Pyrazole compound
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.
1. A compound selected from the group consisting of:
a) 1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
b) 1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-H-pyrazol-3-yl}-N-methylmethanamine; and
c) N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein the compound is 1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine, or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound is 1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine, or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein the compound is N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine, or a pharmaceutically acceptable salt thereof.
5. A citrate of a compound selected from the group consisting of:
a) 1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
b) 1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;
c) N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine.
6. The citrate of claim 5 , wherein the compound is 1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine.
7. The citrate of claim 5 , wherein the compound is 1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine.
8. The citrate of claim 5 , wherein the compound is N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine.
9. A pharmaceutical composition comprising as an active ingredient a compound selected from the group consisting of:
a) 1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
b) 1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine; and
c) N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine,
or a pharmaceutically acceptable salt thereof,
and a pharmaceutically acceptable carrier.
10. The pharmaceutical composition of claim 9 , wherein the compound is 1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine or a pharmaceutically acceptable salt thereof.
11. The pharmaceutical composition of claim 9 , wherein the compound is 1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine or a pharmaceutically acceptable salt thereof.
12. The pharmaceutical composition of claim 9 , wherein the compound is N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine or a pharmaceutically acceptable salt thereof.
13. A method for treating a disease selected from depression, anxiety, Alzheimer's disease, or Parkinson's disease, which comprises administering a therapeutically effective amount of a compound selected from the group consisting of:
a) 1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;
b) 1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine; and
c) N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine,
or a pharmaceutically acceptable salt thereof,
to a mammal in need thereof.
14. The method of claim 12 , wherein the compound is 1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine or a pharmaceutically acceptable salt thereof.
15. The method of claim 12 , wherein the compound is 1-({5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine or a pharmaceutically acceptable salt thereof.
16. The method of claim 12 , wherein the compound is N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine or a pharmaceutically acceptable salt thereof.
17. The method of claim 12 , wherein the disease is depression and the compound is 1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine or a pharmaceutically acceptable salt thereof.
18. The method of claim 12 , wherein the disease is depression and the compound is 1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine or a pharmaceutically acceptable salt thereof.
19. The method of claim 12 , wherein the disease is depression and the compound is N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine or a pharmaceutically acceptable salt thereof.
20. The method of claim 12 , wherein the disease is anxiety and the compound is 1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine or a pharmaceutically acceptable salt thereof.
21. The method of claim 12 , wherein the disease is anxiety and the compound is 1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine or a pharmaceutically acceptable salt thereof.
22. The method of claim 12 , wherein the disease is anxiety and the compound is N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine or a pharmaceutically acceptable salt thereof.
23. The method of claim 12 , wherein the disease is Alzheimer's disease and the compound is 1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine or a pharmaceutically acceptable salt thereof.
24. The method of claim 12 , wherein the disease is Alzheimer's disease and the compound is 1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine or a pharmaceutically acceptable salt thereof.
25. The method of claim 12 , wherein the disease is Alzheimer's disease and the compound is N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine or a pharmaceutically acceptable salt thereof.
26. The method of claim 12 , wherein the disease is Parkinson's disease and the compound is 1-{-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine or a pharmaceutically acceptable salt thereof.
27. The method of claim 12 , wherein the disease is Parkinson's disease and the compound is 1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine or a pharmaceutically acceptable salt thereof.
28. The method of claim 12 , wherein the disease is Parkinson's disease and the compound is N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine or a pharmaceutically acceptable salt thereof.