Thrombin receptor antagonists
View Patent ↗Heterocyclic-substituted tricyclics of the formula or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents an optional single bond; represents an optional double bond; n is 0–2; Q is cycloalkyl, optionally substituted by R 13 and R 14 ; R 13 and R 14 are independently selected from (C 1 –C 6 )alkyl, (C 3 –C 8 )cycloalkyl, —OH, (C 1 –C 6 )alkoxy, R 27 -aryl(C 1 –C 6 )alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen and haloalkyl; or R 13 and R 14 together form a spirocyclic or a heterospirocyclic ring of 3–6 atoms; Het is a mono- or bi-cyclic optionally substituted heteroaryl group; and B is a bond, alkylene, or optionally substituted alkenylene or alkynylene, wherein the remaining substituents are as defined in the specification, are disclosed, as well as pharmaceutical compositions containing them and a method of treating diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, and cancer by administering said compounds. Combination therapy with other cardiovascular agents is also claimed.
1. A compound of the following formula:
or a pharmaceutically acceptable isomer, salt or solvate thereof.
2. A compound of the following formula:
or a pharmaceutically acceptable isomer thereof.
3. A compound of the following formula:
or a pharmaceutically acceptable salt thereof.
4. A bisulfate salt of a compound of the following formula:
5. A compound of the following formula:
or a pharmaceutically acceptable solvate thereof.
6. A compound of the following formula:
7. A pharmaceutical composition comprising an effective amount of a compound, or a pharmaceutically acceptable isomer, salt or solvate thereof, according to claim 1 , and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition comprising an effective amount of a compound or a pharmaceutical acceptable isomer thereof according to claim 2 , and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof salt thereof according to claim 3 , and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition comprising an effective amount of the bisulfate salt according to claim 4 , and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable solvate thereof according to claim 5 , and a pharmaceutically acceptable carrier.
12. A pharmaceutical composition comprising an effective amount of the compound according to claim 6 , and a pharmaceutically acceptable carrier.
13. A pharmaceutical composition comprising an effective amount of a compound, or a pharmaceutically acceptable isomer, salt or solvate thereof, according to claim 1 , and one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel bisulfate.
14. A pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable isomer thereof according to claim 2 , and one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel bisulfate.
15. A pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 3 , and one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel bisulfate.
16. A pharmaceutical composition comprising an effective amount of the bisulfate salt according to claim 4 , and one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel bisulfate.
17. A pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable solvate thereof according to claim 5 , and one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel bisulfate.
18. A pharmaceutical composition comprising an effective amount of the compound according to claim 6 , and one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel bisulfate.
19. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, or cerebral ischemia comprising administering to a mammal an effective amount of a compound, or a pharmaceutically acceptable isomer, salt or solvate thereof, according to claim 1 .
20. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, or cerebral ischemia comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable isomer thereof according to claim 2 .
21. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, or cerebral ischemia comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 3 .
22. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, or cerebral ischemia comprising administering to a mammal an effective amount of the bisulfate salt according to claim 4 .
23. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, or cerebral ischemia comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable solvate thereof according to claim 5 .
24. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, or cerebral ischemia comprising administering to a mammal an effective amount of the compound according to claim 6 .
25. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, or cerebral ischemia comprising administering to a mammal an effective amount of a pharmaceutical composition of any of claims 7 - 18 .
26. A method of treating thrombosis comprising administering to a mammal an effective amount of a compound, or a pharmaceutically acceptable isomer, salt or solvate thereof, according to claim 1 .
27. A method of treating atherosclerosis comprising administering to a mammal an effective amount of a compound, or a pharmaceutically acceptable isomer, salt or solvate thereof, according to claim 1 .
28. A method of treating myocardial infarction comprising administering to a mammal an effective amount of a compound, or a pharmaceutically acceptable isomer, salt or solvate thereof, according to claim 1 .
29. A method of treating thrombotic stroke comprising administering to a mammal an effective amount of a compound, or a pharmaceutically acceptable isomer, salt or solvate thereof, according to claim 1 .
30. A method of treating a peripheral vascular disease comprising administering to a mammal an effective amount of a compound, or a pharmaceutically acceptable isomer, salt or solvate thereof, according to claim 1 .
31. A method of treating thrombosis comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable isomer thereof according to claim 2 .
32. A method of treating atherosclerosis comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable isomer thereof according to claim 2 .
33. A method of treating myocardial infarction comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable isomer thereof according to claim 2 .
34. A method of treating thrombotic stroke comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable isomer thereof according to claim 2 .
35. A method of treating a peripheral vascular disease comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable isomer thereof according to claim 2 .
36. A method of treating thrombosis comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 3 .
37. A method of treating atherosclerosis comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 3 .
38. A method of treating myocardial infarction comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 3 .
39. A method of treating thrombotic stroke comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 3 .
40. A method of treating a peripheral vascular disease comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 3 .
41. A method of treating thrombosis comprising administering to a mammal an effective amount of a bisulfate salt according to claim 4 .
42. A method of treating atherosclerosis comprising administering to a mammal an effective amount of a bisulfate salt according to claim 4 .
43. A method of treating myocardial infarction comprising administering to a mammal an effective amount of a bisulfate salt according to claim 4 .
44. A method of treating thrombotic stroke comprising administering to a mammal an effective amount of a bisulfate salt according to claim 4 .
45. A method of treating a peripheral vascular disease comprising administering to a mammal an effective amount of a bisulfate salt according to claim 4 .
46. A method of treating thrombosis comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable solvate thereof according to claim 5 .
47. A method of treating atherosclerosis comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable solvate thereof according to claim 5 .
48. A method of treating myocardial infarction comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable solvate thereof according to claim 5 .
49. A method of treating thrombotic stroke comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable solvate thereof according to claim 5 .
50. A method of treating a peripheral vascular disease comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable solvate thereof according to claim 5 .
51. A method of treating thrombosis comprising administering to a mammal an effective amount of a compound according to claim 6 .
52. A method of treating atherosclerosis comprising administering to a mammal an effective amount of a compound according to claim 6 .
53. A method of treating myocardial infarction comprising administering to a mammal an effective amount of a compound according to claim 6 .
54. A method of treating thrombotic stroke comprising administering to a mammal an effective amount of a compound according to claim 6 .
55. A method of treating a peripheral vascular disease comprising administering to a mammal an effective amount of a compound according to claim 6 .
56. A method of treating thrombosis comprising administering to a mammal an effective amount of a pharmaceutical composition of any of claims 7 - 18 .
57. A method of treating atherosclerosis comprising administering to a mammal an effective amount of a pharmaceutical composition of any of claims 7 - 18 .
58. A method of treating myocardial infarction comprising administering to a mammal an effective amount of a pharmaceutical composition of any of claims 7 - 18 .
59. A method of treating thrombotic stroke comprising administering to a mammal an effective amount of a pharmaceutical composition of any of claims 7 - 18 .
60. A method of treating a peripheral vascular disease comprising administering to a mammal an effective amount of a pharmaceutical composition of any of claims 7 - 18 .
61. A method of inhibiting platelet aggregation comprising administering to a mammal an effective amount of a compound, or a pharmaceutically acceptable isomer, salt or solvate thereof, according to claim 1 .
62. A method of inhibiting platelet aggregation comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable isomer thereof according to claim 2 .
63. A method of inhibiting platelet aggregation comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 3 .
64. A method of inhibiting platelet aggregation comprising administering to a mammal an effective amount of a bisulfate salt according to claim 4 .
65. A method of inhibiting platelet aggregation comprising administering to a mammal an effective amount of a compound or a pharmaceutically acceptable solvate thereof according to claim 5 .
66. A method of inhibiting platelet aggregation comprising administering to a mammal an effective amount of a compound according to claim 6 .
67. A method of inhibiting platelet aggregation comprising administering to a mammal an effective amount of a pharmaceutical composition of any of claims 7 - 18 .