IP Library › Granted Patent US 8,541,409

Granted Patent B2

US 8,541,409 · App. 12/600,291 · Granted Sep 24, 2013

Carbamoyloxy arylalkanoyl arylpiperazine analgesics

Inventors: Byong Sung Kwak (Daejeon, KR); Hong Sik Moon (Daejeon, KR); Han Ju Yi (Daejeon, KR); Young Soon Kang (Daejeon, KR); Dae Joong Im (Daejeon, KR); Eun Hee Chae (Daejeon, KR); Sang Mi Chae (Seoul, KR); Ki Ho Lee (Daejeon, KR)

Assignee: SK Biopharmaceuticals Co., Ltd.

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Quick Facts

Patent No.: US 8,541,409
App. No.: 12/600,291
Granted: Sep 24, 2013
Kind: B2

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Abstract

There is provided a novel carbamoyloxy arylalkanoyl arylpiperazine derivative compound having abundant racemic or enantiomeric characteristics, represented by the Formula 1, and pharmaceutically available salts or hydrates thereof. Also, there are provided a pharmaceutical composition for treating pain, anxiety or depression including an effective amount of the compound, and a method for treating pain, anxiety or depression in mammals by administering an effective amount of the compound to the mammals in need of treatment thereof.

Claims (154)

1. A compound of Formula 1:

or a pharmaceutically acceptable salt or hydrate thereof, wherein - - - denotes an optional bond forming a cyclic moiety;

each of R 1 and R 2 is independently selected from the group consisting of H- and straight- or branched-chain C 1 -C 6 alkyl, or

R 1 and R 2 are taken together to form piperidinyl or piperazinyl, or R 1 and R 2 are taken together with Ar 1 to form benzo[d][1,3]oxazin-2-one moiety;

Ar 1 is selected from the group consisting of furanyl, methylenedioxyphenyl and phenyl which is optionally substituted by one or more substituents independently selected from the group consisting of H-, straight- or branched-chain C 1 -C 6 alkyl, fluoro, chloro, bromo, straight- or branched-chain C 1 -C 6 alkoxy, nitro and trifluoromethyl;

z is H- or fluoro;

Ar 2 is selected from the group consisting of phenyl, methylenedioxyphenyl, pyridinyl, pyrimidinyl, naphthyl, and quinoxalinyl, wherein Ar 2 is optionally substituted by one or more substituents independently selected from the group consisting of H-, straight- or branched-chain C 1 -C 6 alkyl, hydroxy, halo, straight- or branched- chain C 1 -C 6 alkoxy, nitro, acetyl, t-butylacetyl, trifluoromethyl, amino and acetyloxy;

n is 1 or 2; and

m is 0, 1 or 2.

2. The compound of claim 1 , which is a compound of Formula 2:

wherein

each of R 1 , R 2 , z, n, m and Ar 2 is as defined in claim 1 ; and

X 1 is one or more substituents independently selected from the group consisting of H-, straight- or branched-chain C 1 -C 6 alkyl, fluoro, chloro, bromo, straight- or branched-chain C 1 -C 6 alkoxy, nitro and trifluoromethyl.

3. The compound of claim 1 , which is a compound of Formula 3:

wherein

X 2 is one or more substituents independently selected from the group consisting of H-, straight- or branched-chain C 1 -C 6 alkyl, hydroxy, halo, straight- or branched-chain C 1 -C 6 alkoxy, nitro, acetyl, t-butylacetyl, trifluoromethyl and amino.

4. The compound of claim 3 , wherein X 2 is straight- or branched-chain C 1 -C 6 alkoxy.

5. The compound of claim 3 , wherein X 2 is two methoxy substituents.

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

carbamic acid 3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-[4-(4-methoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-[4-(3,4-dichloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-oxo-1-phenyl-3-(4-p-tolyl-piperazin-1-yl)-propyl ester,

carbamic acid 3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 1-(4-chloro-phenyl)-3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-propyl ester,

carbamic acid 3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-1-(4-flouro-phenyl)-3-oxo-propyl ester,

carbamic acid 3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-p-tolyl-propyl ester,

carbamic acid 3-[4-(2,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-[4-(3,5-dichloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-[4-(3,5-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-[4-(2,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-(4-benzo[1,3]dioxol-5-yl-piperazin-1-yl)-3-oxo-1-phenyl-propyl ester,

carbamic acid 1-(4-methoxy-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester,

carbamic acid 1-(4-chloro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester,

carbamic acid 3-[4-(4-tert-butyl-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

dimethyl-carbamic acid 3-[4-(4-methoxy-phenyl)-piperazin-1 -yl]-3-oxo-1 -phenyl- propyl ester,

carbamic acid 3-[4-(3,4-dimethyl-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-oxo-1-phenyl-3-(4-quinoxalin-2-yl-piperazin-1-yl)-propyl ester,

acetic acid 4-[4-(3-carbamoyloxy-3-phenyl-propionyl)-piperazin-1-yl]-phenyl ester,

carbamic acid 3-oxo-1-phenyl-3-(4-pyridin-2-yl-piperazin-1-yl)-propyl ester,

carbamic acid 3-oxo-1-phenyl-3-(4-pyrimidin-2-yl-piperazin-1-yl)-propyl ester,

carbamic acid 3-[4-(3,5-dichloro-pyridin-2-yl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-[4-(4-chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-oxo-1-phenyl-3[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propyl ester,

carbamic acid 3-[4-(2-flouro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-[4-(3-flouro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-oxo-3-(4-phenyl-piperazin-1 -yl)-1 -(4-trifluoromethyl-phenyl)-propyl ester,

carbamic acid 3-oxo-3-(4-phenyl-piperazin-1-yl)-1-p-tolyl-propyl ester,

carbamic acid 3-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 1 -(4-nitro-phenyl)-3-oxo-3-(4-phenylpiperazin-1 -yl)-propyl ester,

carbamic acid 3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-(4-trifluoromethyl-phenyl)-propyl ester,

carbamic acid 3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-1-(4-nitro-phenyl)-3-oxo-propyl ester,

carbamic acid 3-[4-(3,4-dichloro-benzyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-[4-(4-chloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-{4-[2-(3,4-dichloro-phenyl)-ethyl]-1-piperazin-1 -yl}-3-oxo-1 -phenyl-propyl ester,

carbamic acid 4-[4-(3,4-dichloro-phenyl)-piperazin-1 -yl]-4-oxo-1 -phenyl-butyl ester,

carbamic acid 4-[4-(3,4-dimethoxy-phenyl)-piperazin-1 -yl]-4-oxo-1 -phenyl-butyl ester,

carbamic acid 1-(2-nitro-phenyl)-3-oxo-3-(4-phenylpiperazin-1-yl)-propyl ester,

carbamic acid 1-(2-chloro-phenyl)-3-oxo-3-(4-phenylpiperazin-1-yl)-propyl ester,

carbamic acid 1-(2-methoxy-phenyl)-3-oxo-3-(4-phenylpiperazin-1-yl)-propyl ester

carbamic acid 1-(3-trifluoromethyl-phenyl)-3-oxo-3-(4-phenylpiperazin-1-yl)-propyl ester,

carbamic acid 1-(3-bromo-phenyl)-3-oxo-3-(4-phenylpiperazin-1-yl)-propyl ester,

carbamic acid 1-(3,4-dimethoxy-phenyl)-3-oxo-3-(4-phenylpiperazin-1-yl)-propyl ester,

carbamic acid 1-furan-3-yl-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester,

carbamic acid 1-(3-methyl-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester,

carbamic acid 1-(3-chloro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester,

carbamic acid 1-(3,4-dichloro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester,

carbamic acid 1-(2,3,4,5,6-pentafluoro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester,

carbamic acid 1-(3,5-di-trifluoromethyl-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester,

carbamic acid 1-(2,4-dichloro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester,

carbamic acid 1-(2,5-difluoro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester,

carbamic acid 1-(2,4-dimethyl-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester,

carbamic acid 1-(3,4-methylenedioxy-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)- propyl ester,

carbamic acid 1-(3,4-difluoro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester, and

4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one.

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

carbamic acid 3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-[4-(3,4-dichloro-benzyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 4-[4-(3,4-dichloro-phenyl)-piperazin-1-yl]-4-oxo-1-phenyl-butyl ester,

carbamic acid 3-[4-(3,4-dichloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-[4-(4-methyl-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-[4-(2,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid 3-[4-(3-chloro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester, and

carbamic acid 3-oxo-1-phenyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propyl ester.

8. The compound of claim 1 , wherein the compound is carbamic acid 3-[4-(3,4- dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester.

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

(R)-carbamic acid 3-[4-(4-chloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(R)-carbamic acid 3-[4-(4-flouro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(R)-carbamic acid 3-[4-(4-ethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(S)-carbamic acid 3-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(S)-carbamic acid 3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(S)-carbamic acid 3-[4-(3,4-dichloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(R)-carbamic acid 3-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(R)-carbamic acid 3-[4-(3,4-dichloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(S)-carbamic acid 3-[4-(4-methoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(R)-carbamic acid 3-[4-(4-methoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(R)-carbamic acid 3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

piperidine -1-carboxylic acid-(R)-3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl propyl ester,

butyl-carbamic acid-(R)-3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(R)-carbamic acid 3-[4-(4-amino-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(R)-carbamic acid 3-[4-(3-hydroxy-4-methoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(S)-carbamic acid 3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(R)-carbamic acid 3-[4-(4-methyl-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(S)-carbamic acid 3-[4-(4-methyl-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(R)-carbamic acid 3-[4-(2,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(R)-carbamic acid 3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(S)-carbamic acid 3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(S)-carbamic acid 3-[4-(4-chloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

carbamic acid (R)-3-[4-(3-hydroxy-4-methoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester, and

carbamic acid (R)-3-[4-(3-methoxy-4-hydroxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester.

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

(R)-carbamic acid 3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(R)-carbamic acid 3-[4-(4-methoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(S)-carbamic acid 3-[4-(3,4-dichloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(S)-carbamic acid 3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(R)-carbamic acid 3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(S)-carbamic acid 3-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(R)-carbamic acid 3-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester,

(R)-carbamic acid 3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester, and

(S)-carbamic acid 3-[4-(4-chloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester.

11. The compound of claim 1 , wherein the compound is (R)-carbamic acid 3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester.

12. The compound of claim 1 , wherein the pharmaceutically acceptable salt is selected from the group consisting of methanesulfonate and hydrochloride.

13. A compound which is selected from the group consisting of:

carbamic acid 3-{4-[bis-(4-flouro-phenyl)-methyl]-piperazin-1-yl}-3-oxo-1-phenyl-propyl ester,

carbamic acid 2,2-difluoro-3-oxo-1-phenyl-3-(4-phenylpiperazin-1-yl)-propyl ester,

carbamic acid 2-(4-phenyl-piperazine-1-carbonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl ester,

phenethyl-carbamic acid-(R)-3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester, and

4-methyl-piperazine-1-carboxylic acid-(R)-3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester.

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

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