NMDA Receptor Modulators and Uses Thereof

• US 20110306586A1
• Filed: 03/18/2011
• Published: 12/15/2011
• Est. Priority Date: 09/18/2008
• Status: Abandoned Application

• Current Assignee: Northwestern University
• Original Assignee: Northwestern University
• Inventors: Khan, Amin, Wood, Paul, Moskal, Joseph
• Application Number:
  US13/051,237
• Publication Number:
  US 20110306586A1
• Time in Patent Office: Days
• US Class Current: 514/210.02
• 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 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: C07D 471/20 Spiro-condensed systems
• CPC Class Codes: C07D 487/10 Spiro-condensed systems

Abstract

Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. Such compounds are contemplated for use in the treatment of diseases and disorder such as learning, cognitive activities, and analgesia, particularly in alleviating and/or reducing neuropathic pain. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.

Claims

1. A compound represented by Formula I:

2. The compound of claim 1, represented by:

3. The compound of claim 1, wherein R₁ is C(O)—

O—

C_1-C₄alkyl, wherein C₁-C₄alkyl is substituted by phenyl.

4. The compound of claim 3, wherein R₁ is carbobenzyloxy.

5. The compound of claim 1, wherein R₁ is:

6. The compound of claim 1, wherein R₃ is phenyl.

7. The compound of claim 1, wherein R₃ is H.

8. The compound of claim 1, wherein R₂ is —

C(O)—

C₂-C₄alkyl, substituted at one carbon with NH₂ and another carbon with hydroxyl.

9. The compound of claim 1, wherein C₁-C₄alkyl is selected from the group consisting of methyl, ethyl, propyl, n-butyl or t-butyl, and wherein said C₁-C₄alkyl is optionally substituted by one, two, or three substituents selected from the group consisting of F, Cl, or Br.

10. The compound of claim 1, wherein the compound is represented by:

12. The compound of claim 1, wherein R₁ is selected from the group consisting of:

14. The compound of claim 1, wherein the compound is selected from the group consisting of:

15. A compound of claim 1, which is capable of generating an enhanced single shock evoked NMDA receptor-gated single neuron conductance (I_NMDA) in hippocampal CA1 pyramidal neurons at concentrations of 100 nM to 1 μ

M.

17. A method for treating a cognitive disorder comprising administering to an patient in need thereof an effective amount of a compound of claim 1.

18. The method of claim 17, wherein the cognitive disorder is associated with memory loss or impaired learning.

21. A pharmaceutically acceptable composition comprising a compound of any one of claims 1-16, and a pharmaceutically acceptable excipient.

22. The composition of claim 21, wherein the composition is suitable for oral administration to a patient.

23. A method for treating neuropathic pain in a patient in need thereof comprising administering an effective amount of a compound of claim 1.

24. A method for treating depression, obsessive-compulsive disorder, or schizophrenia in a patient in need thereof comprising administering an effective amount of a compound of claim 1.

25. A method for treating post traumatic stress disorder, an alcohol dependency disorder, or an addiction to an addictive drug in a patient in need thereof comprising administering an effective amount of a compound of claim 1.

11. A compound represented by formula II:

13. The compound of claiml represented by:

16. A non-peptidyl compound selected from the group consisting of:

19. The method of claim 19, wherein the compound is

20. The method of claim 19, wherein the compound is administered orally.

26. The compound represented by:

27. A composition comprising the compound of claim 26, and a pharmaceutically acceptable carrier.