Selective Cox-2 Inhibitors
The invention features compounds that are inhibitors of COX-2 activity. Certain of the compounds are inhibitors of FAAH activity as well as COX-2 activity. The compounds include a 5-membered or 6-membered substituted or unsubstituted heteroaryl or heterocyclyl ring having one or two heteroatoms selected from the group consisting of O, S, and N that is linked to two substituted or unsubstituted 6-membered aryl or heteroaryl groups that can be the same or different.
1 . A compound having the formula
wherein:
A is a 5-membered or 6-membered substituted or unsubstituted heteroaryl or heterocyclyl ring having one or two heteroatoms selected from the group consisting of O, S, and N and having from 1 or 2 independent substituents when the ring is 5-membered and substituted with 1 to 4 independent substituents when the ring is 6-membered and substituted; and
each of B 1 and B 2 is the same or different substituted or unsubstituted 6-membered aryl or heteroaryl ring;
and salts thereof.
2 . (canceled)
3 . The compound of claim 1 wherein at least one of B 1 and B 2 is singly or independently multiply substituted and the substituents are selected from: a methyl group optionally, independently substituted with one or more halogen, an ethyl group optionally, independently substituted with one or more halogen, a halogen, —OH, —OCH 3 , optionally, independently substituted with one or more halogen, and —SCH 3 optionally, independently substituted with one or more halogen.
4 . (canceled)
5 . The compound of claim 1 wherein A is selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolidinyl, pyrazolyl, furanyl, and pyridinyl.
6 . The compound of claim 1 wherein each of B 1 and B 2 is a singly or multiply substituted phenyl group.
7 . (canceled)
8 . The compound of claim 1 wherein one or both of B 1 and B 2 is:
9 . The compound of claim 1 selected from the group consisting of:
wherein:
each X 1 -X 12 is independently: H, halogen, substituted or unsubstituted C 1-12 alkyl, substituted or unsubstituted C 2-12 alkenyl, substituted or unsubstituted C 2-12 alkynyl, substituted or unsubstituted C 1-6 alkoxy, oxo, substituted or unsubstituted C 2-12 alkenyloxy, substituted or unsubstituted C 5-10 cycloalkenyloxy, substituted or unsubstituted (C 2-12 alkynyl)oxy, (C 1-6 alkyl)oxy(C 1-6 alkyl), substituted or unsubstituted C 6-12 aryloxy, (C 3-6 heteroaryl)-(C 1-6 alkyl)oxy, (C 1-12 alkyl)thio, substituted or unsubstituted (C 1-4 alkyl)-thio-(C 1-4 alkyl), substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted styryl, substituted or unsubstituted C 3-12 heteroaryl, substituted or unsubstituted C 4-8 heterocyclic, wherein the substituents are selected from the group consisting of hydroxy, halo, C 1-4 alkyl, C 1-4 trihaloalkyl, C 1-6 alkoxy, C 1-4 trihaloalkoxy, bivalent oxy(C 1-6 )alkyloxy, (C 1-6 ) acylamino, (C 1-6 ) acylthio, amino, and azido; or R 5 and R 6 form a C 5 -C 10 heteroaryl ring, and each of R 4 , R 7 , and R 8 is, independently, hydroxy, halo, C 1-4 alkyl, C 1-4 trihaloalkyl, C 1-6 alkoxy, or C 1-4 trihaloalkoxy.
10 - 16 . (canceled)
17 . A compound having the formula:
wherein
A is a 5-membered or 6-membered substituted or unsubstituted heteroaryl or heterocyclyl ring having one or two heteroatoms selected from the group consisting of O, S, and N and having from 1 or 2 independent substituents when the ring is 5-membered and substituted and 1 to 4 independent substituents when the ring is 6-membered and substituted; and one or both of B 1 and B 2 are selected from H, —OH,
wherein each Z is independently H or a C 1-6 straight chain or branched alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or arylalkyl that is optionally singly or multiply substituted; and and salts thereof.
18 . The compound of claim 17 wherein A is selected from:
wherein each X 1 -X 12 is independently: H, halogen, substituted or unsubstituted C 1-12 alkyl, substituted or unsubstituted C 2-12 alkenyl, substituted or unsubstituted C 2-12 alkynyl, substituted or unsubstituted C 1-6 alkoxy, oxo, substituted or unsubstituted C 2-12 alkenyloxy, substituted or unsubstituted C 5-10 cycloalkenyloxy, substituted or unsubstituted (C 2-12 alkynyl)oxy, (C 1-6 alkyl)oxy(C 1-6 alkyl), substituted or unsubstituted C 6-12 aryloxy, (C 3-6 heteroaryl)-(C 1-6 alkyl)oxy, (C 1-12 alkyl)thio, substituted or unsubstituted (C 1-4 alkyl)-thio-(C 1-4 alkyl), substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted styryl, substituted or unsubstituted C 3-12 heteroaryl, substituted or unsubstituted C 4-8 heterocyclic, wherein the substituents are selected from the group consisting of hydroxy, halo, C 1-4 alkyl, C 1-4 trihaloalkyl, C 1-6 alkoxy, C 1-4 trihaloalkoxy, bivalent oxy(C 1-6 )alkyloxy, (C 1-6 ) acylamino, (C 1-6 ) acylthio, amino, and azido; or R 5 and R 6 form a C 5 -C 10 heteroaryl ring, and each of R 4 , R 7 , and R 8 is, independently, hydroxy, halo, C 1-4 alkyl, C 1-4 trihaloalkyl, C 1-6 alkoxy, or C 1-4 trihaloalkoxy.
19 . The compound of claim 18 wherein A is selected from:
20 . The compound of claim 19 wherein X 2 is selected from H, CH 3 , COOH, —CH 2 —CH 2 —COOH, —CH 2 —COOH and CF 3 ; X 10 and X 11 are H or one or both of X 10 and X 11 are CH 3 or CF 3 ; X 9 is missing; and X 8 is CH 3 or CF 3 .
21 . (canceled)
22 . The compound of claim 17 selected from:
3-[5-(4-hydroxyphenyl)-4-phenyl-1,3-oxazol-2-yl]propionic acid
3-[4-(4-hydroxyphenyl)-5-phenyl-1,3-oxazol-2-yl]propionic acid
[3-(4-hydroxyphenyl)-4-phenylisoxazol-5-yl]acetic acid
[4-(4-hydroxyphenyl)-3-phenylisoxazol-5-yl]acetic acid
3-[4-(4-hydroxyphenyl)-4-phenyl-1,3-thiazol-2-yl]propionic acid
3-[4-(4-hydroxyphenyl)-5-phenyl-1,3-thiazol-2-yl]propionic acid
[3-(4-hydroxyphenyl)-4-phenylisothiazol-5-yl]acetic acid
[4-(4-hydroxyphenyl)-3-phenylisothiazol-5-yl]acetic acid
4-butyl-1-(4-hydroxyphenyl)-2-phenylpyrazolidine-3,5-dione
4-(5-methyl-3-phenylisoxazol-4-yl)phenol
4-(5-methyl-4-phenylisoxazol-3-yl)phenol
-1-(4-hydroxyphenyl)-3-(trifluoromethyl)-5-(4-chlorophenyl)-pyrazole
1-(4-chloroyphenyl)-3-(trifluoromethyl)-5-(4-hydroxyphenyl)-pyrazole
4-(4-hydroxyphenyl)-3-phenyl furan-2(5H)-one
3-(4-hydroxyphenyl)-4-phenylfuran-2(5H)-one
3-(4-hydroxyphenyl)-5,5-dimethyl-4-phenylfuran-2(5H)-one
4-(4-hydroxyphenyl)-5,5-dimethyl-3-phenylfuran-2(5H)-one
4-(5-chloro-6′-methyl-3,3′-bipyridin-2-yl)phenol
4-(5-chloro-6′-methyl-2,3′-bipyridin-3-yl)phenol
2-{[5-(4-chlorophenyl)-4-(4-hydroxyphenyl)-1,3-oxazol-2-yl]thio}propionic acid
2-{[4-(4-chlorophenyl)-5-(4-hydroxyphenyl)-1,3-oxazol-2-yl]thio}propionic acid
3-[5-(4-chlorophenyl)-1-(4-hydroxyphenyl)-1H-pyrazol-3-yl]propionic acid
3-[1-(4-chlorophenyl)-5-(4-hydroxyphenyl)-1H-pyrazol-3-yl]propionic acid.
23 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
24 - 28 . (canceled)
29 . A method for treating inflammation, the method comprising providing a patient with a therapeutically effective serum concentration of the compound of claim 1 .
30 . (canceled)
31 . A method for treating pain, the method comprising providing a patient with a therapeutically effective serum concentration of the compound of claim 1 .
32 - 36 . (canceled)
37 . A method for treating anxiety comprising administering the compound of claim 1 .
38 - 40 . (canceled)
41 . A method for treating a sleep disorder comprising administering the compound of claim 1 .
42 - 44 . (canceled)