Benzoyl-piperazine derivatives

• US 7,319,099 B2
• Filed: 08/04/2004
• Issued: 01/15/2008
• Est. Priority Date: 08/11/2003
• Status: Active Grant

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Stadler, Henri, Jolidon, Synese, Pinard, Emmanuel, Narquizian, Robert, Nettekoven, Matthias Heinrich, Norcross, Roger David
• Primary Examiner(s): BERNHARDT, EMILY B
• Application Number:
  US10/911,359
• Publication Number:
  US 20050209241A1
• Time in Patent Office: 1,259 Days
• Field of Search: None
• US Class Current: 514/245
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 213/85 in position 3
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 241/20 Nitrogen atoms nitro radicals C07D241/16
• CPC Class Codes: C07D 251/42 One nitrogen atom
• CPC Class Codes: C07D 257/04 Five-membered rings
• CPC Class Codes: C07D 263/32 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 271/06 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 295/192 from aromatic carboxylic acids
• CPC Class Codes: C07D 309/12 only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers

Abstract

The invention relates to compounds of formula

wherein the substituents are described herein. The compounds may be used in the treatment of illnesses based on the glycine uptake inhibitor, such as psychoses, pain, neurodegenerative disfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer'"'"'s disease.

Claims

1. A compound of formula

3. A compound of formula I according to claim 1, wherein Ar is a substituted 6-membered heteroaryl group containing one, two or three nitrogen atoms, R² is (C₁-C₆)-alkyl or CH₂)_n—

(C₃-C₇)-cycloalkyl, and R⁵ is SO₂CH₃.

4. A compound of formula I according to claim 3, wherein the compound is selected from the group consisting of

[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-methanone,

6-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-nicotinonitrile, (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,

[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanone,

(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(6-trifluoromethyl-pyridin-3-yl)-piperazin-1-yl]-methanone,

[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone and

(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone.

5. A compound of formula I according to claim 1, wherein Ar is a substituted 6-membered heteroaryl group containing one, two or three nitrogen atoms, R² is (C₁-C₆)-alkyl substituted by halogen and R⁵ is SO₂CH₃.

6. A compound of formula I according to claim 5, wherein the compound is selected from the group consisting of

rac-[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,

rac-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,

rac-[4-(5-bromo-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,

rac-[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,

rac-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(6-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,

[5-methanesulfonyl-2-((S or R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,

[5-methanesulfonyl-2-((R or S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,

[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone and

[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-phenyl]-methanone.

2. A compound of formula

7. A process for preparing a compound of formula

8. A process according to claim 7, wherein the activating agent is TBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoro borate).

9. A process for preparing a compound of formula

10. The process according to claim 9 wherein the catalyst is Cu(I)I and the base is potassium carbonate, cesium carbonate or sodium.

11. A process for preparing a compound of formula

12. A process for preparing a compound of formula

13. A process for preparing a compound of formula

14. A composition comprising one or more compounds of formula

15. A method of treating schizophrenia which comprises administering to an individual an effective amount of one or more compounds of formula