Compounds

Abstract

The present invention relates to benzylpiperazine derivatives such as compounds of formula (I), which have activity as agonists of the GPR38 receptor and the use of such compounds or pharmaceutical compositions thereof in the preparation of medicaments suitable for the treatment of gastrointestinal disorders.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         A is phenyl or a 6-membered heteroaryl ring, optionally substituted with halogen, C (1-4) alkyl or C (1-4) alkoxy; 
         R 1  and R 2  are independently H or C (1-4)  alkyl; 
         R 3  is optionally substituted phenyl or optionally substituted 5 or 6 membered heteroaryl; 
         X is (CR 4 R 5 ) n ; 
         n is 1 or 2; 
         Y is NH, O or CH 2 ; 
         R 4  and R 5  are independently selected from hydrogen and C (1-4)  alkyl; 
         or a pharmaceutically acceptable salt thereof 
       
     
     
         2 . The compound, or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein:
 A is phenyl or pyridyl;   R 1  is hydrogen or methyl;   R 2  is hydrogen or methyl;   R 3  is optionally substituted phenyl;   Y is NH or O;   X is (CR 4 R 5 ) n ;   n is 1 or 2; and   R 4  and R 5  are independently hydrogen or methyl.   
     
     
         3 . The compound, or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein the (piperazinyl)methylene substituent and X are para- to each other across ring A. 
     
     
         4 . The compound, or pharmaceutically acceptable salt thereof, according to  claim 2 , wherein the (piperazinyl)methylene substituent and X are para- to each other across ring A. 
     
     
         5 . The compound, or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein R 1  and R 2  are other than hydrogen and the piperazine C* carbons have the 3R,5S-configuration. 
     
     
         6 . The compound, or pharmaceutically acceptable salt thereof, according to  claim 2 , wherein R 1  and R 2  are other than hydrogen and the piperazine C* carbons have the 3R,5S-configuration. 
     
     
         7 . A compound selected from:
 1-[(4-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]methyl}phenyl)acetyl]-N-(4-fluorophenyl)-4-piperidinamine;   N-(4-fluorophenyl)-1-[(4-{[(3S)-3-methyl-1-piperazinyl]methyl}-phenyl)acetyl]-4-piperidinamine;   3-({1-[(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-4-piperidinyl}amino)benzonitrile;   4-({1-[(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-4-piperidinyl}amino)benzonitrile;   N-(3,4-difluorophenyl)-1-[(4-{[(3S)-3-methyl-1-piperazinyl]methyl}-phenyl)acetyl]-4-piperidinamine;   N-[4-fluoro-3-(methyloxy)phenyl]-1-[(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-4-piperidinamine;   (3S)-1-{[4-(2-{4-[(4-fluorophenyl)oxy]-1-piperidinyl}-2-oxoethyl)phenyl]methyl}-3-methylpiperazine;   (3S)-1-{[4-(2-{4-[(3-fluorophenyl)oxy]-1-piperidinyl}-2-oxoethyl)phenyl]methyl}-3-methylpiperazine;   1-[(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-N-[3-(trifluoromethyl)phenyl]-4-piperidinamine;   1-[(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-N-[4-(trifluoromethyl)phenyl]-4-piperidinamine;   N-(3-fluorophenyl)-1-{[4-(1-piperazinylmethyl)phenyl]acetyl}-4-piperidinamine;   N-(3-fluorophenyl)-1-[(4-{[(3R)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-4-piperidinamine;   N-(3,4-difluorophenyl)-1-[(4-{[(3R)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-4-piperidinamine;   (3R)-1-{[4-(2-{4-[(4-fluorophenyl)oxy]-1-piperidinyl}-2-oxoethyl)phenyl]methyl}-3-methylpiperazine;   (3R)-1-{[4-(2-{4-[(3-fluorophenyl)oxy]-1-piperidinyl}-2-oxoethyl)phenyl]methyl}-3-methylpiperazine;   4-({1-[(4-{[(3R)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-4-piperidinyl}oxy)benzonitrile;   4-({1-[(4-{[(3R)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-4-piperidinyl}amino)benzonitrile;   3-({1-[(4-{[(3R)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-4-piperidinyl}amino)benzonitrile;   1-[(4-{[(3R)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-N-[3-(trifluoromethyl)phenyl]-4-piperidinamine;   N-(3-fluorophenyl)-1-[(3-(methyloxy)-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-4-piperidinamine;   2-fluoro-5-({1-[(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-4-piperidinyl}amino)benzonitrile;   1-[3-(4-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]methyl}phenyl)propanoyl]-N-(4-fluorophenyl)-4-piperidinamine;   1-[3-(4-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]methyl}phenyl)propanoyl]-N-(3-fluorophenyl)-4-piperidinamine;   N-(4-fluorophenyl)-1-[3-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)propanoyl]-4-piperidinamine;   N-(3-fluorophenyl)-1-[3-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl) propanoyl]-4-piperidinamine;   1-[2-(4-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]methyl}phenyl)propanoyl]-N-(4-fluorophenyl)-4-piperidinamine;   1-[2-(4-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]methyl}phenyl)propanoyl]-N-(3-fluorophenyl)-4-piperidinamine;   1-[2-(4-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]methyl}phenyl)-2-methylpropanoyl]-N-(4-fluorophenyl)-4-piperidinamine;   1-[2-(4-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]methyl}phenyl)-2-methylpropanoyl]-N-(3-fluorophenyl)-4-piperidinamine;   (3R,5S)-1-{[4-(2-{4-[(4-fluorophenyl)oxy]-1-piperidinyl}-1,1-dimethyl-2-oxoethyl)phenyl]methyl}-3,5-dimethylpiperazine;   N-(3-fluorophenyl)-1-[3-(5-{[(3S)-3-methyl-1-piperazinyl]methyl}-2-pyridinyl)propanoyl]-4-piperidinamine;   1-[(3-chloro-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-N-(3-fluorophenyl)-4-piperidinamine;   N-(2-fluorophenyl)-1-[(4-{[(3R)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-4-piperidinamine;   N-(3-fluorophenyl)-1-[(5-{[(3S)-3-methyl-1-piperazinyl]methyl}-2-pyridinyl)acetyl]-4-piperidinamine;   2-({1-[(4-{[(3R)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-4-piperidinyl}amino)benzonitrile; and   2-fluoro-4-({1-[(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)acetyl]-4-piperidinyl}amino)benzonitrile hydrochloride.   
     
     
         8 . A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt thereof, according to  claim 1 . 
     
     
         9 . A method of treatment for a condition or disorder which is mediated via GPR-38 receptors in a mammal comprising administering to the mammal the compound or salt according to  claim 1 , wherein the condition or disorder is selected from gastroesophageal reflux disorder, functional dyspepsia, irritable bowel syndrome, constipation, intestinal pseudo-obstruction, paralytic ileus following surgery, emesis, gastric stasis or hypomotility caused by diabetes and/or by the administration of other drugs, Crohn's disease, and colitis.