Claims
- 1. A compound of Formula (I):
- 2. The compound of claim 1 wherein Y is selected from the group consisting of —C(O)—and —SO2—.
- 3. The compound of claim 1 wherein Y is selected from —SO2—.
- 4. The compound of claim 1 wherein R1 is selected from R7.
- 5. The compound of claim 1 wherein R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen and C1-4alkyl.
- 6. The compound of claim 1 wherein R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen and methyl.
- 7. The compound of claim 1 wherein R6 is optionally present and is one to three substituents independently selected from the group consisting of halogen, C1-8alkoxy, R10, R12, —N(R11)C(O)—R10, —N(R11)C(O)—R12, —N(R11)SO2—R10—,—N(R11)C(O)—N(R11,R12), —N(R11)C(O)—N(R12, R17), —OC(O)—N(R11R12), —OC(O)—N(R12,R17), —OC(O)—R10 and R10—(C1-8)alkoxy.
- 8. The compound of claim 1 wherein R6 is optionally present and is one to three substituents independently selected from the group consisting of halogen, C1-4alkoxy, R10, R12, —N(R11)C(O)—R10, —N(R11)C(O)—R12, —N(R11)SO2—R10—, —N(R11)C(O)—N(R11,R12), —N(R11)C(O)—N(R12, R17), —OC(O)—N(R11,R12), —OC(O)—N(R12,R17), —OC(O)—R10 and R10—(C1-4)alkoxy.
- 9. The compound of claim 1 wherein R6 is optionally present and is one to two substituents independently selected from the group consisting of R10, —N(R11)C(O)—R10, —N(R11)C(O)—N(R11,R12), —N(R11)C(O)—N(R12,R17), —OC(O)—N(R11,R12), —OC(O)—N(R12,R17) and R10-methoxy.
- 10. The compound of claim 1 wherein R7 is selected from the group consisting of aryl and heteroaryl optionally substituted with one to five substituents independently selected from the group consisting of halogen, C1-8alkyl, C2alkenyl, C2-8alkynyl, C1-8alkoxy, C1-8alkylcarbonyl, C1-8alkoxycarbonyl, carboxyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, amino, N—(C1-8alkyl)amino, N,N—(C1-8dialkyl)amino, —CF3 and —OCF3; and, wherein the aryl and heteroaryl substituents and the aryl portion of the arylcarbonyl substituent are optionally substituted with one to five substituents independently selected from the group consisting of halogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C1-8alkoxy, carboxyl, amino, N—(C1-8alkyl)amino, N,N—(C1-8dialkyl)amino, —CF3 and —OCF3.
- 11. The compound of claim 1 wherein R10 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted with one to five substituents independently selected from the group consisting of halogen, C1-8alkyl, C1-8alkoxy, C1-8alkoxycarbonyl, carboxyl, arylcarbonyl, arylsulfonyl, —CF3 and —OCF3; wherein cycloalkyl and heterocyclyl are optionally substituted with one to three oxo substituents; and, wherein the aryl portion of the arylcarbonyl substituent is optionally substituted with one to five substituents independently selected from C1-8alkoxy.
- 12. The compound of claim 1 wherein R10 is selected from the group consisting of cyclopropyl, 1,3-dihydro-2H-isoindolyl, 2-azabicyclo[2.2.2]octyl, piperidinyl, morpholinyl, phenyl, naphthalenyl, thienyl, 1H-pyrrolyl and pyridinyl; wherein cyclopropyl, piperidinyl, morpholinyl, phenyl, naphthalenyl, thienyl, 1H-pyrrolyl and pyridinyl are optionally substituted with one to four substituents independently selected from the group consisting of chlorine, fluorine, bromine, methyl, isopropyl, t-butyl, methoxy, t-butoxycarbonyl, carboxyl, phenylcarbonyl, —CF3 and —OCF3; wherein 1,3-dihydro-2H-isoindolyl is optionally substituted with oxo; wherein 2-azabicyclo[2.2.2]octyl is optionally substituted with phenylsulfonyl, and, wherein the phenyl portion of the phenylcarbonyl substituent is optionally substituted with one to two substituents independently selected from methoxy.
- 13. The compound of claim 1 wherein R12 is selected from the group consisting of C1-8alkyl and C2-8alkynyl optionally substituted on a terminal carbon with R14.
- 14. The compound of claim 1 wherein R12 is selected from the group consisting of C1-4alkyl and C2-4alkynyl optionally substituted on a terminal carbon with R14.
- 15. The compound of claim 1 wherein R12 is selected from the group consisting of t-butyl and ethynyl; wherein ethynyl is optionally substituted on a terminal carbon with a substituent independently selected from R14.
- 16. The compound of claim 1 wherein R14 is selected from the group consisting of aryl optionally substituted with one to five substituents independently selected from the group consisting of halogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C1-8alkoxy, C1-8alkylcarbonyl, C1-8alkoxycarbonyl, carboxyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, amino, N—(C1-8alkyl)amino, N,N—(C1-8dialkyl)amino, —CF3 and —OCF3; and, wherein the aryl and heteroaryl substituents and the aryl portion of the arylcarbonyl substituent are optionally substituted with one to five substituents independently selected from the group consisting of halogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C1-8alkoxy, carboxyl, amino, N—(C1-8alkyl)amino, N,N—(C1-8dialkyl)amino, —CF3 and —OCF3.
- 17. The compound of claim 1 wherein R11 is selected from the group consisting of hydrogen and C1-4alkyl.
- 18. The compound of claim 1 wherein R11 is hydrogen.
- 19. The compound of claim 1 wherein A is selected from the group consisting of methylene and ethylene.
- 20. The compound of claim 1 wherein B1 and B2 are independently selected from the group consisting of C1-4alkylene and C2-4alkenylene optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, hydroxy(C1-4)alkyl, hydroxy(C1-4)alkoxy, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, carboxyl, amino, N—(C1-4alkyl)amino, N,N—(C1-4dialkyl)amino, —CF3 and —OCF3.
- 21. The compound of claim 1 wherein B1 and B2 are independently selected from the group consisting of —CH2—, —(CH2)2— and —(CH)2— optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, hydroxy(C1-4)alkyl, hydroxy(C1-4)alkoxy, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, carboxyl, amino, N—(C1-4alkyl)amino, N,N—(C1-4dialkyl)amino, —CF3 and —OCF3.
- 22. The compound of claim 1 wherein B1 is selected from the group consisting of —CH2—, —(CH2)2— and —(CH)2— optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, hydroxy(C1-4)alkyl, hydroxy(C1-4)alkoxy, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, carboxyl, amino, N—(C1-4alkyl)amino, N,N—(C1-4dialkyl)amino, —CF3 and —OCF3; and, wherein, B2 is selected from —(CH2)2—.
- 23. The compound of claim 1 wherein B1 is selected from the group consisting of —CH2—, —(CH2)2— and —(CH)2—.
- 24. The compound of claim 1 wherein the compound of Formula (I) is selected from a compound of the formula:
- 25. A compound having Formula (II):
- 26. A process for preparing a compound of Formula (III):
- 27. The process of claim 25 wherein R15 is selected from the group consisting of hydroxy, iodine, bromine and NO2.
- 28. The compound of claim 1 wherein the compound of Formula (I) is selected from a compound of the formula:
- 29. The compound of claim 1 wherein the compound of Formula (I) is selected from a compound of the formula:
- 30. The compound of claim 1 wherein the compound of Formula (I) is selected from a compound of the formula:
- 31. The compound of claim 1 wherein the compound of Formula (I) is selected from a compound of the formula:
- 32. The compound of claim 1 wherein the compounds are effective antagonists of an integrin receptor.
- 33. The compound of claim 32 wherein the compound is a selective antagonist of an α4 integrin receptor.
- 34. The compound of claim 33 wherein the α4 integrin receptor is selected from the group consisting of the α4β1 and α4β7 integrin receptor.
- 35. The compound of claim 32 wherein the compound is an antagonist of at least two α4 integrin receptors.
- 36. The compound of claim 35 wherein the two α4 integrin receptors are selected from the group consisting of the α4β1 and α4β7 integrin receptor.
- 37. The compound of claim 1 wherein the compounds are effective agents for the treatment of an integrin mediated disorder ameliorated by selective inhibition of the α4β1 integrin receptor.
- 38. The compound of claim 1 wherein the compounds are effective agents for the treatment of an integrin mediated disorder ameliorated by selective inhibition of the α4β7 integrin receptor.
- 39. The compound of claim 1 wherein the compounds are effective agents for the treatment of an integrin mediated disorder ameliorated by inhibition of the α4β1 and α4β7 integrin receptor.
- 40. The compound of claim 1 wherein the compounds are effective agents for the treatment of integrin mediated disorder selected from the group consisting of inflammatory disorders, autoimmune disorders and cell-proliferative disorders.
- 41. The compound of claim 40 wherein the integrin mediated disorder is selected from the group consisting of inflammation disorders, autoimmunity disorders, asthma, bronchoconstriction, restenosis, atherosclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, irritable bowel disease, irritable bowel syndrome, transplant rejection and multiple sclerosis.
- 42. The compound of claim 40 wherein the integrin mediated disorder is selected from the group consisting of asthma, bronchoconstriction, restenosis, atherosclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, irritable bowel disease, irritable bowel syndrome, transplant rejection and multiple sclerosis.
- 43. The compound of claim 40 wherein the integrin mediated disorder is selected from the group consisting of asthma, bronchoconstriction, restenosis, atherosclerosis, irritable bowel syndrome and multiple sclerosis.
- 44. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
- 45. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
- 46. A method for the treatment of an integrin mediated disorder ameliorated by inhibition of an α4 integrin receptor comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1.
- 47. The method of claim 46 wherein the compound inhibiting the α4 integrin receptor is selected from the group consisting of a selective antagonist of an α4 integrin receptor and an antagonist of at least two α4 integrin receptors.
- 48. The method of claim 47 wherein the α4 integrin receptor is selected from the group consisting of the α4β1 and α4β7 integrin receptor.
- 49. The method of claim 46 wherein the compound inhibiting the α4 integrin receptor is selected from the group consisting of a selective antagonist of the α4β1 integrin receptor, a selective antagonist of the α4β7 integrin receptor and an antagonist of the α4β1 and α4β7 integrin receptors.
- 50. The method of claim 46 wherein the integrin mediated disorder is selected from the group consisting of inflammatory disorders, autoimmune disorders and cell-proliferative disorders.
- 51. The method of claim 46 wherein the integrin mediated disorder is selected from the group consisting of inflammation disorders, autoimmunity disorders, asthma, bronchoconstriction, restenosis, atherosclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, irritable bowel disease, irritable bowel syndrome, transplant rejection and multiple sclerosis.
- 52. The compound of claim 46 wherein the integrin mediated disorder is selected from the group consisting of asthma, bronchoconstriction, restenosis, atherosclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, irritable bowel disease, irritable bowel syndrome, transplant rejection and multiple sclerosis.
- 53. The compound of claim 46 wherein the integrin mediated disorder is selected from the group consisting of asthma, bronchoconstriction, restenosis, atherosclerosis, irritable bowel syndrome and multiple sclerosis.
- 54. The method of claim 46 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.01 mg/kg/day to about 300 mg/kg/day.
- 55. The method of claim 46 further comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 44.
- 56. The method of claim 55 wherein the therapeutically effective amount of the pharmaceutical composition of claim 44 is from about 0.01 mg/kg/day to about 300 mg/kg/day.
- 57. The compound of claim 1 wherein R7 is selected from the group consisting tolyl, phenyl and thienyl.
FIELD OF THE INVENTION
[0001] This patent application claims benefit of U.S. patent application Ser. No. 60/215,695 filed on Jun. 30, 2000 entitled “AZA-BICYCLIC AMINO ACID DERIVATIVES AS α4 INTEGRIN ANTAGONISTS”, which is hereby incorporated by reference. This invention relates to novel compounds and methods for use in treating integrin mediated disorders. More particularly, this invention relates to novel derivatives of aza-bridged-bicyclic amino acid compounds useful as α4 integrin receptor antagonists, methods for treating integrin mediated disorders including, but not limited to, inflammatory, autoimmune and cell-proliferative disorders, methods for preparing the compounds and methods for preparing the intermediates, derivatives and pharmaceutical compositions thereof.
Provisional Applications (1)
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Number |
Date |
Country |
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60215695 |
Jun 2000 |
US |