METABOLITES OF (THIO) CARBAMOYL-CYCLOHEXANE DERIVATIVES

• US 20100137335A1
• Filed: 05/15/2008
• Published: 06/03/2010
• Est. Priority Date: 05/18/2007
• Status: Active Grant

• Current Assignee: Richter Gedeon Rt.
• Original Assignee: Richter Gedeon Rt.
• Inventors: Schmidt, Eva, Kirschner, Norbert Antal, Csongor, Eva Againe, Gyertyan, Istvan, Kiss, Bela
• Granted Patent: US 8,765,765 B2
• Time in Patent Office: Days
• US Class Current: 514/255.30
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 295/135 with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/24 Oxygen atoms

Abstract

The present invention relates to metabolites of (thio)carbamoyl cyclohexane derivatives, particularly, metabolites of trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-N,N-dimemylcarbamoyl-cyclohexylamine and pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing the same and to their use in the treatment and/or prevention of a conditions which requires modulation of dopamine receptors.

Claims

1. An isolated metabolite of a compound of formula (I):

wherein

R₁ and R₂ are each, independently, hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aroyl, or R₁ and R₂ form a heterocyclic ring with the adjacent nitrogen atom;

X is O or S;

n is 1 or 2;

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof.

2. An isolated and/or synthetized metabolite of a compound of formula (I) according to claim 1, wherein the compound of formula (I) is

and/or salts and/or hydrates and/or solvates and/or polymorphs thereof.

19. A method of treating and/or preventing a condition which requires modulation of dopamine receptors comprising administering to a patient in need thereof a therapeutically effective amount of a metabolite according to any one of claims 1-2.

21. A method of treating and/or preventing according to any one of claims 19-20 wherein the dopamine receptor is a dopamine D₃ receptor and/or a dopamine D₂ receptor.

24. The use of a metabolite according to any one of claims 1-2 in the manufacture of a medicament for the treatment and/or prevention of a condition which requires modulation of a dopamine receptor.

26. The use according to any one of claims 24-25, wherein the dopamine receptor is a dopamine D₃ receptor and/or a dopamine D₂ receptor.

3. An isolated and/or synthetized compound of formula (II):

wherein

R₁ and R₂ are each, independently, hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aroyl or R₁ and R₂ form a heterocyclic ring with the adjacent nitrogen atom;

X is O or S;

n is 1 or 2;

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof.

5. A compound according to claim 3, wherein formula (II) is represented by formula (IIa)

wherein R₁, R₂, X and n are as defined above for formula (II).

6. A compound according to claim 3, wherein

R₁ and R₂ are each, independently hydrogen, C_1-6 alkyl with straight or branched chain optionally substituted with one or more C_1-6 alkoxycarbonyl, aryl or (C_1-6 alkoxycarbonyl)-C_1-6 alkyl group, C_2-7 alkenyl with 1 to 3 double bonds, 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, an optionally substituted mono-, bi- or tricyclic cycloalkyl group, aroyl, or R₁ and/or R₂ form a heterocyclic ring with the adjacent nitrogen atom, which may be saturated or unsaturated optionally substituted monocyclic or bicyclic ring, which may contain further heteroatoms selected from O, N, or S;

X is oxygen;

n is 1.

7. A compound according to claim 3, wherein

R₁ and R₂ are each, independently hydrogen, C_1-6 alkyl with straight or branched chain and optionally substituted with one or more C_1-6 alkoxycarbonyl, phenyl or (C_1-6 alkoxycarbonyl)-C_1-6 alkyl group, C_2-7 alkenyl with 1 double bond, phenyl or naphthyl 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, cyano, cyclohexyl, adamantyl, benzoyl, or R₁ and/or R₂ form a heterocyclic ring with the adjacent nitrogen atom, which may be saturated optionally by C_1-6 alkyl or hydroxy substituted monocyclic ring, which may contain further heteroatoms selected from O or N;

X is oxygen;

n is 1.

8. A compound according to claim 3, wherein

R₁ and R₂ are each, independently hydrogen, C_1-6 alkyl with straight or branched chain optionally substituted with C_1-6 alkoxycarbonyl or phenyl group, allyl, phenyl optionally substituted with one or more C_1-6 alkoxy, cyano, C_1-6 alkanoyl, cyclohexyl, or R₁ and/or R₂ with the adjacent nitrogen atom an optionally by C_1-6 alkyl or hydroxy substituted pyrrolidine, piperazine, piperidine or morpholine ring;

X is oxygen;

n is 1.

9. A compound according to claim 3, wherein

R₁ and R₂ are each, independently hydrogen or alkyl;

X is oxygen;

n is 1.

14. A compound according to anyone of claims 3-4 selected from

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof.

18. A pharmaceutical composition comprising a compound according to claims 14 and one or more pharmaceutically acceptable carrier.

4. An isolated and/or synthetized compound of formula (III):

wherein

R₁ and R₂ are each, independently, hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aroyl, or R₁ and R₂ form a heterocyclic ring with the adjacent nitrogen atom;

X is O or S;

n is 1 or 2;

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof.

10. A compound according to claim 4, wherein

R₁ and R₂ are each, independently hydrogen, C_1-6 alkyl, with straight or branched chain optionally substituted with one or more C_1-6 alkoxycarbonyl, aryl, or (C_1-6 alkoxycarbonyl)-C_1-6 alkyl group, C_2-7 alkenyl with 1 to 3 double bonds, 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, cyano, an optionally substituted mono-, bi- or tricyclic cycloalkyl group, aroyl, or R₁ and/or R₂ form a heterocyclic ring with the adjacent nitrogen atom, which may be saturated or unsaturated optionally substituted monocyclic or bicyclic ring, which may contain further heteroatoms selected from O, N, or S;

X is oxygen;

n is 1.

11. A compound according to claim 4, wherein

R₁ and R₂ are each, independently, hydrogen, C_1-6 alkyl, with straight or branched chain and optionally substituted with one or more C_1-6 alkoxycarbonyl, phenyl or (C_1-6 alkoxycarbonyl)-C_1-6 alkyl group, C_2-7 alkenyl with 1 double bond, phenyl or naphthyl 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, cyano, cyclohexyl, adamantyl, benzoyl, or R₁ and R₂ form a heterocyclic ring with the adjacent nitrogen atom, which may be saturated optionally by C_1-6 alkyl or hydroxy substituted monocyclic ring, which may contain further heteroatoms selected from O or N.

X is oxygen;

n is 1.

12. A compound according to claim 4, wherein

R₁ and R₂ are each, independently, hydrogen, C_1-6 alkyl with straight or branched chain optionally substituted with C_1-6 alkoxycarbonyl or phenyl, allyl, phenyl optionally substituted with one or more C_1-4 alkoxy, cyano or C_1-6 alkanoyl, cyclohexyl, or R₁ and/or R₂ with the adjacent nitrogen atom an optionally by C_1-6 alkyl or hydroxy substituted pyrrolidine, piperazine, piperidine or morpholine ring;

X is oxygen;

n is 1.

13. A compound according to claim 4, wherein

R₁ and R₂ are each, independently hydrogen or alkyl;

X is oxygen; and

n is 1.

20. A method of treating and/or preventing a condition which requires modulation of dopamine receptors comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 3-14.

25. The use of a compound according to any one of claims 3-14 in the manufacture of a medicament for the treatment and/or prevention of a condition which requires modulation of a dopamine receptor.

15. A pharmaceutical composition comprising an isolated metabolite of a compound of formula (I):

wherein

R₁ and R₂ are each, independently, hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aroyl, or R₁ and R₂ form a heterocyclic ring with the adjacent nitrogen atom;

X is O or S;

n is 1 or 2;

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof and one or more pharmaceutically acceptable carrier.

22. A method of treating and/or preventing a condition which requires modulation of dopamine receptors comprising administering to a patient in need thereof a therapeutically effective amount of a composition according to any one of claims 15-18.

23. A method of treating and/or preventing according to claim 22 wherein the dopamine receptor is a dopamine D₃ receptor and/or a dopamine D₂ receptor.

16. A pharmaceutical composition comprising a compound of formula (II)

wherein

R₁ and R₂, are each, independently, hydrogen, alkyl, alkenyl, aryl, cycloalkyl, or aroyl, or R₁ and R₂ form a heterocyclic ring with the adjacent nitrogen atom;

X is O or S;

n is 1 or 2;

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof and one or more pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising a compound of formula (III):

wherein

R₁ and R₂, are each, independently, hydrogen, alkyl, alkenyl, aryl, cycloalkyl, or aroyl, or R₁ and R₂ form a heterocyclic ring with the adjacent nitrogen atom;

X is O or S;

n is 1 or 2;

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof and one or more pharmaceutically acceptable carrier.