Boron-containing small molecules as anti-inflammatory agents 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
WO2007095638 A2 2007-08-23 [WO200795638]WO2007095638 A3 2008-07-31 [WO200795638] / 2007-08-232008-07-31
申请号/申请日
2007WO-US62350 / 2007-02-16
发明人
BAKER STEPHEN J;SANDERS VIRGINIA;AKAMA TSUTOMU;BELLINGER-KAWAHARA CAROLYN;FREUND YVONNE;MAPLES KIRK R;PLATTNER JACOB J;ZHANG YONG-KANG;ZHOU HUCHEN;HERNANDEZ VINCENT S;
申请人
ANACOR PHARMACEUTICALS;
主分类号
IPC分类号
A01N-055/08A61K-031/69
摘要
(WO200795638) Methods of treating anti-inflammatory conditions through the use of boron-containing small molecules are disclosed.
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
2006US-60774532 2006-02-16 2006US-60823888 2006-08-29
主权利要求
(WO200795638) WHAT IS CLAIMED IS: 1. A method of treating or preventing an inflammatory-related disease in a human or an animal, said method comprising administering to the human or the animal a therapeutically effective amount of a compound having a structure according to Formula I: wherein B is boron; Rlais a member selected from a negative charge, a salt counterion, H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; M is a member selected from oxygen, sulfur and NR2a; R2ais a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; J is a member selected from (CR3aR4a)ni and CR5a; R3a, R4a, and R5aare members independently selected from H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; nl is an integer selected from 0 to 2; W is a member selected from C=O (carbonyl), (CR6aR7a)mi and CR8a; R6a, R7a, and R8aare members independently selected from H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; ml is an integer selected from 0 and 1; A is a member selected from CR9aand N; D is a member selected from CR1Oaand N; E is a member selected from CRllaand N; G is a member selected from CR12aand N; R9a, R1Oa, Rllaand R12aare members independently selected from H, OR*, NR=15R**, SR*, -S(O)R*, -S(O)2R*, -S(O)2NR*R**, - C(O)R*, -C(O)OR*, -C(0)NR*R**, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; wherein each R* and R** are members independently selected from H, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; the combination of nitrogens (A + D + E + G) is an integer selected from 0 to 3; a member selected from R3a, R4aand R5aand a member selected from R6a, R7aand R8a, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring; R3aand R4a, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring; R6aand R7a, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring; R9aand R1Oa, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring; R1Oaand Rl la, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring; Rl laand R12a, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring. 2. The method of claim 1, further comprising administering said compound as part of a pharmaceutical formulation, said formulation further comprising a pharmaceutically acceptable excipient. 3. The method of claim 1, wherein said compound has a structure according to:  4. The method of claim 1, wherein said compound has a structure according to: wherein R , 1aais a member selected from substituted or unsubstituted Ci-C6alkyl and substituted or unsubstituted Ci-C6heteroalkyl; Rlband Rlcare members independently selected from H, OH, NH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. 5. The method of claim 3, wherein said compound has a structure according to: wherein R > 4aais a member selected from H, methyl, ethyl and substituted or unsubstituted aryl and substituted or unsubstituted arylalkyl; R1Oais a member selected from H, halogen, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkoxy, substituted or unsubstituted arylthio and substituted or unsubstituted arylalkylthio; and Rl lais a member selected from H, OH, methyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkoxy, substituted or unsubstituted arylthio and substituted or unsubstituted arylalkylthio. 6. The method of claim 5, wherein said compound has a structure according to the following formula:  7. The method of claim 6, wherein R lOaais a member selected from wherein R15is a member selected from CN, COOH and ; R16and R17are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; p is an integer selected from 1 to 5; z is an integer selected from 1 to 8; and X is a member selected from S and O. 8. The method of claim 3, wherein said compound has a structure according to: wherein R > 4aais a member selected from substituted or unsubstituted aryl and substituted or unsubstituted arylalkyl; R , 10aais a member selected from H, halogen, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkoxy, substituted or unsubstituted arylthio and substituted or unsubstituted arylalkylthio. 9. The method of claim 7, wherein said compound is a member selected from:  10. The method of claim 3, wherein said compound is  11. The method of claim 3, wherein said compound is a member selected from:  12. The method of claim 1, wherein said compound is a member selected from:  13. The method of claim 3, wherein R laa . is H. 14. The method of claim 3, wherein R lOa and R , 11a are H 15. The method of claim 3, wherein one member selected from R lOa and Rl lais H and the other member selected from R1Oaand Rl lais a member sele from halogen, methyl, cyano, methoxy, hydroxymethyl and p-cyanophenyloxy. 16. The method of claim 3, wherein R1Oaand R1 laare members independently selected from fluoro, chloro, methyl, cyano, methoxy, hydroxymethyl, and p-cyanophenyl. 17. The method of claim 1, wherein the compound is in an amount sufficient to treat the inflammatory-related disease by inhibiting pro-inflammatory cytokine expression or by stimulating anti-inflammatory cytokine expression, but the amount is less than sufficient to substantially inhibit cyclin dependent kinases. 18. The method of claim 17, wherein the compound is 5 -(4- cyanophenoxy)- 1 ,3-dihydro- 1 -hydroxy-2, 1 -benzoxaborole. 19. The method of claim 1, wherein the disease is a member selected from arthritis, rheumatoid arthritis, an inflammatory bowel disease, psoriasis, multiple sclerosis, a neurodegenerative disorder, congestive heart failure, stroke, aortic valve stenosis, kidney failure, lupus, pancreatitis, allergy, fibrosis, anemia, atherosclerosis, a metabolic disease, a bone disease, a cardiovascular disease, a chemotherapy/radiation related complication, diabetes type I, diabetes type II, a liver disease, a gastrointestinal disorder, an ophthamological disease, allergic conjunctivitis, diabetic retinopathy, Sjogren's syndrome, uvetitis, a pulmonary disorder, a renal disease, dermatitis, HIV-related cachexia, cerebral malaria, ankylosing spondolytis, leprosy, anemia and fibromyalgia. 20. The method of claim 19, wherein the compound is 5-(4- cyanophenoxy)- 1 ,3-dihydro- 1 -hydroxy-2, 1 -benzoxaborole. 21. The method of claim 19, wherein the neurodegenerative disorder is a member selected from Alzheimer's disease and Parkinson disease, the inflammatory bowel disease is a member selected from Crohn's disease or uncerative colitis; the gastrointestinal complication is diarrhea; the liver disease is a member selected from an autoimmune hepatitis, hepatitis C, primary biliary cirrhosis, primary sclerosing cholangitis and fulminant liver failure; the gastrointestinal disorder is a member selected from celiac disease and non-specific colitis; the pulmonary disorder is a member selected from allergic rhinitis, asthma, chronic obstructive pulmonary disease, chronic granulomatous inflammation, cystic fibrosis, and sarcoidosis; the cardiovascular disease is a member selected from atheroscleotic cardiac disease, congestive heart failure and restenosis; and the renal disease is a member selected from glomerulpnephritis and vasculitis. 22. The method of claim 21, wherein the compound is 5 -(4- cyanophenoxy)- 1 ,3-dihydro- 1 -hydroxy-2, 1 -benzoxaborole. 23. The method according to claim 1, wherein the compound is administered at a concentration sufficient to inhibit a cytokine which is a member selected from IL- lα, β, IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, IL-23,TNF- α, LT, LIF, Oncostatin, and IFNc lα, β, γ. 24. The method of claim 23, wherein the compound is 5 -(4- cyanophenoxy)- 1 ,3-dihydro- 1 -hydroxy-2, 1 -benzoxaborole. 25. The method according to claim 1, where the compound is administered at a concentration sufficient to stimulate expression of a cytokine which is a member selected from IL-4, IL- 10, IL- 11 , W- 13 and TGF-β. 26. The method of claim 25, wherein the compound is 5-(4- cyanophenoxy)- 1 ,3-dihydro- 1 -hydroxy-2, 1 -benzoxaborole. 27. A method of treating an inflammatory-related disease associated with cytokine expression levels, which comprises administering to a human or an animal in need of such treatment the compound of claim 1. 28. The method of claim 27, wherein the compound is 5 -(4- cyanophenoxy)- 1 ,3-dihydro- 1 -hydroxy-2, 1 -benzoxaborole. 29. The method of claim 1, wherein the compound is in an amount sufficient to treat the inflammatory-related disease by inhibiting pro-inflammatory cytokine expression or by stimulating anti-inflammatory cytokine expression, but the amount is less than sufficient to substantially inhibit cyclin dependent kinases. 30. The method of claim 29, wherein the compound is 5-(4- cyanophenoxy)- 1 ,3-dihydro- 1 -hydroxy-2, 1 -benzoxaborole. 31. The method of claim 1, wherein the animal is a human being. 32. A method for inhibiting the production of an inflammatory cytokine protein by cells capable of producing said inflammatory cytokine protein, said method comprising: combining said cells with a therapeutic amount of the compound of claim 1, wherein production of said inflammatory cytokine by said cells is inhibited. 33. The method of claim 32, wherein the compound is 5-(4- cyanophenoxy)- 1 ,3-dihydro- 1 -hydroxy-2, 1 -benzoxaborole. 34. The method according to claim 32, wherein said therapeutic amount is sufficient to inhibit the production of said inflammatory cytokine protein between about 50% and about 99%. 35. A method for inhibiting an inflammatory response in a human or an animal, said method comprising: contacting said human or animal with a therapeutic amount of the compound of claim 1, wherein said inflammatory response is inhibited. 36. The method of claim 35, wherein the compound is 5-(4- cyanophenoxy)- 1 ,3-dihydro- 1 -hydroxy-2, 1 -benzoxaborole. 37. A method of treating or preventing an inflammatory-related disease in a human or an animal, said method comprising administering to the human or the animal a therapeutically effective amount of a compound having a structure according to Formula II: wherein B is boron; R20, R21and R22are members independently selected from a negative charge, a salt counterion, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; A is a member selected from CR9aand N; D is a member selected from CR1Oaand N; E is a member selected from CRllaand N; G is a member selected from CR12aand N; wherein R9a, R1Oa, R1 laand R12aare members independently selected from H, OR*, NR=15R**, SR*, -S(O)R*, -S(O)2R*, -S(O)2NR*R**, - C(O)R*, -C(O)OR*, -C(O)NR*R**, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; wherein each R* and R** are members independently selected from H, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; wherein R9aand R1Oa, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring; R1Oaand Rl la, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring; and Rl laand R12a, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring. 38. The method of claim 37, wherein said compound has a structure according to:  39. The method of claim 37, wherein said compound is a member selected from:
法律状态
(WO200795638) LEGAL DETAILS FOR WO2007095638  Actual or expected expiration date=2010-02-28    Legal state=DEAD    Status=LAPSED     Event publication date=2007-02-16  Event code=WO/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=WO WOUS2007062350  Application date=2007-02-16  Standardized application number=2007WO-US62350     Event publication date=2007-08-23  Event code=WO/A2  Event type=Examination events  International application published without international search report  Publication country=WO  Publication number=WO2007095638  Publication stage Code=A2  Publication date=2007-08-23  Standardized publication number=WO200795638     Event publication date=2008-07-31  Event code=WO/A3  Event indicator=Pos  Event type=Examination events  Later publication of ISR with revised front page  Publication country=WO  Publication number=WO2007095638  Publication stage Code=A3  Publication date=2008-07-31  Standardized publication number=WO200795638     Event publication date=2010-02-28  Event code=WO/EETL  Event type=Event indicating Not In Force  PCT Application validity period expired. 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