Sulfonamide derivatives as D3-receptor ligands

1. A compound of formula (I)

or a salt thereof,

wherein

X represents a nitrogen atom or CH group;

Y represents a bond when X stands for nitrogen, or an oxygen atom or NH or CH 2 or OCH 2 group when X stands for CH group;

R 1 , R 2 , and R 3 may be the same or different and represent independently a substituent selected from hydrogen, halogen, C 1-6 -alkyl, C 1-6 alkoxy, cyano, hydroxy, trifluoromethyl, C 1-6 -alkylsulfonyloxy, trifluoromethanesulfonyloxy, C 1-6 -alkanoyloxy, amino, alkylamino, alkanoylamino, alkylsulfonylamino, arylsulfonylamino, aminocarbonyl, carboxy, N-hydroxycarmamimidoyl, carbamimidoyl, hydroxycarbamoyl, thiocarbamoyl, sulfamoyl, mono or bicyclic heterocyclic group or optionally substituted phenyl, or two adjacent groups of R 1 , R 2 , and R 3 may combine to form an optionally substituted fused mono or bicyclic heterocyclic group; and

Q represents a dialkylamino group or an optionally substituted alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group

wherein “optionally substituted” means, independently at each use, optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, trifluoromethyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkanoyl, methylenedioxy, C 1-6 -alkylamino, C 1-6 -alkanoylamino, optionally substituted aroyl, aryloxy, aminosulfonyl, arylsulfonylamido, optionally substituted mono or bicyclic aromatic ring, and optionally substituted heteroaromatic ring.

2. A compound according to claim 1 wherein

X represents a nitrogen atom or CH group;

Y represents a bond when X stands for nitrogen, or an oxygen atom or NH or CH 2 or OCH 2 group when X stands for CH group;

R 1 , R 2 , and R 3 may be the same or different and represent independently hydrogen, alkyl, alkoxy, halogen, cyano, aminocarbonyl, trifluoromethyl or optionally substituted phenyl or two adjacent groups of R 1 , R 2 , and R 3 may combine to form an optionally substituted fused mono or bicyclic heterocyclic group; and

Q represents dialkylamino, optionally substituted phenyl, biphenyl, pyridyl, thienyl, alkyl or quinolinyl.

3. A compound according to claim 1 wherein

X represents a nitrogen atom or CH group;

Y represents a bond when X stands for nitrogen, or CH 2 group when X stands for CH group;

R 1 , R 2 , and R 3 may be the same or different and represent independently hydrogen, fluorine, bromine, chlorine atoms or cyano, trifluoromethyl, methyl, methoxy, ethoxy, optionally substituted phenyl or aminocarbonyl groups or two adjacent groups of R 1 , R 2 , and R 3 may combine to form an optionally substituted fused mono or bicyclic heterocyclic group; and

Q represents C 1-4 alkyl, dimethylamino, biphenyl, alkylphenyl, alkoxyphenyl, halophenyl, nitrophenyl, trifluoromethylphenyl, aminocarbonylmethylphenyl, pyridyl, or quinolinyl.

4. The compound according to claim 1 , wherein said compound is a geometric isomer, a stereoisomer, or a disastereomer.

5. The compound according to claim 1 , wherein said compound is a trans-isomer.

6. The compound according to claim 1 selected from the group consisting of

trans-N-(4-{2-[4-(3-cyano-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}-cyclohexyl)pyridine-3-sulfonamide;

trans-N′-(4-{2-[4-(3-methoxybiphenyl-4-yl)piperazin-1-yl]-ethyl}cyclohexyl)-N,N-dimethylsulfamide hydrochloride;

trans-4-chloro-N-(4-{2-[4-(3-cyano-5-trifluoromethylphenyl)piperazin-1-yl]-ethyl}cyclohexyl)benzenesulfonamide hydrochloride;

trans-4-chloro-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}-cyclohexyl)benzenesulfonamide hydrochloride;

trans-N-(4-{2-[4-(3-methoxybiphenyl-4-yl)piperazin-1yl]-ethyl}cyclohexyl)-3-pyridinesulfonamide dihydrochloride;

trans-5-chloro-N-(4-{2-[4-(3-cyano-5-trifluoromethylphenyl)piperazin-1-yl]]-ethyl}cyclohexyl)-2-thiophenesulfonamide hydrochloride;

trans-N′-(4-{2-[4-(3-cyano-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}-cyclohexyl)-N,N-dimethylsulfamide;

trans-N-(4-{2-[4-(3-methoxybiphenyl-4-yl)piperazin-1-yl]ethyl}cyclohexyl)-butanesulfonamide hydrochloride;

trans-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-butanesulfonamide hydrochloride;

trans-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-morpholinepropanesulfonamide dihydrochloride;

trans-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-3-pyridinesulfonamide dihydrochloride;

trans-N-(4-{2-[4-(2,3-dichloromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-3-pyridinesulfonamide dihydrochloride;

trans-4-bromo-N-(4-{2-[4-(3-trifluoromethylphenylmethyl)piperidin-1-yl]-ethyl}cyclohexyl)benzenesulfonamide;

trans-4-chloro-N-(4-{2-[4-(3-fluorophenylmethyl)piperidin-1-yl]ethyl}-cyclohexyl)benzenesulfonamide;

trans-N-(4-{2-[4-(3-trifluoromethylphenylmethyl)piperidin-1-yl]ethyl}-cyclohexyl)-3-pyridinesulfonamide dihydrochloride;

trans-4-chloro-N-(4-{2-[4-(3-trifluoromethylphenylmethyl)piperidin-1-yl]-ethyl}cyclohexyl)benzenesulfonamide;

trans-4-chloro-N-(4-{2-[4-(3-cyanophenylmethyl)piperidin-1-yl]ethyl}-cyclohexyl)benzenesulfonamide hydrochloride;

trans-N-(4-{2-[4-(3-trifluoromethylphenylamino)piperidin-1-yl ]ethyl}-cyclohexyl)trifluoroethanesulfonamide hydrochloride;

trans-N-(4-{2-[4-(3-trifluoromethylphenylamino)piperidin-1-yl]ethyl}-cyclohexyl)butanesulfonamide hydrochloride;

trans-4-chloro-N-(4-{2-[4-(3-trifluoromethylphenylamino)piperidin-1-yl]ethyl}-cyclohexyl)benzenesulfonamide hydrochloride;

trans-N′-(4-{2-[4-(3-trifluoromethylphenylamino)piperidin-1-yl]ethyl}-cyclohexyl)-N,N-dimethylsulfamide hydrochloride;

trans-N-(4-{2-[4-(3-trifluoromethylphenylmethoxy)piperidin-1-yl]ethyl}-cyclohexyl)-3-pyridinesulfonamide dihydrochloride;

trans-N-(4-{2-[4-(3-trifluoromethylphenoxy)piperidin-1-yl]ethyl}cyclohexyl)-3-pyridinesulfonamide dihydrochloride; and

trans-N-{4-[2-[4-(3-aminocarbonyl-5-trifluoromethylphenyl)-1-piperizinyl]-ethyl]cyclohexyl}-3-pyridinesulfonamide.

7. A compound according to claim 1 selected from the group consisting of

trans-4-bromo-N-(4-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)-benzenesulfonamide;

2,5-dichloro-N-(4-{2-[4-(3-trifluoromethylphenoxy)piperidin-1-yl]ethyl}-cyclohexyl)benzenesulfonamide;

N-(4-{2-[4-(3-bromophenylamino)piperidin-1-yl]ethyl}cyclohexyl)-4-methoxy-benzenesulfonamide;

4-chloro-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}-cyclohexyl)benzenesulfonamide;

N-(4-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-nitro-benzenesulfonamide;

N-(4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-nitro-benzenesulfonamide;

N-(4-{2-[4-(3-cyano-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-fluorobenzenesulfonamide;

N-[4-(4-{2-[4-(4-bromo-2,3-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl-sulfamoyl)phenyl]acetamide;

N-(4-{2-[4-(3-bromophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2,4,6-trimethyl-benzenesulfonamide;

biphenyl-4-sulfonic acid (4-{2-[4-(4-bromo-2-ethoxyphenyl)piperazin-1-yl]-ethyl}cyclohexyl)amide;

N-(4-{2-[4-(2,5 -dichlorophenylamino)piperidin-1-yl]ethyl}cyclohexyl)-4-nitro-benzenesulfonamide;

biphenyl-4-sulfonic acid (4-{2-[4-(5-chloro-2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide;

N-(4-{2-[4-(3-chlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxy-benzenesulfonamide;

N-(4-{2-[4-(3,5-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methyl-benzenesulfonamide;

N-(4-{2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxy-benzenesulfonamide;

N-(4-{2-[4-(4-bromo-2-ethoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-iodo-benzenesulfonamide;

3,4-dichloro-N-(4-{2-[4-(3-methoxybiphenyl-4-yl)piperazin-1-yl]ethyl}-cyclohexyl)benzenesulfonamide;

quinoline-8-sulfonic acid (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]-ethyl}cyclohexyl)amide;

N-[4-(4-{2-[4-(3,5-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexylsulfamoyl)-phenyl]acetamide;

N-(4-{2-[4-(5-chloro-2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)4-fluorobenzenesulfonamide;

N-[4-(4-{2-[4-(3-chlorophenyl)piperazin-1-yl]-ethyl}cyclohexylsulfamoyl)-phenyl]acetamide;

biphenyl-4-sulfonic acid (4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}-cyclohexyl)amide;

N-(4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxy-benzenesulfonamide;

N-(4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methyl-benzenesulfonamide;

N-(4-{2-[4-(5-chloro-2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)-3-trifluoromethylbenzenesulfonamide;

N-(4-{2-[4-(4-chloro-2-methoxyphenyl)piperazin-1-yl]ethyl)}cyclohexyl)-3,4-dimethoxy-benzenesulfonamide;

N-(4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-3-nitro-benzenesulfonamide;

N-(4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-3,4-dimethoxy-benzenesulfonamide; and

N-(4-{2-[4-(4-chloro-2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methylbenzenesulfonamide.

8. A process for preparing a compound according to any one of claims 1 - 3 and 4 - 7 which comprises reacting a compound of formula (II)

wherein Q is as hereinbefore defined

with a compound of formula (III)

wherein R 1 , R 2 , R 3 , X and Y are as hereinbefore defined; and

optionally, separating enantiomers, diastereomers, cis- and trans-isomers, and mixtures thereof of a compound according to any one of claims 1 - 3 and 4 - 7 ;

thereby obtaining the compound according to any one of claims 1 - 3 and 4 - 7 .

9. A pharmaceutical composition comprising a compound according to any one of claims 1 - 3 and 4 - 7 and one or more physiologically acceptable carriers.

10. A method of treating a neuropsychiatric condition said method comprising administering to a mammalian subject in need thereof an effective amount of a compound according to any of claims 1 - 3 and 4 - 7 .

11. A process for preparing a compound according to claim 1 comprising

i) reacting a compound of formula (VI)

wherein R 6 represents hydrogen or a protecting group,

with a polystyrene resin of formula (V)

wherein R 4 and R 5 can be the same or different and represent hydrogen or methoxy group provided that both R 4 and R 5 are not hydrogen, by reductive amination with a reducing agent;

ii) halogenation of the terminal hydroxy group of a compound of formula (VII)

wherein the meaning of R 6 is as described above for formula (VI), with a halogenation agent, or if it was protected, the protecting group having been removed before the halogenation, which results in a solid phase compound of formula (VIII)

wherein Z represents a halogen and the meaning of R 4 and R 5 is as described above for formula (V);

iii) sulfonylation a compound of formula (VIII) with a sulfonylchloride of formula(II)

wherein the meaning of Q is as described above for formula (I) to form a compound of formula (IX)

iv) alkylation of the compound of formula (IX) with a compound of formula (IV)

wherein the meaning of Z, R 4 and R 5 are as described above for the formula (VIII) and the meaning of Q is as described above for formula (I) of a secondary amine of formula (IV) wherein the meaning of R 1 , R 2 , R 3 , X and Y are as described above for the formula (I); and

v) releasing the products of formula (I) from the solid-phase compound of formula (X)

wherein the meaning of Q, R 1 , R 2 , R 3 , R 4 , R 5 , X and Y are as described above for the formula (I) by acidic cleavage.

12. The method according to claim 10 wherein the compound is an agonist of a dopamine D 3 receptor.

13. The method according to claim 8 wherein the compound of formula (III) is selected from the group consisting of

trans-3-{4-[2-(4-aminocyclohexyl)ethyl]piperazin-1-yl}-5-trifluoromethyl-benzonitrile;

trans-4-{2-[4-(3-methoxybiphenyl-4-yl)-piperazin-1-yl]ethyl}cyclohexylamine dihydrochloride;

trans-4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylamine dihydrochloride;

trans-4-{2-[4-(2,3-dichloro-phenyl)piperazin-1-yl]ethyl}cyclohexylamine dihydrochloride;

trans-4-{2-[4-(3-trifluoromethylphenylmethyl)piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride;

trans-4-{2-[4-(3-fluoro-phenylmethyl)piperidin-1-yl]ethyl}cyclohexylamine dihydrochloride;

trans-4-{2-[4-(3-cyanophenylmethyl)piperidin-1-yl]ethyl}cyclohexylamine dihydrochloride;

trans-4-{2-[4-(3-trifluoromethylphenylamino)piperidin-1-yl]ethyl}-cyclohexylamine dihydrochloride;

trans-4-{2-[4-(3-trifluoromethylphenylmethoxy)piperidin-1-yl]ethyl}-cyclohexylamine dihydrochloride; and

trans-4-{2-[4-(3-trifluoromethylphenoxy)piperidin-1-yl]ethyl}cyclohexylamine dihydrochloride.

14. The process according to claim 8 , further comprising converting the compound obtained from the process of claim 8 to a second compound of formula I, wherein the conversion comprises converting one of R 1 , R 2 , and R 3 :

a) from an alkoxy group to a hydroxy group;

b) from a hydroxy group to an alkoxy group;

c) from a cyano group to an amide group;

d) from a cyano group to an amidine group; or

e) from a hydrogen to a halogen.

15. The pharmaceutical composition according to claim 9 , wherein the composition comprises a compound according to claim 1 and water.

16. The method according to claim 10 wherein said compound is an antagonist of a dopamine D 3 receptor.

17. The method according to claim 10 wherein the compound is a partial agonist of a dopamine D 3 receptor.

18. The method according to claim 10 wherein the condition is Parkinson's disease.

19. The compound according to claim 1 , wherein Q is pyridyl and R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, cyano, and trifluoromethyl.

20. The compound according to claim 1 , which is trans-N-(4-{2-[4-(3-cyano-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}-cyclohexyl)pyridine-3-sulfonamide.

21. The method according to claim 10 , wherein the neuropsychiatric condition is selected from the group consisting of schizophrenia, schizo-affective disorder, psychotic depression, mania, paranoid, and delusional disorders, Parkinson's disease, and neuroleptic induced parkinsonism.

22. The method according to claim 10 , wherein the neuropsychiatric condition is schizophrenia.