Urea/carbamates FAAH MAGL or dual FAAH/MAGL inhibitors and uses thereof
Disclosed are compounds that may be used to inhibit the action of fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL) or dual FAAH/MAGL. More particularly, compounds of formula II have utility in a variety of therapeutic uses such as treatment of pain, inflammation, neuropathy, or appetite disorder.
1. A compound of Formula II
or a pharmaceutically acceptable salt thereof, wherein:
M=O;
Z=O or NH;
n=1;
L 2 is selected from
—CH═CH—, —CONH—,
and —NH—, n=1;
A 2 is phenyl, which may be unsubstituted or substituted with one or two halogens; and
B 2 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, purinyl, benzimidazolyl, indolyl, quinolinyl or quinoxalinyl, and may be unsubstituted or substituted with one or two moieties selected from halogen, —CN, —CONH 2 and —CF 3 , or B 2 is selected from:
wherein:
W 2 is selected from CH 2 , O, SO 2 , CHAr and NAr;
Ar is aryl or heteroaryl containing 1 to 3 heteroatoms; and
R 5 is selected from —H, -Ph and —COOMe.
2. A compound selected from the group consisting of:
3-Cyanophenyl 3-(4-chlorobenzyloxy)azetidine-1-carboxylate,
3-(Trifluoromethyl)phenyl 3-(4-chlorobenzyloxy)azetidine-1-carboxylate,
3-Bromophenyl 3-(4-chlorobenzyloxy)azetidine-1-carboxylate,
3-Carbamoylphenyl 3-(4-chlorobenzyloxy)azetidine-1-carboxylate,
3-Methoxyphenyl 3-(4-Bromobenzyloxy)azetidine-1-carboxylate,
2,4-Dichlorophenyl 3-(4-chlorobenzyloxy)azetidine-1-carboxylate,
3-(Pyridin-3-yl)phenyl 3-(4-chlorobenzyloxy)azetidine-1-carboxylate,
1H-Benzo[d]imidazol-1-yl)(3-(4-phenylpiperidin-1-yl)azetidin-1-yl)methanone,
3-(4-Benzylpiperidine)azetidin-1-yl)(4-phenyl[1H]imizadol-1-yl)methanone,
4-Phenyl-1H-imidazol-1-yl)(3-(4-phenylpiperidin-1-yl)azetidin-1-yl)methanone,
3-(4-Bromobenzyloxy)azetidin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone, and
1H-Benzo[d]imidazol-1-yl)(3-(4-Bromobenzyloxy)azetidin-1-yl)methanone,
or a pharmaceutically acceptable salt of any of the foregoing.
3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
4. The compound of claim 2 , wherein the compound is 3-cyanophenyl 3-(4-chlorobenzyloxy)azetidine-1-carboxylate, or a pharmaceutically acceptable salt thereof.
5. The compound of claim 2 , wherein the compound is 1H-benzo[d]imidazol-1-yl)(3-(4-bromobenzyloxy)azetidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof.
6. A compound of Formula II
or a pharmaceutically acceptable salt thereof, wherein:
M=O;
Z=O, NH, or none; when Z=none, B 2 is directly attached to C=M;
n=1;
L 2 is selected from
—CH═CH—, —CONH—,
and —NH—, n=1;
A 2 is phenyl, which may be unsubstituted or substituted with one or two halogens; and
B 2 is selected from pyrrolyl, pyrazolyl, imidazolyl, purinyl, benzimidazolyl or quinoxalinyl, and may be unsubstituted or substituted with one or two moieties selected from halogen, —CN, —CONH 2 and —CF 3 , or B 2 is selected from:
wherein:
W 2 is selected from CH 2 , O, SO 2 , CHAr and NAr;
Ar is aryl or heteroaryl containing 1 to 3 heteroatoms; and
R 5 is selected from —H, -Ph and —COOMe.
7. The compound of claim 1 , wherein B 2 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, purinyl, benzimidazolyl, indolyl, quinolinyl or quinoxalinyl, and may be unsubstituted or substituted with one or two moieties selected from halogen, —CN, —CONH 2 and —CF 3 .
8. The compound of claim 6 , wherein B 2 is selected from pyrrolyl, pyrazolyl, imidazolyl, purinyl, benzimidazolyl or quinoxalinyl, and may be unsubstituted or substituted with one or two moieties selected from halogen, —CN, —CONH 2 and —CF 3 .
9. The compound of claim 1 , wherein B 2 is selected from:
wherein:
W 2 is selected from CH 2 , O, SO 2 , CHAr and NAr;
Ar is aryl or heteroaryl containing 1 to 3 heteroatoms; and
R 5 is selected from —H, -Ph and —COOMe.
10. The compound of claim 6 , wherein B 2 is selected from:
wherein:
W 2 is selected from CH 2 , O, SO 2 , CHAr and NAr;
Ar is aryl or heteroaryl containing 1 to 3 heteroatoms; and
R 5 is selected from —H, -Ph and —COOMe.