Use of 1,3-diphenylprop-2-en-1-one derivatives for treating liver disorders

Abstract

The invention provides 1,3-diphenylprop-2-en-1-one derivatives and pharmaceutical compositions comprising the same for treating liver disorders, in particular those requiring the reduction of plasma level of biochemical markers such as aminotransferases. The 1,3-diphenylprop-2-en-1-one derivatives of General Formula (I) have hepatoprotective properties and can be used in methods for treating liver disorders involving the pathological disruption, inflammation, degeneration, and/or proliferation of liver cells, such as liver fibrosis or fatty liver disease.

1 . A method for the treatment of a liver disorder, comprising administering to a subject in need thereof a compound of General Formula (I) 
       
         
           
           
               
               
           
         
         in which: 
         X1 represents a halogen, a R1, or G1-R1 group; 
         A represents a CH═CH or a CH2-CH2 group; 
         X2 represents a G2-R2 group; 
         G1 and G2, identical or different, represent an atom of oxygen or sulfur; 
         R1 represents a hydrogen atom, an unsubstituted alkyl group, an aryl group or an alkyl group that is substituted by one or more halogen atoms, an alkoxy or an alkylthio group, cycloalkyl groups, cycloalkylthio groups or heterocyclic groups; 
         R2 represents an alkyl group substituted by at least a —COOR3 group, wherein R3 represents a hydrogen atom, or an alkyl group that is substituted or not by one or more halogen atoms, cycloalkyl groups, or heterocyclic groups; 
         R4 and R5, identical or different, representing an alkyl group that is substituted or not by one or more halogen atoms, cycloalkyl groups, heterocyclic groups. 
       
     
     
         2 . The method of  claim 1  wherein the compound is of general formula (I) in which:
 X1 represents a halogen, a R1, or a G1-R1 group; 
 A represents a CH═CH group; 
 X2 represents a G2-R2 group; 
 G1 and G2, identical or different, represent an atom of oxygen or sulfur; 
 R1 represents an alkyl or cycloalkyl group having from one to seven carbon atoms, in particular, the alkyl or cycloalkyl group being substituted or not by one or more halogen atoms; 
 R2 represents an alkyl group substituted by a —COOR3 group, wherein R3 represents a hydrogen atom or an alkyl group having from one to four carbon atoms; 
 R4 and R5 represent an alkyl group having from one to four carbon atoms. 
 
     
     
         3 . The method of  claim 1  wherein the compound is of general formula (I) in which:
 X1 represents a R1 or G1-R1 group; 
 A represents a CH2-CH2 group; 
 X2 represents a G2-R2 group; 
 G1 represents an atom of oxygen or sulfur and G2 represents an atom of oxygen; 
 R1 represents an alkyl or cycloalkyl group having from one to seven carbon atoms; 
 R2 represents an alkyl group substituted by at least a —COOR3 group, wherein R3 represents a hydrogen atom or an alkyl group having from one to four carbon atoms; 
 R4 and R5 represent an alkyl group having from one to four carbon atoms. 
 
     
     
         4 . The method of  claim 1  wherein the compound is of general formula (I) in which:
 X1 represents a halogen atom or a R1 or G1-R1 group; 
 A represents a CH2-CH2 group; 
 X2 represents a G2-R2 group; 
 G1 represents an atom of oxygen or sulfur and G2 represents an atom of oxygen; 
 R1 represents an alkyl or cycloalkyl group that is substituted by one or more halogen atoms; 
 R2 represents an alkyl group substituted or not by one or more halogen atoms and substituted by at least a —COOR3 group, wherein R3 represents a hydrogen atom or an alkyl group having from one to four carbon atoms; 
 R4 and R5 represent an alkyl group having from one to four carbon atoms. 
 
     
     
         5 . The method of  claim 1 , wherein G2 is an oxygen atom and R2 is an alkyl group substituted by a —COOR3 group, wherein R3 represents a hydrogen atom or an unsubstituted linear or branched alkyl group having from one to four carbon atoms. 
     
     
         6 . The method of  claim 1  wherein X1 is an alkylthio group that comprises an alkyl group that is linear or branched, having from one to seven carbon atoms that is substituted or not by one or more halogen atoms. 
     
     
         7 . The method of  claim 1 , wherein said compound is selected from the group consisting of 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyloxy phenyl]prop-2-en-1-one, 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-isopropyloxy carbonyldimethylmethyloxyphenyl]prop-2-en-1-one, 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl] prop-2-en-1-one, 1-[4-trifluoromethylphenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyl dimethylmethyloxyphenyl]prop-2-en-1-one, 1-[4-trifluoromethylphenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-en-1-one, 1-[4-trifluoromethyl oxyphenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxy phenyl] prop-2-en-1-one, 1-[4-trifluoromethyloxyphenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyl oxyphenyl]prop-2-en-1-one, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl] phenoxy]-2-methylpropanoic acid, and 2-[2,6-dimethyl-4-[3-[4-(methylthio) phenyl]-3-oxo-propyl]phenoxy]-2-methyl-propanoic acid isopropyl ester. 
     
     
         8 . The method of  claim 1 , wherein the compound is administered in combination with metformin, insulin, thiazolidinediones, glitazones, or statins. 
     
     
         9 . A method for the treatment of a liver disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound of General Formula (I) as defined in  claim 1 . 
     
     
         10 . The method of  claim 9 , wherein said composition is formulated in the form of injectable suspensions, gels, oils, pills, suppositories, powders, gel caps, capsules, aerosols or means of galenic forms or devices assuring a prolonged and/or slow release. 
     
     
         11 . The method of  claim 1 , wherein the liver disorder is selected from the group consisting of liver fibrosis, a fatty liver disease, and non-alcoholic steatohepatitis. 
     
     
         12 . The method of  claim 9 , wherein the liver disorder is selected from the group consisting of liver fibrosis, a fatty liver disease, and non-alcoholic steatohepatitis.