Dihydroxy aromatic heterocyclic compound

Patent metadata

Field	Value
Publication number	US-9562020-B2
Application number	US-201514885037-A
Country	US
Kind code	B2
Filing date	Oct 16, 2015
Priority date	Nov 15, 2011
Publication date	Feb 7, 2017
Grant date	Feb 7, 2017

Abstract

Provided is a compound having a D-amino acid oxidase (DAAO) inhibitory action, and useful as for example, a prophylaxis and/or therapeutic agent for schizophrenia or neuropathic pain. The present inventors have studied a compound that inhibits DAAO, and confirm that a dihydroxy aromatic heterocyclic compound has a DAAO inhibitory action, and completed the present invention. That is, the dihydroxy aromatic heterocyclic compound of the present invention has a good DAAO inhibitory action, and can be used as a prophylaxis and/or therapeutic agent for, for example, schizophrenia or neuropathic pain.

First claim

The invention claimed is:

1. An agent for the treatment of schizophrenia or neuropathic pain, comprising a compound of the formula (I) or a salt thereof as an active ingredient:

wherein
X, Y and Z are N,
R 1 is chosen from C 1-10 alkyl, -lower alkylene-OR 3 , halogen, unsubstituted or substituted cycloalkyl, -L 1 -R 4 or -L 2 -N(-R 5 )R 6 ,
R 3 is chosen from H or lower alkyl,
L 1 is chosen from -lower alkylene-, -lower alkenylene-, -lower alkylene-O—, -lower alkylene-S(O) m - or -lower alkylene-C(O)—,
L 2 is chosen from -lower alkylene-, -lower alkylene-S(O) 2 - or -lower alkylene-C(O)—,
R 4 is chosen from unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted nonaromatic heterocycle or unsubstituted or substituted aromatic heterocycle,
R 5 is chosen from H, lower alkyl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted aryl,
R 6 is chosen from lower alkyl, -L 21 -(unsubstituted or substituted cycloalkyl), -L 21 -(unsubstituted or substituted aryl), -L 21 -(unsubstituted or substituted nonaromatic heterocycle), -L 21 -(unsubstituted or substituted aromatic heterocycle), -lower alkylene-OR 7 or -lower alkylene-N(R 8 ) 2 ,
R 7 is chosen from H or lower alkyl,
R 8 are the same or different and each is lower alkyl,
L 21 is chosen from a bond or -lower alkylene-, and
m is chosen from an integer of 0 to 2.

2. A compound of the formula (I) or a salt thereof:

wherein
X, Y, and Z are N,
R 1 is chosen from C 1-10 alkyl, -lower alkylene-OR 3 , halogen, unsubstituted or substituted cycloalkyl, -L 1 -R 4 or -L 2 -N(-R 5 )R 6 ,
R 3 is chosen from H or lower alkyl,
L 1 is chosen from -lower alkylene-, -lower alkenylene-, -lower alkylene-O—, -lower alkylene-S(O) m - or -lower alkylene-C(O)—,
L 2 is chosen from -lower alkylene-, -lower alkylene-S(O) 2 - or -lower alkylene-C(O)—,
R 4 is chosen from unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted nonaromatic heterocycle or unsubstituted or substituted aromatic heterocycle,
R 5 is chosen from H, lower alkyl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted aryl,
R 6 is chosen from lower alkyl, -L 21 -(unsubstituted or substituted cycloalkyl), -L 21 -(unsubstituted or substituted aryl), -L 21 -(unsubstituted or substituted nonaromatic heterocycle), -L 21 -(unsubstituted or substituted aromatic heterocycle), -lower alkylene-OR 7 or -lower alkylene-N(R 8 ) 2 ,
R 7 is chosen from H or lower alkyl,
R 8 are the same or different and each is lower alkyl,
L 21 is chosen from a bond or -lower alkylene-, and
m is chosen from an integer of 0 to 2,
with the proviso that R 1 is not —CH 2 -(phenyl unsubstituted or substituted by a nitro group), or -lower alkylene-S(O) m — unsubstituted or substituted aromatic heterocycle.

3. The compound according to claim 2 , wherein R 1 is -L 1 -R 4 .

4. The compound according to claim 2 , wherein R 1 is -L 1 -R 4 and L 1 is lower alkylene.

5. The compound according to claim 2 , wherein R 1 is -L 1 -R 4 , L 1 is lower alkylene, and R 4 is chosen from unsubstituted or substituted aryl or unsubstituted or substituted aromatic heterocycle.

6. The compound according to claim 5 , wherein R 4 is unsubstituted or substituted aryl.

7. The compound according to claim 5 , wherein R 4 is aryl unsubstituted or substituted by at least one substituent chosen from the group consisting of halogen, lower alkyl unsubstituted or substituted by at least one halogen, —O-(lower alkyl unsubstituted or substituted by at least one halogen), or aryl.

8. The compound according to claim 7 , wherein R 4 is aryl unsubstituted or substituted by at least one substituent chosen from the group consisting of lower alkyl unsubstituted or substituted by at least one halogen or aryl.

9. The compound according to claim 8 , wherein L 1 is C 1 - 4 alkylene.

10. The compound according to claim 2 , which is chosen from
5-hydroxy-3-methyl-1,2,4-triazin-6(1H)-one,
5-hydroxy-3-phenethyl-1,2,4-triazin-6(1H)-one,
or a salt thereof.

11. A pharmaceutical composition comprising the compound according to claim 2 and a pharmaceutically acceptable excipient.

12. The pharmaceutical composition according to claim 11 , which is for the treatment of a disease associated with DAAO.

13. A method for the treatment of a disease associated with DAAO wherein the disease is schizophrenia or neuropathic pain, comprising administering to a subject in need thereof an effective amount of the compound according to claim 2 .

14. The method according to claim 13 , wherein the subject is a human subject.

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Hondo Takeshi
• Nakanishi Keita
• Niimi Tatsuya
• Warizaya Masaichi
• Namatame Ichiji
• Harada Katsuya

Classifications

• A61P39/06

  Free radical scavengers or antioxidants · CPC title

• A61P43/00

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

• A61P39/00

  General protective or antinoxious agents · CPC title

• A61P25/10

  for petit-mal · CPC title

• A61P29/02

  without antiinflammatory effect · CPC title