pulmonary embolism, thrombosis during pregnancy, hemorrhagic skin necrosis, acute or chronic disseminated intravascular coagulation, clot formation from surgery, long bed rest or long periods of immobilization, venous thrombosis, fulminant meningococcemia, acute thrombotic strokes, acute coronary occlusion, acute peripheral arterial occlusion, massive pulmonary embolism, axillary vein thrombosis, massive iliofemoral vein thrombosis, occluded arterial or venous cannulae, cardiomyopathy, venoocclusive disease of the liver, hypotension, decreased cardiac output, decreased vascular resistance, pulmonary hypertension, diminished lung compliance, leukopenia or thrombocytopenia. 50. The method of claim 45, wherein the acute or chronic pain is or is associated with neurological pain, neuropathies, polyneuropathies, diabetes-related polyneuropathies, trauma, migraine, tension headache, cluster headache, Horton's disease, varicose ulcers, neuralgias, musculo-skeletal pain, osteo-traumatic pain, fractures, algodystrophy, spondylarthritis, fibromyalgia, phantom limb pain, back pain, vertebral pain, herniated intervertebral disc-induced sciatica, post-surgery pain, cancer-related pain, vascular pain, visceral pain, childbirth, or HIV-related pain. 51. The method of claim 44, wherein the cytokine-mediated disorder is rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejection, pancreatitis, insulinitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, acute synovitis, Reiter's syndrome, gouty arthritis, Behcet's disease, spondylitis, endometriosis, non-articular inflammatory conditions, acute or chronic pain. 52. The method of claim 44, wherein the cytokine-mediated disorder is 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, or atherosclerosis. 53. The method of claim 44, wherein the cytokine-mediated disorder is allergic conjunctivitis, uveitis, glaucoma, optic neuritis, retinal ischemia, diabetic retinopathy, laser induced optic damage, or surgery or trauma-induced proliferative vitreoretinopathy. 54. The method of claim 44, wherein the cytokine-mediated disorder is allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, obliterative bronchiolitis, emphysema, asthma, bronchitis, mucus hypersecretion, SARS infection, silicosis or respiratory tract inflammation. 55. The method of claim 44, wherein the cytokine-mediated disorder is psoriasis, pemphigus, eczema, atopic dermatitis, contact dermatitis, or acne. 56. The method of claim 44, wherein the cytokine-mediated disorder is Guillain-Barre syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelinating 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, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety, schizophrenia, aneurism, or epilepsy. 57. The method of claim 44, wherein the cytokine-mediated disorder is a bone resorption disease, osteopetrosis, osteoporosis, or osteoarthritis. 58. The method of claim 44, wherein the cytokine-mediated disorder is diabetes, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome, obesity, anorexia or bulimia nervosa. 59. The method of claim 44, wherein the cytokine-mediated disorder is sepsis, HIV infection, HCV infection, malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer, Castleman's disease, or drug resistance. 60. The method of claim 44, wherein 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. 61. The method of claim 44, wherein the cytokine mediated disorder is a neutrophil-mediated disorder. 62. The method of claim 61 , wherein the neutrophil-mediated disorder is 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, leukopheresis, granulocyte transfusion associated syndromes, or necrotizing enterocolitis. 63. The method of claim 44, wherein the cytokine is selected from TNFa, IL-I, IL-6, IL-8, GM-CSF, IFN-gamma or a combination of any two or more thereof. 64. The method of claim 63, wherein the cytokine is TNFa or IL-I . 65. The method of claim 44, 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-borne encephalitis, asphyxia, atopic hypersensitivity, beaver fever, biliary cirrhosis, bone loss, bronchiolitis, cancer of endocrine 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, dyslipidemia, edema, end- stage renal disease, epstein-barr virus infections, fever, gastroenteritis, 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, peripheral neuropathy, peritoneal dialysis, pleural disease, pneumonitis, polymyositis, pulmonary fibrosis, renal cancer, renal dialysis, scleroderma, septic arthritis, Sjogren's syndrome, ankylosing spondylitis, Still's disease, toxemia, tuberculosis, urticaria, viral hepatitis, or Wegener's granulomatosis. 66. A method comprising administering to a subject an amount of a cytokine inhibitor effective to reduce a level of a cytokine relative to the level prior to administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10. 67. The method of claim 66, wherein the cytokine is selected from TNFa, IL-I, IL-6, IL-8, GM-CSF, IFN-gamma, or a combination of any two or more thereof. 68. A method comprising exposing a cell to an amount of a cytokine inhibitor 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 cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10. 69. A method comprising contacting p38 with an amount of a cytokine inhibitor effective to inhibit p38 activity, the phosphorylation of p38, or both, wherein the cytokine inhibitor is a compound of claim 10. 70. A method comprising administering to a subject an amount of a cytokine inhibitor effective to reduce the activity of a pro-inflammatory mediator relative to the activity prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10. 71. A method comprising administering to a subject an amount of cytokine inhibitor 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 cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10. 72. A method comprising administering to a subject an amount of a cytokine inhibitor effective to increase the HDL-I evel of the subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10. 73. A method comprising administering to a subject an amount of a cytokine inhibitor effective to decrease the triglyceride-level of the subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10. 74. A method comprising administering to a subject an amount of a cytokine inhibitor effective to decrease the fasting glucose-level in a subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10. 75. A method comprising administering to a subject an amount of a cytokine inhibitor effective to decrease the HbAIc value in the subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10. 76. A method comprising administering to a subject an amount of a cytokine inhibitor effective to decrease the insulin-level in the subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10. 77. A method comprising administering to a subject an amount of a cytokine inhibitor effective to decrease the HOMA Insulin Resistance Index in the subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10. 78. A method comprising administering to a subject an amount of a cytokine inhibitor effective to increase the indirect bilirubin-level in the subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10. 79. A method of preparing a compound of claim 10, the method comprising contacting a compound of Formula III  Formula III with (i) G-COOH in the presence of a coupling agent and a base; or with (ii) G-CO-Z in the presence of a base; under conditions suitable to provide a compound of Formula I; wherein A, B, D, E, X, Y, L2, Q and G are as defined in Formula I, and Z is an activating moiety. 80. A method of preparing a compound of Formula IV  Formula IV the method comprising contacting a compound of Formula V  Formula V with H-C ≡C-L', under conditions suitable to provide a compound of Formula IV; wherein L' is -L2-Q, -(CH2)n-C(O)OPco>or -(CH2)pNR-PN, wherein PCo is a carboxy protecting group, PNis an amine protecting group, and A, X, Y, L2, n, p and Q are as defined in claim 10. 81. A compound of Formula VI,  Formula VI wherein V is an alkyl or cycloalkyl group, optionally partially or fully halogenated; T is -CN, -SO2NR'2, -C(O)NR'2, or -NR' SO2R"; U is-O(Ci-6alkyl); each R' is independently hydrogen, or a substituted or unsubstituted alkyl, aralkyl, heterocyclyl, or heterocyclylalkyl group; and each R" is independently a substituted or unsubstituted alkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl group. 82. A compound of Formula VII3  Formula VII wherein K is a C2-Galkyl or a cycloalkyl group, optionally partially or fully halogenated; J is -CN, -SO2NR'2, or-NR'SOaR"; each R' is independently hydrogen, or a substituted or unsubstituted alkyl, aralkyl, heterocyclyl, or heterocyclylalkyl group; each R" is independently a substituted or unsubstituted alkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl group; and Rpis H or a substituted on unsubstituted alkyl, aralkyl or heterocyclalkyl group. 83. A compound of Formula VIII  Formula VIII wherein Rmis hydrogen or a substituted or unsubstituted Ci .6alkyl group; and m is 0, 1 or 2. 84. The compound of claim 82, wherein Rn, is H. 85. The compound of claim. 10, wherein the compound is selected from List 1.
法律状态
(WO200775896) LEGAL DETAILS FOR WO2007075896  Actual or expected expiration date=2009-06-22    Legal state=DEAD    Status=LAPSED     Event publication date=2006-12-20  Event code=WO/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=WO WOUS2006048803  Application date=2006-12-20  Standardized application number=2006WO-US48803     Event publication date=2007-07-05  Event code=WO/A2  Event type=Examination events  International application published without international search report  Publication country=WO  Publication number=WO2007075896  Publication stage Code=A2  Publication date=2007-07-05  Standardized publication number=WO200775896     Event publication date=2008-03-06  Event code=WO/A3  Event indicator=Pos  Event type=Examination events  Later publication of ISR with revised front page  Publication country=WO  Publication number=WO2007075896  Publication stage Code=A3  Publication date=2008-03-06  Standardized publication number=WO200775896     Event publication date=2009-06-22  Event code=WO/EETL  Event type=Event indicating Not In Force  PCT Application validity period expired. LEGAL DETAILS FOR DESIGNATED STATE DE  Actual or expected expiration date=2008-06-24    Legal state=DEAD    Status=LAPSED   Corresponding cc:  Designated or member state=DE     Event publication date=2008-06-24  Event code=WO/NENP  Event type=Event indicating Not In Force  Non-entry into the national phase in: Corresponding cc:  Designated or member state=DE
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