Inhibitors of monoacylglycerol lipase and methods of their use
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.
1. A compound of formula (II′):
or a pharmaceutically acceptable form thereof, wherein:
R 10 is halogen or an optionally substituted (C 1 -C 6 )alkyl;
R 11 is hydrogen, halogen or an optionally substituted (C 1 -C 6 )alkyl;
R 12 is —C(O)NH 2 or —(CH 2 ) n —NHR 14 and R 13 is hydrogen; or
R 14 is an optionally substituted (C 1 -C 6 )alkyl, —SO 2 R 16 or —C(O)R 17 ;
R 15 , R 16 and R 17 are each independently an optionally substituted (C 1 -C 6 )alkyl or an optionally substituted amino; and
n is 0, 1, 2 or 3.
2. A compound selected from:
or a pharmaceutically acceptable form thereof.
3. The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable form thereof.
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.
10. A compound of formula (II):
or a pharmaceutically acceptable form thereof,
wherein:
R 10 is hydrogen;
R 11 is halogen or an optionally substituted (C 1 -C 6 )alkyl;
R 12 is —C(O)NH 2 or —(CH 2 ) n —NHR 14 and R 13 is hydrogen; or
R 12 and R 13 taken together can form a 5 to 7 membered ring containing one or more heteroatoms selected from N, S and O, wherein one or more carbon or sulfur atoms on the ring can optionally be substituted with one or more oxo group;
R 14 is an optionally substituted (C 1 -C 6 )alkyl, —SO 2 R 16 or —C(O)R 17 ;
R 16 and R 17 are each independently an optionally substituted (C 1 -C 6 )alkyl or an optionally substituted amino; and
n is 0, 1, 2 or 3.
11. The compound of claim 10 , wherein the compound is selected from:
12. The compound of claim 1 , wherein R 11 is hydrogen.
13. The compound of claim 12 , wherein R 10 is hydrogen or F.
14. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
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 .
20. A compound of formula (II′):
or a pharmaceutically acceptable form thereof, wherein:
R 10 is halogen or an optionally substituted (C 1 -C 6 )alkyl;
R 11 is hydrogen, halogen or an optionally substituted (C 1 -C 6 )alkyl;
R 12 is —C(O)NH 2 or —(CH 2 ) n —NHR 14 and R 13 is hydrogen; or
R 12 and R 13 taken together can form a 5 to 7 membered ring containing one or more heteroatoms selected from N, S and O, wherein one or more carbon or sulfur atoms on the ring can optionally be substituted with one or more oxo group;
R 14 is an optionally substituted (C 1 -C 6 )alkyl, —SO 2 R 16 or —C(O)R 17 ;
R 16 and R 17 are each independently an optionally substituted (C 1 -C 6 )alkyl or an optionally substituted amino; and
n is 0, 1, 2 or 3.
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 .