Inhibitors for the soluble epoxide hydrolase
Inhibitors of the soluble epoxide hydrolase (sEH) are provided that incorporate multiple pharmacophores and are useful in the treatment of diseases.
1. A compound having a formula:
and their pharmaceutically acceptable salts, wherein
R 1 is adamantyl;
P 1 is a primary pharmacophore selected from the group consisting of —NHC(O)NH—, —OC(O)NH—, and —NHC(O)O—;
P 2 is a secondary pharmacophore selected from the group consisting of —C(O)—, —CH(OH)—, —O(CH 2 CH 2 O) q —, —C(O)O—, —OC(O)—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —C(O)NH— and —NHC(O)—;
P 3 is a tertiary pharmacophore selected from the group consisting of C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , and —C(O)OR 2 , wherein R 2 is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4 alkyl;
the subscripts n and m are each 1, and the subscript q is 0 to 3;
L 1 is a first linker selected from unsubstituted C 2 -C 6 alkylene; and
L 2 is a second linker selected from the group consisting of substituted and unsubstituted C 2 -C 12 alkylene, substituted and unsubstituted arylene, and combinations thereof.
2. A compound selected from the group consisting of
and their pharmaceutically acceptable salts, wherein n is 2 to 11, A and B are CH 2 , O or NH, R 2 and R 3 are H or methyl, Y is CH 2 , O or NH, Z is O or NH, and R is ethyl or butyl.
3. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 .
4. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 2 .
5. The compound in accordance with claim 1 , wherein the compound has formula (I), wherein
P 2 is selected from the group consisting of —C(O)O—, —CH(OH)—, —O(CH 2 CH 2 O) q —, —OC(O)—, —C(O)NH— and —NHC(O)—;
L 2 is selected from the group consisting of substituted or unsubstituted C 2 -C 6 alkylene; and
P 3 is selected from the group consisting of —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , and —C(O)OR 2 , wherein R 2 is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4 alkyl.
6. The compound in accordance with claim 1 , wherein the compound has formula (I), wherein
L 2 is selected from the group consisting of substituted or unsubstituted C 2 -C 6 alkylene; and
P 3 is selected from the group consisting of C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 ,—NHS(O) 2 R 2 , and —C(O)OR 2 , wherein R 2 is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4 alkyl.
7. The compound in accordance with claim 1 , wherein
P 1 is selected from the group consisting of —NHC(O)NH—;
P 2 is selected from the group consisting of —O(CH 2 CH 2 O) q — and —C(O)O—;
P 3 is selected from the group consisting of C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, —NHS(O) 2 R 2 , and —C(O)OR 2 , wherein R 2 is a member selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4 alkyl; and
L 2 is selected from the group consisting of substituted and unsubstituted C 2 -C 12 alkylene.