Prodrugs of pyridone amides useful as modulators of sodium channels

Patent metadata

Field	Value
Publication number	US-10787472-B2
Application number	US-201916283904-A
Country	US
Kind code	B2
Filing date	Feb 25, 2019
Priority date	Dec 13, 2013
Publication date	Sep 29, 2020
Grant date	Sep 29, 2020

Abstract

The invention relates to prodrug compounds of formula I:

wherein R 2 , R 3 , R 5 , R 7 and X are as defined herein. 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. The compounds of formula I possess advantageous solubility and physicochemical properties.

First claim

We claim:

1. A compound of formula I:

wherein, independently for each occurrence:
R 2 and R 3 are independently hydrogen, halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen;
R 5 is hydrogen, halogen, OH, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
R 7 is F; and
X is —PO(OH) 2 , —PO(OH)O − M + , —PO(O − ) 2 ⋅2M + , or —PO(O − ) 2 ⋅D 2+ ; M + is a pharmaceutically acceptable monovalent cation; and D 2+ is a pharmaceutically acceptable divalent cation.

2. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject a compound according to claim 1 .

3. The method of claim 2 , wherein the voltage-gated sodium channel is Nav1.8.

4. The method of claim 2 , wherein the compound is:

(4-(4-chloro-2-(4-fluoro-2-methylphenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate.

5. The method of claim 4 , wherein the voltage-gated sodium channel is Nav1.8.

6. The method of claim 2 , wherein the compound is:

(4-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate.

7. The method of claim 6 , wherein the voltage-gated sodium channel is Nav1.8.

8. 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, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering to the subject an effective amount of a compound according to claim 1 .

9. The method of claim 8 , wherein the compound is:

(4-(4-chloro-2-(4-fluoro-2-methylphenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate.

10. The method of claim 9 , wherein the method comprises treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.

11. The method of claim 9 , wherein the method comprises treating or lessening the severity in a subject of neuropathic pain.

12. The method of claim 11 , wherein neuropathic pain comprises trigeminal neuralgia.

13. The method of claim 11 , wherein neuropathic pain comprises idiopathic small-fiber neuropathy.

14. The method of claim 11 , wherein neuropathic pain comprises postherpetic neuralgia.

15. The method of claim 9 , wherein the method comprises treating or lessening the severity in a subject of musculoskeletal pain.

16. The method of claim 15 , wherein musculoskeletal pain comprises osteoarthritis pain.

17. The method of claim 9 , wherein the method comprises treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain.

18. The method of claim 9 , wherein the method comprises treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

19. The method of claim 9 , wherein the method comprises treating or lessening the severity in a subject of acute pain.

20. The method of claim 19 , wherein acute pain comprises acute post-operative pain.

21. The method of claim 9 , wherein the method comprises treating or lessening the severity in a subject of postsurgical pain.

22. The method of claim 9 , wherein the method comprises treating or lessening the severity in a subject of visceral pain.

23. The method according to claim 9 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound.

24. The method of claim 8 , wherein the compound is:

(4-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate.

25. The method of claim 24 , wherein the method comprises treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.

26. The method of claim 24 , wherein the method comprises treating or lessening the severity in a subject of neuropathic pain.

27. The method of claim 26 , wherein neuropathic pain comprises trigeminal neuralgia.

28. The method of claim 26 , wherein neuropathic pain comprises idiopathic small-fiber neuropathy.

29. The method of claim 26 , wherein neuropathic pain comprises postherpetic neuralgia.

30. The method of claim 24 , wherein the method comprises treating or lessening the severity in a subject of musculoskeletal pain.

31. The method of claim 30 , wherein musculoskeletal pain comprises osteoarthritis pain.

32. The method of claim 24 , wherein the method comprises treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain.

33. The method of claim 24 , wherein the method comprises treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

34. The method of claim 24 , wherein the method comprises treating or lessening the severity in a subject of acute pain.

35. The method of claim 34 , wherein acute pain comprises acute post-operative pain.

36. The method of claim 24 , wherein the method comprises treating or lessening the severity in a subject of postsurgical pain.

37. The method of claim 24 , wherein the method comprises treating or lessening the severity in a subject of visceral pain.

38. The method according to 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.

39. The method according to claim 11 , wherein neuropathic pain comprises diabetic neuropathy.

40. The method according to claim 26 , wherein neuropathic pain comprises diabetic neuropathy.

Assignees

• Vertex Pharma

Inventors

• Anderson Corey
• Hadida Ruah Sara Sabina
• Golec Julian Marian Charles
• Zhang Beili
• Littler Benjamin Joseph
• Keshavarz-Shokri Ali
• Alcacio Tim Edward
• Belmont Daniel T

Classifications

• C07F9/576 Primary

  Six-membered rings · CPC title

• C07D213/18

  Salts thereof · CPC title

• C07F9/59

  Hydrogenated pyridine rings · CPC title

• C07F9/58 Primary

  Pyridine rings · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title