Pyridin-2-YL Methylamine Derivatives for Treating Opiate Dependence

Abstract

The invention concerns the use of compounds of general formula (I) for treating opioid drug dependence, hyperalgesia induced by opiate drug withdrawal and psychological craving induced by opiate drug withdrawal.

1 . A method for preventing opiate drug dependence, comprising administering an effective amount of at least one compound of formula (I): 
       
         
           
           
               
               
           
         
         and/or its therapeutically acceptable salts, with pharmaceutically acceptable organic or mineral acids, to a patient in need thereof 
         in which: 
         u represents a hydrogen atom or a methyl radical, with the proviso that when u is a methyl radical then v and w represent a hydrogen atom; 
         v represents a hydrogen atom, a chlorine atom or a methyl radical, with the proviso that when v is a methyl radical then u and w represent a hydrogen atom; 
         w represents a hydrogen atom, a fluorine atom or a methyl radical, with the proviso that when w is a methyl radical then u and v represent a hydrogen atom; 
         x represents a hydrogen atom or a fluorine atom; 
         y represents a chlorine atom or a methyl radical; 
         z represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl radical; 
         A represents:
 a. a hydrogen atom, a fluorine atom or a chlorine atom; 
 b. a straight or branched chain saturated aliphatic hydrocarbon radical having from 1 to 5 carbon atoms; 
 c. a fluoroalkyl radical; 
 d. a cyclopropyl, cyclobutyl or cyclopentyl radical; 
 e. a 5-membered aromatic heterocyclic group, substituted or not, having 1, 2, 3 or 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein at most one oxygen and/or one sulfur atom is present in the 5-membered heterocyclic group; 
 f. an alkoxy (R 1 O—) or alkylthio (R 1 S—) group in which the R 1  radical represents:
 (1) an alkyl radical in C 1 -C 5  as defined above; 
 (2) a monofluoromethyl or trifluoromethyl radical; 
 (3) a cyclopropyl, cyclobutyl or cyclopentyl radical; 
 (4) an amino group of formula (II): 
 
 
       
       
         
           
           
               
               
           
         
         
           
             
               in which R 2  and R 3 , which may be identical or different, represent hydrogen, a straight or branched chain saturated aliphatic hydrocarbon radical having from 1 to 5 carbon atoms, a cyclopropyl group or a trifluoromethyl group; 
             
             (5) a saturated cyclic amino group of formula (III): 
           
         
       
       
         
           
           
               
               
           
         
         
           
             
               in which n is 1 or 2; or 
             
             (6) an alkoxycarbonyl group. 
           
         
       
     
     
         2 . The method of  claim 1 , wherein A represents a straight or branched chain saturated aliphatic hydrocarbon radical having from 1 to 5 carbon atoms selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, isopropyl, 1-methyl-ethyl, 1-methyl-propyl, 1-methyl-butyl, 2-methyl-propyl, 2-methyl-butyl, 3-methyl-butyl, 1-ethyl-propyl and 2-ethyl-propyl. 
     
     
         3 . The method of  claim 1 , wherein A represents a fluoroalkyl radical selected from the group consisting of monofluoromethyl (—CH 2 F), difluoromethyl (—CHF 2 ), trifluoromethyl (—CF 3 ), 1-fluoro-1-ethyl (—CHFCH 3 ) and 1,1-difluoro-1-ethyl (—CF 2 CH 3 ). 
     
     
         4 . The method of  claim 1 , wherein A represents a methoxycarbonyl group (CH 3 OCO—) or an ethoxycarbonyl (CH 3 CH 2 OCO—) group. 
     
     
         5 . The method of preventing opiate drug dependence according to  claim 1 , where in the compound of formula (I), A represents a hydrogen atom, u represents a methyl radical, v and n each represent a hydrogen atom, x represents a fluorine atom, y represents a chlorine atom and z represents a fluorine atom. 
     
     
         6 . A method for preventing hyperalgesia induced by opiate drug withdrawal, comprising administering an effective amount of at least one compound of formula (I): 
       
         
           
           
               
               
           
         
         and/or its therapeutically acceptable salts, with pharmaceutically acceptable organic or mineral acids, to a patient in need thereof
 in which: 
 u represents a hydrogen atom or a methyl radical, with the proviso that when u is a methyl radical then v and w represent a hydrogen atom; 
 v represents a hydrogen atom, a chlorine atom or a methyl radical, with the proviso that when v is a methyl radical then u and w represent a hydrogen atom; 
 w represents a hydrogen atom, a fluorine atom or a methyl radical, with the proviso that when w is a methyl radical then u and v represent a hydrogen atom; 
 x represents a hydrogen atom or a fluorine atom; 
 y represents a chlorine atom or a methyl radical; 
 z represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl radical; 
 A represents:
 a. a hydrogen atom, a fluorine atom or a chlorine atom; 
 b. a straight or branched chain saturated aliphatic hydrocarbon radical having from 1 to 5 carbon atoms; 
 c. a fluoroalkyl radical; 
 d. a cyclopropyl, cyclobutyl or cyclopentyl radical; 
 e. a 5-membered aromatic heterocyclic group, substituted or not, having 1, 2, 3 or 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein at most one oxygen and/or one sulfur atom is present in the 5-membered heterocyclic group; 
 f. an alkoxy (R 1 O—) or alkylthio (R 1 S—) group in which the R 1  radical represents:
 (1) an alkyl radical in C 1 -C 5  as defined above; 
 (2) a monofluoromethyl or trifluoromethyl radical; 
 (3) a cyclopropyl, cyclobutyl or cyclopentyl radical; 
 (4) an amino group of formula (II): 
 
 
 
       
       
         
           
           
               
               
           
         
         
           
             
                in which R 2  and R 3 , which may be identical or different, represent hydrogen, a straight or branched chain saturated aliphatic hydrocarbon radical having from 1 to 5 carbon atoms, a cyclopropyl group or a trifluoromethyl group; 
               (5) a saturated cyclic amino group of formula (III): 
             
           
         
       
       
         
           
           
               
               
           
         
         
           
             
                in which n is 1 or 2; or 
               (6) an alkoxycarbonyl group. 
             
           
         
       
     
     
         7 . The method for preventing and/or treating hyperalgesia induced by opiate drug withdrawal according to  claim 6 , where in the compound of formula (I), A represents a hydrogen atom, u represents a methyl radical, v and n each represent a hydrogen atom, x represents a fluorine atom, y represents a chlorine atom and z represents a fluorine atom. 
     
     
         8 . A method for preventing psychological craving induced by opiate drug withdrawal, comprising the administration of an effective amount of compounds of formula (I) 
       
         
           
           
               
               
           
         
         and/or its therapeutically acceptable salts, with pharmaceutically acceptable organic or mineral acids, to a patient in need thereof. 
         in which: 
         u represents a hydrogen atom or a methyl radical, with the proviso that when u is a methyl radical then v and w represent a hydrogen atom; 
         v represents a hydrogen atom, a chlorine atom or a methyl radical, with the proviso that when v is a methyl radical then u and w represent a hydrogen atom; 
         w represents a hydrogen atom, a fluorine atom or a methyl radical, with the proviso that when w is a methyl radical then u and v represent a hydrogen atom; 
         x represents a hydrogen atom or a fluorine atom; 
         y represents a chlorine atom or a methyl radical; 
         z represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl radical; 
         A represents:
 a. a hydrogen atom, a fluorine atom or a chlorine atom; 
 b. a straight or branched chain saturated aliphatic hydrocarbon radical having from 1 to 5 carbon atoms; 
 c. a fluoroalkyl radical; 
 d. a cyclopropyl, cyclobutyl or cyclopentyl radical; 
 e. a 5-membered aromatic heterocyclic group, substituted or not, having 1, 2, 3 or 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein at most one oxygen and/or one sulfur atom is present in the 5-membered heterocyclic group; 
 f. an alkoxy (R 1 O—) or alkylthio (R 1 S—) group in which the R 1  radical represents:
 (1) an alkyl radical in C 1 -C 5  as defined above; 
 (2) a monofluoromethyl or trifluoromethyl radical; 
 (3) a cyclopropyl, cyclobutyl or cyclopentyl radical; 
 (4) an amino group of formula (II): 
 
 
       
       
         
           
           
               
               
           
         
         
           
             
               in which R 2  and R 3 , which may be identical or different, represent hydrogen, a straight or branched chain saturated aliphatic hydrocarbon radical having from 1 to 5 carbon atoms, a cyclopropyl group or a trifluoromethyl group; 
             
             (5) a saturated cyclic amino group of formula (III): 
           
         
       
       
         
           
           
               
               
           
         
         
           
             
               in which n is 1 or 2; or 
             
             (6) an alkoxycarbonyl group. 
           
         
       
     
     
         9 . Method for preventing and/or treating psychological craving induced by opiate drug withdrawal according to  claim 8 , where in the compound of formula (I), A represents a hydrogen atom, u represents a methyl radical, v and n each represent a hydrogen atom, x represents a fluorine atom, y represents a chlorine atom and z represents a fluorine atom. 
     
     
         10 . The method for preventing opiate drug dependence of  claim 1 , wherein the at least one compound of formula (I) is administered simultaneously, separately, or sequentially with an opiate drug to a patient in need thereof. 
     
     
         11 . The method for preventing opiate drug dependence of  claim 10 , where in the compound of formula (I), A represents a hydrogen atom, u represents a methyl radical, v and n each represent a hydrogen atom, x represents a fluorine atom, y represents a chlorine atom and z represents a fluorine atom. 
     
     
         12 . The method of  claim 6 , wherein said method prevents the symptoms of hyperalgesia induced by opiate drug withdrawal by reducing the reaction threshold for pain to normal levels. 
     
     
         13 . The method of  claim 8 , wherein said method prevents the symptoms of hyperalgesia induced by opiate drug withdrawal by reducing the reaction threshold for pain to normal levels. 
     
     
         14 . The method of  claim 1 , where in the compound of formula (I) A=H, u=CH 3 , v=H, w=H, X=f, y=Cl and z=F. 
     
     
         15 . The method of  claim 6 , where in the compound of formula (I) A=H, u=CH 3 , v=H, w=H, X=f, y=Cl and z=F. 
     
     
         16 . The method of  claim 8 , where in the compound of formula (I) A=H, u=CH 3 , v=H, w=H, X=f, y=Cl and z=F.