N-[(4,5-diphenyl-2-thienyl)methyl]amine derivatives, their preparation and their therapeutic application

Abstract

The subject of the present invention is compounds corresponding to formula (I): Wherein X, R 1 , R 2 , R 3 and R 4 are as described herein. The invention also relates to a method for the preparation and application of said compounds as cannabinoid CB1 receptor antagonists.

1 . A compound of the formula (I): 
     
       
         
         
             
             
         
       
       in which:
 X represents a group 
 
     
     
       
         
         
             
             
         
       
       
         
           R 1  represents: 
         
       
       a (C 6 -C 12 )alkyl; 
       a nonaromatic (C 3 -C 12 ) carbocyclic radical which is unsubstituted or substituted once or several times with a (C 1 -C 4 )alkyl; 
       a methyl which is substituted with a nonaromatic C 3 -C 12  carbocyclic radical and which is unsubstituted or substituted once or several times on the carbocycle with a (C 1 -C 4 )alkyl; 
       a phenyl which is mono-, di- or -trisubstituted with substituents independently chosen from a halogen atom, a (C 1 -C 4 )alkoxy, a (C 1 -C 4 )alkylamino, a di-(C 1 -C 4 )alkylamino, a cyano, a trifluoromethyl radical, a trifluoromethoxy radical, an S(O) n Alk group, a (C 1 -C 4 )alkylcarbonyl group, and methylenedioxy;
 or substituents chosen from phenyl, phenoxy, pyrrolyl, imidazolyl, pyridyl and pyrazolyl radical, said radicals being unsubstituted or substituted once or several times with a (C 1 -C 4 )alkyl; 
 
       a benzyl which is mono- or disubstituted on the phenyl with substituents independently chosen from a halogen atom, a (C 1 -C 4 )alkyl, a (C 1 -C 4 )alkoxy, a trifluoromethyl radical, and (trifluoromethyl)thio radical;
 or the phenyl substituted at the alpha-position with one or two similar or different groups chosen from a (C 1 -C 4 )alkyl, a (C 3 -C 7 )cycloalkyl, or a pyrrolyl radical; 
 
       a phenethyl which is unsubstituted or mono- or disubstituted on the phenyl with substituents independently chosen from the halogen atom, a (C 1 -C 4 )alkyl, a (C 1 -C 4 )alkoxy, and a trifluoromethyl radical; 
       a 1, 2, 3, 4-tetrahydronaphthyl or a 5, 6, 7, 8-tetrahydronaphthyl which is unsubstituted or mono- or disubstituted with substituents independently chosen from a (C 1 -C 4 )alkyl, a (C 1 -C 4 )alkoxy and a trifluoromethyl radical; 
       a benzhydryl; or a benzhydrylmethyl;
 R 2  represents a hydrogen atom or a (C 1 -C 3 )alkyl; 
 R 3  represents a phenyl which is unsubstituted or mono-, di- or trisubstituted with substituents independently chosen from a halogen atom, a (C 1 -C 4 )alkyl, a (C 1 -C 4 )alkoxy, a trifluoromethyl radical or an S(O) n Alk group; 
 R 4  represents a phenyl which is unsubstituted or mono-, di- or trisubstituted with substituents independently chosen from a halogen atom, a (C 1 -C 4 )alkyl, a (C 1 -C 4 )alkoxy, a trifluoromethyl radical or an S(O) n Alk group; 
 R 5  represents a hydrogen atom or a (C 1 -C 3 )alkyl; 
 n represents 0, 1 or 2; and 
 Alk represents a (C 1 -C 4 )alkyl. 
 
     
   
   
       2 . The compound of formula (I) according to  claim 1 , in which —X— represents a —CON(R 5 )— radical and the substituents R 1  to R 5  are as defined for the compounds of formula (I) in  claim 1 . 
   
   
       3 . The compound of formula (I) according to  claim 1 , in which —X— represents a —CSN(R 5 )— radical and the substituents R 1  to R 5  are as defined for the compounds of formula (I) in  claim 1 . 
   
   
       4 . The compound of formula (I) according to  claim 1 , in which:
 X represents a —CONH— group or a —CSNH— group;   R 1  represents:   
     a 1-propylbutyl; a 1-ethylpentyl; a 1-methylpentyl; 
     a cycloheptyl; a 1-methylcyclopropyl; a cyclobutyl; a cyclopentyl; a cyclohexyl; 
     a 1-methylcyclohexyl; a bicyclo[2.2.1]hept-2-yl; a bicyclo [2.2.1]hept-5-en-2-yl; 
     a cyclohexylmethyl; a cycloheptylmethyl; a bicyclo[2.2.1]hept-2-ylmethyl; 
     a 4-bromophenyl; a 4-chlorophenyl; a 2-fluorophenyl; a 3-fluorophenyl; a 4-fluorophenyl; a 3,5-difluorophenyl; a 2,5-difluorophenyl; a 2-methoxyphenyl; a 3-methoxyphenyl; a 3-cyanophenyl; a 4-cyanophenyl; a 3-(trifluoromethyl)-phenyl; a 4-(trifluoromethyl)phenyl: a 4-(trifluoromethoxy)phenyl; a 3-acetylphenyl; a biphenyl-2-yl; a biphenyl-4-yl; a 1,3-benzodioxo1-5-y1; a 4-phenoxyphenyl; a 4-(1H-pyrrol-1-yl)phenyl;
 a 2-fluorobenzyl; a 3-fluorobenzyl; a 4-fluorobenzyl; a 4-(trifluoromethyl)benzyl; 
 a 4-[(trifluoromethyl)thio]benzyl; an α-cyclohexylbenzyl; an α-(1H-pyrrol-1-yl)benzyl; 
 a 4-(trifluoromethyl)phenethyl; 
 a benzhydryl; a benzhydrylmethyl; 
 a 1, 2, 3, 4-tetrahydronaphth-2-yl; a 1, 2, 3, 4-tetrahydronaphth-l-y1; or a 5, 6, 7, 8-tetrahydronaphth-l-yl;
 R 2  represents a hydrogen atom or a methyl; 
 R 3  represents a 4-bromophenyl; a 4-chlorophenyl; a 2,4-dichlorophenyl; or a 4-methoxyphenyl; and 
 R 4  represents a 4-chlorophenyl; a 2,4 dichlorophenyl; a 4-methoxyphenyl. 
 
 
   
   
       5 . The compound of formula (I) according to  claim 1 , in which:
 X represents a —CONH— group;   R 1  represents:   
     a 1-propylbutyl; a 1-ethylpentyl; a 1-methylpentyl; 
     a cycloheptyl; 
     a cycloheptylmethyl; or
 a biphenyl-2-yl; 
 R 2  represents a hydrogen atom or a methyl; 
 R 3  represents a 4-bromophenyl; a 4-chlorophenyl; or a 2,4-dichlorophenyl; 
 R 4  represents a 4-chlorophenyl; or a 2,4-dichlorophenyl. 
 
   
   
       6 . The compound of formula (I) according to  claim 1 , chosen from:
 N-bipheny1-2-yl-N′-[[4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-thienyl]methyl]urea;   1-[[4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-thienyl]methyl]-3-(4-fluorophenyl)urea; and   1-(4-bromophenyl)-3-[[4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-thienyl]methyl]urea.   
   
   
       7 . A method for preparing the compounds of formula (I) according to  claim 1 , comprising:
 treating a compound of formula (II):   
     
       
         
         
             
             
         
       
       in which R 2 , R 3  and R 4  are as defined for a compound of formula (I) in  claim 1 ,
 either with a haloformate of formula (IV):
   HalCOOAr   (IV) 
 
 
       in which Hal represents a halogen atom and Ar represents a phenyl or a 4-nitrophenyl, to give an intermediate compound of formula (V): 
     
     
       
         
         
             
             
         
       
       in which R 2 , R 3  and R 4  are as defined for a compound of formula (I) in  claim 1 ; 
       reacting a compound of formula (V) thus formed with an amine of formula (VI):
   HN(R 5 )R 1    (VI) 
 
       in which R 1  and R 5  are as defined for a compound of formula (I), when a compound of formula (I) has to be prepared in which —X— represents a —CON(R 5 )— group;
 or with an isothiocyanate of formula (XX):
   S═C═N—R 1    (XX) 
 
 
       in which R 1  is as defined for a compound of formula (I) in  claim 1 , when a compound of formula (I) has to be prepared in which —X— represents a —CSNH— group. 
     
   
   
       8 . A pharmaceutical composition comprising a compound of formula (I) according to  claim 1  and at least one pharmaceutically acceptable excipient. 
   
   
       9 . A pharmaceutical composition comprising a compound of formula (I) according to  claim 2  and at least one pharmaceutically acceptable excipient. 
   
   
       10 . A pharmaceutical composition comprising a compound of formula (I) according to  claim 3  and at least one pharmaceutically acceptable excipient. 
   
   
       11 . A pharmaceutical composition comprising a compound of formula (I) according to  claim 4  and at least one pharmaceutically acceptable excipient. 
   
   
       12 . A pharmaceutical composition comprising a compound of formula (I) according to  claim 5  and at least one pharmaceutically acceptable excipient. 
   
   
       13 . A pharmaceutical composition comprising a compound of formula (I) according to  claim 6  and at least one pharmaceutically acceptable excipient. 
   
   
       14 . A method of treatment of appetite disorder, alcohol dependence and nicotine dependence comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to  claim 1 . 
   
   
       15 . A method of treatment of appetite disorder, alcohol dependence and nicotine dependence comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to  claim 2 . 
   
   
       16 . A method of treatment of appetite disorder, alcohol dependence and nicotine dependence comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to  claim 3 . 
   
   
       17 . A method of treatment of appetite disorder, alcohol dependence and nicotine dependence comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to  claim 4 . 
   
   
       18 . A method of treatment of appetite disorder, alcohol dependence and nicotine dependence comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to  claim 5 . 
   
   
       19 . A method of treatment of appetite disorder, alcohol dependence and nicotine dependence comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to  claim 6 .