Pyrimidines as sodium channel blockers

Patent metadata

Field	Value
Publication number	US-10774050-B2
Application number	US-201815996053-A
Country	US
Kind code	B2
Filing date	Jun 1, 2018
Priority date	Sep 2, 2011
Publication date	Sep 15, 2020
Grant date	Sep 15, 2020

Abstract

The present disclosure provides substituted pyrimidine compounds of Formula (I), and the pharmaceutically acceptable salts, prodrugs, and solvates thereof, wherein A 1 , X, A 2 , W 1 , W 2 , W 3 , E, Z, and R 4 are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of sodium channels. Compounds of the present disclosure are especially useful for treating pain.

First claim

What is claimed is:

1. A compound of Formula XIV, or a pharmaceutically acceptable salt or solvate thereof:

Wherein
W 1 and W 2 are N, and W 3 is CH; or
W 1 and W 3 are N, and W 2 is CH; or
W 2 and W 3 are N, and W 1 is CH;
A 1 is selected from the group consisting of optionally substituted phenyl and optionally substituted pyridyl; and

Z is selected from the group consisting of —O— and —NH—.

2. The compound of claim 1 , wherein
W 1 and W 2 are N, and W 3 is CH;
A 1 is selected from the group consisting of optionally substituted phenyl and optionally substituted pyridyl; and
Z is —NH—.

3. The compound of claim 1 , wherein A 1 is optionally substituted pyridyl.

4. The compound of claim 3 , wherein A 1 is pyridyl having one or two substituents.

5. The compound of claim 3 , wherein A 1 is pyridyl having one or two substituents, each independently selected from the group consisting of halo, cyano, hydroxy, amino, haloalkyl, alkoxy, haloalkoxy, and alkyl.

6. The compound of claim 3 , wherein A 1 is pyridyl having one substituent selected from the group consisting of fluoro, chloro, cyano, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and C 1-4 alkyl.

7. The compound of claim 1 , wherein Z is —NH—.

8. A compound of Formula XV, or a pharmaceutically acceptable salt or solvate thereof:

Wherein
W 1 and W 2 are N, and W 3 is CH; or
W 1 and W 3 are N, and W 2 is CH; or
W 2 and W 3 are N, and W 1 is CH;
A 1 is selected from the group consisting of optionally substituted phenyl and optionally substituted pyridyl; and
Z is selected from the group consisting of —O— and —NH—.

9. The compound of claim 8 , wherein
W 1 and W 2 are N, and W 3 is CH;
A 1 is selected from the group consisting of optionally substituted phenyl and optionally substituted pyridyl; and
Z is —NH—.

10. The compound of claim 8 , wherein A 1 is optionally substituted pyridyl.

11. The compound of claim 10 , wherein A 1 is pyridyl having one or two substituents.

12. The compound of claim 10 , wherein A 1 is pyridyl having one or two substituents, each independently selected from the group consisting of halo, cyano, hydroxy, amino, haloalkyl, alkoxy, haloalkoxy, and alkyl.

13. The compound of claim 10 , wherein A 1 is pyridyl having one substituent selected from the group consisting of fluoro, chloro, cyano, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and C 1 -C 4 alkyl.

14. The compound of claim 8 , wherein Z is —NH—.

15. The compound of claim 1 , wherein said compound is (S)-2-(4-(4-fluorophenoxy)phenyl)-6-((2-oxopyrrolidin-3-yl)amino)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt or solvate thereof.

16. The compound of claim 1 , wherein said compound is (S)-2-(4-(4-chloro-2-fluorophenoxy)phenyl)-6-((2-oxopyrrolidin-3-yl)amino)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt or solvate thereof.

17. The compound of claim 1 , wherein said compound is (S)-6-((2-oxopyrrolidin-3-yl)amino)-2-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt or solvate thereof.

18. A method of modulating Nav1.7 sodium channel in a mammal, comprising administering to the mammal at least one compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

19. A method of treating pain in a mammal, comprising administering to the mammal identified as in need of such treatment an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

20. The method of claim 19 , wherein said pain is selected from the group consisting of chronic pain, inflammatory pain, neuropathic pain, acute pain, and surgical pain.

21. The method of claim 19 , wherein said method is for pre-emptive or palliative treatment of pain.

Assignees

• Purdue Pharma Lp

Inventors

• Ni Chiyou
• Tafesse Laykea
• Yao Jiangchao
• Youngman Mark A
• Park Minnie
• Shao Bin

Classifications

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• C07D239/48

  Two nitrogen atoms · CPC title

• C07D239/34

  One oxygen atom · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title