5-HT4 receptor antagonists

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof, and the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof: X—CO—CH 2 -Z wherein X is a monocyclic or polycyclic aromatic group, Z is of sub-formula (h), (j) or (k): wherein n 1 is 1, 2, 3 or 4; n 2 is 0, 1, 2, 3 or 4; n 3 is 2, 3, 4 or 5; q is 0, 1, 2 or 3; p is 0, 1 or 2; m is 0, 1 or 2; R 5 is hydrogen, C 1-2 alkyl, aralkyl or R 5 is (CH 2 ) z -R 10 wherein z is 2 or 3 and R 10 is selected from cyano, hydroxyl, C 1-6 alkoxy, phenoxy, C(O)C 1-6 alkyl, COC 6 H 5 , —CONR 11 R 12 , NR 11 COR 12 , SO 2 NR 11 R 12 or NR 11 SO 2 R 12 wherein R 11 and R 12 are hydrogen or C 1-6 alkyl; or R 5 is straight or branched chain alkylene of chain length 1-6 carbon atoms terminally substituted by aryl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 5 or 6 membered monocyclic heteroaryl or 9 or 10 membered fused bicyclic heteroaryl linked through carbon, C 2-7 alkoxycarbonyl, or secondary or tertiary hydroxy substituted C 1-6 alkyl; ; and R 6 , R 7 and R 8 are independently hydrogen or C 1-6 alkyl; and R 9 is hydrogen or C 1-10 alkyl; and their use as pharmaceuticals in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders.

1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof:  
       X—CO—CH 2 -Z   (I)  
     wherein 
 X is of formula (d):  
                     
 X 1 —(CH 2 ) x —X 2  forms a 5-7 membered ring wherein X 1  is O or S; X 2  is O, S, —CH 2 —, NR or NRCO wherein R is hydrogen or C 1-6  alkyl; and  
 x is 1, 2 or 3;  
 R 1   d  is hydrogen, amino, halo, C 1-6  alkyl, hydroxy or C 1-6  alkoxy;  
 R 2   d  is hydrogen, halo, C 1-6  alkyl, C 1-6  alkoxy, nitro, amino or C 1-6  alkylthio;  
 R 3   d  is hydrogen, halo, C 1-6  alkyl, C 1-6  alkoxy or amino;  
 R 4   d  and R 5   d  are independently hydrogen or C 1-6  alkyl;  
 Z is of sub-formula (h), (j) or (k):  
                     
 wherein  
 n 1  is 1, 2, 3 or 4; n 2 is 0, 1, 2, 3 or 4; n 3 is 2, 3, 4 or 5;  
 q is 0, 1, 2 or 3; p is 0, 1 or 2; m is 0, 1 or 2;  
 R 5  is hydrogen, C 1-12  alkyl, aralkyl or R 5  is (CH 2 ) z —R 10  wherein z is 2 or 3 and R 10  is selected from cyano, hydroxyl, C 1-6  alkoxy, phenoxy, C(O)C 1-6  alkyl, COC 6 H 5 , —CONR 11 R 12 , NR 11 COR 12 , SO 2 NR 11 R 12  or NR 11 SO 2 R 12  wherein R 11  and R 12  are hydrogen or C 1-6  alkyl; or R 5  is straight or branched chain alkylene of chain length 1-6 carbon atoms terminally substituted by aryl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 5 or 6 membered monocyclic heteroaryl or 9 or 10 membered fused bicyclic heteroaryl linked through carbon, C 2-7  alkoxycarbonyl, or secondary or tertiary hydroxy substituted C 1-6  alkyl; ; and  
 R 6 , R 7  and R 8  are independently hydrogen or C 1-6  alkyl; and  
 R 9  is hydrogen or C 1-10  alkyl;  
 having 5-HT 4  receptor antagonist activity.  
 
   
   
       2 . A compound according to  claim 1  wherein: X 1 —(CH 2 ) x —X 2  is O—(CH 2 ) 2 —O, O—(CH 2 ) 3 —O, O—CH 2 —O, O—(CH 2 ) 2 —NR, O—(CH 2 ) 2 —S, O—CH 2 —CONR, O—(CH 2 ) 2 —CH 2 , O—(CH 2 ) 3 —CH 2 , or O—CH 2 —CH 2 , wherein any of the methylene linkages are optionally mono- or di- substituted by C 1-6  alkyl groups; 
 R 1   d  is hydrogen or amino;    R 2   d  is hydrogen or halo;    R 3   d  is hydrogen or halo.    
   
   
       3 . A pharmaceutical composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable carrier.  
   
   
       4 . A method of treating a gastrointestinal disorder selected from the group consisting of irritable bowel syndrome, emesis, urinary incontinence associated with irritable bowel syndrome, dyspepsia and gastro-oesophageal reflux disease which comprises administering a compound according to  claim 1 .  
   
   
       5 . A method of treating atrial arrhythmia or stroke which comprises administering a compound according to  claim 1 .  
   
   
       6 . A method of treating a CNS disorder selected from the group consisting of migraine, schizophrenia, Parkinson's disease, Huntingdon's chorea and anxiety which comprises administering a compound according to  claim 1.