Derivatives of pyrrolizine, indolizine and quinolizine, preparation thereof and therapeutic use thereof

Abstract

The disclosure relates to a compound of formula (I): wherein m, n, Ar, and R are as defined in the disclosure, to compositions containing them and to their therapeutic use. The disclosure also relates to processes for preparing these compounds and to certain intermediate compounds.

1 . A method for treating a disease selected from the group consisting of behavioral disorders associated with dementia, psychoses, schizophrenia, acute or chronic extrapyramidal symptoms induced by neuroleptics, anxiety, panic attacks, phobias, obsessive-compulsive disorders, depression, psychotic depression, disorders due to alcohol abuse or withdrawal, disorders of sexual behavior, eating disorders, migraine, and epilepsy, in a patient comprising administering to said patient a therapeutically effective amount of a compound corresponding to formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         m and n each represent, independently of one another, 1 or 2; 
         Ar represents a group chosen from phenyl, naphth-1-yl, naphth-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl, thiazol-2-yl and oxazol-2-yl groups, and wherein the Ar group is optionally substituted by one or more substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyloxy, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyloxy, (C 1 -C 6 )alkylthio, (C 3 -C 7 )cycloalkylthio, (C 3 -C 7 )cycloalkyl-(C 1 -C 6 )alkylthio, mono- or polyfluoro(C 1 -C 6 )alkyl and mono- or polyfluoro(C 1 -C 6 )alkyloxy groups; and 
         R represents either a hydrogen atom or one or more substituents, identical to or different from one another, chosen from halogen atoms and mono- or polyfluoro(C 1 -C 6 )alkyl and mono- or polyfluoro(C 1 -C 6 )alkyloxy, linear (C 1 -C 6 )alkyl, branched or cyclic (C 3 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyloxy, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyloxy, (C 1 -C 6 )alkylthio, cyano, amino, phenyl, acetyl, benzoyl, (C 1 -C 6 )alkylsulphonyl, carboxyl, (C 1 -C 6 )alkoxycarbonyl and pentafluorosulphanyl groups; 
         or an addition salt thereof with an acid; or a solvate or hydrate of said compound or said salt; 
         wherein said compound is in the form of a pure enantiomer or of an erythro or threo diastereoisomer or of a mixture of such isomers. 
       
     
     
         2 . The method according to  claim 1 , wherein, for the compound of formula (I):
 Ar represents a group chosen from phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thien-2-yl and thien-3-yl groups, and wherein the Ar group is optionally substituted by one or more substituents, which are identical to or different from one another, chosen from halogen atoms and (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cyclo alkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyloxy, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyloxy, (C 1 -C 6 )alkylthio, (C 3 -C 7 )cycloalkylthio, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkylthio, mono- or polyfluoro(C 1 -C 6 )alkyl and mono- or polyfluoro(C 1 -C 6 )alkyloxy groups; or   an addition salt thereof with an acid; or a solvate or hydrate of said compound or said salt.   
     
     
         3 . The method according to  claim 1 , wherein, for the compound of formula (I):
 Ar represents a group chosen from the phenyl, pyridin-3-yl and thien-3-yl groups, and wherein the Ar group is optionally substituted by one or more substituents, identical to or different from one another, chosen from halogen atoms; or   an addition salt thereof with an acid; or a solvate or hydrate of said compound or said salt.   
     
     
         4 . The method according to  claim 1 , wherein, for the compound of formula (I):
 R represents either a hydrogen atom or one or more substituents, which are identical to or different from one another, chosen from halogen atoms and mono- or polyfluoro(C 1 -C 6 )alkyl, mono- or polyfluoro(C 1 -C 6 )alkyloxy, linear (C 1 -C 6 )alkyl and pentafluorosulphanyl groups; or   an addition salt thereof with an acid; or a solvate or hydrate of said compound or said salt.   
     
     
         5 . The method according to  claim 1 , wherein, for the compound of formula (I):
 R represents either a hydrogen atom or one or more substituents, which are identical to or different from one another, chosen from halogen atoms and mono- or polyfluoro(C 1 -C 6 )alkyl, mono- or polyfluoro(C 1 -C 6 )alkyloxy, linear (C 1 -C 6 )alkyl and pentafluorosulphanyl groups; or   an addition salt thereof with an acid; or a solvate or hydrate of said compound or said salt.   
     
     
         6 . The method according to  claim 1 , wherein, for the compound of formula (I):
 R represents either a hydrogen atom or one or more substituents, which are identical to or different from one another, chosen from halogen atoms and mono- or polyfluoro(C 1 -C 6 )alkyl, mono- or polyfluoro(C 1 -C 6 )alkyloxy, linear (C 1 -C 6 )alkyl and pentafluorosulphanyl groups; or   an addition salt thereof with an acid; or a solvate or hydrate of said compound or said salt.   
     
     
         7 . The method according to  claim 1 , wherein, for the compound of formula (I):
 m and n each represent, independently of one another, 1 or 2;   Ar represents a group chosen from the phenyl, pyridin-3-yl and thien-3-yl groups, and wherein the Ar group is optionally substituted by one or more halogen atoms;   R represents either a hydrogen atom or one or more substituents, identical to or different from one another, chosen from chlorine and methyl, trifluoromethyl, trifluoromethoxy and pentafluorosulphanyl groups; or   an addition salt thereof with an acid; or a solvate or hydrate of said compound or said salt.   
     
     
         8 . The method according to  claim 1 , wherein the compound is selected from the group consisting of:
 trans-threo-2-chloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;   trans-erythro-2-chloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;   trans-threo-2,6-dichloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;   trans-erythro-2,6-dichloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;   trans-threo-2-chloro-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;   2-chloro-N—[(S)-(3S,8aR)-(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;   trans-threo-2-methyl-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;   cis-erythro-2-methyl-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;   2-chloro-N—[(S)-(3S,8aR)-(octahydroindolizin-3-yl)(pyridin-3-yl)methyl]-3-trifluoromethylbenzamide hydrochloride;   2-chloro-N—[(S)-(3S,8aR)-(octahydroindolizin-3-yl)(thiophen-3-yl)methyl]-3-trifluoromethylbenzamide hydrochloride;   cis-erythro-2-chloro-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;   2-chloro-N—[(S)-(3R,8aR)-(octahydroindolizin-3-yl)(thiophen-3-yl)methyl]-3-trifluoromethylbenzamide hydrochloride;   2-chloro-N—[(S)-(3R,8aR)-(octahydroindolizin-3-yl)(pyridin-3-yl)methyl]-3-trifluoromethylbenzamide hydrochloride;   trans-threo-2-chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;   trans-erythro-2-chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-5-trifluoromethylbenzamide hydrochloride;   trans-threo-2,6-dichloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;   trans-erythro-2,6-dichloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;   trans-erythro-2-methyl-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;   trans-threo-2,6-dichloro-N-[(4-fluorophenyl)(octahydroquinolizin-4-yl)methyl]-3-trifluoromethylbenzamide hydrochloride;   trans-threo-2-chloro-N-[(octahydroquinolizin-4-yl)(pyridin-3-yl)methyl]-3-trifluoromethylbenzamide hydrochloride;   trans-erythro-2-chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;   trans-threo-2-chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-5-trifluoromethylbenzamide hydrochloride;   trans-threo-2-methyl-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;   trans-erythro-2-chloro-N-[(octahydroquinolizin-4-yl)(thiophen-3-yl)methyl]-3-trifluoromethylbenzamide hydrochloride;   trans-threo-2-chloro-3-methyl-N-[(octahydroquinolizin-4-yl)phenylmethyl]benzamide hydrochloride;   trans-threo-2-chloro-N-[(4-fluorophenyl)(octahydroquinolizin-4-yl)methyl]-3-trifluoromethylbenzamide hydrochloride;   trans-erythro-2-chloro-N-[(4-fluorophenyl)(octahydroquinolizin-4-yl)methyl]-3-trifluoromethylbenzamide hydrochloride;   trans-threo-2-chloro-3-methoxy-N-[(octahydroquinolizin-4-yl)phenylmethyl]benzamide hydrochloride;   trans-threo-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethoxybenzamide hydrochloride;   trans-threo-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-(pentafluorosulphanyl)benzamide hydrochloride; and   2-chloro-N-[(hexahydropyrrolizin-3-yl)phenylmethyl]benzamide hydrochloride.   
     
     
         9 . The method according to  claim 1 , wherein the compound inhibits the GlyT1 glycine transporters. 
     
     
         10 . The method according to  claim 2 , wherein the compound inhibits the GlyT1 glycine transporters. 
     
     
         11 . The method according to  claim 3 , wherein the compound inhibits the GlyT1 glycine transporters. 
     
     
         12 . The method according to  claim 4 , wherein the compound inhibits the GlyT1 glycine transporters. 
     
     
         13 . The method according to  claim 5 , wherein the compound inhibits the GlyT1 glycine transporters. 
     
     
         14 . The method according to  claim 6 , wherein the compound inhibits the GlyT1 glycine transporters. 
     
     
         15 . The method according to  claim 7 , wherein the compound inhibits the GlyT1 glycine transporters. 
     
     
         16 . The method according to  claim 8 , wherein the compound inhibits the GlyT1 glycine transporters.