Adamantyl benzamide derivatives
View Patent ↗Embodiments of the present invention provide adamantyl benzamide derivatives and pharmaceutical compositions comprising adamantyl benzamide derivatives. Methods of use of such compounds and compositions to modulate the activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in a subject are also provided.
1. A compound, which is:
3-(5-chloro-pyridin-2-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide;
N-(5-hydroxy-adamantan-2-yl)-3-(5-trifluoromethyl-pyridin-2-yloxy)-benzamide;
3-(5-chloro-pyridin-2-ylsulfanyl)-N-(5-hydroxy-adamantan-2-yl)-benzamide;
3-(5-chloro-pyridine-2-sulfinyl)-N-(5-hydroxy-adamantan-2-yl)-benzamide;
3-(5-chloro-pyridine-2-sulfonyl)-N-(5-hydroxy-adamantan-2-yl)-benzamide;
3-(6-chloro-pyridazin-3-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide;
3-(3,5-dichloro-pyridin-2-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide;
3-(4,6-dimethyl-pyrimidin-2-ylamino)-N-(5-hydroxy-adamantan-2-yl)-benzamide;
or a pharmaceutically acceptable salt of any of the foregoing;
where with respect to the E- and Z-isomers of the compound, at least 90% of the compound is in the form of the E-isomer.
2. The compound of claim 1 , where at least 95% of the compound is in the form of the E-isomer.
3. The compound of claim 1 , where at least 98% of the compound is in the form of the E-isomer.
4. A compound, which is 3-(5-chloro-pyridin-2-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide or a pharmaceutically acceptable salt thereof, where with respect to the E- and Z-isomers of the compound, at least 90% of the compound is in the form of the E-isomer.
5. The compound of claim 4 , where at least 95% of the compound is in the form of the E-isomer.
6. The compound of claim 4 , where at least 98% of the compound is in the form of the E-isomer.
7. The compound of claim 4 , where the compound is 3-(5-chloro-pyridin-2-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide.
8. The compound of claim 7 , where at least 95% of the compound is in the form of the E-isomer.
9. The compound of claim 7 , where at least 98% of the compound is in the form of the E-isomer.
10. The compound of claim 4 , where the compound is a pharmaceutically acceptable salt of 3-(5-chloro-pyridin-2-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide.
11. The compound of claim 10 , where at least 95% of the compound is in the form of the E-isomer.
12. The compound of claim 10 , where at least 98% of the compound is in the form of the E-isomer.
13. A compound, which is N-(5-hydroxy-adamantan-2-yl)-3-(5-trifluoromethyl-pyridin-2-yloxy)-benzamide or a pharmaceutically acceptable salt thereof, where with respect to the E- and Z-isomers of the compound, at least 90% of the compound is in the form of the E-isomer.
14. The compound of claim 13 , where at least 95% of the compound is in the form of the E-isomer.
15. The compound of claim 13 , where at least 98% of the compound is in the form of the E-isomer.
16. The compound of claim 13 , where the compound is N-(5-hydroxy-adamantan-2-yl)-3-(5-trifluoromethyl-pyridin-2-yloxy)-benzamide.
17. The compound of claim 16 , where at least 95% of the compound is in the form of the E-isomer.
18. The compound of claim 16 , where at least 98% of the compound is in the form of the E-isomer.
19. The compound of claim 13 , where the compound is a pharmaceutically acceptable salt of N-(5-hydroxy-adamantan-2-yl)-3-(5-trifluoromethyl-pyridin-2-yloxy)-benzamide.
20. The compound of claim 19 , where at least 95% of the compound is in the form of the E-isomer.
21. The compound of claim 19 , where at least 98% of the compound is in the form of the E-isomer.
22. A compound, which is 3-(5-chloro-pyridin-2-ylsulfanyl)-N-(5-hydroxy-adamantan-2-yl)-benzamide or a pharmaceutically acceptable salt thereof, where with respect to the E- and Z-isomers of the compound, at least 90% of the compound is in the form of the E-isomer.
23. The compound of claim 22 , where at least 95% of the compound is in the form of the E-isomer.
24. The compound of claim 22 , where at least 98% of the compound is in the form of the E-isomer.
25. The compound of claim 22 , where the compound is 3-(5-chloro-pyridin-2-ylsulfanyl)-N-(5-hydroxy-adamantan-2-yl)-benzamide.
26. The compound of claim 25 , where at least 95% of the compound is in the form of the E-isomer.
27. The compound of claim 25 , where at least 98% of the compound is in the form of the E-isomer.
28. The compound of claim 22 , where the compound is a pharmaceutically acceptable salt of 3-(5-chloro-pyridin-2-ylsulfanyl)-N-(5-hydroxy-adamantan-2-yl)-benzamide.
29. The compound of claim 28 , where at least 95% of the compound is in the form of the E-isomer.
30. The compound of claim 28 , where at least 98% of the compound is in the form of the E-isomer.
31. A compound, which is 3-(6-chloro-pyridazin-3-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide or a pharmaceutically acceptable salt thereof, where with respect to the E- and Z-isomers of the compound, at least 90% of the compound is in the form of the E-isomer.
32. The compound of claim 31 , where at least 95% of the compound is in the form of the E-isomer.
33. The compound of claim 31 , where at least 98% of the compound is in the form of the E-isomer.
34. The compound of claim 31 , where the compound is 3-(6-chloro-pyridazin-3-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide.
35. The compound of claim 34 , where at least 95% of the compound is in the form of the E-isomer.
36. The compound of claim 34 , where at least 98% of the compound is in the form of the E-isomer.
37. The compound of claim 31 , where the compound is a pharmaceutically acceptable salt of 3-(6-chloro-pyridazin-3-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide.
38. The compound of claim 37 , where at least 95% of the compound is in the form of the E-isomer.
39. The compound of claim 37 , where at least 98% of the compound is in the form of the E-isomer.
40. A compound, which is 3-(3,5-dichloro-pyridin-2-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide or a pharmaceutically acceptable salt thereof, where with respect to the E- and Z-isomers of the compound, at least 90% of the compound is in the form of the E-isomer.
41. The compound of claim 40 , where at least 95% of the compound is in the form of the E-isomer.
42. The compound of claim 40 , where at least 98% of the compound is in the form of the E-isomer.
43. The compound of claim 40 , where the compound is 3-(3,5-dichloro-pyridin-2-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide.
44. The compound of claim 43 , where at least 95% of the compound is in the form of the E-isomer.
45. The compound of claim 43 , where at least 98% of the compound is in the form of the E-isomer.
46. The compound of claim 40 , where the compound is a pharmaceutically acceptable salt of 3-(3,5-dichloro-pyridin-2-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide.
47. The compound of claim 46 , where at least 95% of the compound is in the form of the E-isomer.
48. The compound of claim 46 , where at least 98% of the compound is in the form of the E-isomer.
49. A compound, which is 3-(4,6-dimethyl-pyrimidin-2-ylamino)-N-(5-hydroxy-adamantan-2-yl)-benzamide or a pharmaceutically acceptable salt thereof, where with respect to the E- and Z-isomers of the compound, at least 90% of the compound is in the form of the E-isomer.
50. The compound of claim 49 , where at least 95% of the compound is in the form of the E-isomer.
51. The compound of claim 49 , where at least 98% of the compound is in the form of the E-isomer.
52. The compound of claim 49 , where the compound is 3-(4,6-dimethyl-pyrimidin-2-ylamino)-N-(5-hydroxy-adamantan-2-yl)-benzamide.
53. The compound of claim 52 , where at least 95% of the compound is in the form of the E-isomer.
54. The compound of claim 52 , where at least 98% of the compound is in the form of the E-isomer.
55. The compound of claim 49 , where the compound is a pharmaceutically acceptable salt of 3-(4,6-dimethyl-pyrimidin-2-ylamino)-N-(5-hydroxy-adamantan-2-yl)-benzamide.
56. The compound of claim 55 , where at least 95% of the compound is in the form of the E-isomer.
57. The compound of claim 55 , where at least 98% of the compound is in the form of the E-isomer.
58. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier or excipient, where the compound is:
3-(5-chloro-pyridin-2-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide;
N-(5-hydroxy-adamantan-2-yl)-3-(5-trifluoromethyl-pyridin-2-yloxy)-benzamide;
3-(5-chloro-pyridin-2-ylsulfanyl)-N-(5-hydroxy-adamantan-2-yl)-benzamide;
3-(5-chloro-pyridine-2-sulfinyl)-N-(5-hydroxy-adamantan-2-yl)-benzamide;
3-(5-chloro-pyridine-2-sulfonyl)-N-(5-hydroxy-adamantan-2-yl)-benzamide;
3-(6-chloro-pyridazin-3-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide;
3-(3,5-dichloro-pyridin-2-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide;
3-(4,6-dimethyl-pyrimidin-2-ylamino)-N-(5-hydroxy-adamantan-2-yl)-benzamide;
or a pharmaceutically acceptable salt of any of the foregoing;
where with respect to the E- and Z-isomers of the compound at least 90% of the compound present in the composition is in the form of the E-isomer.
59. The composition of claim 58 , where at least 95% of the compound present in the composition is in the form of the E-isomer.
60. The composition of claim 58 , where at least 98% of the compound present in the composition is in the form of the E-isomer.
61. A pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable carrier or excipient.
62. A pharmaceutical composition comprising a compound of claim 13 and a pharmaceutically acceptable carrier or excipient.
63. A pharmaceutical composition comprising a compound of claim 22 and a pharmaceutically acceptable carrier or excipient.