(THIO) Carbamoyl-Cyclohexane Derivatives as D3/D2 Receptor Antagonists

Abstract

The present invention relates to new D3 and D2 dopamine receptor subtype preferring ligands of formula (I): wherein R 1 and R 2 represent independently a substituent selected from hydrogen, alkyl, aryl, cycloalkyl, aroyl, or R 1 and R 2 may form a heterocyclic ring with the adjacent nitrogen atom; X represents an oxygen or sulphur atom; n is an integer of from 1 to 2, and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, to the processes for producing the same, to pharmaceutical compositions containing the same and to their use in therapy and/or prevention of a condition which requires modulation of dopamine receptors.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  represent independently a substituent selected from hydrogen, alkyl, alkenyl, aryl, cycloalkyl, or aroyl, or R 1  and R 2  together with the adjacent nitrogen atom form a heterocyclic ring; 
 X represents an oxygen or sulphur atom; and 
 n is an integer of 1 to 2, 
 
       and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof. 
     
     
         2 . A compound of  claim 1 ,
 wherein
 R 1  and R 2  represent independently hydrogen, or
 a straight or branched C 1-6  alkyl optionally substituted with one or more C 1-6  alkoxycarbonyl, aryl, or (C 1-6  alkoxycarbonyl)-C 1-6  alkyl group, or R 1  and R 2  together with the adjacent nitrogen atom form a heterocyclic ring, which is a saturated or unsaturated optionally substituted monocyclic or bicyclic ring, which may contain further heteroatoms selected from O, N, or S, or 
 C 2-7  alkenyl with 1 to 3 double bonds, or 
 a mono-, bi- or tricyclic aryl optionally substituted with one or more C 1-6  alkoxy, trifluoro C 1-6  alkoxy, C 1-6  alkoxycarbonyl, C 1-6  alkanoyl, aryl, C 1-6  alkylthio, halogen or cyano, or 
 an optionally substituted mono-, bi- or tricyclic cycloalkyl group, or aroyl group. 
 
   
     
     
         3 . A compound of  claim 2 ,
 wherein
 R 1  and R 2  represent independently hydrogen, or
 a straight or branched C 1-6  alkyl optionally substituted with one or more C 1-6  alkoxycarbonyl, phenyl or (C 1-6  alkoxycarbonyl)-C 1-6  alkyl group or R 1  and R 2  together with the adjacent nitrogen atom form a hetero-monocyclic ring, which may be unsaturated or optionally saturated by C 1-6  alkyl or hydroxyl and which may contain further heteroatoms selected from O or N, or 
 C 2-7  alkenyl with 1 double bond, or 
 phenyl or naphthyl group optionally substituted with one or more C 1-6  alkoxy, trifluoro-C 1-6  alkoxy, C 1-6  alkoxycarbonyl, C 1-6  alkanoyl, aryl, C 1-6  alkylthio, halogen or cyano, or 
 cyclohexyl or adamantyl group, or 
 
 benzoyl group. 
   
     
     
         4 . A compound of  claim 3 ,
 wherein
 R 1  and R 2  represent independently hydrogen,
 a straight or branched C 1-6  alkyl optionally substituted with C 1-6  alkoxycarbonyl, or phenyl or R 1  and R 2  together with the adjacent nitrogen atom form a pyrrolidine, piperazine, piperidine or morpholine ring, which is optionally substituted by C 1-6  alkyl or a hydroxy group, 
 allyl, 
 phenyl optionally substituted with one or more C 1-6  alkoxy, cyano or C 1-6  alkanoyl, or 
 cyclohexyl; 
 
 X represents oxygen or sulphur; and 
 n is 1. 
   
     
     
         5 . A compound selected from
 trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-methyl-urea,   trans-1-{-4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-propyl-urea,   trans-1-{-4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-isopropyl-urea,   trans-1-{-4-[2-[4-(2,3-dichlorophenyl)-hexahydro[1,4]diazepin-1-yl]-ethyl]-cyclohexyl}-3-ethyl-urea,   trans-1-{-4-[2-[4-(2,3-dichlorophenyl)-hexahydro[1,4]diazepin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,   trans-N-{-4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-pyrrolidine-1-carboxamide,   trans-N-{4-[2-[4-(2,3-dichlorophenyl)-hexahydro[1,4]diazepin-1-yl]-ethyl]-cyclohexyl}-pyrrolidine-1-carboxamide,   trans-1-{-4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-diethyl-urea;   trans-1-{-4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-ethyl-3-methyl-urea;   trans-1-{-4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-methyl-3-propyl-urea;   trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-urea;   trans-N-{-4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-piperazine-1-carboxamide;   trans-N-{-4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl-]cyclohexyl}-4-methyl-piperazine-1-carboxamide;   trans-N-{-4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-morpholine-4-carboxamide;   trans-N-{-4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-piperidine-1-carboxamide;   trans-N-{-4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-4-hydroxy-piperidine-1-carboxamide;   trans-1-{-4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,   trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-ethyl-urea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(2-methoxy-phenyl)-urea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(3-methoxy-phenyl)-urea,   trans-1-allyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-urea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(2,4-dimethoxy-phenyl)-urea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(2-ethoxy-phenyl)-urea,   trans-1-butyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-urea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(4-trifluoromethoxy-phenyl)-urea,   trans-1-adamantan-1-yl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexylyurea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl)-cyclohexyl}-3-(4-methylsulfanyl-phenyl)-urea,   trans-1-biphenyl-2-yl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexylyurea   trans-2-[3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl)-cyclohexyl}-ureido]-3-methyl-butyric acid methyl ester,   trans-2-[3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethylycyclohexyl}-ureido]-benzoic acid methyl ester,   trans-1-(3-cyano-phenyl)-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-urea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}cyclohexyl)-3-(3,4,5-trimethoxy-phenyl)-urea,   trans-1-cyclohexyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-urea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}cyclohexyl)-3-propyl-urea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}cyclohexyl)-3-phenyl-thiourea,   trans-1-adamantan-1-yl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-thiourea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}cyclohexyl)-3-ethoxycarbonyl-thiourea,   trans-1-tert-butyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-thiourea,   trans-1-benzyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexylythiourea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(2-methoxy-phenyl)-thiourea,   trans-1-butyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-thiourea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}cyclohexyl)-3-propyl-thiourea,   trans-1-benzoyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-thiourea,   trans-[3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-thioureido]-acetic acid ethyl ester   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-ethyl-thiourea,   trans-1-(4-{2-[4-(2,3-dichloro-phenylypiperazin-1-yl]-ethyl}-cyclohexyl)-3-naphthalen-1-yl-thiourea,   trans-1-tert-butyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-urea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-phenyl-urea,   trans-1-benzyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexylyurea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(4-methoxy-phenyl)-urea,   trans-[3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-ureido]-acetic acid ethyl ester,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(2-methoxy-phenyl)-urea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(3-methoxy-phenyl)-urea,   trans-1-allyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-urea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(2,4-dimethoxy-phenyl)-urea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(2-ethoxy-phenyl)-urea,   trans-1-butyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-urea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(4-trifluoromethoxy-phenyl)-urea,   trans-1-adamantan-1-yl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexylyurea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(4-methylthio-phenyl)-urea,   trans-1-biphenyl-2-yl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-urea,   trans-2,3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-ureido]-3-methyl-butyric acid methyl ester,   trans-2-[3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl)-ureido}-benzoic acid methyl ester,   trans-1-(3-cyano-phenyl)-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-urea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}cyclohexyl)-3-(3,4,5-trimethoxy-phenyl)-urea,   trans-1-cyclohexyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-urea   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-phenyl-thiourea,   trans-1-adamantan-1-yl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexylythiourea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-ethoxycarbonyl-thiourea,   trans-1-tert-butyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-thiourea,   trans-1-benzyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexylythiourea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(2-methoxy-phenyl)-thiourea,   trans-1-butyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-thiourea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-propyl-thiourea,   trans-1-benzoyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-thiourea,   trans-[3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-thioureido]-acetic acid ethyl ester,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-ethyl-thiourea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-naphthalen-1-yl-thiourea,   trans-1-tert-butyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexylyurea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-phenyl-urea,   trans-1-benzyl-3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexylyurea,   trans-1-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(4-methoxy-phenyl)-urea,   trans-[3-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-ureido]acetic acid ethyl ester,   
       and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof. 
     
     
         6 . A process for preparing a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein
 R 1  and R 2  represent independently a substituent selected from hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aroyl, or R 1  and R 2  together with the adjacent nitrogen atom form a heterocyclic ring; 
 X represents an oxygen or sulphur atom; and 
 n is an integer of 1 to 2, 
 
       
       and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, which comprises:
 a) forming an amide bond between a (thio)carbamoylchloride of formula (II): 
 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and X are as defined above for formula (I), and an amine of formula (III): 
       
         
           
           
               
               
           
         
         wherein n is as defined above for formula (I), 
       
       or derivatives thereof, or
 b) forming an amide bond between the iso(thio)cyanate of formula (IV):
   R 1 —N═C═X  (IV)
 
 
 wherein R 1  and X are as defined above for the formula (I), 
 
       and an amine of formula (III): 
       
         
           
           
               
               
           
         
         wherein n is as defined above for the formula (I), 
       
       or derivatives thereof, or
 c) transforming in situ an amine of formula (III) to an iso(thio)cyanate derivative and reacting the latter with an amine of formula (V): 
 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are as described above for the formula (I), 
       
       or derivatives thereof, and
 interconverting one compound (I) obtained by any of method a) to c), wherein R 1 , R 2 , X and n are as defined for compound (I) to a different compound of formula (I) wherein R 1 , R 2 , X and n are as defined for compound (I); 
 where appropriate, separating the enantiomers and/or diastereomers, and/or cis- and/or trans-isomers of compounds of formula (I), or intermediates thereto wherein R 1 , R 2 , X and n are as defined for compound (I) by conventional methods; 
 and optionally thereafter forming salts and/or hydrates and/or solvates. 
 
     
     
         7 . The process of  claim 6 , wherein
 R 1  and R 2  represent independently hydrogen, or
 a straight or branched C 1-6  alkyl optionally substituted with one or more C 1-6  alkoxycarbonyl, aryl, or (C 1-6  alkoxycarbonyl)-C 1-6  alkyl group, or R 1  and R 2  together with the adjacent nitrogen atom form a heterocyclic ring, which is a saturated or unsaturated optionally substituted monocyclic or bicyclic ring, which may contain further heteroatoms selected from O, N, or S, or 
 C 2-7  alkenyl with 1 to 3 double bond, or 
 a mono-, bi- or tricyclic aryl optionally substituted with one or more C 1-6  alkoxy, trifluoro C 1-6  alkoxy, C 1-6  alkoxycarbonyl, C 1-6  alkanoyl, aryl, C 1-6  alkylthio, halogen or cyano, or 
 an optionally substituted mono-, bi- or tricyclic cycloalkyl group, or aroyl group. 
   
     
     
         8 . The process of  claim 7 , wherein
 R 1  and R 2  represent independently hydrogen, or
 a straight or branched C 1-6  alkyl optionally substituted with one or more C 1-6  alkoxycarbonyl, phenyl or (C 1-6  alkoxycarbonyl)-C 1-6  alkyl group or R 1  and R 2  may form a heterocyclic ring with the adjacent nitrogen atom, which may be unsaturated or saturated optionally by C 1-6  alkyl or hydroxy substituted monocyclic ring, which may contain further heteroatoms selected from O or N, or 
 C 2-7  alkenyl with 1 double bond, or 
 phenyl or naphthyl group optionally substituted with one or more C 1-6  alkoxy, trifluoro-C 1-6  alkoxy, C 1-6  alkoxycarbonyl, C 1-6  alkanoyl, aryl, C 1-6  alkylthio, halogen or cyano, or 
 cyclohexyl or adamantyl group, or 
   
       benzoyl group. 
     
     
         9 . The process of  claim 8 , wherein
 R 1  and R 2  represent independently
 hydrogen, or 
 a straight or branched C 1-6  alkyl optionally substituted with C 1-6  alkoxycarbonyl, or phenyl or R 1  and R 2  form with the adjacent nitrogen atom an optionally by C 1-6  alkyl or hydroxy substituted pyrrolidine, piperazine, piperidine or morpholine ring, 
 allyl, 
 phenyl optionally substituted with one or more C 1-6  alkoxy, cyano or C 1-6  alkanoyl, 
 cyclohexyl; 
   X represents oxygen or sulphur; and   n is 1.   
     
     
         10 . An amine of formula (III): 
       
         
           
           
               
               
           
         
         wherein
 n is 2, 
 
         and/or protected forms thereof and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof. 
       
     
     
         11 . A pharmaceutical composition comprising a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein
 R 1  and R 2  represent independently a substituent selected from hydrogen, alkyl, alkenyl, aryl, cycloalkyl, or aroyl, or R 1  and R 2  together with the adjacent nitrogen atom form a heterocyclic ring; 
 X represents an oxygen or sulphur atom; and 
 n is an integer of from 1 to 2, 
 
         and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof and one or more physiologically acceptable carriers therefore. 
       
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein
 R 1  and R 2  represent independently hydrogen, or
 a straight or branched C 1-6  alkyl optionally substituted with one or more C 1-6  alkoxycarbonyl, aryl, or (C 1-6  alkoxycarbonyl)-C 1-6  alkyl group, or R 1  and R 2  together with the adjacent nitrogen atom form a heterocyclic ring, which is a saturated or unsaturated optionally substituted monocyclic or bicyclic ring, which may contain further heteroatoms selected from O, N, or S, or 
 C 2-7  alkenyl with 1 to 3 double bond, or 
 a mono-, bi- or tricyclic aryl optionally substituted with one or more C 1-6  alkoxy, trifluoro-C 1-6  alkoxy, C 1-6  alkoxycarbonyl, C 1-6  alkanoyl, aryl, C 1-6  alkylthio, halogen or cyano, or 
 an optionally substituted mono-, bi- or tricyclic cycloalkyl group, or aroyl group. 
   
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein
 R 1  and R 2  represent independently hydrogen, or
 a straight or branched C 1-6  alkyl optionally substituted with one or more C 1-6  alkoxycarbonyl, phenyl or (C 1-6  alkoxycarbonyl)-C 1-6  alkyl group or R 1  and R 2  together with the adjacent nitrogen atom form a hetero-monocyclic ring, which may be unsaturated or optionally saturated by C 1-6  alkyl or hydroxyl and which may contain further heteroatoms selected from O or N, or 
 C 2-7  alkenyl with 1 double bond, or 
 phenyl or naphthyl group optionally substituted with one or more C 1-6  alkoxy, trifluoro-C 1-6  alkoxy, C 1-6  alkoxycarbonyl, C 1-6  alkanoyl, aryl, C 1-6  alkylthio, halogen or cyano, or 
 cyclohexyl or adamantyl group, or 
 benzoyl group. 
   
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein
 R 1  and R 2  represent independently hydrogen,
 a straight or branched C 1-6  alkyl optionally substituted with C 1-6  alkoxycarbonyl, or phenyl or R 1  and R 2  together with the adjacent nitrogen atom form a pyrrolidine, piperazine, piperidine or morpholine ring, which is optionally substituted by C 1-6  alkyl or a hydroxy group, 
 allyl, 
 phenyl optionally substituted with one or more C 1-6  alkoxy, cyano or C 1-6  alkanoyl, or 
 cyclohexyl; 
   X represents oxygen or sulphur; and   n is 1.   
     
     
         15 . A method of treating and/or preventing a condition which requires modulation of dopamine receptor(s) which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein
 R 1  and R 2  represent independently a substituent selected from hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aroyl, or R 1  and R 2  together with the adjacent nitrogen atom form a heterocyclic ring; 
 X represents an oxygen or sulphur atom; and 
 n is an integer of 1 to 2, 
 
         and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof. 
       
     
     
         16 . The method of  claim 15 , wherein
 R 1  and R 2  represent independently hydrogen, or
 a straight or branched C 1-6  alkyl optionally substituted with one or more C 1-6  alkoxycarbonyl, aryl, or (C 1-6  alkoxycarbonyl)-C 1-6  alkyl group, or R 1  and R 2  together with the adjacent nitrogen atom form a heterocyclic ring, which is a saturated or unsaturated optionally substituted monocyclic or bicyclic ring, which may contain further heteroatoms selected from O, N, or S, or 
 C 2-7  alkenyl with 1 to 3 double bond, or 
 a mono-, bi- or tricyclic aryl optionally substituted with one or more C 1-6  alkoxy, trifluoro C 1-6  alkoxy, C 1-6  alkoxycarbonyl, C 1-6  alkanoyl, aryl, C 1-6  alkylthio, halogen or cyano, or 
   an optionally substituted mono-, bi- or tricyclic cycloalkyl group, or aroyl group.   
     
     
         17 . The method of  claim 16 , wherein
 R 1  and R 2  represent independently hydrogen, or
 a straight or branched C 1-6  alkyl optionally substituted with one or more C 1-6  alkoxycarbonyl, phenyl or (C 1-6  alkoxycarbonyl)-C 1-6  alkyl group or R 1  and R 2  together with the adjacent nitrogen atom form a hetero-monocyclic ring, which may be unsaturated or optionally saturated by C 1-6  alkyl or hydroxyl and which may contain further heteroatoms selected from O or N, or 
 C 2-7  alkenyl with 1 double bond, or 
 phenyl or naphthyl group optionally substituted with one or more C 1-6  alkoxy, trifluoro-C 1-6  alkoxy, C 1-6  alkoxycarbonyl, C 1-6  alkanoyl, aryl, C 1-6  alkylthio, halogen or cyano, or 
 cyclohexyl or adamantyl group, or 
 benzoyl group. 
   
     
     
         18 . The method of  claim 17 , wherein
 R 1  and R 2  represent independently hydrogen, or
 a straight or branched C 1-6  alkyl optionally substituted with C 1-6  alkoxycarbonyl, or phenyl or R 1  and R 2  together with the adjacent nitrogen atom form a pyrrolidine, piperazine, piperidine or morpholine ring, which is optionally substituted by C 1-6  alkyl or a hydroxy group, 
 allyl, 
 phenyl optionally substituted with one or more C 1-6  alkoxy, cyano or C 1-6  alkanoyl, or 
 cyclohexyl, 
   X represents oxygen or sulphur, and   n is 1.   
     
     
         19 . The method of any of  claims 15  to  18 , wherein the dopamine receptor is a dopamine D 3  and/or D 2  receptor.