Pyrimidine carboxamides as sodium channel blockers

Patent metadata

Field	Value
Publication number	US-10196364-B2
Application number	US-201715481150-A
Country	US
Kind code	B2
Filing date	Apr 6, 2017
Priority date	Mar 4, 2013
Publication date	Feb 5, 2019
Grant date	Feb 5, 2019

Abstract

The present disclosure provides substituted pyrimidine carboxamides of Formula (I) and the pharmaceutically acceptable salts 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 II:

or a pharmaceutically acceptable salt or solvate thereof, wherein:
W 2 is N and W 3 is CH; or
W 2 is CH and W 3 is N;
A 1 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and aralkyl;
—X-A 2 - is selected from the group consisting of:

E is selected from the group consisting of —N(H)R 1 and —OH;
R 1 is selected from the group consisting of hydrogen and (heterocyclo)alkyl;
Z is selected from the group consisting of —NR 5 — and —O—;
R 4 is selected from the group consisting of:

R 1a is selected from the group consisting of hydrogen and (heterocyclo)alkyl;
R 10a is selected from the group consisting of alkyl and hydroxyalkyl;
R 12 is selected from the group consisting of hydrogen, alkyl, alkenyl, and hydroxyalkyl;
R 5 is hydrogen; or
R 4 and R 5 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclo selected from the group consisting of:

and R 14 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein W 2 is N and W 3 is CH.

3. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
E is NH 2 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein A 1 is selected from the group consisting of:

wherein:
R 28a is selected from the group consisting of hydrogen, fluoro, chloro, cyano, C 1-4 haloalkyl, C 1-4 haloalkoxy, (C 1 -C 4 haloalkoxy)alkyl, C 1-4 alkoxy, C 1 -C 4 alkyl, and C 1 -C 6 cycloalkyl;
R 28b is selected from the group consisting of hydrogen, fluoro, chloro, cyano, C 1-4 haloalkyl, C 1 -C 4 haloalkoxy, (C 1 -C 4 haloalkoxy)alkyl, C 1-4 alkoxy, C 1 -C 4 alkyl, and C 1 -C 6 cycloalkyl; or
R 28a and R 28b taken together with two adjacent carbon atoms form a 5- or 6-membered cycloalkyl or heterocyclo, and
R 28c is selected from the group consisting of hydrogen, heteroaryl, and (heterocyclo)alkyl.

5. The compound of claim 4 having Formula V:

or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of claim 5 , or a pharmaceutically acceptable salt or solvate thereof, wherein A 1 is selected from the group consisting of A 1 -1, A 1 -2, A 1 -3, and A 1 -4.

7. The compound of claim 4 having Formula VI:

or a pharmaceutically acceptable salt or solvate thereof.

8. The compound of claim 4 having Formula VII:

or a pharmaceutically acceptable salt or solvate thereof.

9. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein Z is —N(H)— or —O—.

10. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is:

11. The compound of claim 10 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a is hydrogen and R 10a is C 1-4 alkyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is:

13. A pharmaceutical composition, comprising the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

14. A method for treating pain, migraine, cardiac arrhythmia, or of providing local anesthesia in a mammal, comprising administering an effective amount of a compound as claimed in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need of such treatment.

15. The method of claim 14 , wherein said method is for treating pain.

16. The method of claim 15 , wherein said method is for preemptive or palliative treatment of pain.

17. The method of claim 15 , wherein said pain is selected from the group consisting of chronic pain, inflammatory pain, neuropathic pain, acute pain, and surgical pain.

18. The compound of claim 5 having Formula V(A):

or a pharmaceutically acceptable salt or solvate thereof.

19. The compound of claim 18 , or a pharmaceutically acceptable salt or solvate thereof, wherein A 1 is selected from the group consisting of A 1 -1, A 1 -2, A 1 -3, and A 1 -4.

Assignees

• Purdue Pharma Lp

Inventors

• Lockman Jeffrey
• Ni Chiyou
• Park Jae Hyun
• Park Minnie
• Shao Bin
• Tafesse Laykea
• Yao Jiangchao
• Youngman Mark A

Classifications

• A61P43/00

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

• A61P9/06

  Antiarrhythmics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P29/02

  without antiinflammatory effect · CPC title