Pyridone amides as modulators of sodium channels
The invention relates to pyridone amide compounds of formula I and I′ or pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels: The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders, including pain.
1. A compound selected from the group consisting of:
2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;
2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;
4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;
2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide; and
4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide.
2. A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable carriers or vehicles.
3. The pharmaceutical composition of claim 2 , wherein the compound is present in a therapeutically effective amount.
4. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound of claim 1 .
5. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, postsurgical pain, or idiopathic pain comprising administering an effective amount of the compound of claim 1 .
6. The method of claim 5 , wherein the method comprises treating or lessening the severity in a subject of neuropathic pain.
7. The method of claim 6 , wherein the neuropathic pain is idiopathic small-fiber neuropathy.
8. The method of claim 5 , wherein the method comprises treating or lessening the severity in a subject of musculoskeletal pain.
9. The method of claim 8 , wherein the musculoskeletal pain comprises osteoarthritis pain.
10. The method of claim 5 , wherein the method comprises treating or lessening the severity in a subject of acute pain.
11. The method of claim 10 , wherein the acute pain comprises acute post-operative pain.
12. The method of claim 5 , wherein the method comprises treating or lessening the severity in a subject of inflammatory pain.
13. The method of claim 5 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound.
14. The compound of claim 1 , wherein the compound is:
2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide.
15. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 14 and one or more pharmaceutically acceptable carriers or vehicles.
16. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, postsurgical pain, or idiopathic pain comprising administering an effective amount of the compound of claim 14 .
17. The method of claim 16 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound.
18. The compound of claim 1 , wherein the compound is:
2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide.
19. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 18 and one or more pharmaceutically acceptable carriers or vehicles.
20. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, postsurgical pain, or idiopathic pain comprising administering an effective amount of the compound of claim 18 .
21. The method of claim 20 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound.
22. The compound of claim 1 , wherein the compound is:
4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide.
23. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 22 and one or more pharmaceutically acceptable carriers or vehicles.
24. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, postsurgical pain, or idiopathic pain comprising administering an effective amount of the compound of claim 22 .
25. The method of claim 24 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound.
26. The compound of claim 1 , wherein the compound is:
2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide.
27. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 26 and one or more pharmaceutically acceptable carriers or vehicles.
28. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, postsurgical pain, or idiopathic pain comprising administering an effective amount of the compound of claim 26 .
29. The method of claim 28 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound.
30. The compound of claim 1 , wherein the compound is:
4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide.
31. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 30 and one or more pharmaceutically acceptable carriers or vehicles.
32. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, postsurgical pain, or idiopathic pain comprising administering an effective amount of the compound of claim 30 .
33. The method of claim 32 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound.
34. The method of claim 6 , wherein the neuropathic pain is postherpetic neuralgia.
35. The method of claim 5 , wherein the method comprises treating or lessening the severity in a subject of postsurgical pain.