Neuroprotective substituted piperidine compounds with activity as NMDA NR2B subtype selective antagonists

• US 6,432,985 B2
• Filed: 03/19/2001
• Issued: 08/13/2002
• Est. Priority Date: 04/25/2000
• Status: Expired due to Fees

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Buettelmann, Bernd, Pinard, Emmanuel, Jaeschke, Georg, Alanine, Alexander, Wyler, Rene, Neidhart, Marie-Paule Heitz
• Primary Examiner(s): COVINGTON, RAYMOND K
• Application Number:
  US09/811,888
• Publication Number:
  US 20010047014A1
• Time in Patent Office: 512 Days
• Field of Search: 546/217, 546/219, 514/328
• US Class Current: 514/328
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 25/22 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 211/48 having an acyclic carbon atom attached in position 4

Abstract

The invention relates to a compound of the formula

its R,R-, S,S-enantiomers and racemic mixtures thereof and to their pharmaceutically acceptable acid addition salts.

The compound of formula I and its R,R- and S,S-enantiomers may be used as medicaments for the treatment of diseases, wherein the therapeutic indications include acute forms of neurodegeneration caused by stroke or brain trauma; chronic forms of neurodegeneration such as Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s disease or ALS (amyotrophic lateral sclerosis); neurodegeneration associated with bacterial or viral infections, and, diseases such as schizophrenia, anxiety, depression and chronic/acute pain.

Claims

1. A compound with the structure of formula I

its R,R- and S,S-enantiomers and their pharmaceutically acceptable acid addition salts.

2. A compound of formula I in accordance with claim 1, selected from the group consisting of (3R, 4R) 4-benzyl-1-[2-(4-hydroxy-phenoxy)-ethyl]-piperidine-3,4-diol, (3S, 4S) 4-benzyl-1-[2-(4-hydroxy-phenoxy)-ethyl]-piperidine-3,4-diol and racemic mixtures thereof.

3. A compound of formula I in accordance with claim 2, which is (3 R,4R)-4-benzyl-1-[2-(4-hydroxy-phenoxy)-ethyl] -piperidine-3,4-diol.

4. A compound of formula I in accordance with claim 2, which is (3S,4S)-4-benzyl-1-[2-(4-hydroxy-phenoxy)-ethyl]-piperidine-3,4-diol.

5. A medicament containing one or more compounds according to claim 2 and pharmaceutically inert excipients.

6. A medicament in accordance with claim 5 useful for the treatment of diseases including disease states caused by overactivation of respective NMDA receptor subtypes including acute forms of neurodegeneration caused by stroke or brain trauma;

chronic forms of neurodegeneration such as Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s disease or ALS (amyotrophic lateral sclerosis);

neurodegeneration associated with bacterial or viral infections, and, diseases such as schizophrenia, anxiety, depression and chronic/acute pain.

7. A process for preparing a compound of formula I as defined in claim 1, which process comprises

reacting a compound of formula

with a compound of formula

and deprotecting the hydroxy group to give compounds of formulae

8. The method of claim 7 further comprising reacting the compounds obtained with pharmaceutically acceptable inorganic and organic acids thereby forming addition salts.

9. The method of claim 8 wherein said pharmaceutically acceptable acids are selected from the group consisting of hydrochloric acid, nitric acid, sulfuric acid, lactic acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, and p-toluenesulfonic acid.

10. A method of treatment of a disease state caused by malfunction of the NMDA receptor subtypes comprising administering to a patient in need of such treatment, an effective amount of a composition for treating said disease state, said composition containing an effective amount of a compound that functions as a NDMA receptor subtype specific blocker in a pharmaceutically acceptable carrier, said compound having the structure of formula I

11. The method of treatment of claim 10 wherein the disease state being treated consists of acute forms of neurodegeneration caused by stroke or brain trauma;

chronic forms of neurodegeneration such as Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s disease or ALS (amyotrophic lateral sclerosis);

neurodegeneration associated with bacterial or viral infections, and, diseases such as schizophrenia, anxiety, depression and chronic/acute pain.