Sepiapterin reductase inhibitors for the treatment of pain

Patent metadata

Field	Value
Publication number	US-10059664-B2
Application number	US-201514853709-A
Country	US
Kind code	B2
Filing date	Sep 14, 2015
Priority date	Oct 15, 2009
Publication date	Aug 28, 2018
Grant date	Aug 28, 2018

Abstract

Disclosed herein are small molecule heterocyclic inhibitors of sepiapterin reductase (SPR), and prodrugs and pharmaceutically acceptable salts thereof. The Also featured are pharmaceutical compositions of the compounds and uses of these compounds for the treatment or prevention of pain (e.g., inflammatory pain, nociceptive pain, functional pain, and neuropathic pain).

First claim

What is claimed is:

1. A compound of Formula (II),

or pharmaceutically acceptable salt thereof, wherein
X is N or CH;
m is 0 or 1;
R 1 is (CH 2 ) n OR 1A , halogen, CN, amino, SO 2 R 1A , NHSO 2 R 1A , NHC(═O)R 1A , or C(═O)N(R 1A ) 2 ;
wherein R 1A is H;
n is 0, 1, or 2;
R 2 is H or optionally substituted C 1-3 alkyl;
R 3 is C(═O)R 3A or SO 2 R 3A ; and
R 3A is optionally substituted C 1-6 alkyl.

2. The compound of claim 1 , wherein the compound has the following formula,

3. The compound of claim 1 , wherein the compound the following formula,

4. The compound of claim 1 , wherein the compound has the following formula,

5. The compound of claim 1 , wherein X is N, m is 1, and R 2 is H.

6. The compound of claim 5 , wherein R 1 is amino.

7. The compound of claim 6 , wherein R 3 is C(═O)R 3A , and R 3A is C 1-3 alkyl having a C 1-3 alkoxy substituent.

8. The compound of claim 7 , wherein the compound is

9. The compound of claim 1 , wherein X is CH, m is 1, and R 2 is H.

10. The compound of claim 9 , wherein
R 1 is F, OH, CN, CH 2 OR 1A , SO 2 R 1A , NHSO 2 R 1A , or C(═O)NH 2 ; and
R 1A is H.

11. The compound of claim 10 , wherein R 3 is C(═O)R 3A , and R 3A is C 1-3 alkyl comprising a C 1-3 alkoxy substituent.

12. The compound of claim 11 , wherein the compound is selected from the group consisting of:

13. The compound of claim 10 , wherein R 3 is SO 2 R 3A , and R 3A is optionally substituted C 1-4 alkyl.

14. The compound of claim 13 , wherein the compound is selected from the group consisting of:

15. A method of treating or reducing pain in a mammal, wherein the method comprises the administration of the compound of claim 1 ,
or a pharmaceutically acceptable salt thereof to the mammal in a dosage sufficient to inhibit sepiapterin reductase (SPR).

16. The method of claim 15 , wherein the compound is administered in a formulation comprising the compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17. The method of claim 15 , wherein the pain is neuropathic, inflammatory, nociceptive, or functional pain.

18. The method of claim 15 , wherein the pain is chronic pain.

19. The method of claim 15 , wherein the pain is acute pain.

Assignees

• Childrens Medical Center

Inventors

• Blagg Julian

Classifications

• A61P43/00

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

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D209/18

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D209/16

  Tryptamines · CPC title

• C07D209/14 Primary

  Radicals substituted by nitrogen atoms, not forming part of a nitro radical · CPC title