Kappa opioid agonists and uses thereof
View Patent ↗Provided are compounds of Formula I; and pharmaceutically acceptable salts and solvates thereof. The present disclosure relates to novel compounds and to their use as agonists of the kappa opioid receptor. The disclosure also relates to methods for preparation of the compounds and to pharmaceutical compositions containing such compounds. Kappa opioid agonists that exhibit full agonist properties at the kappa opioid receptor have been widely shown to be efficacious in preclinical models of pain, particularly visceral pain.
1. A compound having the structure:
wherein:
R 1 is
R 2 is hydrogen;
R 3 is hydrogen;
R 4 is —X-POLY;
R 5 is hydrogen;
R 6 is hydrogen;
X is —O— or —OC(O)NH—;
POLY is —(CH 2 CH 2 O) n —Y;
n is 1 to 30; and
Y is hydrogen or substituted or unsubstituted lower alkyl;
and pharmaceutically acceptable salts and solvates thereof.
2. A compound selected from:
2-(3, 4-dichlorophenyl)-N-{(1S)-2-[(3S)-3-(2-methoxyethoxy)pyrrolidin-1-yl]-1-phenylethyl}-N-methylacetamide;
2-(3, 4-Dichlorophenyl)-N-{(1S)-2-[(3S)-3-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)pyrrolidin-1-yl]-1-phenylethyl}-N-methylacetamide;
(3S)-1-[(2S)-2-{[(3,4-Dichlorophenyl)acetyl](methyl)amino}-2-phenylethyl]pyrrolidin-3-yl{2-[2-(2-methoxyethoxy)ethoxy]ethyl}carbamate;
(3S)-1-[(2S)-2-{[(3,4-Dichlorophenyl)acetyl](methyl)amino}-2-phenylethyl]pyrrolidin-3-yl 2,5,8,11,14-pentaoxahexadecan-16-ylcarbamate; and
2-(3,4-Dichlorophenyl)-N-methyl-N-{(1S)-2-[(3S)-3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)pyrrolidin-1-yl]-1-phenylethyl}acetamide;
and pharmaceutically acceptable salts thereof.
3. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient.
4. A method of treating pain or inflammation comprising administering a compound of claim 1 to a patient in need thereof.
5. The compound of claim 1 , having the structure:
wherein:
n is 1 to 30;
R 10 is hydrogen; and
R 11 is —H, —CH 3 , or —CF 3 ;
and pharmaceutically acceptable salts and solvates thereof.