Metabolites of (thio) carbamoyl-cyclohexane derivatives

• US 8,765,765 B2
• Filed: 05/15/2008
• Issued: 07/01/2014
• Est. Priority Date: 05/18/2007
• Status: Active Grant

• Current Assignee: Richter Gedeon Rt.
• Original Assignee: Richter Gedeon Rt.
• Inventors: Csongor, Eva Againe, Kirschner, Norbert Antal, Schmidt, Eva, Gyertyan, Istvan, Kiss, Bela
• Primary Examiner(s): Leeser, Erich A
• Application Number:
  US12/600,826
• Publication Number:
  US 20100137335A1
• Time in Patent Office: 2,238 Days
• Field of Search: 544/395, 514/255.03
• US Class Current: 514/255.03
• 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-dimethylcarbamoyl-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 or synthesized compound of formula (II):

2. A compound according to claim 1, wherein formula (II) is represented by formula (IIa)

3. A compound according to claim 1, 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 or R₂ or both R₁ and 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, and S;

X is oxygen;

n is 1.

4. A compound according to claim 1, 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 or R₂ or both 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.

6. A compound according to claim 1, wherein

R₁ and R₂ are each, independently hydrogen or alkyl;

X is oxygen;

n is 1.

10. A method of inhibiting a dopamine receptor, the method comprising contacting a dopamine receptor with an effective amount of a compound according to claim 1.

11. A method of inhibiting a dopamine receptor according to claim 10 wherein the dopamine receptor is a dopamine D₃ receptor, a dopamine D₂ receptor, or a combination thereof.

12. A method of claim 10, wherein the contacting is done in vitro.

5. A compound according to claim , 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.

7. A compound selected from

9. A pharmaceutical composition comprising a compound according to claim 7 and one or more pharmaceutically acceptable carriers.

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