IP Library › Patent Application 11587759

Patent Application

App. No. 11/587,759

Therapeutic Agent for Nonviral Hepatitis

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Patent No.: US None
App. No.: 11/587,759

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Abstract

The present invention provides a therapeutic drug for non-viral hepatitis, which contains a piperazine compound represented by the following formula (I) or pharmaceutically acceptable salt thereof as an active ingredient.

Claims (114)

1 . A method for treating non-viral hepatitis, comprising administering to a patient in need thereof an effective amount of a therapeutic drug comprising, as an active ingredient, a piperazine compound represented by the following formula (I)

wherein R 1 and R 2 are the same or different and each is an amino, a nitro, a hydroxy or a cyano, which is mono- or di-substituted by a group selected from a hydrogen, a halogen, a lower alkyl, a lower alkoxy, an amino, a lower alkyl and a lower acyl;

R 3 , R 4 and R 5 are the same or different and each is an amino or a hydroxy, which is mono- or di-substituted by a group selected from a hydrogen, a halogen, a lower alkyl, a lower alkoxy, a nitro, an amino, a lower alkyl and a lower acyl;

R 6 and R 7 are the same or different and each is a hydrogen, a lower alkyl, a lower alkyl substituted by 1 to 3 halogens, an aralkyl, an acyl or a lower acyl substituted by 1 to 3 halogens;

R 8 and R 9 are the same or different and each is a hydrogen or a lower alkyl; and

Y is a group represented by

wherein R 10 and R 11 are the same or different and each is a hydrogen or a lower alkyl;

R 12 and R 13 are the same or different and each is a hydrogen or a lower alkyl; or R 12 and R 3 in combination form alkylene;

R 14 and R 15 are the same or different and each is a hydrogen or a lower alkyl;

m is an integer of 0-2, n is an integer of 0-2, and 0≦m+n≦2; and

ring A is a phenyl, a pyrimidyl, a thiazolyl, a pyridyl, a pyradyl or an imidazolyl, or a pharmaceutically acceptable salt thereof.

2 . The method of claim 1 , wherein the active ingredient is a compound of the formula (I) wherein R 1 and R 2 are each a hydrogen, R 3 , R 4 and R 5 are the same or different and each is a halogen or a lower alkoxy, R 6 and R 7 are each an acyl, R 8 and R 9 are the same or different and each is a hydrogen or a lower alkyl, R 10 and R 11 are each a hydrogen, R 14 and R 15 are each a hydrogen, ring A is a phenyl, a pyrimidyl, a thiazolyl or a pyridyl, or a pharmaceutically acceptable salt thereof.

3 . The method of claim 1 , wherein the active ingredient is the following compound:

N-(4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide;

N-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide;

N-(4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide;

N-(3-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)propyl)acetamide;

N-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide;

N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamide;

N-(4-((4-(pyridin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide;

N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide;

N-(4-((4-(pyridin-3-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide;

N-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide;

N-(1-methyl-1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide;

N-(1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide;

N-(1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)propyl)acetamide;

N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide;

N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide;

N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide;

N-(1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide;

N-(4-((4-(6-fluoropyridin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide;

N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide;

N-(1-(4-(1-(4-phenylpiperazin-1-yl)ethyl)phenyl)-1-methylethyl)acetamide;

N-(1-(4-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)phenyl)cyclopropyl)acetamide;

N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide;

N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide;

N-(4-((4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide;

N-(1-methyl-1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide;

N-(1-methyl-1-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide;

N-(1-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide;

N-(1-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide;

N-(1-(4-((4-(6-fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)-1-methylethyl)acetamide;

N-(1-(4-((4-(6-fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide;

N-(1-(4-((4-(pyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide;

N-(1-methyl-1-(4-((4-(pyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide;

N-(1-(4-(1-(4-(pyridin-2-yl)piperazin-1-yl)ethyl)phenyl)-1-methylethyl)acetamide;

N-(1-(4-((4-(pyridin-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide;

N-(1-(4-((4-(6-fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide;

(S)—N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide;

(R)—N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide;

N-(4-(1-(4-(pyridin-2-yl)piperazin-1-yl)ethyl)phenylmethyl)acetamide;

N-(1-(4-(1-(4-(6-fluoropyridin-2-yl)piperazin-1-yl)ethyl)phenyl)-1-methylethyl)acetamide; or

N-(1-(4-(1-(4-(6-fluoropyridin-2-yl)piperazin-1-yl)ethyl)phenyl)methyl)acetamide,

or a pharmaceutically acceptable salt thereof.

4 . The method of claim 1 , wherein the active ingredient is N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide, or a pharmaceutically acceptable salt thereof.

5 . The method of claim 1 , wherein the active ingredient is N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide hydrochloride.

6 . The method of claim 1 , wherein the non-viral hepatitis is selected from acute hepatitis, hepatic encephalopathy, cirrhosis, primary biliary hepatitis, autoimmune hepatitis, alcoholic hepatitis and nonalchoholic steatohepatitis.

7 . A method for treating a liver transplant patient, comprising administering to a patient in need thereof an effective amount of a hepatic function-improving drug or hepatoprotector, which comprises, as an active ingredient, a piperazine compound represented by the following formula (I)

R 3 , R 4 and R 5 are the same or different and each is an amino or hydroxy, which is mono- or di-substituted by a group selected from a hydrogen, a halogen, a lower alkyl, a lower alkoxy, a nitro, an amino, a lower alkyl and lower an acyl;

R 6 and R 7 are the same or different and each is a hydrogen, a lower alkyl, a lower alkyl substituted by 1 to 3 halogens, an aralkyl, an acyl or a lower acyl substituted by 1 to 3 halogens;

R 8 and R 9 are the same or different and each is a hydrogen or a lower alkyl;

Y is

wherein R 10 and R 11 are the same or different and each is a hydrogen or a lower alkyl;

R 12 and R 13 are the same or different and each is a hydrogen or a lower alkyl, or R 12 and R 13 in combination form alkylene;

R 14 and R 15 are the same or different and each is a hydrogen or a lower alkyl;

m is an integer of 0-2, n is an integer of 0-2, and 0≦m+n≦2; and

ring A is a phenyl, a pyrimidyl, a thiazolyl, a pyridyl, a pyradyl or an imidazolyl,

or a pharmaceutically acceptable salt thereof.

8 . The method of claim 7 , wherein the active ingredient is a compound of the formula (I), wherein R 1 and R 2 are each a hydrogen, R 3 , R 4 and R 5 are the same or different and each is a halogen or a lower alkoxy, R 6 and R 7 are each an acyl, R 8 and R 9 are the same or different and each is a hydrogen or a lower alkyl, R 10 and R 11 are each a hydrogen, R 14 and R 15 are each a hydrogen, ring A is a phenyl, a pyrimidyl, a thiazolyl or a pyridyl, or a pharmaceutically acceptable salt thereof.

9 . The method of claim 7 , wherein the active ingredient is the following compound: