(Pyrrolidin-2-yl)phenyl derivatives
View Patent ↗The invention relates to (pyrrolidin-2-yl)phenyl derivatives having the general Formula I wherein R 1 is (C 1-4 )alkyl, halo(C 1-4 )alkyl, (C 1-4 )alkyloxy, or halo(C 1-4 )alkyloxy; R 2 is H, (C 1-4 )alkyl, halo(C 1-4 )alkyl, (C 1-4 )alkyloxy, halo(C 1-4 )alkyloxy or halogen; R 3 is H, (C 1-4 )alkyl or halo(C 1-4 )alkyl; R 4 is H, (C 1-4 )alkyl or halo(C 1-4 )alkyl; R 5 is H, (C 1-4 )alkyl or halo-(C 1-4 )-alkyl; or R 4 and R 5 , when bonded to the same carbon atom, can together with the carbon atom form a spiro(C 3-6 )cycloalkyl group, optionally substituted with halogen; R 6 is H, (C 1-4 )alkyl, halo(C 1-4 )alkyl, (C 1-4 )alkyloxy, halo(C 1-4 )alkyloxy or halogen; or a pharmaceutically acceptable salt thereof, to pharmaceutical compositions comprising the same, as well as to the use of these (pyrrolidin-2-yl)phenyl derivatives for the treatment of pain, such as neuropathic pain or inflammatory pain.
1. A (pyrrolidin-2-yl)phenyl derivative having the general Formula I
wherein
R 1 is (C 1-4 )alkyl, halo(C 1-4 )alkyl, (C 1-4 )alkyloxy, or halo(C 1-4 )alkyloxy;
R 2 is H, (C 1-4 )alkyl, halo(C 1-4 )alkyl, (C 1-4 )alkyloxy, halo(C 1-4 )alkyloxy or halogen;
R 3 is H, (C 1-4 )alkyl or halo(C 1-4 )alkyl;
R 4 is H, (C 1-4 )alkyl or halo(C 1-4 )alkyl;
R 5 is H, (C 1-4 )alkyl or halo(C 1-4 )alkyl; or
R 4 and R 5 , when bonded to the same carbon atom, can together with the carbon atom form a spiro(C 3-6 )cycloalkyl group, optionally substituted with halogen;
R 6 is H, (C 1-4 )alkyl, halo(C 1-4 )alkyl, (C 1-4 )alkyloxy, halo(C 1-4 )alkyloxy or halogen; or a pharmaceutically acceptable salt thereof.
2. The (pyrrolidin-2-yl)phenyl derivative of claim 1 , wherein R 1 is halo(C 1-4 )alkyl.
3. The (pyrrolidin-2-yl)phenyl derivative of claim 1 , wherein R 2 , R 3 , R 4 and R 5 are H.
4. The (pyrrolidin-2-yl)phenyl derivative of claim 3 , wherein R 6 is H or F.
5. The (pyrrolidin-2-yl)phenyl derivative of claim 1 , wherein the stereochemistry is that of the S-stereoisomer.
6. The (pyrrolidin-2-yl)phenyl derivative of claim 1 which is selected from:
2-(2-((S)-pyrrolidin-2-yl)phenyl)-3-(trifluoromethyl)pyridine;
2-(2-((R)-pyrrolidin-2-yl)phenyl)-3-(trifluoromethyl)pyridine;
2-(5-fluoro-2-(pyrrolidin-2-yl)phenyl)-3-(trifluoromethyl)pyridine;
6-(2-(3-(trifluoromethyl)pyridin-2-yl)phenyl)-5-azaspiro[2.4]heptane;
2-(5-methyl-2-(pyrrolidin-2-yl)phenyl)-3-(trifluoromethyl)pyridine;
2-(2-(pyrrolidin-2-yl)phenyl)-3-methylpyridine;
2-(4-fluoro-2-(pyrrolidin-2-yl)phenyl)-3-methylpyridine;
2-(5-fluoro-2-(pyrrolidin-2-yl)phenyl)-3-methylpyridine;
2-(2-(pyrrolidin-2-yl)phenyl)-3-methoxypyridine;
2-(4-fluoro-2-(pyrrolidin-2-yl)phenyl)-3-methoxypyridine;
2-(5-fluoro-2-(pyrrolidin-2-yl)phenyl)-3-methoxypyridine; or
a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a (pyrrolidin-2-yl)phenyl derivative of claim 1 or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable auxiliaries.
8. A pharmaceutical composition comprising a (pyrrolidin-2-yl)phenyl derivative of claim 6 or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable auxiliaries.
9. A method of treatment of pain which is mediated through modulation of the Ih channel, the method comprising administering to a patient in need thereof a therapeutically effective amount of a (pyrrolidin-2-yl)phenyl derivative of claim 1 or a pharmaceutically acceptable salt thereof.
10. The method of claim 9 , wherein the pain is selected from the group consisting of neuropathic pain or inflammatory pain.
11. A method of treatment of pain which is mediated through modulation of the Ih channel, the method comprising administering to a patient in need thereof a therapeutically effective amount of a (pyrrolidin-2-yl)phenyl derivative of claim 6 or a pharmaceutically acceptable salt thereof.
12. The method of claim 11 , wherein the pain is selected from the group consisting of neuropathic pain or inflammatory pain.
13. The (pyrrolidin-2-yl)phenyl derivative of claim 6 which is -2-(2-((S)-pyrrolidin-2-yl)phenyl)-3-(trifluoromethyl) pyridine or a pharmaceutically acceptable salt thereof.
14. The (pyrrolidin-2-yl)phenyl derivative of claim 6 which is -2-(2-((R)-pyrrolidin-2-yl)phenyl)-3-(trifluoromethyl) pyridine or a pharmaceutically acceptable salt thereof.
15. The (pyrrolidin-2-yl)phenyl derivative of claim 6 which is -2-(5-fluoro-2-(pyrrolidin-2-yl)phenyl)-3-(trifluoromethyl) pyridine or a pharmaceutically acceptable salt thereof.
16. The (pyrrolidin-2-yl)phenyl derivative of claim 6 which is -6-(2-(3-(trifluoromethyl)pyridin-2-yl)phenyl)-5-azaspiro[2.4]heptane or a pharmaceutically acceptable salt thereof.
17. The (pyrrolidin-2-yl)phenyl derivative of claim 6 which is -2-(5-methyl-2-(pyrrolidin-2-yl)phenyl)-3-(trifluoromethyl) pyridine or a pharmaceutically acceptable salt thereof.
18. The (pyrrolidin-2-yl)phenyl derivative of claim 6 which is -2-(2-(pyrrolidin-2-yl)phenyl)-3-methylpyridine or a pharmaceutically acceptable salt thereof.
19. The (pyrrolidin-2-yl)phenyl derivative of claim 6 which is -2-(4-fluoro-2-(pyrrolidin-2-yl)phenyl)-3-methylpyridine or a pharmaceutically acceptable salt thereof.
20. The (pyrrolidin-2-yl)phenyl derivative of claim 6 which is -2-(5-fluoro-2-(pyrrolidin-2-yl)phenyl)-3-methylpyridine or a pharmaceutically acceptable salt thereof.
21. The (pyrrolidin-2-yl)phenyl derivative of claim 6 which is -2-(2-(pyrrolidin-2-yl)phenyl)-3-methoxypyridine or a pharmaceutically acceptable salt thereof.
22. The (pyrrolidin-2-yl)phenyl derivative of claim 6 which is -2-(4-fluoro-2-(pyrrolidin-2-yl)phenyl)-3-methoxypyridine or a pharmaceutically acceptable salt thereof.
23. The (pyrrolidin-2-yl)phenyl derivative of claim 6 which is -2-(5-fluoro-2-(pyrrolidin-2-yl)phenyl)-3-methoxypyridine or a pharmaceutically acceptable salt thereof.