Signaling-biased mu opioid receptor agonists
The invention provides—opioid receptor agonists that are analgesic agents and that promote diminished side effects relative to a comparably effective dose of morphine. The side effects that are absent or attenuated include one or more of the following: constipation, respiratory depression, tolerance, dependence, nausea, confusion, sedation, hypotension, and post-treatment withdrawal symptoms.
1. A compound of structure 1
with substituents R 1 -R 9 , specified as follows:
R 1 , R 2 , R 3 , and R 4 are each independently H, Cl, Br, F, OCF 3 , Me, or lower alkyl, provided that one or more of groups R 1 -R 4 is not a hydrogen atom;
R 5 is H, Cl, Br, F, Me, CF 3 , OCF 3 , OCHF 2 , OCH 2 F, OMe, O-alkyl, SMe, S-alkyl, NH-acyl, or N(Me)-acyl;
R 6 is H, Cl, Br, F, Me, Et, lower alkyl, CF 3 , OCF 3 , OCHF 2 , OCH 2 F, OMe, O-alkyl, SMe, S-alkyl, NH-acyl, or N(Me)-acyl
wherein when R 5 and R 6 both are O-alkyl they may be connected together in a ring of 5-7 atoms by 1-3 CH 2 groups;
R 7 ═Cl, Br, F, Me, CF 3 , OCF 3 , OCHF 2 , or OCH 2 F;
provided that one or more of groups R 5 -R 7 is also not a hydrogen atom;
R 8 ═H, Me, or Et; and
R 9 ═H, Me, Et, lower alkyl, or CH 2 -cycloalkyl;
or, where a chiral carbon is present, an R-enantiomer, S-enantiomer, or racemic mixture thereof;
and/or a pharmaceutically acceptable salt thereof.
2. A compound selected from any of the following compounds or, where a chiral carbon is present, an R-enantiomer, S-enantiomer, or racemic mixture thereof:
and/or a pharmaceutically acceptable salt thereof:
3. A pharmaceutical composition comprising a compound or, where a chiral carbon is present, an R-enantiomer, S-enantiomer, or racemic mixture thereof, and/or a or pharmaceutically acceptable salt thereof of claim 1 or 2 and a pharmaceutically acceptable excipient.
4. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 , wherein when a chiral carbon is present, the compound is a racemate.
5. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 , wherein when a chiral carbon is present, the compound is the R-enantiomer.
6. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 , wherein when a chiral carbon is present, the compound is the S-enantiomer.