2-3-dihydro-1H-isoindole derivatives useful as modulators of dopamine D3 receptors (an-tipsychotic agents)

Abstract

Oompounds of formula (I), wherein R 2 represents a hydrogen atom or a C 1-4 alkyl group; q is 1 or 2; A represents a group of formula (a), (b), (c) or (d), wherein Ar represents an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring; or an optionally substituted bicyclic ring system; Ar 1 and Ar 2 each independently represent an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring; and Y represents a bond, —NHCO—, —CONH—, —CH 2 —, or —(CH 2 ) m Y 1 (CH 2 ) n —, wherein Y 1 represents O, S, SO 2 or CO and m and n each represent zero or (I) such that the sum of m+n is zero or 1; providing that when A represents a group of formula (a), any substituent present in Ar ortho to the carboxamide moiety is necessarily a hydrogen or methoxy group; r and s independently represent an integer from zero to 3 such that the sum of r and s is equal to an integer from 1 to 4; V represents a bond, O or S; and salts thereof. Compounds of formula (I) and their salts have affinity for dopamine receptors, in particular the D 3 receptor, and thus potential in the treatment of conditions wherein modulation of the D 3 receptor is beneficial, e.g. as antipsychotic agents.

1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, C 1-4 alkyl, C 1-4 alkoxy, arylC 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkoxyC 1-4 alkyl, C 3-6 cycloalkylC 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkoxycarbonyl, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonyloxy, C 1-4 alkylsulfonylC 1-4 alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC 1-4 alkyl, C 1-4 alkylsulfonamido, C 1-4 alkylamido, C 1-4 alkylsulfonamidoC 1-4 alkyl, C 1-4 alkylamidoC 1-4 alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC 1-4 alkyl, arylcarboxamidoC 1-4 alkyl, aroyl, aroylC 1-4 alkyl, or arylC 1-4 alkanoyl group; a group R 3 OCO(CH 2 ) p , R 3 CON(R 4 )(CH 2 ) p , R 3 R 4 NCO(CH 2 ) p  or R 3 R 4 NSO 2 (CH 2 ) p  where each of R 3  and R 4  independently represents a hydrogen atom or a C 1-4 alkyl group or R 3 R 4  forms part of a C 3-6 azacyloalkane or C 3-6 (2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4; or a group Ar 3 —Z, wherein Ar 3  represents an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring and Z represents a bond, O, S, or CH 2 ;  
 R 2  represents a hydrogen atom or a C 1-4 alkyl group;  
 q is 1 or 2;  
 A represents a group of the formula (a), (b), (c) or (d):  
                     
 wherein  
 Ar represents an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring; or an optionally substituted bicyclic ring system;  
 Ar 1  and Ar 2  each independently represent an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring; and  
 Y represents a bond, —NHCO—, —CONH—, —CH 2 —, or —(CH 2 ) m Y 1 (CH 2 ) n —, wherein Y 1  represents O, S, SO 2 , or CO and m and n each represent zero or 1 such that the sum of m+n is zero or 1; providing that when A represents a group of formula (a), any substituent present in Ar ortho to the carboxamide moiety is necessarily a hydrogen or a methoxy group;  
 r and s independently represent an integer from zero to 3 such that the sum of r and s is equal to an integer from 1 to 4;  
 V represents a bond, O or S;  
 and salts thereof.  
 
     
     
         2 . A compound according to  claim 1  wherein q represents 1.  
     
     
         3 . A compound according to any of the preceding claims wherein rings Ar, Ar 1 , or Ar 2  are each independently optionally substituted by one or more substituents selected from: a hydrogen or halogen atom, cyano, methoxy, methylenedioxy, acetyl, acetylamino, methylsulfonyl, methylsulfonyloxy, methylaminosulfonyl, methylsulfonylamino, or methylaminocarbonyl group.  
     
     
         4 . A compound of formula (I) which is: 
 trans-2-(2-(1-(4-(4-quinolinyl)carboxamido)cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-(E)-2-(2-(1-(4-(3-(3-methanesulfonyl)phenylpropenoyl)amino)cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-(E)-2-(2-(1-(4-(3-(4-fluoro)phenylpropenoyl)amino)cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-2-(2-(1-(4-(3-(3-pyridyl)benzamido))cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-2-(2-(1-(4-(2-naphthyl)acetamido))cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-2-(2-(1-(4-(3-indolyl)acetamido))cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-2-(2-(1-(4-(4-quinolinyl)acetamido))cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-5-Cyano-2-(2-(1-(4-(3-pyrrolo[2,3-b]pyridyl)carboxamido)cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-(E)-5-Cyano-2-(2-(1-(4-(3-(4-fluoro)phenylpropenoyl)amino)cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-(E)-5-Cyano-2-(2-(1-(4-(3-(3-methoxy)phenylpropenoyl)amino)cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-(E)-5-Cyano-2-(2-(1-(4-(3-(2-methoxy)phenylpropenoyl)amino)cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-(E)-5-Cyano-2-(2-(1-(4-(3-(2-cyano)phenylpropenoyl)amino)cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-(E)-5-Cyano-2-(2-(1-(4-(3-(3-thiophenyl)propenoyl)amino)cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-(E)-5-Cyano-2-(2-(1-(4-(3-(2-thiophenyl)propenoyl)amino)cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-(E)-5-Methanesulfonyloxy-2-(2-(1-(4-(3-(4-fluoro)phenylpropenoyl)amino)cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-5-Methanesulfonyloxy-2-(2-(1-(4-(5-(2-methyl)quinolinyl)carboxamido)cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    trans-5-Methanesulfonyloxy-2-(2-(1-(4-(3-(3-(1-pyrazolyl)benzamido)))cyclohexyl)ethyl)-2,3-dihydro-1H-isoindole;    or a salt thereof.    
     
     
         5 . A process for preparing compounds of formula (I) which process comprises: 
 (a) reacting a compound of formula(II):                          wherein R 1 , R 2 , and q are as hereinbefore defined, with a compound of formula (III):   A—COX  Formula (III)   wherein A is as hereinbefore defined and X is a halogen atom or the residue of an activated ester;    (b) to prepare a compound of formula (I) by reacting a compound of formula (II) with a compound A—Br, or A—I, or A—OSO 2 CF 3  in the presence of carbon monoxide and a catalyst;    (c) to prepare a compound of formula (I) wherein R 1  is Ar 3 —Z and Z is a bond, reacting a compound of formula (IV):                          wherein A, R 2 , and q are as hereinbefore defined, one R 1a  represents a group W wherein W is a halogen atom or a trifluoromethylsulfonyloxy group, or W is a group M selected from a boron derivativeor a metal function, and when q is 2 the other R 1a  is R 1 ; with a compound Ar 3 —W 1 , wherein W 1  is a halogen atom or a trifluoromethylsulfonyloxy group when W is a group M or W 1  is a group M when W is a halogen atom or a trifluoromethylsulfonyloxy group;    (d) to prepare a compound of formula (I) wherein R 1  is Ar 3 —Z and Z is O or S, reacting a compound of formula (V):                          wherein A, R 2 , and q are as hereinbefore defined, one R 1b  represents a group ZH and when q is 2 the other R 1b  represents R 1 ; with a reagent serving to introduce the group Ar 3 ;    (e) to prepare a compound of formula (I) where Y is a bond, reaction of a compound of formula (VI):                          wherein R 1 , R 2 , q, Ar 1  and W are as hereinbefore defined, with a compound Ar 2 —W 1 , wherein W 1  is a halogen atom or a trifluoromethylsulfonyloxy group when W is a group M, or W 1  is a group M when W is a halogen atom or a trifluoromethylsulfonyloxy group.    (f) interconversion of one compound of formula (I) to a different compound of formula (I) e.g. (i) alkylation of a compound (I) wherein R 2  represents hydrogen, (ii) conversion of one R 1  from alkoxy (e.g.methoxy) to hydroxy, or (iii) conversion of R 1  from hydroxy to sulfonyloxy, eg alkylsulfonyloxy or trifluoromethanesulfonyloxy; (iv) conversion of a compound wherein Y represents S to a compound wherein Y is SO 2  or (v) conversion of Y from CO to CH 2 ;    (g) separation of cis- and trans-isomers of compounds of formula (I) by conventional methods;    and optionally thereafter forming a salt of formula (I).    
     
     
         6 . A pharmaceutical composition comprising a compound of formula (I) as claimed in any of  claims 1  to  4  or a physiologically acceptable salt thereof and a physiologically acceptable carrier therefor.  
     
     
         7 . The use of a compound of formula (I) as claimed in any of  claims 1  to  4  or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition which requires modulation of a dopamine receptor.  
     
     
         8 . Use acording to  claim 7  wherein the dopamine receptor is a dopamine D 3  receptor.  
     
     
         9 . Use according to  claim 7  or  claim 8  wherein a dopamine antagonist is required.  
     
     
         10 . Use according to any of  claims 7  to  9  wherein the condition is a psychotic condition.  
     
     
         11 . Use according to  claim 10  wherein the psychotic condition is schizophrenia.  
     
     
         12 . A method of treating a condition which requires modulation of a dopamine receptor which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) as claimed in  claim 1  or a physiologically acceptable salt thereof.