(Thio) carbamoyl-cyclohexane derivatives as D3/D2 receptor antagonists

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 1,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts 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

(i) hydrogen,

(ii) a straight or branched C 1-6 alkyl optionally substituted with one or more alkoxycarbonyl, phenyl or (C 1-6 alkoxycarbonyl)-C 1-6 alkyl group,

(iii) R 1 and R 2 together with the adjacent nitrogen atom form a hetero-monocyclic ring, which may be optionally substituted by C 1-6 alkyl or hydroxyl and which may contain further heteroatoms selected from O or N,

(iv) C 2-7 alkenyl with 1 double bond,

(v) 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,

(vi) cyclohexyl or adamantyl group, or

(vii) 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-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-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}-cyclohexyl)-urea,

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}-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}-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}-cyclohexyl)-thiourea,

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}-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}-cyclohexyl)-urea,

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 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 1,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts 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

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

c) transforming in situ an amine of formula (III) to an iso(thio)cyanate and reacting the latter with an amine of formula (V):

wherein R 1 and R 2 are as described above for the formula (I),

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.

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 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 optionally substituted 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

(i) hydrogen,

(ii) a straight or branched C 1-6 alkyl optionally substituted with C 1-6 alkoxycarbonyl,

(iii) R 1 and R 2 form with the adjacent nitrogen atom a pyrrolidine, piperazine, piperidine or morpholine ring optionally substituted by C 1-6 alkyl or hydroxy,

(iv) allyl,

(v) phenyl optionally substituted with one or more C 1-6 alkoxy, cyano or alkanoyl, or

(vi) cyclohexyl;

X represents oxygen or sulphur; and

n is 1.

10. 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 1,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts thereof and one or more physiologically acceptable carriers therefore.

11. The pharmaceutical composition of claim 10 , wherein

R 1 and R 2 represent independently

hydrogen, or

a straight or branched C 1-6 alkyl optionally substituted with one or more 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.

12. The pharmaceutical composition of claim 11 , wherein

R 1 and R 2 represent independently

(i) hydrogen,

(ii) 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

(iii) R 1 and R 2 together with the adjacent nitrogen atom form a hetero-monocyclic ring, which may be optionally substituted 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,

(iv) a 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

(v) a cyclohexyl or adamantyl group, or

(vi) a benzoyl group.

13. The pharmaceutical composition of claim 12 , 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.

14. A method of treating 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 1,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts thereof; and

the condition which requires modulation of dopamine receptor(s) is selected from the group consisting of: psychosis, cognitive impairment accompanying schizophrenia, mild-to-moderate cognitive deficits, dementia, psychotic states associated with dementia, psychotic depression, mania, paranoid and delusional disorders, dyskinetic disorders, neuroleptics-induced parkinsonism, tardive dyskinesia, eating disorders, attention deficit disorder, hyperactivity disorders in children, depression, anxiety, sexual dysfunction, sleep disorders, emesis, aggression, autism, and drug abuse.

15. The method of claim 14 , wherein

R 1 and R 2 represent independently

hydrogen, or

a straight or branched C 1-6 alkyl optionally substituted with one or more 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.

16. The method of claim 15 , wherein R 1 and R 2 represent independently

(i) hydrogen,

(ii) 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,

(iii) R 1 and R 2 together with the adjacent nitrogen atom form a hetero-monocyclic ring, which may be optionally substituted by C 1-6 alkyl or hydroxyl and which may contain further heteroatoms selected from O or N,

(iv) C 2-7 alkenyl with 1 double bond,

(v) 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,

(vi) cyclohexyl or adamantyl group, or

(vii) benzoyl 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 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.

18. The method of any of claims 14 to 17 , wherein the dopamine receptor is a dopamine D 3 and/or D 2 receptor.

19. A compound having the formula:

or a salt thereof.

20. A pharmaceutical composition comprising the compound of claim 19 and a physiologically acceptable carrier.

21. A method for treating a condition in a patient comprising administering to the patient the pharmaceutical composition of claim 20 , wherein the condition is selected from the group consisting of: psychosis, cognitive impairment accompanying schizophrenia, mild-to-moderate cognitive deficits, dementia, psychotic states associated with dementia, psychotic depression, mania, paranoid and delusional disorders, dyskinetic disorders, neuroleptics-induced parkinsonism, tardive dyskinesia, eating disorders, attention deficit disorder, hyperactivity disorders in children, depression, anxiety, sexual dysfunction, sleep disorders, emesis, aggression, autism, and drug abuse.

22. A method for treating schizophrenia comprising administering to a patient with schizophrenia the pharmaceutical composition of claim 20 .

23. A method for treating mania comprising administering to a patient with mania the pharmaceutical composition of claim 20 .

24. A compound having the formula:

or a salt thereof.

25. A pharmaceutical composition comprising the compound of claim 24 and a physiologically acceptable carrier.

26. A method for treating a condition in a patient comprising administering to the patient the pharmaceutical composition of claim 24 , wherein the condition is selected from the group consisting of: psychosis, cognitive impairment accompanying schizophrenia, mild-to-moderate cognitive deficits, dementia, psychotic states associated with dementia, psychotic depression, mania, paranoid and delusional disorders, dyskinetic disorders, neuroleptics-induced parkinsonism, tardive dyskinesia, eating disorders, attention deficit disorder, hyperactivity disorders in children, depression, anxiety, sexual dysfunction, sleep disorders, emesis, aggression, autism, and drug abuse.

27. A method for treating schizophrenia comprising administering to a patient with schizophrenia the pharmaceutical composition of claim 24 .

28. A method for treating mania comprising administering to a patient with mania the pharmaceutical composition of claim 24 .