INHIBITORS OF MONOACYLGLYCEROL LIPASE AND METHODS OF THEIR USE

• US 20140235580A1
• Filed: 09/27/2012
• Published: 08/21/2014
• 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.
• Granted Patent: US 9,630,979 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• 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 (I):

2. The compound of claim 1, which is a compound of formula (II):

3. The compound of claim 2, wherein R¹¹ is hydrogen.

4. The compound of claim 3, wherein R¹⁰ is hydrogen or F.

5. The compound of claim 2, wherein R¹⁰ is halogen or an optionally substituted (C₁-C₆)alkyl, and R¹⁰ is para to the —

B(OH)₂ group.

6. The compound of claim 2, wherein R¹³ is hydrogen.

7. The compound of claim 6, wherein R¹² is —

C(O)NH₂ or —

(CH₂)_n—

NHR¹⁴.

8. The compound of claim 7, wherein R¹⁴ is an optionally substituted (C₁-C₆)alkyl, —

SO₂R¹⁶, or —

C(O)R¹⁷.

9. The compound of claim 2, wherein R¹² is para to the covalent bond connecting the two phenyl rings.

10. The compound of claim 2, wherein R¹² and R¹³ together form a 5 membered ring, optionally having one or more heteroatoms selected from N, S and O.

11. The compound of claim 2, which is a compound of formula (II′

);

12. The compound of claim 2, wherein the compound is selected from:

13. The compound of claim 2, wherein the compound is selected from:

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

26. A method for treating a disorder or condition mediated by monoacylglycerol lipase (MAGL) comprising administering to a patient a therapeutically effective amount of a compound of claim 1.

27. The method of claim 26, wherein the disorder or condition is a CNS disorder.

28. The method of claim 27, wherein the CNS disorder is neurotoxicity, neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, a learning disorder or schizophrenia.

29. The method of claim 28, wherein the stroke is ischemic stroke.

30. The method of claim 28, wherein the learning disorder is attention deficit disorder.

14. A compound of formula (III):

15. The compound of claim 14, wherein R¹⁸ is hydrogen or halogen.

16. The compound of claim 14, wherein R¹⁸ is methyl.

17. The compound of claim 14, wherein R¹⁹ is hydrogen.

18. The compound of claim 14, wherein R¹⁹ is —

C(O)O—

Y and Y is phenyl.

19. The compound of claim 14, wherein R²¹ is an optionally substituted (C₁-C₆)alkyl.

20. The compound of claim 14, wherein R²² is an optionally substituted (C₁-C₆)alkyl.

21. The compound of claim 14, wherein R¹⁸ and R¹⁹ are both hydrogen.

22. The compound of claim 14, wherein the compound is selected from:

23. A compound of formula (IV):

24. The compound of claim 23, wherein the compound is: