Inhibitors for the soluble epoxide hydrolase
View Patent ↗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:
wherein
R 1 is a substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl;
P 1 is a primary pharmacophore selected from the group consisting of —C(O)O—, —NHC(NH)NH—, —NHC(NH)CH 2 —, —CH 2 C(NH)NH—, —NHC(NH)—, —C(NH)NH—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —NHC(S)NH—, —CH 2 C(O)NH—, —NHC(O)CH 2 —, —C(O)NH—, —NHC(O)—, and
P 2 is a secondary pharmacophore selected from the group consisting of —NH—, —C(O)—, —CH(OH)—, —O(CH 2 CH 2 O)q—, —C(O)O——OC(O)—, —NHC(NH)NH—, —NHC(NH)CH 2 —, —CH 2 C(NH)NH—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —C(O)NH—, —NHC(O)— and —NHC(S)NH—;
P 3 is a tertiary pharmacophore selected from the group consisting of substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, —O(CH 2 CH 2 O) q R 2 , OR 2 , —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , —OC 2 -C 4 alkyl-C(O)OR 2 , —C(O)R 2 , —C(O)OR 2 and carboxylic acid analogs, 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 heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4 alkyl;
the subscript q is 0 to 6;
the subscript m is 0 or 1; and
L 1 is a substituted or unsubstituted C 3 -C 6 cycloalkylene;
L 2 is a linker selected from the group consisting of substituted or unsubstituted C 1 -C 12 alkylene, substituted or unsubstituted C 3 -C 6 cycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene; an amino acid, a dipeptide and a dipeptide analog; and combinations thereof,
such that when P 2 is —C(O)O— or —O(CH 2 CH 2 O) q — and L 2 is unsubstituted C 1 -C 12 alkylene, then m=1,
P 3 is selected from the group consisting of substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, —O(CH 2 CH 2 O) q R 2 , OR 2 , —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , —OC 2 -C 4 alkyl-C(O)OR 2 , —C(O)R 2 and carboxylic acid analogs, and
R 2 of —O(CH 2 CH 2 O) q R 2 is selected from the group consisting of hydrogen, substituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4 alkyl.
2. The compound in accordance with claim 1 , wherein L 1 cyclohexylene.
3. The compound in accordance with claim 1 , wherein P 1 is selected from the group consisting of —NHC(O)NH—, —NHC(NH)NH—, —NHC(NH)CH 2 —, —CH 2 C(NH)NH—, —NHC(NH)—, —C(NH)NH—, —NHC(S)NH—, —NHC(O)CH 2 —, CH 2 C(O)NH—, NHC(O)— and —C(O)NH—.
4. The compound in accordance with claim 3 , wherein P 1 is selected from the group consisting of —NHC(O)NH—, —C(O)NH— and —NHC(O)—.
5. The compound in accordance with claim 1 , wherein P 1 is selected from the group consisting of —NHC(O)NH—, —C(O)NH— and —CH 2 C(O)NH—.
6. The compound in accordance with claim 1 , wherein P 1 is selected from the group consisting of —NHC(O)NH—, —C(O)NH— and —NHC(O)—; P 2 is selected from the group consisting of —NH—, —C(O)—, —CH(OH)—, —O(CH 2 CH 2 O) q —, —C(O)O—, —OC(O)—, —NHC(NH)NH—, —NHC(NH)CH 2 —, —CH 2 C(NH)NH—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —C(O)NH—, —NHC(O)—, and —NHC(S)NH—; m is 0; and L 2 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 12 alkylene, substituted or unsubstituted C 3 -C 12 cycloalkylene, substituted or unsubstituted arylene and substituted or unsubstituted heteroarylene.
7. The compound in accordance with claim 1 , wherein P 1 is selected from the group consisting of —NHC(O)NH—, —C(O)NH— and —NHC(O)—; P 2 is selected from the group consisting of —CH(OH)—, —C(O)O—, —O(CH 2 CH 2 O) q —, —OC(O)—, —C(O)NH— and —NHC(O)—; m is 1; L 2 is selected from the group consisting of substituted or unsubstituted C 1 -C 12 alkylene, substituted or unsubstituted C 3 -C 6 cycloalkylene, and substituted or unsubstituted arylene; and P 3 is selected from the group consisting of C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, heterocyclyl, OR 2 , —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , —OC 2 -C 4 alkyl-C(O)OR 2 , —C(O)R 2 and carboxylic acid analogs, 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 heterocyclyl; substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4 alkyl.
8. The compound in accordance with claim 1 , wherein P 1 is selected from the group consisting of —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—; m is 1; L 2 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkylene, substituted or unsubstituted C 3 -C 12 cycloalkylene, and substituted or unsubstituted arylene and substituted or unsubstituted heteroarylene; and P 3 is selected from the group consisting of C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, heterocyclyl, OR 2 , —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , —OC 2 -C 4 alkyl—C(O)OR 2 , —C(O)R 2 and carboxylic acid analogs, 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 heterocyclyl; substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4 alkyl.
9. The compound in accordance with claim 1 , wherein P 3 is selected from the group consisting of C 2 -C 6 alkenyl, heterocyclyl, OR 2 , —OC 2 -C 4 alkyl—C(O)OR 2 and —C(O)R 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 heterocyclyl; substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4 alkyl.
10. The compound in accordance with claim 1 , wherein P 3 is selected from the group consisting of haloalkoxy, morpholino, dioxothiomorpholino.
11. The compound in accordance with claim 1 , wherein L 2 is selected from the group consisting of substituted or unsubstituted C 3 -C 6 cycloalkylene, substituted or unsubstituted arylene and substituted or unsubstituted heteroarylene.
12. The compound in accordance with claim 11 , wherein L 2 is selected from the group consisting of substituted or unsubstituted C 3 -C 6 cycloalkylene and substituted or unsubstituted heteroarylene.
13. The compound in accordance with claim 1 , wherein P 1 is selected from the group consisting of —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—; 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)—; m is 1; L 2 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkylene; and P 3 is selected from the group consisting of —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , and —NHS(O) 2 R 2 , wherein R 2 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 heterocyclyl; substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4 alkyl.
14. The compound in accordance with claim 1 , wherein P 1 is selected from the group consisting of —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—; m is 1; L 2 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkylene; and P 3 is selected from the group consisting of C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, heterocyclyl, OR 2 , —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , —OC 2 -C 4 alkyl—C(O)OR 2 , —C(O)R 2 and carboxylic acid analogs, 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 heterocyclyl; substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4 alkyl.
15. The compound in accordance with claim 1 , wherein R 1 is a member selected from the group consisting of C 5 -C 12 cycloalkyl, wherein said cycloalkyl portions are monocyclic or polycyclic; P 1 is —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 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, heterocyclyl, OR 2 , —C(O)NHR 2 , —C(O)NHS(O) 2 R 2 , —NHS(O) 2 R 2 , —OC 2 -C 4 alkyl—C(O)OR 2 , —C(O)R 2 and carboxylic acid analogs, 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 heterocyclyl; substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4 alkyl; m is 1 and q is 0 to 6; and L 2 is selected from the group consisting of substituted or unsubstituted C 1 -C 12 alkylene.
16. The compound in accordance with claim 1 , wherein L 2 is a dipeptide or dipeptide analog.
17. The compound in accordance with claim 1 , wherein L 2 is a dipeptide having an N-terminal residue selected from the group consisting of Tyr, His, Lys, Phe and Trp, and a C-terminal residue selected from the group consisting of Ala, Arg, Asp, Gly, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val.
18. The compound in accordance with claim 1 , having the formula:
19. The compound of claim 18 , R 1 is substituted or unsubstituted aryl.
20. The compound of claim 18 , wherein R 1 is substituted or unsubstituted C 5 -C 12 cycloalkyl.
21. The compound in accordance with claim 18 , wherein P 2 is selected from the group consisting of —O(CH 2 CH 2 O) q —, —C(O)O—, and —C(O)NH—.
22. The compound in accordance with claim 21 , having the formula:
wherein L 2 is selected from the group consisting of substituted or unsubstituted C 1 -C 12 alkylene, substituted or unsubstituted C 3 -C 6 cycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene.
23. The compound in accordance with claim 21 , having the formula:
24. The compound in accordance with claim 21 , wherein L 2 is substituted or unsubstituted arylene.
25. The compound in accordance with claim 24 , wherein L 2 is substituted or unsubstituted alkylene.
26. The compound in accordance with claim 1 , having the formula:
wherein R 1 is a member selected from the group consisting of alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylaryl, optionally substituted with from 1 to 2 substituents each independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, nitro, haloalkoxy, thioalkyl and phenyl; and
L 2 is selected from the group consisting of phenylene or methylenephenylene, heteroarylene, optionally substituted with from 1 to 2 substituents each independently selected from the group consisting of halo and haloalkyl.
27. The compound in accordance with claim 26 , having the formula:
28. The compound in accordance with claim 26 , having the formula:
29. The compound in accordance with claim 1 , wherein the substituents for each substituted group are each independently selected from the group consisting of halo, cyano, nitro, alkyl, alkylamino, hydroxyalkyl, haloalkyl, carboxyl, hydroxyl, alkoxy, alkoxyalkoxy, haloalkoxy, thioalkyl, aryl, aryloxy, cycloalkyl, cycloalkylalkyl, heteroaryl, aralkyl, heteroaralkyl, alkenyl, alkynyl, haloalkyl and polyhaloalkyl, formyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, amino, dialkylamino, arylamino, alkylarylamino, alkylcarbonylamino, arylcarbonylamino, azido, mercapto, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl and arylaminosulfonyl, wherein heteroaryl and arylcarbonyl are each optionally substituted with 1 or more, substituents selected from halo, haloalkyl and alkyl.
30. A compound selected from the group consisting of:
3-(3-Adamantan-1-yl-ureido)-N-pentylcyclohexanecarboxamide,
1-(Adamantan-1-yl)-3-(4-(2-(2-(2,2,2-trifluoroethoxy)ethoxy)ethoxy)cyclohexyl)urea,
ethyl 4-((trans-3-(3-Adamantan-1-yl-ureido)cyclohexanecarbonyloxy)(cyano)methyl)benzoate,
ethyl 4-((cis-3-(3-Adamantan-1-yl-ureido)cyclohexanecarbonyloxy)(cyano)methyl)benzoate,
ethyl 4-((3-(3-Adamantan-1-yl-ureido)cyclohexanecarbonyloxy)methyl)benzoate,
3-(3-Adamantan-1-yl-ureido)-N-(2-(2-hydroxyethoxy)ethyl)cyclohexanecarboxamide,
ethyl 4-[(trans-3-(3-Adamantan-1-yl-ureido)cyclohexanecarbonyloxy)(phenyl)methyl]benzoate,
1-(Adamantan-1-yl)-3-(cis-4-methoxycyclohexyl)urea,
4-(trans-4-(3-Adamantan-1-yl-ureido)cyclohexyloxy)benzoic acid,
1-(Adamantan-1-yl)-3-(4-(allyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(4-(3-methylbut-2-enyloxy)cyclohexyl)urea,
(E)-1-(Adamantan-1-yl)-3-(4-(3,7-dimethylocta-2,6-dienyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(4-(2-(2-(2,2,2-trifluoroethoxy)ethoxy)ethoxy)cyclohexyl)urea,
ethyl 4-((trans-3-(3-Adamantan-1-yl-ureido)cyclohexanecarbonyloxy)(cyano)methyl)benzoate,
ethyl 4-((cis-3-(3-Adamantan-1-yl-ureido)cyclohexanecarbonyloxy)(cyano)methyl)benzoate,
ethyl 4-((3-(3-Adamantan-1-yl-ureido)cyclohexanecarbonyloxy)methyl)benzoate,
3-(3-Adamantan-1-yl-ureido)-N-(2-(2-hydroxyethoxy)ethyl)cyclohexanecarboxamide,
trans-1-(4-Benzyloxy-cyclohexyl)-3-tricyclo [3.3.1.13,7]decan-1-yl-urea,
1-(Adamantan-1-yl)-3-(trans-4-(4-bromobenzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(trans-4-(2,6-dichlorobenzyloxy)cyclohexyl)urea,
trans-1-(4-Hydroxy-cyclohexyl)-3-tricyclo[3.3.1.13,7]decan-1-yl-urea,
1-(Adamantan-1-yl)-3-(trans-4-(2-chlorobenzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(trans-4-(2-methylbenzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-trans-4-(cyclohexylmethoxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(trans-4-(3-morpholinopropoxy)cyclohexyl)urea,
2-(Adamantan-1-yl)-N-(trans-4-hydroxycyclohexyl)acetamide,
2-(Adamantan-1-yl)-N-(3-hydroxyAdamantan-1-yl)acetamide,
1-(Adamantan-1-yl)-3-trans-4-hydroxycyclohexyl)urea,
1-(Adamantan-1-yl)-3-(4-(4-bromophenoxy)cyclohexyl)urea,
4-(3-Adamantan-1-yl-ureido)cyclohexyl benzoate,
trans-4-Nitro-benzoic acid 4-(3-tricyclo[3.3.1.13,7]decan-1-yl-ureido)-cyclohexyl ester,
cis-1-(4-Hydroxy-cyclohexyl)-3-tricyclo[3.3.1.13,7]decan-1-yl-urea,
cis-1-(4-Benzyloxy-cyclohexyl)-3-tricyclo[3.3.1.13,7]decan-1-yl-urea,
1-(Adamantan-1-yl)-3-(cis-4-(2,6-difluorobenzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(cis-4-(cyclohexyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(cis-4-(2,6-dichlorobenzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(cis-4-(2-methylbenzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(trans-4-(2,6-difluoro-4-isopropoxybenzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(cis-4-(2,6-difluoro-4-isopropoxybenzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(cis-4-(4-bromobenzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(cis-4-(2-chlorobenzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(trans-4-(2,6-difluoro-4-(methoxymethoxy)benzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(cis-4-(2,6-difluoro-4-(methoxymethoxy)benzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-trans-4-(4-bromobenzyloxy)cyclohexyl)urea,
cis-1-[4-(4-Fluoro-phenoxy)-cyclohexyl]-3-tricyclo[3.3.1.13,7]decan-1-yl-urea,
trans-1-[4-(4-Fluoro-phenoxy)-cyclohexyl]-3-tricyclo [3.3.1.13,7]decan-1-yl-urea,
1-(Adamantan-1-yl)-3-(trans-4-(4-nitrobenzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(cis-4-(4-rnethoxyphenoxy)cyclohexyl)urea,
1,3-bis(trans-4-hydroxycyclohexyl)urea,
1-(Adamantan-1-yl)-3-(cis-4-(4-nitrobenzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(cis-4-(3,5-difluorophenoxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-N-(cis-4-hydroxycyclohexyl)formamide,
1-(Adamantan-1-yl)-3-(trans-4-(2-(trifluoromethyl)benzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(trans-4-(2-(trifluoromethoxy)benzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(trans-4-(4-methoxyphenoxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(trans-4-(3,5-difluorophenoxy)cyclohexyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-phenylurea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-phenylurea,
2-(Adamantan-1-yl)-N-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)acetarnide,
1-(Adamantan-1-yl)-3-(trans-4-(2-fluorobenzyloxy)cyclohexyl)urea,
4-(3-Adamantan-1-yl-ureido)cyclohexanecarboxylic acid,
1-tert-butyl-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(2-fluorophenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(3-fluorophenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(2-(trifluoromethyl)phenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(3-(trifluoromethyl)phenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(naphthalen-1-yl)urea,
1(cis-4-(4-fluorophenoxy)cyclohexyl)-3-phenylurea,
1-benzyl-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-m-tolylurea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-p-tolylurea,
1-(4-chlorophenyl)-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(2,6-dimethylphenyl)-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(4-methoxyphenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(2-nitrophenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(3-nitrophenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(4-nitrophenyl)urea,
1-(2,6-difluorophenyl)-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(4-bromophenyl)-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyi)-3-(2-methoxyphenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(3-methoxyphenyl)urea,
1-(3-chlorophenyl)-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(2-(trifluoromethoxy)phenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(4-(trifluoromethoxy)phenyl)urea,
1-(2-bromophenyl)-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(2-chlorophenyl)-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(2-chlorophenyl)-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(3-bromophenyl)-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(2,6-diisopropylphenyl)-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-phenethylurea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(naphthalen-2-yl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(2-iodophenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(4-(methylthio)phenyl)urea,
1-(9H-fluoren-9-yl)-3-(cis-4-(4-fluorophenoxy)cyclohexyDurea,
1-benzhydryl-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-cyclopentyl-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(3-phenylpropyl)urea,
1-cycloheptyl-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-cyclooctyl-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-cyclododecyl-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(3-iodophenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(4-iodophenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(2-(methylthio)phenyl)urea,
1-cyclohexyl-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(4-fluorophenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(3(methylthio)phenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-o-tolylurea,
1-tert-butyl-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(2-fluorophenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(3-fluorophenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(2-(trifluorornethyl)phenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(3-(trifluoromethyl)phenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(naphthalen-1-yl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-phenylurea,
1-benzyl-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-m-tolylurea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-p-tolylurea,
1-(4-chlorophenyl)-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(2,6-dimethylphenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(4-methoxyphenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(2-nitrophenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(3-nitrophenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(4-nitrophenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(2,6-difluorophenyl)urea,
1-(4-bromophenyl)-3-(trans-4-(2,6-difluorobenzyloxy)cycloheXyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(2-methoxyphenyl)urea,
1-(trans-4(2,6difluorobenzyloxy)cyclohexyl)-3-(3-methoxyphenyl)urea,
1-(3-chlorophenyl)-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexYl)Urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(2-(trifluoromethoxy)phenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(4-(trifluoromethoxy)phenyl)urea,
1-(2-bromophenyl)-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)Urea,
1-(2,6-dichlorophenyl)-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)urea,
1-(2-chlorophenyl)-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)urea,
1-(3-bromophenyl)-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(2,6-diisopropylphenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-phenethylurea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(naphthalen-2-yl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(2-iodophenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(4-(methylthio)phenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(9H-fluoren-9-yl)urea,
1-benzhydryl-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)urea,
1-cyclopentyl-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(3-phenylpropyl)urea,
1-cycloheptyl-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)urea,
1-cyclooctyl-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)urea,
1-cyclododecyl-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(3-iodophenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(4-iodophenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(2-(methylthio)phenyl)urea,
1-cyclohexyl-3-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(4-fluorophenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-(3-(methylthio)phenyl)urea,
1-(trans-4-(2,6-difluorobenzyloxy)cyclohexyl)-3-o-tolylurea,
benzhydryl 3-(3-adamant-1-ylureido)cyclohexanecarboxylate,
1-(Adamantan-1-yl)-3-(cis-4-(4-(2-methoxyacetyl)phenoxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(trans-4-(4-(2-methoxyacetyl)phenoxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(trans-4-(5-(trifluoromethyl)pyridin-2-yloxy)cyclohexyl)urea,
1-(4-chlorophenyl)-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-cycloheptyl-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(4-bromophenyl)-3-(cis-4-(4-fluorophenoxy)cyclohexyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(4-iodophenyl)urea,
1-(cis-4-(4-fluorophenoxy)cyclohexyl)-3-(4-(trifluoromethoxy)phenyl)urea,
and their pharmaceutically acceptable salts.
31. A compound having a formula:
wherein
R 1 is a substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl;
P 1 is a primary pharmacophore selected from the group consisting of —C(O)O—, —NHC(NH)NH—, —NHC(NH)CH 2 —, —CH 2 C(NH)NH—, —NHC(NH)—, —C(NH)NH—, —NHC(O)NH—, —OC(O)NH—, —NHC(O)O—, —NHC(S)NH—, —CH 2 C(O)NH—, —NHC(O)CH 2 —, —C(O)NH—, —NHC(O)—, and
P 2 is a secondary pharmacophore selected from the group consisting of —O(CH 2 CH 2 O) q — and —C(O)O—;
P 3 is a tertiary pharmacophore selected from the group consisting of —O(CH 2 CH 2 O) q —(unsubstituted alkyl) 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 heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl C 1 -C 4 alkyl;
the subscript q is 0 to 6;
the subscript m is 0 or 1;
L 1 is a substituted or unsubstituted C 3 -C 6 cycloalkylene; and
L 2 is unsubstituted C 1 -C 12 alkylene.
32. The compound in accordance with claim 31 , wherein L 1 cyclohexylene.
33. The compound in accordance with claim 31 , wherein P 3 is —C(O)OR 2 .
34. The compound in accordance with claim 31 , wherein P 1 is selected from the group consisting of —NHC(O)NH—, —NHC(NH)NH—, —NHC(NH)CH 2 —, —CH 2 C(NH)NH—, —NHC(NH)—, —C(NH)NH—, —NHC(S)NH—, —NHC(O)CH 2 —, CH 2 C(O)NH—, NHC(O)— and —C(O)NH—.
35. The compound in accordance with claim 34 , wherein P 1 is selected from the group consisting of —NHC(O)NH—, —C(O)NH— and —NHC(O)—.
36. The compound in accordance with claim 31 , wherein P 1 is selected from the group consisting of —NHC(O)NH—, —C(O)NH— and —CH 2 C(O)NH—.
37. The compound in accordance with claim 31 , having the formula:
38. The compound of claim 37 , R 1 is substituted or unsubstituted aryl.
39. The compound of claim 37 , wherein R 1 is substituted or unsubstituted C 5 -C 12 cycloalkyl.
40. The compound in accordance with claim 37 , having the formula:
41. The compound in accordance with claim 31 , having the formula:
wherein R 1 is a member selected from the group consisting of alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylaryl, optionally substituted with from 1 to 2 substituents each independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, nitro, haloalkoxy, thioalkyl and phenyl.
42. The compound in accordance with claim 41 , having the formula:
43. The compound in accordance with claim 41 , having the formula:
44. The compound in accordance with claim 31 , wherein the substituents for each substituted group are each independently selected from the group consisting of halo, cyano, nitro, alkyl, alkylamino, hydroxyalkyl, haloalkyl, carboxyl, hydroxyl, alkoxy, alkoxyalkoxy, haloalkoxy, thioalkyl, aryl, aryloxy, cycloalkyl, cycloalkylalkyl, heteroaryl, aralkyl, heteroaralkyl, alkenyl, alkynyl, haloalkyl and polyhaloalkyl, formyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, amino, dialkylamino, arylamino, alkylarylamino, alkylcarbonylamino, arylcarbonylamino, azido, mercapto, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl and arylaminosulfonyl, wherein heteroaryl and arylcarbonyl are each optionally substituted with 1 or more, substituents selected from halo, haloalkyl and alkyl.
45. A compound selected from the group consisting of:
pentyl 3-(3-Adamantan-1-yl-ureido)cyclohexanecarboxylate,
pentyl 4-(3-Adamantan-1-yl-ureido)cyclohexanecarboxylate,
heptan-3-yl 3-(3-Adamantan-1-yl-ureido)cyclohexanecarboxylate,
1-(Adamantan-1-yl)-3-(4-(pentyloxy)cyclohexyl)urea,
ethyl 7-(4-(3-Adamantan-1-yl-ureido)cyclohexyloxy)heptanoate,
1-(Adamantan-1-yl)-3-(4-(2-(2-ethoxyethoxy)ethoxy)cyclohexyl)urea,
1-(Adamantan-1-yl)-3-(trans-4-methoxycyclohexyl)urea,
1-(Adamantan-1-yl)-3-(cis-4-methoxycyclohexyl)urea,
and their pharmaceutically acceptable salts.
46. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 , 30 , 31 or 45 .
47. A method for inhibiting a soluble epoxide hydrolase, comprising contacting said soluble epoxide hydrolase with an inhibiting amount of a compound of claim 1 , 30 , 31 or 45 .
48. A method of treating diseases modulated by soluble epoxide hydrolases, said method comprising administering to a subject in need of such treatment an effective amount of claim 1 , 30 , 31 or 45 .
49. The method in accordance with claim 48 , wherein said disease is selected from the group consisting of hypertension, inflammation, adult respiratory distress syndrome; diabetic complications; end stage renal disease; Raynaud syndrome and arthritis.
50. A method for reducing renal deterioration in a subject, said method comprising administering to said subject an effective amount of a compound of claim 1 , 30 , 31 or 45 .
51. A method for inhibiting progression of nephropathy in a subject, said method comprising administering to said subject an effective amount of a compound of claim 1 , 30 , 31 , or 45 .
52. A method for reducing blood pressure in a subject, said method comprising administering to said subject an effective amount of claim 1 , 30 , 31 or 45 .
53. The method in accordance with claim 52 , said method further comprising administering to said subject an effective amount of a cisepoxyeicosantrienoic acid.
54. A method of increasing vasodilation in a subject, said method comprising administering to said subject an effective amount of claim 1 , 30 , 31 or 45 .
55. A method of inhibiting the progression of obstructive pulmonary disease, an interstitial lung disease, or asthma in a subject, said method comprising administering to said subject an effective amount of claim 1 , 30 , 31 or 45 .
56. A method of reducing vascutar inflammation in a subject, said method comprising administering to said subject an effective amount of claim 1 , 30 , 31 or 45 .
57. A method of reducing renal inflammation in a subject, said method comprising administering to a subject an effective amount of claim 1 , 30 , 31 or 45 .
58. A method of regulating endothelial cell function in a subject, said method comprising administering to said subject an effective amount of claim 1 , 30 , 31 or 45 .