Antagonists of the kappa opioid receptor
The present technology is directed to compounds, compositions, and methods related to non-morphinan-like kappa opioid receptor (KOR) antagonists. The technology is suited to treat addiction, diuresis, depression, post traumatic stress disorder, an eating disorder, panic disorder, social anxiety disorder, general anxiety disorder, obsessive compulsive disorders, excessive or unreasonable specific phobias, and/or other conditions related to anxiety or aversion-reward responses.
1. A compound according to formula I
or stereoisomers, tautomers, solvates, and/or salts thereof; wherein
G 1 and G 2 are each independently C═O or S(O) 2 ;
R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently H, halo, hydroxy, amino, cyano, trifluoromethyl, thiol, alkylthio, sulfoxide, sulfone, nitro, pentafluorosulfanyl, carboxylate, amide, ester, or a substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, aryloxy, C 1 -C 6 alkanoyl, C 1 -C 8 alkanoyloxy, aryloyl, or aryloyloxy group, where any two adjacent R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , and R 11 may join to form a 5-membered or 6-membered substituted or unsubstituted heteroalkyl group;
R 6 is a branched C 1 -C 8 alkyl group or a substituted or unsubstituted cycloalkyl or aryl group; and
R 12 and R 13 are each independently H or a substituted or unsubstituted C 1 -C 8 alkyl or C 5 -C 7 cycloalkyl group; and
n is 0, 1, or 2;
provided that when G 1 is S(O) 2 , G 2 is C═O, R 1 , R 2 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 are each H, R 6 is isopropyl, and n is 1, then R 3 is not methyl.
2. The compound of claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , and R 11 is halo, hydroxy, cyano, trifluoromethyl, thiol, alkylthio, nitro, pentafluorosulfanyl, carboxylate, ester, or a substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, aryloxy, C 1 -C 6 alkanoyl, C 1 -C 6 alkanoyloxy, aryloyl, or aryloyloxy group.
3. The compound of claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , and R 11 is hydroxy or a substituted or unsubstituted C 1 -C 6 alkoxy or C 1 -C 6 alkanoyloxy group.
4. The compound of claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , and R 11 is hydroxy or an unsubstituted C 1 -C 6 alkoxy group.
5. The compound of claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is halo, hydroxy, carboxylate, ester, or a substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, or C 1 -C 6 alkanoyloxy group.
6. The compound of claim 1 , wherein at least one of R 7 , R 8 , R 9 , R 10 , and R 11 is halo, hydroxy, cyano, trifluoromethyl, thiol, alkylthio, sulfoxide, sulfone, nitro, pentafluorosulfanyl, carboxylate, ester, or a substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, aryloxy, C 1 -C 6 alkanoyl, C 1 -C 6 alkanoyloxy, aryloyl, or aryloyloxy group.
7. The compound of claim 1 , wherein at least one of R 7 , R 8 , R 9 , R 10 , and R 11 is hydroxy or an unsubstituted C 1 -C 6 alkoxy group.
8. The compound of claim 1 , wherein at least two of R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently halo, hydroxy, cyano, trifluoromethyl, nitro, pentafluorosulfanyl, carboxylate, ester, or a substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, aryloxy, C 1 -C 6 alkanoyl, C 1 -C 6 alkanoyloxy, aryloyl, or aryloyloxy group.
9. The compound of claim 1 , wherein
G 1 is S(O) 2 ;
G 2 is C═O;
R 1 , R 4 , R 5 , R 7 , R 10 , and R 11 are each H;
R 2 , R 3 , R 8 , and R 9 are each independently halo, hydroxy, amino, cyano, trifluoromethyl, thiol, alkylthio, sulfoxide, sulfone, nitro, pentafluorosulfanyl, carboxylate, amide, ester, or a substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, aryloxy, C 1 -C 6 alkanoyl, C 1 -C 8 alkanoyloxy, aryloyl, or aryloyloxy group, where any two adjacent R 2 , R 3 , R 8 , and R 9 may join to form a 5-membered or 6-membered substituted or unsubstituted heteroalkyl group;
R 6 is a branched C 1 -C 8 alkyl group;
R 12 and R 13 are each H; and
n is 1.
10. The compound of claim 1 , wherein
G 1 is S(O) 2 ;
G 2 is C═O;
R 1 , R 4 , R 5 , R 7 , R 10 , and R 11 are each H;
one of R 2 and R 3 is halo, hydroxy, or a unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, or C 1 -C 8 alkanoyloxy group and the other R 2 or R 3 is H;
one of R 8 and R 9 is halo, hydroxy, amino, cyano, trifluoromethyl, thiol, alkylthio, sulfoxide, sulfone, nitro, pentafluorosulfanyl, carboxylate, amide, ester, or a substituted or unsubstituted C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, or C 1 -C 8 alkanoyloxy group, and the other R 8 or R 9 is H;
R 6 is a branched C 1 -C 8 alkyl group;
R 12 and R 13 are each H; and
n is 1.
11. The compound of claim 1 , wherein R 6 is a branched C 1 -C 8 alkyl group or a substituted or unsubstituted cycloalkyl group.
12. The compound of claim 1 , wherein R 6 is isopropyl, sec-butyl, tert-butyl, isopentyl, neopentyl, or adamantyl.
13. The compound of claim 1 , wherein R 6 is tert-butyl, neopentyl, or adamantyl.
14. The compound of claim 1 , wherein the compound is selected from the group consisting of
15. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
16. A method comprising inhibiting β-arrestin recruitment in a subject by administering an effective amount of a compound of claim 1 .
17. The method of claim 16 , wherein the subject is suffering from depression, alcohol addiction, or cocaine addiction.
18. A method of inhibiting β-arrestin recruitment wherein the method comprises contacting a kappa opioid receptor with a compound of claim 1 .