IP Library › Granted Patent US 10,662,159

Granted Patent B2

US 10,662,159 · App. 16/198,261 · Granted May 26, 2020

ABHD6 and dual ABHD6/MGL inhibitors and their uses

Inventors: Alexandros Makriyannis (Watertown, MA); Michael Malamas (Jamison, PA); Manjunath Lamani (Medford, MA); Shrouq I. Farah (Everett, MA)

Assignee: MAKSCIENTIFIC, LLC

C07D217/04 C07D205/12 C07D209/44 C07D217/06 C07D223/16 C07D401/12 C07D401/14 C07D403/12 C07D413/12 C07D471/04

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Quick Facts

Patent No.: US 10,662,159
App. No.: 16/198,261
Granted: May 26, 2020
Kind: B2

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Abstract

Provided herein are compounds and pharmaceutical compositions for selectively inhibiting serine hydrolase a/b-hydrolase domain 6 (ABHD6) and dually inhibiting ABHD6 and monoacylglycerol lipase (MGL). The compounds and pharmaceutical compositions disclosed herein are useful for treating a number of therapeutic conditions related to cannabinergic receptor function such as pain, inflammation, neuropathy, neurodegenerative diseases, anxiety disorders, motor function disorder, metabolic disorder, glaucoma and chemotherapy-induced nausea and vomiting and cancer.

Claims (66)

1. A compound of formula II:

or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing,

wherein:

D=O or S;

E=O, NH, or none, when E is none, F is directly attached to C=D;

F is selected from

each n is 1, and each m is independently 1 or 2;

G=O, NH, NR 13 , or none, when G is none, G is directly attached to the cyclic ring;

Z is selected from H; halogen; C 1 -C 10 alkyl; C 1 -C 10 alkyl-oxy; C 3 -C 8 cycloalkyl; C 3 -C 8 cycloalkyl-oxy; C 1 -C 10 alkyl or C 1 -C 10 alkyl-oxy substituted at the terminal carbon with halogen, haloalkyl, haloalkoxy, alkoxy, alkenyl, alkynyl, NR 8 R 9 , CN, ONO 2 , aryl, O-aryl, O-aralkyl, NR 10 -aryl, NR 11 -aralkyl, O-heteroaryl, NR 12 -heteroaryl, or saturated or unsaturated four-, five-, six- or seven-membered ring which can contain up to 3 heteroatoms selected from N, N-oxide, S and O; or saturated or unsaturated four-, five-, six- or seven-membered ring which can contain up to 3 heteroatoms selected from N, N-oxide, S and O;

R 4 , R 5 , R 6 , and R 7 are each independently H or C 1 -C 3 alkyl; and

R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 are each independently H, C 1 -C 5 alkyl, or C 3 -C 8 cycloalkyl.

2. The compound according to claim 1 , wherein E=O or NH.

3. The compound according to claim 2 , wherein E=O.

4. The compound according to claim 1 , selected from the group consisting of:

1,1,1,3,3,3-Hexafluoropropan-2-yl 6-(3-(trifluoromethyl)phenoxy)-2-azaspiro [3.3] heptane-2-carboxylate;

1,1,1,3,3,3-Hexafluoropropan-2-yl-6-(3-fluorophenoxy)-2-azaspiro[3.3]heptane-2-carboxylate;

1,1,1,3,3,3-Hexafluoropropan-2-yl-6-(3-methoxyphenoxy)-2-azaspiro[3.3]heptane-2-carboxylate;

1,1,1,3,3,3-Hexafluoropropan-2-yl-6-(3-phenoxyphenoxy)-2-azaspiro[3.3]heptane-2-carboxylate;

1,1,1,3,3,3-Hexafluoropropan-2-yl 6-(3-(trifluoromethoxy)phenoxy)-2-azaspiro[3.3] heptane-2-carboxylate;

1,1,1,3,3,3-Hexafluoropropan-2-yl 2-(3-fluorophenoxy)-6-azaspiro[3.4]octane-6-carboxylate;

1,1,1,3,3,3-Hexafluoropropan-2-yl 6-(3-fluorophenoxy)-2-azaspiro[3.4]octane-2-carboxylate;

1,1,1,3,3,3-Hexafluoropropan-2-yl 6-((5-fluoropyridin-3-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

1,1,1,3,3,3-Hexafluoropropan-2-yl 6-(5-fluoropyridin-3-yl)oxy)-2-azaspiro[3.4]octane-2-carboxylate;

1,1,1,3,3,3-Hexafluoropropan-2-yl 6-(benzo[d]isoxazol-6-yloxy)-2-azaspiro[3.3]heptane-2-carboxylate;

6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl 6-(3-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carboxylate;

6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl 6-(5-fluoropyridin-3-yl)oxy)-2-azaspiro[3.4]octane-2-carboxylate;

1,1,1,3,3,3-Hexafluoropropan-2-yl 6-((3-(trifluoromethyl)phenyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate;

1,1,1,3,3,3-hexafluoropropan-2-yl 6-((3-methoxyphenyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate;

1,1,1,3,3,3-Hexafluoropropan-2-yl (2r,4s)-2-(bis(4-fluorophenyl)methoxy)-6-azaspiro[3.4]octane-6-carboxylate;

1,1,1,3,3,3-Hexafluoropropan-2-yl (2s,4r)-2-(bis(4-fluorophenyl)methoxy)-6-azaspiro[3.4]octane-6-carboxylate;

1,1,1,3,3,3-hexafluoropropan-2-yl 6-(bis(4-fluorophenyl)methoxy)-2-azaspiro[3.4]octane-2-carboxylate;

1,1,1,3,3,3-Hexafluoropropan-2-yl 6-(bis(4-fluorophenyl)methoxy)-2-azaspiro[3.3]heptane-2-carboxylate;

1,1,1,3,3,3-Hexafluoropropan-2-yl 2-(benzyloxy)-6-azaspiro[3.4]octane-6-carboxylate;

1,1,1,3,3,3-hexafluoropropan-2-yl (2s,4r)-2-((bis(4-fluorophenyl)methyl)amino)-6-azaspiro[3.4]octane-6-carboxylate;

1,1,1,3,3,3-hexafluoropropan-2-yl 6-((5-methoxypyridin-3-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate; and

1,1,1,3,3,3-hexafluoropropan-2-yl 6-(5-fluoropyridin-3-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate, or

a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing.

5. A method of treating a cannabinoid receptor-mediated disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing.

6. The method of claim 5 , wherein the disease or disorder is Type-2 diabetes, ocular disease, pain, neuropathic pain, a neurodegenerative disease, spinal cord injury, a mental disorder, a gastrointestinal motility disorder, a coronary artery disease, ocular hypertension, or an eating disorder.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing.

8. The composition according to claim 7 , wherein the compound is selected from the group consisting of: