Substituted piperidine derivatives

Abstract

The present invention relates to certain novel substituted piperidine derivatives, to processes for their preparation, to pharmaceutical formulations containing them and to their use in medical therapy, particularly in the treatment of psychotic disorders.

1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein R 1  is benzothienyl, benzofuranyl, naphthyl (where the benzothienyl, benzofuranyl or naphthyl moiety may be optionally substituted by one or more substituents selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy and C 2-6 alkenyl), substituted-thienyl or substituted-furanyl (where the thienyl or furanyl moiety is substituted by one or more substituents selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy and C 2-6 alkenyl);  
       R 2  is substituted-phenyl or substituted-thienyl (where the phenyl or thienyl moiety is substituted by one or more substituents selected from C 1-6 alkyl and halogen);  
       R 3  is —(CH 2 ) m XCONR 4 R 5  or —(CH 2 ) m NR 6 COR 7  wherein R 4  is hydrogen or C 1-6 alkyl and R 5  is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-12 aryl, C 6-12 aryl-C 1-6 alkyl or a C 3-9 heterocyclic group (where the alkyl, aryl or heterocyclic moiety may be optionally substituted by one or more substituents selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy and C 2-6 alkenyl) or R 4  and R 5  together with the nitrogen atom to which they are attached form a 4-10-membered heterocyclic group optionally substituted by one or more substituents selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy and C 2-6 alkenyl), R 6  is hydrogen or C 1-6 alkyl, R 7  is C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 6-12 aryl, C 6-12 arylC 1-6 alkyl or a C 3-9 heterocyclic group (where the alkyl, aryl heterocyclic moiety may be optionally substituted by one or more substituents selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C, 1-6 alkoxy and C 2-6 alkenyl), X is a bond, C 6-12 aryl or a 5- or 6-membered heteroaryl (where the aryl or heteroaryl moiety is optionally substituted by one or more substituents selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy and C 2-6 alkenyl);  
       wherein m is an integer 1, 2, 3 or 4; or a pharmaceutically acceptable salt or solvate thereof.  
     
     
         2 . A compound according to  claim 1  wherein R 1  is benzothienyl or substituted-thienyl (where the thienyl moiety substituent is C 1-6 alkyl); or a pharmaceutically acceptable salt or solvate thereof.  
     
     
         3 . A compound according to  claim 1  wherein R 2  is a substituted-phenyl (where the phenyl moiety substituent is a halogen); or a pharmaceutically acceptable salt or solvate thereof  
     
     
         4 . A compound according to  claim 1  wherein R 3  IS —(CH 2 ) m XCONR 4 R 5  wherein R 4  and R 5  together with the nitrogen atom to which they are attached form a 4, 5 or 6-membered heterocyclic group, X is a bond or a C 6 aryl, and m is an integer 1, 2, 3 or 4 or R 3  is —(CH 2 ) m NR 6 COR 7  wherein R 6  is hydrogen, R 7  is C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl, C 6 aryl, optionally subsituted by one or more C 1-6 alkyl groups, m is an integer 1, 2, 3 or 4, or a pharmaceutically acceptable salt or solvate thereof.  
     
     
         5 . A compound according to  claim 1  wherein R 1  is benzothienyl or substituted-thienyl (where the thienyl moiety substituent is C 1-6 alkyl); R 2  is a substituted-phenyl (where the phenyl moiety substituent is a halogen); R 3  is —(CH 2 ) m XCONR 4 R 5  wherein R 4  and R 5  together with the nitrogen atom to which they are attached form a 4, 5 or 6-membered heterocyclic group, X is a bond or a C 6 aryl, and m is an integer 1, 2, 3 or 4 or R 3  is —(CH 2 ) m NR 6 COR 7  wherein R 6  is hydrogen, R 7  is C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl, C 6 aryl, optionally subsituted by one or more C 1-6 alkyl groups, m is an integer 1, 2, 3 or 4; or a pharmaceutically acceptable salt or solvate thereof.  
     
     
         6 . A compound according to  claim 1  wherein X is C 6-12 aryl or a 5- or 6-membered heteroaryl (where the aryl or heteroaryl moiety is optionally substituted by one or more substituents selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy and C 2-6 alkenyl), or a pharmaceutically acceptable salt or solvate thereof.  
     
     
         7 . A compound according to any of  claims 1  to  5  selected from: 
 1-[4-[4-[(4-fluorophenyl)(4-methylthien-2-yl)methylene]piperidin-1-yl]-1-oxobutyl]-piperidine (1:1) ethanedicarboxylate  
 1-[4-[4-[(4-fluorophenyl)(4-methylthien-2-yl)methylene]piperidin-1-yl]-1-oxobutyl]-pyrrolidine dihydrochloride.  
 1-[4-[4-[(3-fluorophenyl)(4-methylthien-2-yl)methylene]piperidin-1-yl]-1-oxobutyl]-piperidine hydrochloride.  
 1-[3-[4-[(4-fiuorophenyl)(4-methylthien-2-yl)methylene]piperidin-1-ylmethyl] benzoyl]piperidine;  
 1-[3-[4-[(4-fluorophenyl)(4-methylthien-2-yl)methylene]piperidin-1-ylmethyl] benzoyl]pyrrolidine. hydrochloride;  
 1-[3-[4-[(4-fluorophenyl)(benzothien-2-yl)methylene]piperidin-1-ylmethyl] benzoyl]piperidine. maleate;  
 1-[3-[4-[(4-fluorophenyl)(benzothien-2-yl)methylene]piperidin-1-ylmethyl] benzoyl]pyrroiidine. maleate;  
 1-[3-[4-[(4-fluorophenyl)(4-ethylthien-2-yl)methylene]piperidin-1-ylmethyl] benzoyllpiperidine. fumarate;  
 1-[3-[4-[(4-fluorophenyl)(4-ethylthien-2-yl)methylene]piperidin-1-ylmethyl] benzoyl]pyrrolidine. dihydrochloride;  
 4,4-dimethyl-1-[3-[4-[(4-fluorophenyl)(4-methylthien-2-yl)methylene]-piperidin-1-ylmethyl]benzoyl]azetidine. maleate;  
 and pharmaceutically acceptable salts and solvates thereof  
 
     
     
         8 . A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined according to any of  claims 1  to  5  for use in therapy.  
     
     
         9 . A pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined according to any of  claims 1  to  7 , together with a pharmaceutically acceptable carrier therefor.  
     
     
         10 . A process for the preparation of a compound of formula (I) as defined in any of  claims 1  to  7  comprising: 
 (A) reacting a compound of formula (II)  
                     
 wherein R 1  and R 2  are as defined in  claim 1 , with a compound of formula R 3 -L wherein L is a suitable leaving group  
 (B) reacting an amine of formula (III)  
                     
 wherein R 1 , R 2 , and R 6  are as defined in  claim 1 , with a suitable acylating agent, and thereafter, or simultaneously therewith, effecting one or more of the following optional conversions  
 (i) converting a pharmaceutically acceptable salt or solvate of a compound of formula (I) into a compound of formula (I).  
 (ii) converting a pharmaceutically acceptable salt or solvate of a compound of formula (I) into another pharmaceutically acceptable salt or solvate of formula (I).  
 (iii) converting a compound of formula (I) into a pharmaceutically acceptable salt or solvate of a compound of formula (I)