Claims
- 1. A compound having the structure:
- 2. The compound of claim 1 wherein:
R2 is —R4, —(CH2)bC(═O)R5, —(CH2)bC(═O)OR5, —(CH2)bC(═O)NR5R6, —(CH2)bC(═O)NR5(CH2)cC(═O)R6, —(CH2)bNR5C(═O)R6, —(CH2)bNR5C(═O)NR6R7, —(CH2)bNR5R6, —(CH2)bOR5, —(CH2)bSOdR5 or —(CH2)bSO2NR5R6.
- 3. The compound of claim 1 wherein A is a direct bond.
- 4. The compound of claim 1 wherein A is —(CH2)a—.
- 5. The compound of claim 1 wherein A is —(CH2)bCH═CH(CH2)c—.
- 6. The compound of claim 1 wherein A is —(CH2)bC≡C(CH2)c—.
- 7. The compound of claim 1 wherein R1 is aryl optionally substituted with one four substituents independently selected from R3.
- 8. The compound of claim 1 wherein R1 is heteroaryl optionally substituted with one to four substituents independently selected from R3.
- 9. The compound of claim 1 wherein R1 is heterocycle fused to phenyl optionally substituted with one to four substituents independently selected from R3.
- 10. The compound of claim 1 wherein R2 is —(CH2)bC(═O)R5.
- 11. The compound of claim 1 wherein R2 is —(CH2)bC(═O)NR5R6.
- 12. The compound of claim 1 wherein R2 is —(CH2)bNR5C(═O)R6.
- 13. The compound of claim 1 wherein R2 is —(CH2)bNR5R6.
- 14. The compound of claim 1 wherein R2 is R4.
- 15. The compound of claim 14 wherein R4 is substituted alkyl.
- 16. The compound of claim 14 wherein R4 is substituted arylalkyl.
- 17. The compound of claim 14 wherein R4 is substituted heterocycle.
- 18. The compound of claim 14 wherein R4 is 3-triazolyl, optionally substituted at its 5-position with:
(a) a C1-C4 straight or branched chain alkyl group optionally substituted with a hydroxyl, methylamino, dimethylamino or 1-pyrrolidinyl group; or (b) a 2-pyrrolidinyl group.
- 19. The compound of claim 14 wherein R4 is tetrazole.
- 20. The compound of claim 14 wherein R4 is imidazole.
- 21. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
- 22. A method for treating a condition responsive to JNK inhibition, comprising administering to a patient in need thereof an effective amount of a compound having the structure:
- 23. The method of claim 22 wherein:
R2 is —R4, —(CH2)bC(═O)R5, —(CH2)bC(═O)OR5, —(CH2)bC(═O)NR5R6, —(CH2)bC(═O)NR5(CH2)cC(═O)R6, —(CH2)bNR5C(═O)R6, —(CH2)bNR5C(═O)NR6R7, —(CH2)bNR5R6, —(CH2)bOR5, —(CH2)bSOdR5 or —(CH2)bSO2NR5R6.
- 24. The method of claim 22 wherein the condition is cancer.
- 25. The method of claim 22 wherein the condition is rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout; asthma, bronchitis; allergic rhinitis; chronic obstructive pulmonary disease; cystic fibrosis; inflammatory bowel disease; inritable bowel syndrome; mucous colitis; ulcerative colitis; Crohn's disease; Huntington's disease; gastritis; esophagitis; hepatitis; pancreatitis; nephritis; multiple sclerosis; endotoxin shock; lupus erythematosus; Type II diabetes; psoriasis; burn caused by exposure to fire, chemicals or radiation; eczema; denmatitis; skin graft; ischemiiia; ischemic conditions associated with surgery or traumatic injury; cachexia or angiogenic and proliferative diseases.
- 26. The method of claim 22 wherein the condition is atherosclerosis, restenosis following angioplasty, left ventricular hypertrophy, or myocardial infarction.
- 27. The method of claim 22 wherein the condition is stroke or ischemic damages of heart, lung, gut, kidney, liver, pancreas, spleen or brain.
- 28. The method of claim 22 wherein the condition is acute or chronic organ transplant rejection, preservation of the organ for transplantation, graft versus host disease or multiple organ failure.
- 29. The method of claim 22 wherein the condition is epilepsy, Alzheimer's disease, or Parkinson's disease.
- 30. The method of claim 22 wherein the condition is an immunological response to bacterial or viral infection.
- 31. The method of claim 22 wherein the condition is solid tumor or cancers of a variety of tissues such as colon, rectum, prostate, liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, mouth, pharynx, urinary bladder, ovary or uterine.
- 32. The method of claim 22 wherein A is a direct bond.
- 33. The method of claim 22 wherein A is —(CH2)a—.
- 34. The method of claim 22 wherein A is —(CH2)bCH═CH(CH2)c—.
- 35. The method of claim 22 wherein A is —(CH2)bC≡C(CH2)c—.
- 36. The method of claim 22 wherein R1 is aryl optionally substituted with one to four substituenits independently selected from R3.
- 37. The method of claim 22 wherein R1 is heteroaryl optionally substituted with one to four substituenits independently selected from R3.
- 38. The method of claim 22 wherein R1 is heterocycle fused to phenyl optionally substituted with one to four substituents independently selected from R3.
- 39. The method of claim 22 wherein R2 is —(CH2)bC(═O)R5.
- 40. The method of claim 22 wherein R2 is —(CH2)bC(═O)NR5R6.
- 41. The method of claim 22 wherein R2 is —(CH2)NR5C(═O)R6.
- 42. The method of claim 22 wherein R2 is —(CH2)bNR5R6.
- 43. The method of claim 22 wherein R2 is R4.
- 44. The method of claim 43 wherein R4 is substituted alkyl.
- 45. The method of claim 43 wherein R4 is substituted arylalkyl.
- 46. The method of claim 43 wherein R4 is substituted heterocycle.
- 47. The method of claim 43 wherein R4 is 3-triazolyl, optionally substituted at its 5-position with:
(a) a C1-C4 straight or branched chain alkyl group optionally substituted with a hydroxyl, methylamino, dimethylamino or 1-pyrrolidinyl group; or (b) a 2-pyrrolidinyl group.
- 48. The method of claim 43 wherein R4 is tetrazole.
- 49. The method of claim 43 wherein R4 is imidazole.
- 50. A method for treating or preventing rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout; asthma, bronchitis; allergic rhinitis; chronic obstructive pulmonary disease; cystic fibrosis; inflammatory bowel disease; irritable bowel syndrome; mucous colitis; ulcerative colitis; Crohn's disease; Huntington's disease; gastritis; esophagitis; hepatitis; pancreatitis; nephritis; multiple sclerosis; lupus erythematosus; Type II diabetes; atherosclerosis; restenosis following angioplasty; left ventricular hypertrophy; myocardial infarction; stroke; ischemiic damages of heart, lung, gut, kidney, liver, pancreas, spleen and brain; acute or chronic organ transplant rejection; preservation of an organ for transplantation; graft versus host disease; endotoxin shock; multiple organ failure; psoriasis; burn caused by exposure to fire, chemicals, or radiation; eczema; dennatitis; skin graft; ischemia; ischemic conditions associated with surgery or traumatic injury; epilepsy; Alzheimer's disease; Parkinson's disease; immunological response to bacterial or viral infection; cachexia; angiogenic and proliferative dieseases; solid tumor; and cancers of a variety of tissues such as colon, rectum, prostate, liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, mouth, pharynx, urinary bladder, ovary, or uterine comprising administering to a patient in need of such treatment or prevention an effective amount of a compound having the structure:
- 51. The method of claim 50 wherein:
R2 is —R4, —(CH2)bC(═O)R5, —(CH2)bC(═O)OR5, —(CH2)bC(═O)NR5R6, —(CH2)bC(═O)NR5(CH2)cC(═O)R6, —(CH2)bNR5C(═O)R6, —(CH2)bNR5C(═O)NR6R7, —(CH2)bNR5R6, —(CH2)bOR5, —(CH2)bSOdR5 or —(CH2)bSO2NR5R6.
- 52. The method of claim 50 wherein A is a direct bond.
- 53. The method of claim 50 wherein A is —(CH2)a—.
- 54. The method of claim 50 wherein A is —(CH2)bCH═CH(CH2)c—.
- 55. The method of claim 50 wherein A is —(CH2)bC≡C(CH2)c—.
- 56. The method of claim 50 wherein R1 is aryl optionally substituted with one to four substituents independently selected from R3.
- 57. The method of claim 50 wherein R1 is heteroaryl optionally substituted with one to four substituents independently selected from R3.
- 58. The method of claim 50 wherein R1 is heterocycle fused to phenyl optionally substituted with one to four substituents independently selected from R3.
- 59. The method of claim 50 wherein R2 is —(CH2)bC(═O)R5.
- 60. The method of claim 50 wherein R2 is —(CH2)bC(═O)NR5R6.
- 61. The method of claim 50 wherein R2 is —(CH2)NR5C(═O)R6.
- 61. The method of claim 50 wherein R2 is —(CH2)bNR5R6.
- 63. The method of claim 50 wherein R2 is R4.
- 64. The method of claim 63 wherein R4 is substituted alkyl.
- 65. The method of claim 63 wherein R4 is substituted arylalkyl.
- 66. The method of claim 63 wherein R4 is substituted heterocycle.
- 67. The method of claim 63 wherein R4 is 3-triazolyl, optionally substituted at its 5-position with:
(a) a C1-C4 straight or branched chain alkyl group optionally substituted with a hydroxyl, methylamino, dimethylamino or 1-pyrrolidinyl group; or (b) a 2-pyrrolidinyl group.
- 68. The method of claim 63 wherein R4 is tetrazole.
- 69. The method of claim 63 wherein R4 is imidazole.
- 70. The compound of claim 1, wherein —A—R1 is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —NR8C(═O)R9, —C(═O)NR8R9, and —O(CH2)bNR8R9, wherein b is 2 or 3.
- 71. The compound of claim 1, wherein R2 is —(CH2)bC(═O)NR5R6, —(CH2)bNR5C(═O)R6, 3-triazolyl or 5-tetrazolyl, wherein b is 0.
- 72. The compound of claim 1, wherein R2 is 3-triazolyl or 5-tetrazolyl.
- 73. The compound of claim 1, wherein:
(a) —A—R1 is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —NR8C(═O)R9, —C(═O)NR8R9, and —O(CH2)bNR8R9 wherein b is 2 or 3; and (b) R2 is —(CH2)bC(═O)NR5R6, —(CH2)bNR5C(═O)R6, 3-triazolyl or 5-tetrazolyl, wherein b is 0..
- 74. The compound of claim 1, wherein
(a) 13 A—R1 is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —NR8C(═O)R9, —C(═O)NR8R9, and —O(CH2)bNR8R9, wherein b is 2 or 3; and (b) R2 is 3-triazolyl or 5-tetrazolyl.
- 75. The method of claim 22, wherein —A—R1 is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —NR8C(═O)R9, —C(═O)NR8R9, and —O(CH2)bNR8R9, wherein b is 2 or 3.
- 76. The method of claim 22, wherein R2 is —(CH2)bC(═O)NR5R6, —(CH2)bNR5C(═O)R6, 3-triazolyl or 5-tetrazolyl, wherein b is 0.
- 77. The method of claim 22, wherein R2 is 3-triazolyl or 5-tetrazolyl.
- 78. The method of claim 22, wherein:
(a) —A—R1 is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —NR8C(═O)R9, —C(═O)NR8R9, and —O(CH2)bNR8R9, wherein b is 2 or 3; and (b) R2 is —(CH2)bC(═O)NR5R6, —(CH2)bNR5C(═O)R6, 3-triazolyl or 5-tetrazolyl, wherein b is 0.
- 79. The method of claim 22, wherein
(a) —A—R1 is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —NR8C(═O)R9, —C(═O)NR8R9, and —O(CH2)bNR8R9, wherein b is 2 or 3; and (b) R2 is 3-triazolyl or 5-tetrazolyl.
- 80. The method of claim 50, wherein —A—R1 is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —NR8C(═O)R9, —C(═O)NR8R9, and —O(CH2)bNR8R9, wherein b is 2 or 3.
- 81. The method of claim 50, wherein R2 is —(CH2)bC(═O)NR5R6, —(CH2)bNR5C(═O)R6, 3-triazolyl or 5-tetrazolyl, wherein b is 0.
- 82. The method of claim 50, wherein R2 is 3-triazolyl or 5-tetrazolyl.
- 83. The method of claim 50, wherein:
(a) —A—R1 is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —NR8C(═O)R9, —C(═O)NR8R9, and —O(CH2)bNR8R9, wherein b is 2 or 3; and (b) R2 is —(CH2)bC(═O)NR5R6, —(CH2)bNR5C(═O)R6, 3-triazolyl or 5-tetrazolyl, wherein b is 0.
- 84. The method of claim 50, wherein:
(a) —A—R1 is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —NR8C(═O)R9, —C(═O)NR8R9, and —O(CH2)bNR8R9 wherein b is 2 or 3; and (b) R2 is 3-triazolyl or 5-tetrazolyl.
- 85. The compound of claim 18 wherein R4 is methyl, n-propyl, isopropyl, 1-hydroxyethyl, 3-hydroxypropyl, methylaminomethyl, dimethylaminomethyl, 1-(dimethylamino)ethyl, 1-pyrrolidinylmethyl or 2-pyrrolidinyl.
- 86. The method of claim 47 wherein R4 is methyl, n-propyl, isopropyl, 1-hydroxyethyl, 3-hydroxypropyl, methylaminomethyl, dimethylaminomethyl, 1-(dimethylamino)ethyl, 1-pyrrolidinylmethyl or 2-pyrrolidinyl.
- 87. The method of claim 67 wherein R4 is methyl, n-propyl, isopropyl, 1-hydroxyethyl, 3-hydroxypropyl, methylaminomethyl, dimethylaminomethyl, 1-(dimethylamino)ethyl, 1-pyrrolidinylmethyl or 2-pyrrolidinyl.
Parent Case Info
[0001] This application claims the benefit of U.S. Provisional Application No. 60/221,799, filed Jul. 31, 2000.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60221799 |
Jul 2000 |
US |
Continuations (1)
|
Number |
Date |
Country |
Parent |
09910950 |
Jul 2001 |
US |
Child |
10673121 |
Sep 2003 |
US |