Benzimidazolone derivatives having mixed serotonin and dopamine receptors affinity

• US 6,281,218 B1
• Filed: 08/08/2000
• Issued: 08/28/2001
• Est. Priority Date: 09/22/1999
• Status: Expired due to Term

• Current Assignee: Sprout Pharmaceuticals, Inc. (Sprout2, Inc.)
• Original Assignee: Ingelheim Italia SPA
• Inventors: Cereda, Enzo, Schiavi, Giovanni Battista, Bignotti, Maura
• Primary Examiner(s): BERNHARDT, EMILY A
• Application Number:
  US09/634,120
• Time in Patent Office: 385 Days
• Field of Search: 544/370, 514/254.06
• US Class Current: 514/254.06
• 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 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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

Abstract

Compounds of general formula (I)

wherein R₁, R₂, R₃, and R₄ denote hydrogen or hydroxy with the proviso that R₁, R₂, R₃, and R₄ cannot simultaneously represent hydrogen, processes for their preparation of the compounds of general formula (I), and their use as pharmaceuticals.

Claims

1. A compound of the general formula (I)

wherein:

R₁, R₂, R₃, and R₄ are each hydrogen or hydroxy, with the proviso that R₁, R₂, R₃, and R₄ cannot simultaneously represent hydrogen, or a physiologically acceptable acid addition salt thereof.

2. The compound of general formula (I) according to claim 1, wherein two or three of the four radicals R₁, R₂, R₃, and R₄ are hydrogen, or a physiologically acceptable acid addition salt thereof.

10. The physiologically acceptable acid addition salt according to claim 1, wherein the physiologically acceptable acid addition salt is the salt of hydrochloric, maleic, or fumaric acid.

11. A process for the preparation of compounds of general formula (I) according to claim 1, which comprises liberation of the hydroxy group or groups by cleavage of the corresponding protective group.

12. The process for the preparation of compounds of general formula (I) according to claim 11, wherein the protective group is methyl.

13. The process for the preparation of compounds of general formula (I) according to claim 11, wherein the deprotection of the hydroxy group is carried out by treatment with a strong aqueous acid at high temperatures.

14. The process for the preparation of compounds of general formula (I) according to claim 11, wherein the deprotection of the hydroxy group is carried out by treatment with boron derivatives at low temperatures in chlorinated solvents.

3. 5-Hydroxy-1-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}-1,3-dihydro benzimidazol-2-one, or a physiologically acceptable acid addition salt thereof.

4. 6-Hydroxy-1-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}-1,3-dihydro-benzimidazol-2-one, or a physiologically acceptable acid addition salt thereof.

5. 4-Hydroxy-1-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}-1,3-dihydro-benzimidazol-2-one, or a physiologically acceptable acid addition salt thereof.

6. 7-Hydroxy-1-{2-[4-(3-trifluoromethylphenyl)piperazi-1-yl]ethyl}-1,3-dihydro-benzimidazol-2-one, or a physiologically acceptable acid addition salt thereof.

7. 1-{2-[4-(4-Hydroxy-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}-1,3-dihydro-benzimidazol-2-one, or a physiologically acceptable acid addition salt thereof.

8. 1-{2-[4-(3-Hydroxy-5-trifluoromethylphenyl)piperazIn-1-yl]ethyl}-1,3-dihydro-benzimidazol-2-one, or a physiologically acceptable acid addition salt thereof.

9. 1{-2-[4-(2-Hydroxy-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}-1,3-dihydro-benzimidazol-2-one, or a physiologically acceptable acid addition salt thereof.