Aryl- and heteroaryl-pyrrolidine-2-carboxamide compounds
The application relates to novel compounds and their use in treating and preventing diseases and conditions mediated by modulation of voltage-gated sodium channels. Novel aryl- and heteroaryl-pyrrolidine-2-carboxamide compounds and pharmaceutically acceptable salts or solvates thereof and their use are described.
1. A compound of formula I:
or a pharmaceutically acceptable salt, hydrate, or alcoholate thereof, wherein:
X 1 , X 2 , X 3 , and X 4 are each independently selected from N and CH;
R 1 is selected from F, CF 3 , CH 2 F, CHF 2 , OCF 3 , OCH 2 F, and OCHF 2 ;
R 2 is hydrogen; and
R 3 and R 4 are each independently selected from hydrogen and C 1 -C 3 alkyl;
or R 2 and R 3 or R 4 taken together with the atoms to which they are attached form a 5-membered ring.
2. The compound of claim 1 , wherein the compound is of formula II:
or a pharmaceutically acceptable salt, hydrate, or alcoholate thereof.
3. The compound of claim 1 , wherein the compound is of formula III:
or a pharmaceutically acceptable salt, hydrate, or alcoholate thereof.
4. The compound of claim 1 , wherein the compound is of formula IV:
or a pharmaceutically acceptable salt, hydrate, or alcoholate thereof.
5. The compound of claim 1 , wherein the compound is of formula V, VI, VII, VIII, or IX:
or a pharmaceutically acceptable salt, hydrate, or alcoholate thereof.
6. The compound of claim 1 , wherein R 2 and R 3 or R 4 taken together with the atoms to which they are attached form a 5-membered ring.
7. The compound of claim 1 , wherein R 3 or R 4 is hydrogen.
8. The compound of claim 1 , wherein R 2 , R 3 , and R 4 are each hydrogen.
9. The compound of claim 1 , wherein R 1 is selected from F, CF 3 , CH 2 F, and CHF 2 .
10. The compound of claim 9 , wherein R 1 is CF 3 .
11. The compound of claim 1 , wherein R 1 is selected from OCF 3 , OCH 2 F, and OCHF 2 .
12. The compound of claim 11 , wherein R 1 is OCF 3 .
13. The compound of claim 1 , wherein R 4 is C 1 -C 3 alkyl.
14. The compound of claim 1 , wherein R 4 is methyl, ethyl, or propyl.
15. A compound selected from
or a pharmaceutically acceptable salt, hydrate, or alcoholate thereof.
16. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, hydrate, or alcoholate thereof and a pharmaceutical carrier, diluent, or excipient.
17. A method of treating a disease or condition selected from epilepsy, inflammatory pain, neuropathic pain, and a bipolar disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, hydrate, or alcoholate thereof.
18. A pharmaceutical composition comprising a compound of claim 15 or a pharmaceutically acceptable salt, hydrate, or alcoholate thereof and a pharmaceutical carrier, diluent, or excipient.
19. A method of treating a disease or condition selected from epilepsy, inflammatory pain, neuropathic pain, and a bipolar disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 15 or a pharmaceutically acceptable salt, hydrate, or alcoholate thereof.