IP Library › Granted Patent US 8,546,576

Granted Patent B2

US 8,546,576 · App. 12/477,369 · Granted Oct 1, 2013

3 or 4-substituted piperidine compounds

Inventors: Ki-Ho Lee (Daejeon, KR); Chun-Eung Park (Seoul, KR); Kyung-Hyun Min (Daejeon, KR); Yong-Je Shin (Daejeon, KR); Yu-Jin Shin (Daejeon, KR); Hae-Jeong Yoon (Daejeon, KR); Won Kim (Daejeon, KR); Eun-Ju Ryu (Daejeon, KR)

Assignee: SK Biopharmaceuticals Co., Ltd.

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Quick Facts

Patent No.: US 8,546,576
App. No.: 12/477,369
Granted: Oct 1, 2013
Kind: B2

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Abstract

There are disclosed racemic or enantiomerically enriched 3- or 4-substituted piperidine compounds represented by the following structural formula (I): or any of their isomers, or pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical compositions containing the subject compounds. The subject compounds are useful for the treatment of diseases of the central nervous system, particularly depression, anxiety and pain disorder.

Claims (200)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

A is selected from the group consisting of phenyl, naphthyl, benzothiophenyl, pyridyl, quinolyl and isoquinolyl, wherein A is optionally substituted by one or more substituents selected from the group consisting of H-, halo, straight- or branched-chain C 1 -C 4 alkyl, straight- or branched-chain C 1 -C 3 alkoxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, methanesulfonyl, phenyloxy, phenyl and thienyl;

B is a substitution group selected from Formulae (II);

one of X and Y is -CH 2 - and the other is -NR-, wherein R is H- or straight- or branched-chain C 1 -C 4 alkyl.

2. The compound of claim 1 , which is a compound selected from Formulae (III):

or a pharmaceutically acceptable salt thereof,

wherein each of A, B and R is as defined in claim 1 .

3. The compound of claim 1 , which is a compound selected from Formulae (IV):

or a pharmaceutically acceptable salt thereof,

wherein each of A, B and R is as defined in claim 1 .

4. The compound of claim 2 , which is a compound selected from Formulae (XXII):

or a pharmaceutically acceptable salt thereof, wherein

each of R 1 , R 2 and R 3 is independently selected from the group consisting of H-, halo, straight- or branched-chain C 1 -C 4 alkyl, straight- or branched-chain C 1 -C 3 alkoxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, methanesulfonyl, phenyloxy, phenyl and thienyl; and

each of B and R is as defined in claim 1 .

5. The compound of claim 4 , wherein B is

6. The compound of claim 4 , wherein each of R 1 , R 2 and R 3 is independently selected from the group consisting of H-, halo, methyl and methoxy.

7. The compound of claim 4 , which is selected from the group consisting of:

3-[naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine,

3-[(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(R)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(S)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

3-[(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(R)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(S)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine, and

(3S)-3-[(R)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

8. The compound of claim 1 , which is selected from the group consisting of:

(3R)-3-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(R)-naphthalen-2-yl(1 H-tetrazol-1-yl)methyl]piperidine,

(3S)-3-[(S)-naphthalen-2-yl(1 H-tetrazol-1-yl)methyl]piperidine,

(3R)-3-[(S)-naphthalen-2-yl(1 H-tetrazol-1-yl)methyl]piperidine,

(3S)-3-[(R)-naphthalen-2-yl(1 H-tetrazol-1-yl)methyl]piperidine,

(3S)-3-[(R)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine,

(3S)-3-[(S)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine,

(3R)-3-[(S)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine,

(3R)-3-[(R)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine,

(3R)-3-[(R)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine,

(3R)-3-[(R)-naphthalen-1-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-naphthalen-1-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(6-methoxynaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(6-methoxynaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(4-methyl-naphthalen-1-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(4-methyl-naphthalen-1-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(R)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(S)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-1-ethyl-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine, (3R)-3-[(R)-naphthalen-2-yl-(5-phenyl-tetrazol-2-yl)methyl]piperidine, (3S)-3-[(S)-naphthalen-2-yl-(5-phenyl-tetrazol-2-yl)methyl]piperidine, (3R)-3-[(S)-naphthalen-2-yl-(5-phenyl-tetrazol-2-yl)methyl]piperidine, (3S)-3-[(R)-naphthalen-2-yl-(5-phenyl-tetrazol-2-yl)methyl]pipendine,

1-{(S)-naphthalen-2-yl[(3S)-pipericlin-3-yl]methyl}-1 H-benzotriazole,

1-{(R)-naphthalen-2-yl[(3S)-pipericlin-3-yl]methyl}-1 H-benzotriazole,

2-{(S)-naphthalen-2-yl[(3S)-pipenclin-3-yl]methyl}-2H-benzotriazole,

2-{(R)-naphthalen-2-yl[(3S)-pipericlin-3-yl]methyl}-2H-benzotriazole,

(3R)-3-[(R)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]pipendine,

(3R)-3-[(S)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]pipendine,

(3S)-3-[(S)-(6-methylnaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]pipendine,

(3S)-3-[(R)-(6-methylnaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]pipendine,

(3S)-3-[(S)-(4-fluoronaphthalen-1 -yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(4-fluoronaphthalen-1 -yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-naphthalen-2-yl(4H-1 ,2,4-triazol-4-yl)methyl]piperidine,

(3S)-3-[(S)-naphthalen-2-yl(1H-1 ,2,4-triazol-1-yl)methyl]piperidine,

(3S)-3-[(R)-naphthalen-2-yl(1H-1 ,2,4-triazol-1-yl)methyl]piperidine,

(3R)-3-[(R)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(S)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]pipendine,

(3S)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(R)-(6-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine

(3S)-1-butyl-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine,

4-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine,

4-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine,

4-[(S)-naphthylene-2-yl(1H-tetrazol-2-yl)methyl]piperidine,

4-[(R)-naphthalen-2-yl(1H-tetrazol-2-yl)methyl]piperidine,

4-[(S)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine,

4-[(R)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine,

4-[(S)-naphthalen-2-yl(1H-1,2,3-triazol-2-yl)methyl]piperidine, and

4-[(R)-naphthalen-2-yl(1H-1,2,3-triazol-2-yl)methyl]piperidine.

9. The compound of claim 1 , which is selected from the group consisting of:

(3R)-3-[(R)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(R)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(S)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(R)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(S)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(3,4-dimethoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(3,4-dimethoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(3,4-dimethoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine,

(3S)-3-[(R)-(3,4-dimethoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine,

(3S)-3-[(S)-phenyl(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-phenyl(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-{(S)-2H-tetrazol-2-yl[4-trifluoromethyl)phenyl]methyl}piperidine,

(3S)-3-{(R)-2H-tetrazol-2-yl[4-(trifluoromethyl)phenyl]methyl}piperidine,

(3S)-3-[(S)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(3-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(3-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(2,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(2,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(4-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(4-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(4-methoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine,

(3S)-3-[(R)-(4-methoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine,

(3S)-3-[(S)-(4-phenoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(4-phenoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(4-phenoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine,

(3S)-3-[(R)-(4-phenoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine,

(3S)-3-[(S)-(4-fluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(4-fluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-biphenyl-4-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-biphenyl-4-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-{(S)-2H-tetrazol-2-yl[3-(trifluoromethyl)phenyl]methyl}piperidine,

(3S)-3-{(R)-2H-tetrazol-2-yl[3-(trifluoromethyl)phenyl]methyl}piperidine,

(3S)-3-[(S)-(4-propylphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(4-propylphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(3-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(3-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(3-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(3-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(3,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(3,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(2,3-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(2,3-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

4-[(S)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

4-[(R)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine,

4-[(S)-(4-methylphenyl)(1 H-tetrazol-2-yl)methyl]piperidine,

4-[(R)-(4-methylphenyl)(1 H-tetrazol-2-yl)methyl]piperidine,

4-[(S)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine, and

4-[(R)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

10. The compound of claim 1 , which is selected from the group consisting of:

(3S)-3-[(S)-1-benzothiophen-5-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-1-benzothiophen-5-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-1-benzothiophen-3-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-1-benzothiophen-2-yl(2H-tetrazol-2-yl)methyl]piperidine, and

(3S)-3-[(R)-1-benzothiophen-2-yl(2H-tetrazol-2-yl)methyl]piperidine.

11. The compound of claim 1 , which is selected from the group consisting of:

(3R)-3-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(R)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine,

(3R)-3-[(R)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine,

(3)-3-[(S)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine,

(3R)-3-[(R)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(6-methoxynaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(R)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(R)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3R)-3-[(R)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine,

(3S)-3-[(S)-(6-methylnaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine, and

(3S)-3-[(R)-(6-methylnaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

12. The compound of claim 1 , which is

(3R)-3-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine or

(3S)-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine.

13. The compound of claim 1 , which is (3S)-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 2 and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 3 and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 4 and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition of claim 14 , wherein the compound is selected from the group consisting of: