Prodrugs of pyridone amides useful as modulators of sodium channels

Patent metadata

Field	Value
Publication number	US-9828397-B2
Application number	US-201615260778-A
Country	US
Kind code	B2
Filing date	Sep 9, 2016
Priority date	Dec 13, 2013
Publication date	Nov 28, 2017
Grant date	Nov 28, 2017

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 selected from the group consisting of:

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

(4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate;

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

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

(4-(2-(4-fluorophenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate; and

(4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate;

or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1 , wherein the compound or salt is:

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

or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising the compound or salt according to claim 2 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

4. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject a compound or salt according to claim 2 or a pharmaceutical composition according to claim 3 .

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

6. 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 or salt according to claim 2 or a pharmaceutical composition according to claim 3 .

7. The method of claim 6 , 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.

8. The method of claim 6 , wherein the method comprises treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

9. The method of claim 8 , wherein neuropathic pain comprises trigeminal neuralgia.

10. The method of claim 8 , wherein neuropathic pain comprises idiopathic small-fiber neuropathy.

11. The method of claim 8 , wherein neuropathic pain comprises postherpetic neuralgia.

12. The method of claim 6 , wherein the method comprises treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.

13. The method of claim 12 , wherein musculoskeletal pain comprises osteoarthritis pain.

14. The method of claim 6 , wherein the method comprises treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain.

15. The method of claim 6 , wherein the method comprises treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

16. The method of claim 6 , wherein the method comprises treating or lessening the severity in a subject of acute pain.

17. The method of claim 16 , wherein acute pain comprises acute post-operative pain.

18. The method of claim 6 , wherein the method comprises treating or lessening the severity in a subject of postsurgical pain.

19. The method according to claim 6 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, salt, or pharmaceutical composition.

20. The compound or salt of claim 1 , wherein the compound or salt is:

(4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate;

or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising the compound or salt according to claim 20 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

22. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject a compound or salt according to claim 20 or a pharmaceutical composition according to claim 21 .

23. The method of claim 22 , wherein the voltage-gated sodium channel is Nav1.8.

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, 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 or salt according to claim 20 or a pharmaceutical composition according to claim 21 .

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, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy induced neuralgia, cancer

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

• A61P43/00

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

• A61P9/06

  Antiarrhythmics · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title