4-[(arylmethyl)aminomethyl]piperidine derivatives, their preparation and their therapeutic application

Abstract

The invention relates to 4-[(arylmethyl)aminomethyl]piperidine derivatives of general formula (I) in the form of a base or an addition salt with an acid, and also in the form of a hydrate or solvate, and their preparation process and therapeutic application.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         n is 1 or 2; 
         R 1  is trifluoromethyl; 
         R 2  is hydrogen or (C 1 -C 3 )alkyl; 
         R 3  is an aromatic group selected from: 
       
       
         
           
           
               
               
           
         
         wherein the aromatic group is unsubstituted or mono- or disubstituted by a substituent selected independently from halogen, (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy; and 
         R 4  is hydrogen or (C 1 -C 3 )alkyl; 
         or an addition salt with an acid thereof, or a hydrate or solvate thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein:
 n is 1;   or an addition salt with an acid thereof, or a hydrate or solvate thereof.   
     
     
         3 . The compound according to  claim 1 , wherein:
 R 1  is in position 3 of the phenyl and is trifluoromethyl;   or an addition salt with an acid thereof, or a hydrate or solvate thereof.   
     
     
         4 . The compound according to  claim 1 , wherein:
 R 2  is hydrogen or methyl;   or an addition salt with an acid thereof, or a hydrate or solvate thereof.   
     
     
         5 . The compound according to  claim 1 , wherein:
 R 3  is 1-methyl-1H-pyrrol-2-yl; 1-methyl-1H-imidazol-2-yl; 1,3-thiazol-2-yl; 2-furyl; 3-furyl; 5-methyl-2-furyl; 4,5-dimethyl-2-furyl; 5-chloro-2-furyl; 2-thienyl; 3-thienyl; phenyl; pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; pyrazin-2-yl; 6-methylpyridin-2-yl; 3-methyl-2-thienyl; 5-methyl-2-thienyl; pyrimidin-5-yl; 1H-imidazol-2-yl; 1H-imidazol-5-yl; or 4-methyl-1H-imidazol-5-yl;   or an addition salt with an acid thereof, or a hydrate or solvate thereof.   
     
     
         6 . The compound according to  claim 1 , wherein:
 n is 1;   R 1  is in position 3 of the phenyl and is trifluoromethyl;   R 2  is hydrogen or methyl; and   R 3  is 1-methyl-1H-pyrrol-2-yl; 1-methyl-1H-imidazol-2-yl; 1,3-thiazol-2-yl; 2-furyl; 3-furyl; 5-methyl-2-furyl; 4,5-dimethyl-2-furyl; 5-chloro-2-furyl; 2-thienyl; 3-thienyl; phenyl; pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; pyrazin-2-yl; 6-methylpyridin-2-yl; 3-methyl-2-thienyl; 5-methyl-2-thienyl; pyrimidin-5-yl; 1H-imidazol-2-yl; 1H-imidazol-5-yl; or 4-methyl-1H-imidazol-5-yl;   or an addition salt with an acid thereof, or a hydrate or solvate thereof.   
     
     
         7 . A process for preparing the compound according to  claim 1 , comprising:
 reacting a compound of formula (II)   
       
         
           
           
               
               
           
         
         wherein, R 1  and R 2  are as defined in  claim 1 , with a compound of formula (III) 
       
       
         
           
           
               
               
           
         
         wherein R 3  is as defined in  claim 1 , in the presence of an acid and in a solvent to form an iminium salt, and reducing the iminium salt by a reducing agent. 
       
     
     
         8 . A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to  claim 1 , or an addition salt with an acid thereof, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         9 . A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to  claim 2 , or an addition salt with an acid thereof, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         10 . A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to  claim 3 , or an addition salt with an acid thereof, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         11 . A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to  claim 4 , or an addition salt with an acid thereof, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         12 . A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to  claim 5 , or an addition salt with an acid thereof, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         13 . A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to  claim 6 , or an addition salt with an acid thereof, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         14 . A method for preventing or treating a central or peripheral neurodegenerative disease, amyotrophic lateral sclerosis, multiple sclerosis, a cardiovascular conditions, peripheral neuropathies, damage to the optic nerve or to the retina, spinal cord trauma or cranial trauma, atherosclerosis, stenoses, cicatrisation, alopecia, cancers, tumours, metastases, leukaemias, chronic neuropathic or inflammatory pain, an autoimmune disease, bone fracture or a bone disease, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 1 , or an addition salt with an acid thereof, or a hydrate or solvate thereof.