(;)-3-((3;,4;)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one and its prodrugs for the treatment of psychiatric disorders

• US 9,187,506 B2
• Filed: 01/07/2015
• Issued: 11/17/2015
• Est. Priority Date: 01/09/2014
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Thompson, Lorin A. III, Macor, John E.
• Primary Examiner(s): Rozof, Timothy R
• Application Number:
  US14/591,372
• Publication Number:
  US 20150191496A1
• Time in Patent Office: 314 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• 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 25/16 Anti-Parkinson drugs
• 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: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07F 9/59 Hydrogenated pyridine rings
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom

Abstract

The disclosure generally relates to compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands for the NR2B NMDA receptor and may be useful for the treatment of various disorders of the central nervous system.

Claims

1. A compound of the formula I

2. A compound of claim 1 with the formula

3. The compound of claim 2:

4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate, or a pharmaceutically acceptable salt thereof

4. The compound of claim 2:

(S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-amino-3-methylbutanoate hydrochloride, or a pharmaceutically acceptable salt thereof

5. The compound of claim 2:

(S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-aminopropanoate hydrochloride, or a pharmaceutically acceptable salt thereof;

6. The compound of claim 2:

(S)-2-amino-4-(4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenoxy)-4-oxobutanoic acid hydrochloride, or a pharmaceutically acceptable salt thereof;

7. The compound of claim 1:

4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate, or a pharmaceutically acceptable salt thereof;

8. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

9. A method for the treatment of depression, Alzheimer'"'"'s disease, neuropathic pain, or Parkinson'"'"'s disease, which comprises administering to a patient a therapeutically affective amount of a compound of claim 1.

10. The method of claim 9 directed to the treatment of depression.

11. The method of claim 9 directed to the treatment of Alzheimer'"'"'s disease.

12. The method of claim 9 directed to the treatment of neuropathic pain.