Positive allosteric modulators of group II mGluRs

• US 8,748,632 B2
• Filed: 03/18/2011
• Issued: 06/10/2014
• Est. Priority Date: 03/19/2010
• Status: Active Grant

• Current Assignee: Sanford Burnham Prebys Medical Discovery Institute, Regents of the University of California (University of California)
• Original Assignee: Sanford-Burnham Medical Research Institute (Sanford Burnham Prebys Medical Discovery Institute), Regents of the University of California (University of California)
• Inventors: Cosford, Nicholas D. P., Panickar, Dhanya Raveendra, Sidique, Shyama, Semenova, Svetlana, Markou, Athinia
• Primary Examiner(s): HAVLIN, ROBERT H
• Application Number:
  US13/051,798
• Publication Number:
  US 20120071503A1
• Time in Patent Office: 1,180 Days
• Field of Search: 548/472, 514/416
• US Class Current: 548/472
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• 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 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: C07D 209/46 with an oxygen atom in position 1
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 215/20 Oxygen atoms
• CPC Class Codes: C07D 217/24 Oxygen atoms
• CPC Class Codes: C07D 261/20 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 275/04 condensed with carbocyclic rings or ring systems

Abstract

The disclosure provides compounds and compositions, and methods of using these compounds and compositions, as positive allosteric modulators of the metabotropic glutamate subtype 2 (mGlu2) receptor, and for treating CNS disorders associated with the mGlu2 receptor including schizophrenia, anxiety, addiction, e.g. cocaine addiction, nicotine addiction, and the like.

Claims

1. A compound of Formula IV:

2. The compound of claim 1, wherein the compound of Formula IV has Formula V:

3. The compound of claim 1, wherein the compound of Formula IV is:

4. A method of treating a CNS disorder including schizophrenia, anxiety and addiction, the method comprising the step of administering to a subject in need thereof, an effective amount of the compound of claim 1 having Formula IV, thereby treating the disorder.

5. The method of claim 4, wherein the disorder is an addictive disorder.

6. The method of claim 5, wherein the addictive disorder is nicotine addiction, alcohol addiction, opiate addiction, amphetamine addiction, methamphetamine addiction, or cocaine addiction.

7. The method of claim 6, wherein the addictive disorder is nicotine addiction.

8. The method of claim 6, wherein the addictive disorder is cocaine addiction.

9. The method of claim 4, wherein the CNS disorder is schizophrenia.

10. A method of treating a warm-blooded animal having an addictive disorder or schizophrenia, the method comprising the step of administering to the animal an effective amount of the compound of claim 1 having Formula IV, thereby treating the disorder or schizophrenia.

11. A pharmaceutical composition comprising the compound of claim 1 having Formula IV, and a pharmaceutically acceptable carrier.

12. A method of treating substance abuse, the method comprising the step of administering to a subject in need thereof, an effective amount of the compound of claim 1 having Formula IV, wherein the effective amount is sufficient to diminish, inhibit or eliminate desire for and/or consumption of the substance in the subject.

13. The method of claim 1, wherein the substance is nicotine, alcohol, opiates, amphetamines, methamphetamines, or cocaine.

14. A method for treating an addictive disorder, the method comprising the steps of:

a) administering to a subject in need thereof, an effective amount of the compound of claim 1 having Formula IV, during a first time period, wherein the first time period is a time period wherein the subject expects to be in an environment wherein, or exposed to stimuli in the presence of which, the subject habitually uses an addictive substance; and

b) administering an effective amount of the compound of claim 1 having Formula IV during a second time period, wherein the second time period is a time period wherein the subject is suffering from withdrawal.

15. The compound of claim 1, wherein R³ is cycloalkyl.

16. The compound of claim 1, wherein m is 2.

17. The compound of claim 1, wherein:

m is an integer selected from 1, 2, and 3; and

at least one R¹ is halogen.