N-adamantyl benzamides as inhibitors of 11-β-hydroxysteroid dehydrogenase
View Patent ↗Novel substituted benzamide based inhibitors, their use in therapy, pharmaceutical compositions comprising the compounds, the use of said compounds in the manufacture of medicaments, and therapeutic methods comprising the administration of said compounds are described. The present compounds modulate the activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, such as the metabolic syndrome.
1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is hydrogen;
R 2 is 5-hydroxy-adamantan-2-yl;
R 4 is hydrogen;
R 5 is hydrogen; and
Y is selected from the group consisting of 2-[1-(carboxylic acid isopropylamide)-piperidin-4-yl]-ethoxy, 6-chloro-pyridin-3-ylmethoxy, tetrahydropyran-4-yl-methoxy, 2-(2-oxo-pyrrolidin-1-yl)-ethoxy, 5-chloro-pyridin-2-yloxy, 6-bromo-pyridin-3-yloxy, phenethyloxy, 2-(tetrahydropyran-4-yl)-ethoxy, benzyloxy, 2-(1-cyclopropane-sulfonyl-piperidin-4-yl)-ethoxy, and 4-fluorobenzyloxy.
2. 4-{2-[3-(5-Hydroxy-adamantan-2-ylcarbamoyl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid isopropylamide, or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , where the compound is 4-{2-[3-(5-hydroxy-adamantan-2-ylcarbamoyl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid isopropylamide.
4. 3-(6-Chloro-pyridin-3-ylmethoxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide, or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4 , where the compound is 3-(6-chloro-pyridin-3-ylmethoxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide.
6. N-(5-Hydroxy-adamantan-2-yl)-3-(tetrahydro-pyran-4-ylmethoxy)-benzamide, or a pharmaceutically acceptable salt thereof.
7. The compound of claim 6 , where the compound is N-(5-hydroxy-adamantan-2-yl)-3-(tetrahydro-pyran-4-ylmethoxy)-benzamide.
8. N-(5-Hydroxy-adamantan-2-yl)-3-[2(2-oxo-pyrrolidin-1-yl)-ethoxy]-benzamide, or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 , where the compound is N-(5-hydroxy-adamantan-2-yl)-3-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-benzamide.
10. 3-(5-Chloro-pyridin-2-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide, or a pharmaceutically acceptable salt thereof.
11. The compound of claim 10 , where the compound is 3-(5-chloro-pyridin-2-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide.
12. 3-(6-Bromo-pyridin-3-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide, or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12 , where the compound is 3-(6-bromo-pyridin-3-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide.
14. N-(5-Hydroxy-adamantan-2-yl)-3-phenethyloxy-benzamide, or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 , where the compound is N-(5-hydroxy-adamantan-2-yl)-3-phenethyloxy-benzamide.
16. N-(5-Hydroxy-adamantan-2-yl)-3-[2-(tetrahydro-pyran-4-yl)-ethoxy]-benzamide, or a pharmaceutically acceptable salt thereof.
17. The compound of claim 16 , where the compound is N-(5-hydroxy-adamantan-2-yl)-3-[2-(tetrahydro-pyran-4-yl)-ethoxy]-benzamide.
18. 3-Benzyloxy-N-(5-hydroxy-adamantan-2-yl)-benzamide, or a pharmaceutically acceptable salt thereof.
19. The compound of claim 18 , where the compound is 3-benzyloxy-N-(5- hydroxy-adamantan-2-yl)-benzamide.
20. 3-[2-(1-Cyclopropane-sulfonyl-piperidin-4-yl)-ethoxy]-N-(5-hydroxy-adamantan-2-yl)-benzamide, or a pharmaceutically acceptable salt thereof.
21. The compound of claim 20 , where the compound is 3-[2(1-cyclopropane-sulfonyl-piperidin-4-yl)-ethoxy]-N-(5-hydroxy-adamantan-2-yl)-benzamide.
22. 3-(4-Fluoro-benzyloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide, or a pharmaceutically acceptable salt thereof.
23. The compound of claim 22 , where the compound is 3-(4-fluoro-benzyloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide.
24. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
25. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier or excipient.
26. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier or excipient.
27. A pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable carrier or excipient.
28. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier or excipient.
29. A pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable carrier or excipient.
30. A pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable carrier or excipient.
31. A pharmaceutical composition comprising a compound of claim 8 and a pharmaceutically acceptable carrier or excipient.
32. A pharmaceutical composition comprising a compound of claim 9 and a pharmaceutically acceptable carrier or excipient.
33. A pharmaceutical composition comprising a compound of claim 10 and a pharmaceutically acceptable carrier or excipient.
34. A pharmaceutical composition comprising a compound of claim 11 and a pharmaceutically acceptable carrier or excipient.
35. A pharmaceutical composition comprising a compound of claim 12 and a pharmaceutically acceptable carrier or excipient.
36. A pharmaceutical composition comprising a compound of claim 13 and a pharmaceutically acceptable carrier or excipient.
37. A pharmaceutical composition comprising a compound of claim 14 and a pharmaceutically acceptable carrier or excipient.
38. A pharmaceutical composition comprising a compound of claim 15 and a pharmaceutically acceptable carrier or excipient.
39. A pharmaceutical composition comprising a compound of claim 16 and a pharmaceutically acceptable carrier or excipient.
40. A pharmaceutical composition comprising a compound of claim 17 and a pharmaceutically acceptable carrier or excipient.
41. A pharmaceutical composition comprising a compound of claim 18 and a pharmaceutically acceptable carrier or excipient.
42. A pharmaceutical composition comprising a compound of claim 19 and a pharmaceutically acceptable carrier or excipient.
43. A pharmaceutical composition comprising a compound of claim 20 and a pharmaceutically acceptable carrier or excipient.
44. A pharmaceutical composition comprising a compound of claim 21 and a pharmaceutically acceptable carrier or excipient.
45. A pharmaceutical composition comprising a compound of claim 22 and a pharmaceutically acceptable carrier or excipient.
46. A pharmaceutical composition comprising a compound of claim 23 and a pharmaceutically acceptable carrier or excipient.