Alpha-ketoheterocycles and methods of making and using
Compounds are disclosed that are effective in inhibition of fatty acid amide hydrolase, an enzyme responsible for catabolism of endogenous cannabinoids such as anandamide. The compounds are useful as analgesic compounds and as sleep-inducing compounds, that can be orally administered, and that can have a relatively long duration of effect. Methods of preparation of the compounds are also provided. The compounds are conformationally constrained analogs of heterocyclylketones such as oxazolylketones.
1. A compound of formula (I)
wherein:
R 2 is hydrogen, halo, haloalkyl, nitrile, C(O)OR′, C(O)N(R′) 2 , aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally mono- or independently multisubstituted with J;
X is CH 2 or CH 2 Ch 2;
Y is CH or N;
R 1 is selected from the group consisting of H, aryl, —Z-aryl, heteroaryl, and —Z-heteroaryl, wherein Z is selected from C 1-6 alkylene, oxy, —O—C 1-6 alkylene, —S(O) w , —S(O) w —C 1-6 alkylene, wherein w is 0, 1 or 2, NR′, and alkyleneNR′, wherein aryl or heteroaryl can be mono- or independently multi-substituted with J, or can be fused with a 5-7 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally further mono- or independently multi-substituted with J, or both;
* indicates a chiral carbon atom which can be of the S absolute configuration, the R absolute configuration, or any mixture thereof, including a racemic mixture;
J is selected from the group consisting of F, Cl, Br, I, OR′, OC(O)N(R′) 2 , CN, NO, NO 2 , ONO 2 , N 3 , CF 3 , OCF 3 , R′, methylenedioxy, ethylenedioxy, N(R′) 2 , SR′, SOR′, SO 2 R′, SO 2 N(R′) 2 , SO 3 R′, C(O)R′,C(O)C(O)R′, C(O)CH 2 C(O)R′, C(S)R′, C(O)OR′, OC(O)R′, C(O)N(R′) 2 , OC(O)N(R′) 2 , C(S)N(R′) 2 , (CH 2 ) 0-2 N(R′)C(O)R′, (CH 2 ) 0-2 N(R′)N(R′) 2 , N(R′)N(R′)C(O)R′, N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′) 2 , N(R′)SO 2 R′, N(R′)SO 2 N(R′) 2 , N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)C(S)R′, N(R′)C(O)N(R′) 2 , N(R′)C(S)N(R′) 2 , N(COR′)COR′, N(OR′)R′, C(═NH)N(R′) 2 , C(O)N(OR′)R′, and C(═NOR′)R′; R′ is selected, independently for each occurrence, from the group consisting of hydrogen, C 1-6 alkyl, acyl, C 3-6 cycloalkyl, C 2-6 alkenyl, phenyl, heterocyclyl, heteroaryl, and heteroarylalkyl, wherein alkyl, acyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl, or heteroarylalkyl is optionally substituted with one, two or three substituents selected from the group consisting of halogen, cyano, hydroxyl, phenyl, and heterocyclyl, or wherein two R′ groups, when bonded to a nitrogen atom or to two adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl, which can be mono- or independently multi-substituted with one, two or three substitutents selected from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkyl, acyl, C 3-6 cycloalkyl, C 2-6 alkenyl, phenyl, and heterocyclyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein R 2 is heteroaryl.
3. The compound of claim 1 wherein R 2 is a 2-, 3-, or 4-pyridyl, wherein the pyridyl is optionally mono- or independently multi-substituted with J, and wherein any pyridyl is optionally fused with a 5-7 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, any of which cycloalkyl, heterocyclyl, aryl, or heteroaryl can be further mono- or independently multi-substituted with J.
4. The compound of claim 1 wherein R 2 is 2-pyridyl, optionally mono- or independently multi-substituted with J.
5. The compound of claim 4 wherein the 2-pyridyl is unsubstituted or is substituted with carboxylic acid, alkoxycarbonyl or carboxamido group.
6. The compound of claim 4 , wherein R 2 is
wherein R 3 is selected from the group consisting of hydrogen, hydroxyl, cyano, and —C(O)O—R 4 , wherein R 4 is H or C 1-4 alkyl., and wherein a wavy line indicates a point of bonding.
7. The compound of claim 6 wherein R 2 is selected from the set consisting of
wherein a wavy line indicates a point of attachment.
8. The compound of claim 1 wherein R 1 is aryl, aralkyl, aryloxy, or aralkoxy, and of which aryl, aralkyl, aryloxy, or aralkoxy is optionally mono- or independently multi-substituted with J.
9. The compound of claim 8 wherein R 1 is phenyl, phenoxy, or benzyloxy, any of which optionally mono- or independently multi-substituted with J.
10. The compound of claim 1 wherein the chiral center is of the S absolute configuration.
11. A compound of claim 1 wherein the compound inhibits the bioactivity of a fatty acid amide hydrolase (FAAH) at a therapeutically achievable concentration.
12. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
13. The composition of claim 12 adapted for oral administration.
14. A compound selected from one of the following
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising the compound of claim 14 and a pharmaceutically acceptable excipient.
17. A method of inhibiting FAAH, comprising contacting the FAAH with an effective amount or concentration of a compound of claim 1 .
18. The method of claim 17 wherein the contacting takes place in vitro or in vivo.
19. A method of treating pain or of treating a sleep disorder in a patient afflicted therewith, comprising administering to the patient an effective amount of a compound of claim 1 at a frequency and for a duration of time sufficient to provide a beneficial effect to the patient.
20. The method of claim 19 further comprising administration of a second medicament.
21. The method of claim 20 wherein the second medicament comprises an opiate analgesic, a non-opiate analgesic, a cannabinoid, an anti-inflammatory, a COX-2 inhibitor, a soporific, or a febricide.
22. The method of claim 19 wherein the compound is administered orally.
23. The method of claim 19 wherein the administration of a single dose of the compound results in a long-lasting amelioration of pain.