N,N'-disubstituted benzimidazolone derivatives with affinity at the serotonin and dopamine receptors

• US 20030027823A1
• Filed: 08/21/2001
• Published: 02/06/2003
• Est. Priority Date: 09/19/2000
• Status: Active Grant

• Current Assignee: Sprout Pharmaceuticals, Inc. (Sprout2, Inc.)
• Original Assignee: Boehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Schiavi, Giovanni Battista, Monferini, Eugenia, Brambilla, Alessandro, Giraldo, Ettore, Maiocchi, Luciano, Cereda, Enzo
• Granted Patent: US 6,521,623 B1
• Time in Patent Office: Days
• US Class Current: 514/234.5
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 235/26 Oxygen atoms
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 471/10 Spiro-condensed systems

Abstract

A compound of formula (I)

wherein:

R¹ is C₁-C₆-alkyl substituted by a group selected from OH, C₁-C₆-alkoxy, —OCONHC₁-C₆-alkyl, —OCONHC₁-C₆-alkyl, —NHSO₂C₁-C₆-alkyl, and —NHCOC₁-C₆-alkyl, or

R¹ is C₁-C₆-alkyl substituted by a saturated or unsaturated 5- or 6-membered heterocycle containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen, the heterocycle optionally substituted by a group selected from C₁-C₄-alkyl, halogen, and benzyl;

R² and R³ together with the nitrogen form a saturated or unsaturated 5- or 6-membered heterocyclic ring optionally containing nitrogen or oxygen as an additional heteroatom, the heterocyclic ring thereof substituted by a group selected from phenyl, benzyl, and diphenylmethyl, each of these groups optionally mono- or di-substituted by one or two groups selected from CF₃, C₁-C₄-alkyl, C₁-C₄-alkoxy, phenyl, benzyl, halogen, and OH, or

R² and R³ together with the nitrogen form a saturated or unsaturated 5- or 6-membered heterocyclic ring optionally containing nitrogen or oxygen as an additional heteroatom, the heterocyclic ring thereof linked via a single bond, a methylene-bridge, or spiro-connected to a saturated or unsaturated heterocyclic group containing one or two heteroatoms selected from oxygen and nitrogen, the heterocyclic group optionally mono- or di-substituted by a group selected from CF₃, C₁-C₄-alkyl, C₁-C₄-alkoxy, phenyl, benzyl, halogen, ═O, and OH, or

R² and R³ together with the nitrogen form a saturated or unsaturated bi- or tricyclic heterocyclic ring-system optionally containing nitrogen or oxygen as an additional heteroatom, the heterocyclic ring-system being optionally substituted by a group selected from CF₃, C₁-C₄-alkyl, C₁-C₄-alkoxy, phenyl, benzyl, halogen, ═O, and OH; and

A is C₁-C₆-alkylene, C₂-C₆-alkenylene, or C₂-C₆-alkynylene,

their pharmaceutically acceptable salts, their preparation, and their use for therapeutic purposes.

Claims

1. A compound of formula (I)

2. The compound of formula (I) according to claim 1, wherein:

R¹ is C₁-C₄-alkyl substituted by a group selected from OH, C₁-C₄-alkoxy, —

OCONHC₁-C₄-alkyl, —

OCONHC₁-C₄-alkyl, —

NHSO₂C₁-C₄-alkyl, and —

NHCOC₁-C₄-alkyl, or

R¹ is C₁-C₄-alkyl substituted by a saturated or unsaturated 6-membered heterocycle containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen;

R² and R³ together with the nitrogen form a saturated or unsaturated 5- or 6-membered heterocyclic ring optionally containing nitrogen as an additional heteroatom, the heterocyclic ring thereof substituted by a group selected from phenyl, benzyl, diphenylmethyl, pyridinyl, pyrimidinyl, benzimidazolonyl, and 3,4-methylenedioxibenzyl, each of these groups optionally mono- or di-substituted by a group selected from CF₃, C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen, and OH; and

A is C₁-C₄-alkylene or C₂-C₄-alkenylene,

or a pharmaceutically acceptable salt thereof.

3. The compound of formula (I) according to claim 1, wherein:

R¹ is ethyl substituted by a group selected from OH, OCH₃, OCH₂CH₃, —

OCONHCH₃, —

OCONHCH₂CH₃, —

NHSO₂CH₃, —

NHSO₂CH₂CH₃, —

NHCOCH₃, —

NHCOCH₂CH₃, morpholinyl, piperazinyl, and piperidinyl;

R² and R³ together with the nitrogen form a 6-membered saturated or unsaturated heterocyclic ring optionally containing nitrogen as an additional heteroatom, the heterocyclic ring thereof substituted by a group selected from phenyl, pyridinyl, pyrimidinyl, benzimidizalonyl, and phenyl mono- or di-substituted by a group selected from CF₃, CH₃, OCH₃, F, and Cl;

A is C₁-C₄-alkylene or C₂-C₄-alkenylene,

or a pharmaceutically acceptable salt thereof.

4. The compound of formula (I) according to claim 1, wherein:

R¹ is ethyl substituted by a group selected from OH, OCH₃, —

OCONHCH₂CH₃, —

NHSO₂CH₃, —

NHCOCH₃, morpholinyl, and piperidinyl;

R² and R³ together with the nitrogen form a 6-membered saturated or unsaturated heterocyclic ring optionally containing nitrogen as an additional heteroatom, the heterocyclic ring thereof substituted by a group selected from pyridinyl, phenyl, and phenyl mono- or di-substituted by a group selected from CF₃, CH₃, OCH₃, F, and Cl; and

A is ethylene, propylene, butylene, or butenylene,

or a pharmaceutically acceptable salt thereof.

5. The compound of formula (I) according to claim 1, wherein:

R¹ is ethyl substituted by a group selected from OH, OCH₃, —

OCONHCH₂CH₃, —

NHSO₂CH₃, —

NHCOCH₃, morpholinyl, and piperidinyl

R² and R³ together with the nitrogen form a heterocyclic ring selected from the group consisting of piperazine, piperidine, and tetrahydropyridine, the heterocyclic ring thereof substituted by a group selected from pyridinyl, phenyl, and phenyl mono- or di-substituted by a group selected from CF₃, CH₃, and Cl; and

A is ethylene, butylene, or butenylene,

or a pharmaceutically acceptable salt thereof.

6. The compound of formula (I) according to claim 1, wherein:

R¹ is ethyl substituted by a group selected from OH, OCH₃, —

OCONHCH₂CH₃, and —

NHSO₂CH₃;

R¹ and R³ together with the nitrogen form a piperazine ring, the piperazine ring thereof substituted by a group selected from trifluoromethylphenyl, methylphenyl, dimethylphenyl, and chlorophenyl; and

A is ethylene, butylene, or butenylene,

or a pharmaceutically acceptable salt thereof.

7. The compound of formula (I) according to claim 1, wherein R¹ is a C₁-C₄-alkyl group.

8. The compound of formula (I) according to claim 1, wherein A is C₁-C₄-alkylene, C₂-C₄-alkenylene, or C₂-C₄-alkynylene.

10. A pharmaceutical composition comprising an effective amount of a compound of formula (I) according to one of claims 1 to 9 and a pharmaceutical carrier, diluent, or excipient.

11. A method for treatment or prophylaxis of anxiety disorders and affective disorders, in a host in need of such treatment or prophylaxis, which method comprises administering the host an effective amount of a compound according to one of claims 1 to 9.

12. A method for treatment or prophylaxis of treatment of a disease selected from the group consisting of depression, psychosis, schizophrenia, eating disorders, sexual disorders, Parkinson'"'"'s disease, and stroke and traumatic brain injury, in a host in need of such treatment or prophylaxis, which method comprises administering the host an effective amount of a compound according to one of claims 1 to 9.

9. A compound selected from the group consisting of:

(a) 1-(2-methoxyethyl)-3-(4-{4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}butyl)-1,3-dihydro-2H-benzimidazol-2-one;

(b) 1-{4-[4-(2,3-dimethylphenyl)-1-piperazinyl]butyl}-3-(2-hydroxyethyl)-1,3-dihydro-2H-benzimidazol-2-one;

(c) 2-[2-oxo-3-(4-{4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}butyl)-2,3-dihydro-1H-benzimidazol-1-yl]ethyl-ethylcarbamate;

(d) 1-(2-methoxyethyl)-3-(2-{4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}ethyl)-1,3-dihydro-2H-benzimidazol-2-one;

(e) 1-{[2-[4-(2,3-dimethylphenyl)-1-piperazinyl]ethyl}-3-(2-methoxyethyl)-1,3-dihydro-2H-benzimidazol-2-one;

(f) 1-{2-[4-(3-chlorophenyl)-1-piperazinyl]ethyl}-3-(2-hydroxyethyl)-1,3-dihydro-2H-benzimidazol-2-one;

(g) 2-[2-oxo-3-(2-{4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}ethyl)-2,3-dihydro-1H-benzimidazol-1-yl]ethyl-ethylcarbamate;

(h) 2-(3-{2-[4-(2,3-dimethylphenyl)-1-piperazinyl]ethyl}-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl-ethylcarbamate;

(i) N-[2-(3-{2-[4-(2,3-dimethylphenyl)-1-piperazinyl]ethyl}-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]methanesulfonamide;

(j) N-[2-(3-{(2Z)-4-[4-(3-methylphenyl)-1-piperazinyl]-2-butenyl}-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]methanesulfonamide; and

(k) N-[2-(3-{(2E)-4-[4-(3-chlorophenyl)-1-piperazinyl]-2-butenyl}-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]methanesulfonamide,

or a pharmaceutically acceptable salt thereof.