μ-opioid receptor agonist and preparation method therefor and use thereof in field of medicine
Disclosed are a class of μ-opioid receptor agonists and a preparation method therefor and the use thereof in the field of medicine, belonging to the field of medicinal chemistry. The μ-opioid receptor agonists significantly increase the selectivity for a G protein signaling pathway, and not only can exhibit excellent pharmacodynamic effects, but also significantly improve safety.
1. A compound represented by the general formula I, and stereoisomers, tautomers, enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof,
wherein,
A is a —C 1-2 alkylene;
B is —NH—CH 2 —Ar 2 , wherein
Ar 1 is
Ar 2 is
2. A compound according to claim 1 or stereoisomers, tautomers, enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof, the compound is:
(3-trifluoromethoxybenzyl)-[2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl]amine; (2-chloro-4-trifluoromethoxybenzyl)42-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl]amine;
N-methyl-2-(((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)amino)methyl)aniline;
(3-chloro-2-methylbenzyl)-[2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl]amine;
((3-chloro-thiophen-2-methyl)-[2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl]amine;
(4-trifluoromethoxybenzyl)-[2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-ethyl]amine;
(3,4-dimethylbenzyl)-[2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl]amine;
(2,4-dimethylbenzyl)-[2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl]amine;
(2-trifluoromethoxybenzyl)42-(9-(3-chloro-5-fluoropyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl]amine;
(2-trifluoromethoxybenzyl)42-(9-(3-methyl-5-fluoropyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl]amine;
(4-bromo-2-trifluoromethoxybenzyl)42-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl]amine;
(4-methyl-2-trifluoromethoxybenzyl)42-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl]amine;
3-{[(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl]aminomethyl}-2-trifluoromethoxylbenzonitrile;
((3-trifluoromethylthiophen-2-yl)methyl)42-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl]amine;
4-{[2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethylamine]methyl-3-trifluoromethoxphenol;
(2-difluoromethoxybenzyl)42-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-ethyl]amine;
(5-chloro-2-trifluoromethoxybenzyl)42-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl]amine;
((3-difluoromethoxythiophen-2-yl)methyl)42-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl]amine;
{249-(5-fluoro-pyridin-2-yl)-6-oxa-spiro[4.5]decan-9-A-ethyl-(2-(trifluoromethoxy)-benzyl)-amine;
(2-trifluoromethoxybenzyl)-[2-(9-pyridin-2-yl-6-oxa-spiro[4.5]decan-9-yl)-ethyl]-amine;
[(5-methoxy-1 [(5-methoxy-1H-pyrazol-4-yl)methyl]-[2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl]amine;
(3-bromo-2-trifluoromethoxybenzyl)42-(9-pyridin-2-yl-6-oxa-spiro[4.5]decan-9-yl)-ethylamine;
{2-(5-fluoro-pyridin-2-yl)-6-oxa-spiro[4.5]decan-9-yl]-ethyl-(2-(difluoromethoxy)-benzyl)-amine;
{2-(5-fluoro-pyridin-2-yl)-6-oxa-spiro[4.5]decan-9-yl)ethyl((3-chlorothiophene-2-yl)-methyl)-amine;
{2-[9-(5-fluoro-pyridin-2-yl)-6-oxa-spiro[4.5]decan-9-A-ethyl-(3,4-dimethyl-benzyl)-amine;
{249-(5-fluoro-pyridin-2-yl)-6-oxa-spiro[4.5]decan-9-yl]-ethyl-(3-chloro-2-methyl-benzyl)-amine; or
{2-[9-(5-fluoro-pyridin-2-yl)-6-oxa-spiro[4.5]decan-9-A-ethyl-((3-difluoromethoxythiophen-2-yl)-methyl)-amine.
3. A pharmaceutical composition, characterized by including a therapeutically effective amount of the compound according to claim 1 or stereoisomers, tautomers, enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof, and optionally one or more of the medically acceptable carriers and/or additives, the carriers such as saline, hot-pressed water, Ringer solution, buffered saline, glucose, maltodextrin, glycerol, ethanol, and mixtures thereof; the additives such as diluents, lubricants, adhesives, glidants, disintegrants, sweeteners, flavoring agents, wetting agents, dispersants, surfactants, buffered saline, coating agents, foaming agents, preservatives, stabilizers or fragrances.
4. A method for preparing a compound as defined in claim 1 , wherein
when A is a —C 1-2 alkylene, and B is —NH—CH 2 —Ar 2 , the synthesis route is as shown in Scheme 1:
wherein Ar1 and Ar2 are as defined in claim 1 ,
5. The method according to claim 4 , wherein in the Scheme 1, the acid is sulfuric acid, hydrochloric acid, phosphoric acid, trifluoromethanesulfonic acid, hydrobromic acid or a combination thereof; the oxidizing agent is pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), or a combination thereof;
the aryl Grignard reagent is aryl magnesium bromide, aryl magnesium chloride, or a combination thereof; the base is potassium hydroxide, sodium hydroxide or a combination thereof; the reducing agent 1 is lithium aluminum tetrahydride, borane tetrahydrofuran, borane dimethyl sulfide or a combination thereof; and the reducing agent 2 is sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or a combination thereof.