Piperidine Compounds, Pharmaceutical Composition Comprising The Same And Its Use

Abstract

Piperidine compounds and pharmaceutically useful salts thereof, a pharmaceutical composition including an effective amount of the racemic or enantiomerically enriched piperidine compounds to treat gastrointestinal diseases, and a method of treating gastrointestinal diseases in a mammal are provided.

1 - 16 . (canceled) 
     
     
         17 . A method of preparing a piperidine compound of structural formula (VI) and pharmaceutically acceptable salts thereof, comprising:
 a step of reacting the compound represented by structural formula (XXXIII) with an alkyl halide represented by the structural formula (XII-1) or (XII-2), an epoxide represented by the structural formula (XIII), or a Weinreb amide represented by the following general structural formula (XIV):   
       
         
           
           
               
               
           
         
         wherein 
         m is an integer of 1 or 2; 
         n is an integer from 0 to 2; 
         A is selected from a phenyl group and a benzimidazole group, wherein the phenyl group is substituted with one or more groups independently selected from hydrogen, a C 1 -C 6  linear or branched alkyl group, a C 1 -C 6  linear or branched alkoxy group, an amino group, and a halogen, and the benzimidazole group is substituted with one or more groups independently selected from hydrogen, a C 1 -C 6  linear or branched alkyl group, a C 1 -C 6  linear or branched alkoxy group, a C 3 -C 7  cyclic alkyl group, an amino group, a halogen, and an oxo group; 
         B is selected from a phenyl group, a phenoxy group, a thienyl group, and a naphthyl group, wherein the phenyl group, phenoxy group, thienyl group, or naphthyl group is substituted with one or more groups independently selected from hydrogen, halogen, nitro, cyano, methanesulfonyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, phenyl, a C 1 -C 6  linear or branched alkyl group, and a C 1 -C 6  linear or branched alkoxy group, and 
         Z is a halogen. 
       
     
     
         18 . The method of  claim 17 , wherein the piperidine compound of structural formula (VI) is represented by the structural formula (X): 
       
         
           
           
               
               
           
         
         wherein B, m, and n are as defined in  claim 17 . 
       
     
     
         19 . The method of  claim 18 , wherein the piperidine compound of the structural formula (X) is prepared by the alkylation of a compound of structural formula (XI) with the alkyl halide represented by the structural formula (XII-2); 
       
         
           
           
               
               
           
         
         wherein B, m, and n are as defined in  claim 17 . 
       
     
     
         20 . The method of  claim 19 , wherein the reaction is performed at the amount of 1 equivalent of the compound represented by the structural formula (XI), with 1.1 to 3.0 equivalents of (XII-2) and 1.5 to 5.0 equivalent of a base. 
     
     
         21 . The method of  claim 20 , wherein the base is potassium carbonate, cesium carbonate or triethyleneamine. 
     
     
         22 . The method of  claim 19 , wherein the reaction is performed in ethereal solvent, a halogenated hydrocarbon solvent, an alcohol solvent or acetonitrile, at a temperature of 20 to 80° C. 
     
     
         23 . The method of  claim 18 , wherein the piperidine compound of the structural formula (X) is prepared by reacting a compound of structural formula (XI) with an epoxide represented by the structural formula (XIII); 
       
         
           
           
               
               
           
         
       
     
     
         24 . The method of  claim 23 , wherein the reaction is performed at the amount of 0.005 to 0.1 moles of the compound represented by the structural formula (XI), with 1.1 to 3.0 equivalents of an epoxide represented by the structural formula (XIII). 
     
     
         25 . The method of  claim 23 , wherein the reaction is performed in solvent of an ethereal solvent, a halogenated hydrocarbon solvent, an alcohol solvent or acetonitrile, at a temperature of 20 to 80° C. 
     
     
         26 . The method of  claim 17 , wherein the piperidine compound of structural formula (VI) is represented by the structural formula (XIX): 
       
         
           
           
               
               
           
         
         wherein B, m, and n are as defined in  claim 17 , and 
         R 4  is C 1 -C 6  linear or branched alkyl group, or a C 3 -C 7  cyclic alkyl that may be substituted or unsubstituted. 
       
     
     
         27 . The method of  claim 17 , wherein the piperidine compound of structural formula (XIX) is prepared by reacting piperidine benzimidazole represented by the general structural formula (XX) with the alkyl halide or the epoxide: 
       
         
           
           
               
               
           
         
         wherein R is C 1 -C 6  linear or branched alkyl group, or a C 3 -C 7  cyclic alkyl that may be substituted or unsubstituted. 
       
     
     
         28 . The method of  claim 17 , wherein the piperidine compound of structural formula (VI) is selected from the group consisting of the following compounds and pharmaceutically acceptable salts thereof:
 4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide,   4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,   4-amino-5-chloro-N-[[1-[2-hydroxy-2-(3-methoxy phenyl)ethyl]piperidin-4-yl]-methyl]-2-methoxybenzamide,   4-amino-5-chloro-N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]-methyl]-2-methoxybenzamide,   (S)-4-amino-5-chloro-N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide,   (R)-4-amino-5-chloro-N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide, and   4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenylpropyl)piperidin-1-ium-4-yl]methyl]-2-methoxybenzamide.