Pyrazole compound

Patent metadata

Field	Value
Publication number	US-2019084938-A1
Application number	US-201816193232-A
Country	US
Kind code	A1
Filing date	Nov 16, 2018
Priority date	Jul 15, 2010
Publication date	Mar 21, 2019
Grant date	—

Abstract

The present invention relates to a novel serotonin reuptake inhibitor which also exhibits 5-HT 2C antagonistic action (antidepressive and anxiolytic effects), in particular, 5-HT 2C inverse agonistic action comprising Compound (1):

or a pharmaceutically acceptable salt thereof
wherein R 1 , R 2 , R 3 and R 4 are independently hydrogen or C 1-6 alkyl etc.; R 5 is C 4-7 alkyl or —(CR 8 R 9 ) r -E; R 6 , R 7 , R 8 and R 9 are independently hydrogen, fluorine or C 1-6 alkyl; A is C 6-10 aryl or heteroaryl etc.; r is 1, 2, 3 or 4; E is C 3-8 cycloalkyl or C 6-10 aryl etc.; L is oxygen, sulfur or —NR 10 —; n is 1, 2 or 3; R 10 is hydrogen or C 1-6 alkyl etc.; and X is hydrogen or halogen etc.

First claim

1 . A compound of Formula (1):

or a pharmaceutically acceptable salt thereof wherein
R 1 and R 2 are independently selected from the group consisting of hydrogen atom, a C 1-6 alkyl group and a C 3-8 cycloalkyl group,
R 3 and R 4 are independently selected from the group consisting of hydrogen atom and a C 1-6 alkyl group,
R 5 is an optionally-substituted C 4-7 alkyl group or —(CR 8 R 9 ) r -E,
R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of hydrogen atom, fluorine atom and an optionally-substituted C 1-6 alkyl group,
A is an optionally-substituted C 6-10 aryl group or an optionally-substituted 5- to 10-membered heteroaryl group,
r is 1, 2, 3 or 4,
E is an optionally-substituted C 3-8 cycloalkyl group, an optionally-substituted C 4-8 cycloalkenyl group, an optionally-substituted 5- to 10-membered saturated heterocyclic group which comprises 1 to 3 heteroatoms independently selected from the group consisting of oxygen atom and sulfur atom as a constituent atom of the ring, an optionally-substituted C 6-10 aryl group or an optionally-substituted 5- to 10-membered heteroaryl group,
L is oxygen atom, sulfur atom or —NR 10 —,
n is 1, 2 or 3,
R 10 is hydrogen atom, a C 1-6 alkyl group or a C 3-8 cycloalkyl group, and
X is hydrogen atom, a C 1-6 alkyl group optionally-substituted with fluorine atom or a halogen atom.

2 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein
R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen atom and methyl group, and
R 4 is hydrogen atom.

3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein A is an optionally-substituted C 6-10 aryl group.

4 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein X is hydrogen atom.

5 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein L is oxygen atom.

6 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein n is 1.

7 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein
R 1 , R 3 and R 4 are hydrogen atom, and
R 2 is methyl group.

8 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 6 , R 7 , R 8 and R 9 are hydrogen atom.

9 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein E is an optionally-substituted C 3-8 cycloalkyl group, an optionally-substituted 5- to 10-membered saturated heterocyclic group which comprises 1 to 3 oxygen atoms as a constituent atom of the ring, or an optionally-substituted phenyl group.

10 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein E is an optionally-substituted C 3-8 cycloalkyl group.

11 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein r is 1 or 2.

12 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 5 is an optionally-substituted C 4-7 alkyl group.

13 . The compound of claim 1 wherein the compound of Formula (1) is any one of the following compounds, or a pharmaceutically acceptable salt thereof:
1-[5-(benzyloxy)-1-(cyclohexylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine;
1-{1-(cyclohexylmethyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclohexylmethyl)-5-[(3-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclohexylmethyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(2-chlorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(3-chlorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclohexylmethyl)-5-[(2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclohexylmethyl)-5-[(3-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclohexylmethyl)-5-[(2,4-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(2-chloro-4-fluorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclohexylmethyl)-5-[(4-fluoro-2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclohexylmethyl)-5-[(2-fluoro-5-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(2-chloro-5-fluorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclohexylmethyl)-5-[(2,5-dichlorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(2-chloro-5-methylbenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-[5-(benzyloxy)-1-(cyclopentylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine;
1-{1-(cyclopentylmethyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclopentylmethyl)-5-[(3-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclopentylmethyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(2-chlorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(3-chlorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclopentylmethyl)-5-[(2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclopentylmethyl)-5-[(3-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclopentylmethyl)-5-[(2,4-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(2-chloro-4-fluorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclopentylmethyl)-5-[(4-fluoro-2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclopentylmethyl)-5-[(2-fluoro-5-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(2-chloro-5-fluorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclopentylmethyl)-5-[(2,5-dichlorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(2-chloro-5-methylbenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-[5-(benzyloxy)-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl]-N-methylmethanamine;
1-{5-[(3-chlorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-[5-(benzyloxy)-1-(3-methylbutyl)-1H-pyrazol-3-yl]-N-methylmethanamine;
1-{5-[(2,5-difluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(2,5-difluorobenzyl)oxy]-1-(3-methoxy-3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3-methoxy-3-methylbutyl)-1H-pyrazol-3-yl)}-N-methylmethanamine;
1-{1-(cyclopentylmethyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(cyclohexylmethyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{1-(2-cyclopentylethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylethanamine;
N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine;
1-{1-(3,3-dimethylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
1-{

Assignees

• Sumitomo Dainippon Pharma Co Ltd

Inventors

• Sasaki Izumi
• Toyoda Tomohiro
• Yoshinaga Hidefumi
• Natsutani Itaru
• Takahashi Yoko

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P43/00

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

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P25/04

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