Inhibitors of monoacylglycerol lipase and methods of their use

• US 9,630,979 B2
• Filed: 09/27/2012
• Issued: 04/25/2017
• Est. Priority Date: 09/29/2011
• Status: Active Grant

• Current Assignee: Infinity Pharmaceuticals, Inc.
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Castro, Alfredo C., Peluso, Stephane, Snyder, Daniel A., Tibbitts, Thomas T.
• Primary Examiner(s): Seaman, D M
• Application Number:
  US14/347,922
• Publication Number:
  US 20140235580A1
• Time in Patent Office: 1,671 Days
• 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: C07F 5/025 Boronic and borinic acid compounds

Abstract

Provided herein are compounds which mediate the activity of monoacyglycerol lipase (MAGL). Also provided are pharmaceutical compositions comprising a compound provided herein, and methods for treating, preventing and/or managing a MAGL mediated condition using a compound or pharmaceutical composition as provided herein.

Claims

1. A compound of formula (II′

);

3. The compound of claim 1, wherein the compound is selected from:

4. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable carriers or excipients.

5. A method for inhibiting monoacylglycerol lipase (MAGL) in a patient in need thereof, wherein the patient has disorder or condition mediated by monoacylglycerol lipase (MAGL), and the method comprises administering to the patient a therapeutically effective amount of a compound of claim 1.

6. The method of claim 5, wherein the disorder or condition is a CNS disorder.

7. The method of claim 6, wherein the CNS disorder is neurotoxicity, neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, a learning disorder or schizophrenia.

8. The method of claim 7, wherein the stroke is ischemic stroke.

9. The method of claim 7, wherein the learning disorder is attention deficit disorder.

12. The compound of claim 1, wherein R¹¹ is hydrogen.

13. The compound of claim 12, wherein R¹⁰ is hydrogen or F.

14. The compound of claim 1, wherein the compound is:

15. A pharmaceutical composition comprising a compound of claim 14 and one or more pharmaceutically acceptable carriers or excipients.

16. A method for treating a condition selected from NSAID-induced gastric hemorrhage, peptic ulcer and gastritis in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of claim 14.

17. A method for treating a condition selected from neuropathic and inflammatory pain in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of claim 14.

18. A method for reducing pain or providing an analgesic effect in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of claim 14.

19. A method for treating allodynia in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of claim 14.

21. A method for treating a condition selected from NSAID-induced gastric hemorrhage, peptic ulcer, gastritis, neuropathic pain, inflammatory pain, allodynia and a painful condition, in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of claim 1.

22. A method for reducing pain or providing an analgesic effect in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of claim 1.

2. A compound selected from:

10. A compound of formula (II):

11. The compound of claim 10, wherein the compound is selected from:

20. A compound of formula (II′

);