Tricyclic inhibitors of fatty acid amide hydrolase
A series of substituted oxazole compounds having an alpha keto side chain at the 2 position and an aromatic, heteroaromatic or heterocycle substituent at the 5 position are disclosed. These compounds exhibit inhibition of fatty acid amid hydrolase and arc useful for treatment of malconditions involving that enzyme.
1. A compound having the following structure:
wherein Ar is a phenyl or pyridyl having a carbon as its point of attachment to the oxazole;
R 1 is independently selected from the group consisting of hydrogen, —(C 1 -C 6 alkyl), —(C 3 -C 6 alkyl), —CF 3 , —CN, —C(O)C 1 -C 4 alkyl optionally substituted with one, two, or three fluoro substituents, —CO 2 (C 1 -C 4 alkyl), —CO 2 H, —C(O)N(R a )R b , —OH, —O(C 1 -C 6 alkyl), halo, —NO 2 , —NR a R b , —N(R a )C(O)R b , —N(R a )SO 2 R b , —SO 2 N(R a )R b , —SR a , —S(O)R a , and —SO 2 R a ;
where R a and R b are each independently selected from the group consisting of —H, —(C 1 -C 6 alkyl), and —(C 3 -C 6 cycloalkyl); and
R 2 is independently selected from the group consisting of hydrogen, —(C 1 -C 6 alkyl), —(C 3 -C 6 alkyl), —CF 3 , —CN, —C(O)C 1 -C 4 alkyl optionally substituted with one, two, or three fluoro substituents, —CO 2 (C 1 -C 4 alkyl), —CO 2 H, —C(O)N(R c )R d , —OH, —O(C 1 -C 6 alkyl), -halo, —NO 2 , —NR c R d , —N(R c )C(O)R d , —N(R c )SO 2 R d , —SO 2 N(R c )R d , —SR C , —S(O)R C , —SO 2 R c ;
where R c and R d are each independently selected from the group consisting of —H, —(C 1 -C 6 alkyl), and —(C 3 -C 6 cycloalkyl); and
Ar 1 is selected from the group consisting of:
X is selected from the group of diradicals consisting of —CH 2 —, —O—, —S—, —S(O)—, —S(O) 2 —, —NR 5 —, —CH(OH)—, and —C(O)NH—; and
R 3 is selected from the group consisting of —NHBOC, —Cl, —Br, —I, —NH 2 , —NO 2 , —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —S(O) 2 (C 1 -C 6 alkyl), —CF 3 , —COOH, and —CO 2 (C 1 -C 6 alkyl);
R 4 is selected from the group consisting of —H, —NHBOC, —Cl, —Br, —I, —NH 2 , —NO 2 , —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —S(O) 2 (C 1 -C 6 alkyl), —CF 3 , —COOH, and —CO 2 (C 1 -C 6 alkyl); and
R 5 is selected from the group consisting —H, and —(C 1 -C 6 alkyl); and
Z is selected from the group of diradicals consisting of —O—, —S—, and —NR 5 —; and
m is an integer between 0 and 6; and
n is an integer between 0 and 6;
with the following provisos:
if m is 0, then n cannot be 0; and
if X is —CH 2 —, then Ar 1 cannot be phenyl;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein Ar is selected from the group consisting of the following
3. A compound according to claim 1 , wherein R 1 is selected from the group consisting of —CH 3 , —CF 3 , —CN, —C(O)CF 3 , —CO 2 CH 3 , —CO 2 H, —C(O)NH 2 , —OH, —OCH 3 , —F, —NO 2 , —NH 2 , and —SO 2 NH 2 .
4. A compound according to claim 1 , wherein R 2 is —H.
5. A compound according to claim 2 , wherein R 1 is selected from the group consisting of —CH 3 , —CF 3 , —CN, —C(O)CF 3 , —CO 2 CH 3 , —CO 2 H, —C(O)NH 2 , —OH, —OCH 3 , —F, —NO 2 , —NH 2 , and —SO 2 NH 2 .
6. A compound according to claim 2 , wherein R 2 is —H.
7. A compound according to claim 2 , wherein R 1 is selected from the group consisting of —CH 3 , —CF 3 , —CN, —C(O)CF 3 , —CO 2 CH 3 , —CO 2 H, —C(O)NH 2 , —OH, —OCH 3 , —F, —NO 2 , —NH 2 , and —SO 2 NH 2 .
8. A compound according to claim 2 , wherein R 2 is —H.
9. A compound according to claim 7 , wherein R 2 is —H.
10. A compound according to claim 1 , having the following structure:
11. A compound according to claim 10 , having any of the following structures, or a pharmaceutically acceptable salt thereof:
12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
13. A pharmaceutical combination comprising a compound of claim 1 in combination with another FAAH modulator or another biologically active agent.
14. A pharmaceutical combination of claim 13 wherein the active ingredient is an opiod, an NSAID, gabapentin, pregabalin, tramadol, acetaminophen or aspirin.