Use of N-[Phenyl(piperidin-2-yl)methyl]benzamide derivatives in therapy

Abstract

The present invention discloses and claims therapeutic use of a series of compounds of general formula (I) in which A, X and R 2 are as described herein. Specifically, the compounds of formula (I) exhibit a particular activity as specific inhibitors of the glycine transporters glyt1 and/or glty2.

1 . A method for the treatment of a disorder selected from the group consisting of dementia, psychoses, schizophrenia, extrapyramidal symptom induced by neuroleptics, anxiety, panic attack, depression, obsessive compulsive disorder, alcohol abuse and migraine, comprising administering to a patient in need of said treatment an effective amount of a compound in the form of an enantiomer (1R,2R) or (1S,2S) or in the form of a threo diastereoisomer, corresponding to formula (I) or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein A represents 
 a group of general formula N—R 1 , a group of general formula N +  (O − )R 1  or a group of general formula N +  (R′)R 1 , and in which R 1  represents either a hydrogen atom, or a linear or branched (C 1 -C 7 )alkyl group optionally substituted with one or more fluorine atoms, or a (C 4 -C 7 )cycloalkyl group, or a (C 3 -C 7 )cycloalkyl(C 1 -C 3 )alkyl group, or a phenyl(C 1 -C 3 )alkyl group optionally substituted with one or two hydroxyl or methoxy groups, or a (C 2 -C 4 )alkenyl group, or a (C 2 -C 4 )alkynyl group;  
 R′ represents a linear or branched (C 1 -C 7 )alkyl group;  
 X represents a hydrogen atom or one or more substituents chosen from halogen atoms and trifluoromethyl, linear or branched (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy groups;  
 R 2  represents either a hydrogen atom, or one or more substituents chosen from halogen atoms and trifluoromethyl, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy groups, or amino groups of general formula NR 3 R 4 ; and wherein 
 R 3  and R 4  each represent, independently of each other, a hydrogen atom or a (C 1 -C 4 )alkyl group, or form with the nitrogen atom carrying them a pyrrolidine, piperidine or morpholine ring, or a phenyl group optionally substituted with an atom or a group as defined for the symbol X above.  
 
 
     
     
         2 . The method according to  claim 1 , wherein the compound is having the configuration (1S,2S) and in that R 2  represents one or more halogen atoms or trifluoromethyl groups.  
     
     
         3 . The method according to  claim 1 , wherein the compound is 2-chloro-N-[(S)-phenyl-[(2S)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide.  
     
     
         4 . The method according to  claim 3 , wherein the compound is 2-chloro-N-[(S)-phenyl-[(2S)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide hydrochloride 1:1.  
     
     
         5 . The method according to  claim 1 , wherein A represents a group of general formula N—R 1  in which R 1  represents either a hydrogen atom, or a linear or branched (C 1 -C 7 )alkyl group optionally substituted with one or more fluorine atoms or a pharmaceutically acceptable salt thereof.  
     
     
         6 . The method according to  claim 1 , wherein the compound is selected from the group consisting of: 
 threo-2-chloro-N-[(1-ethylpiperidin-2-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;    threo-2-chloro-N-[(1-ethylpiperidin-2-yl)phenylmethyl]-3-trifluoromethylbenzamide;    2-chloro-N-[(1S)-[(2S)-1-methylpiperidin-2-yl]phenylmethyl]-3-trifluoromethyl-benzamide hydrochloride;    2-chloro-N-[(1S)-[(2S)-l-methylpiperidin-2-yl]phenylmethyl]-3-trifluoromethyl-benzamide;    threo-4-amino-3-chloro-N-[(1-methylpiperidin-2-yl)phenylmethyl]-5-trifluoromethyl-benzamide hydrochloride;    threo-4-amino-3-chloro-N-[(1-methylpiperidin-2-yl)phenylmethyl]-5-trifluoromethyl-benzamide;    4-amino-3-chloro-N-[(1R)-[(2R)-1-methylpiperidin-2-yl]phenylmethyl]-5-trifluoro-methylbenzamide hydrochloride;    4-amino-3-chloro-N-[(1R)-[(2R)-1-methylpiperidin-2-yl]phenylmethyl]-5-trifluoro-methylbenzamide;    threo-2-chloro-N-[phenyl(piperidin-2-yl)methyl]-3-trifluoromethylbenzamide hydrochloride;    threo-2-chloro-N-[phenyl(piperidin-2-yl)methyl]-3-trifluoromethylbenzamide;    b  2 -chloro-N-[(S)-phenyl-[(2S)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide hydrochloride;    2-chloro-N-[(S)-phenyl-[(2S)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide;    2-chloro-N-[[l-methyl-l-oxido-piperidin-2-yl](phenyl)methyl]-3-trifluoromethyl-benzamide; and    2(S)-2[(1S)-[[2-chloro-3-(trifluoromethyl)benzoyl]amino](phenyl)methyl]-1,1-dimethylpiperidinium iodide or a pharmaceutically acceptable salt thereof.    
     
     
         7 . The method according to  claim 1 , wherein the compound is 2-chloro-N-[(1S)-[(2S)-1-methylpiperidin-2-yl]phenylmethyl]-3-trifluoromethylbenzamide.  
     
     
         8 . The method according to  claim 1 , wherein the compound is 2-chloro-N-[(1S)-[(2S)-1-methylpiperidin-2-yl]phenylmethyl]-3-trifluoromethylbenzamide hydrochloride 1:1.  
     
     
         9 . The method according to  claim 1 , wherein the disorder is dementia.  
     
     
         10 . The method according to  claim 1 , wherein the disorder is psychoses.  
     
     
         11 . The method according to  claim 1 , wherein the disorder is schizophrenia.  
     
     
         12 . The method according to  claim 1 , wherein the disorder is extrapyramidal symptom induced by neuroleptics.  
     
     
         13 . The method according to  claim 1 , wherein the disorder is anxiety.  
     
     
         14 . The method according to  claim 1 , wherein the disorder is panic attack.  
     
     
         15 . The method according to  claim 1 , wherein the disorder is depression.  
     
     
         16 . The method according to  claim 1 , wherein the disorder is obsessive compulsive disorder.  
     
     
         17 . The method according to  claim 1 , wherein the disorder is  
     
     
         18 . The method according to  claim 1 , wherein the disorder is alcohol abuse.  
     
     
         19 . The method according to  claim 1 , wherein the disorder is migraine.  
     
     
         20 . A method for the treatment of a disorder selected from the group consisting of painful muscular contractures in rheumatology, spinal pathology, pain including neurogenic pain, rebellious algia, Parkinson's disease, epilepsy and sleep apnea, comprising administering to a patient in need of said treatment an effective amount of a compound in the form of an enantiomer (1R,2R) or (1S,2S) or in the form of a threo diastereoisomer, corresponding to formula (I) or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein A represents 
 a group of general formula N—R 1 , a group of general formula N +  (O − )R 1  or a group of general formula N +  (R′)R 1 , and in which R 1  represents either a hydrogen atom, or a linear or branched (C 1 -C 7 )alkyl group optionally substituted with one or more fluorine atoms, or a (C 4 -C 7 )cycloalkyl group, or a (C3-C 7 )cycloalkyl(C 1 -C 3 )alkyl group, or a phenyl(C 1 -C3)alkyl group optionally substituted with one or two hydroxyl or methoxy groups, or a (C 2 -C 4 )alkenyl group, or a (C 2 -C 4 )alkynyl group;  
 R′ represents a linear or branched (C 1 -C 7 )alkyl group;  
 X represents a hydrogen atom or one or more substituents chosen from halogen atoms and trifluoromethyl, linear or branched (C1-C 4 )alkyl and (C 1 -C 4 )alkoxy groups;  
 R 2  represents either a hydrogen atom, or one or more substituents chosen from halogen atoms and trifluoromethyl, (C 1 -C 4 )alkyl or (C1-C 4 )alkoxy groups, or amino groups of general formula NR 3 R 4 ; and wherein 
 R 3  and R 4  each represent, independently of each other, a hydrogen atom or a (C 1 -C 4 )alkyl group, or form with the nitrogen atom carrying them a pyrrolidine, piperidine or morpholine ring, or a phenyl group optionally substituted with an atom or a group as defined for the symbol X above.  
 
 
     
     
         21 . The method according to  claim 9  wherein the compound is having the configuration (1R,2R) and in that R 2  represents a halogen atom and an amino group of general formula NR 3 R 4  as defined in  claim 9 .  
     
     
         22 . The method according to  claim 9  wherein A represents a group of general formula N—R 1  in which R 1  represents either a hydrogen atom, or a linear or branched (C 1 -C 7 )alkyl group optionally substituted with one or more fluorine atoms or a pharmaceutically acceptable salt of said compound.  
     
     
         23 . The method according to  claim 9  wherein the compound is selected from the group consisting of: 
 threo-2-chloro-N-[(1-ethylpiperidin-2-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride;    threo-2-chloro-N-[(1-ethylpiperidin-2-yl)phenylmethyl]-3-trifluoromethylbenzamide;    2-chloro-N-[(1S)-[(2S)-1-methylpiperidin-2-yl]phenylmethyl]-3-trifluoromethyl-benzamide hydrochloride;    2-chloro-N-[(1S)-[(2S)-1-methylpiperidin-2-yl]phenylmethyl]-3-trifluoromethyl-benzamide;    threo-4-amino-3-chloro-N-[(1-methylpiperidin-2-yl)phenylmethyl]-5-trifluoromethyl-benzamide hydrochloride;    threo-4-amino-3-chloro-N-[(1-methylpiperidin-2-yl)phenylmethyl]-5-trifluoromethyl-benzamide;    4-amino-3-chloro-N-[(1R)-[(2R)-1-methylpiperidin-2-yl]phenylmethyl]-5-trifluoro-methylbenzamide hydrochloride;    4-amino-3-chloro-N-[(1R)-[(2R)-1-methylpiperidin-2-yl]phenylmethyl]-5-trifluoro-methylbenzamide;    threo-2-chloro-N-[phenyl(piperidin-2-yl)methyl]-3-trifluoromethylbenzamide hydrochloride;    threo-2-chloro-N-[phenyl(piperidin-2-yl)methyl]-3-trifluoromethylbenzamide;    2-chloro-N-[(S)-phenyl-[(2S)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide hydrochloride;    2-chloro-N-[(S)-phenyl-[(2S)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide;    2-chloro-N-[[1-methyl-1-oxido-piperidin-2-yl](phenyl)methyl]-3-trifluoromethyl-benzamide; and    2(S)-2[(1S)-[[2-chloro-3-(trifluoromethyl)benzoyl]amino](phenyl)methyl]-1,1-dimethylpiperidinium iodide or a pharmaceutically acceptable salt thereof.    
     
     
         24 . The method according to  claim 9  wherein the compound is 4-amino-3-chloro-N-[(1R)-[(2R)-1-methylpiperidin-2-yl]phenylmethyl]-5-trifluoromethylbenzamide hydrochloride 1:1.  
     
     
         25 . The method according to  claim 20 , wherein the disorder is painful muscular contractures in rheumatology.  
     
     
         26 . The method according to  claim 20 , wherein the disorder is spinal pathology.  
     
     
         27 . The method according to  claim 20 , wherein the disorder is pain.  
     
     
         28 . The method according to  claim 20 , wherein the disorder is neurogenic pain.  
     
     
         29 . The method according to  claim 20 , wherein the disorder is rebellious algia.  
     
     
         30 . The method according to  claim 20 , wherein the disorder is Parkinson's disease.  
     
     
         31 . The method according to  claim 20 , wherein the disorder is epilepsy.  
     
     
         32 . The method according to  claim 20 , wherein the disorder is sleep apnea.