Monocyclic and bicyclic himbacine derivatives useful as thrombin receptor antagonists

Abstract

Monocyclic and bicyclic himbacine derivatives of the formula

Description

Claims

1. A compound represented by structural formula I:

2. A compound of claim 1 wherein R8 is OH or alkoxy and R3 is H.

3. A compound of claim 2 wherein R8 is methoxy.

4. A compound of claim 1 wherein R3 and R8 together are ═NOH or ═NO-alkyl.

5. A compound of claim 4 wherein R3 and R8 together are ═NO-ethyl.

6. A compound of claim 1 wherein R32 and R33 are combined to form the ring structure Q.

7. A compound of claim 6 wherein Q is

8. A compound of claim 1 wherein R32 is alkyl and R33 is alkyl.

9. A compound of claim 8 wherein R32 is methyl and R33 is methyl.

10. A compound of claim 1 wherein B is —(CH2)n4CR12═CR12a(CH2)n5— wherein n4 and n5 are 0.

11. A compound of claim 1 wherein Het is W-substituted pyridyl.

12. A compound of claim 11 wherein W is aryl, heteroaryl or aryl substituted by halogen or —CN.

13. A compound of claim 12 wherein W is phenyl substituted by halogen or cyano.

14. A compound of claim 1 wherein Jn is —CH2— and Gn is —(CR1R2)— wherein R1 is H and R2 is H or alkyl.

15. A compound of claim 14 wherein Gn is —CH2— or —CH(CH2CH3)—.

16. A compound of claim 1 wherein R9, R10 and R8 are H.

17. A compound of claim 1 wherein: R8 is OH or alkoxy and R3 is H, or R3 and R8 together are ═NOH or ═NO-alkyl;

18. A pharmaceutical composition comprising an effective amount of at least one compound of claim 1 and a pharmaceutically acceptable carrier.

19. A method of inhibiting thrombin receptors comprising administering to a mammal in need of such treatment an effective amount of at least one compound of claim 1.

20. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, angiogenesis related disorders, arrhythmia, a cardiovascular or circulatory disease or condition, heart failure, acute coronary syndrome, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, deep vein thrombosis, venous thromboembolism, a cardiovascular disease associated with hormone replacement therapy, disseminated intravascular coagulation syndrome, cerebral infarction, migraine, erectile dysfunction, rheumatoid arthritis, rheumatism, astrogliosis, a fibrotic disorder of the liver, kidney, lung or intestinal tract, systemic lupus erythematosus, multiple sclerosis, osteoporosis, renal disease, acute renal failure, chronic renal failure, renal vascular homeostasis, renal ischemia, bladder inflammation, diabetes, diabetic neuropathy, cerebral stroke, cerebral ischemia, nephritis, cancer, melanoma, renal cell carcinoma, neuropathy, malignant tumors, neurodegenerative and/or neurotoxic diseases, conditions or injuries, Alzheimer's disease, an inflammatory disease or condition, asthma, glaucoma, macular degeneration, psoriasis, endothelial dysfunction disorders of the liver, kidney or lung, inflammatory disorders of the lungs and gastrointestinal tract, respiratory tract disease or condition, radiation fibrosis, endothelial dysfunction, periodontal diseases or wounds, or a spinal cord injury, or a symptom or result thereof, comprising administering to a mammal in need of such treatment an effective amount of at least one compound of claim 1.

21. The method of claim 20 wherein the inflammatory disease or condition is irritable bowel syndrome, Cohn's disease, nephritis or a radiation- or chemotherapy-induced proliferate or inflammatory disorder of the gastrointestinal tract, lung, urinary bladder, gastrointestinal tract or other organ.

22. The method of claim 20 wherein the respiratory tract disease or condition is reversible airway obstruction, asthma, chronic asthma, bronchitis or chronic airways disease.

23. The method of claim 20 wherein the cancer is renal cell carcinoma or an angiogenesis related disorder.

24. The method of claim 20 wherein the neurodegenerative disease is Parkinson's disease, amyotropic lateral sclerosis, Alzheimer's disease, Huntington's disease or Wilson's disease.

25. The method of claim 20 further comprising administering at least two therapeutically effective agents.

26. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, angiogenesis related disorders, arrhythmia, a cardiovascular or circulatory disease or condition, heart failure, acute coronary syndrome, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, deep vein thrombosis, venous thromboembolism, a cardiovascular disease associated with hormone replacement therapy, disseminated intravascular coagulation syndrome, cerebral infarction, migraine, erectile dysfunction, rheumatoid arthritis, rheumatism, astrogliosis, a fibrotic disorder of the liver, kidney, lung or intestinal tract, systemic lupus erythematosus, multiple sclerosis, osteoporosis, renal disease, acute renal failure, chronic renal failure, renal vascular homeostasis, renal ischemia, bladder inflammation, diabetes, diabetic neuropathy, cerebral stroke, cerebral ischemia, nephritis, cancer, melanoma, renal cell carcinoma, neuropathy, malignant tumors, neurodegenerative and/or neurotoxic diseases, conditions or injuries, Alzheimer's disease, an inflammatory disease or condition, asthma, glaucoma, macular degeneration, psoriasis, endothelial dysfunction disorders of the liver, kidney or lung, inflammatory disorders of the lungs and gastrointestinal tract, respiratory tract disease or condition, radiation fibrosis, endothelial dysfunction, periodontal diseases or wounds, or a spinal cord injury, or a symptom or result, comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1 in combination with at least one additional cardiovascular agent.

27. The method of claim 26 wherein the additional cardiovascular agent or agents is selected from the group consisting of thromboxane A2 biosynthesis inhibitors, GP IIb/IIIa antagonists, thromboxane antagonists, adenosine diphosphate inhibitors, cyclooxygenase inhibitors, angiotensin antagonists, endothelin antagonists, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, anticoagulants, diuretics, and platelet aggregation inhibitors.

28. The method of claim 27 wherein the additional cardiovascular agent or agents are selected from the group consisting of aspirin, cangrelor, clopidogrel bisulfate, parsugrel and fragmin.

29. The method of claim 28 wherein the additional cardiovascular agents are aspirin and clopidogrel bisulfate.

30. The method of claim 28 wherein the additional cardiovascular agents are aspirin and parsugrel.

31. A method of inhibiting cannabinoid receptors comprising administering to a mammal in need of such treatment an effective amount of at least one compound of claim 1.

32. A compound of claim 1 in purified form.

33. A compound of claim 1 in isolated form.

34. A method of treating or preventing radiation- or chemical-induced toxicity in non-malignant tissue in a patient comprising administering a therapeutically effective amount of at least one compound of claim 1.

35. The method of claim 34 wherein the radiation- and/or chemical-induced toxicity is one or more of intestinal fibrosis, pneumonitis, intestinal mucositis, oral mucositis, intestinal radiation syndrome, or pathophysiological manifestations of intestinal radiation exposure.

36. A method of reducing structural radiation injury in a patient that will be exposed, is concurrently exposed, or was exposed to radiation and/or chemical toxicity; reducing inflammation in a patient that will be exposed, is concurrently exposed, or was exposed to radiation and/or chemical toxicity; adverse tissue remodeling in a patient that will be exposed, is concurrently exposed, or was exposed to radiation and/or chemical toxicity; or reducing fibroproliferative tissue effects in a patient that will be exposed, is concurrently exposed, or was exposed to radiation and/or chemical toxicity, comprising administering a therapeutically effective amount of at least one compound of claim 1.

37. A method of treating a cell proliferative disorder in a patient suffering therefrom comprising administering a therapeutically effective amount of at least one compound of claim 1.

38. The method of claim 37 wherein the cell proliferative disorder is pancreatic cancer, glioma, ovarian cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, thyroid cancer, lung cancer, melanoma, or stomach cancer.

39. The method of claim 38 wherein the glioma is an anaplastic astrocytoma or a glioblastoma multiforme.

40. A compound of the formula: