Design And Synthesis Of Diarylaminopiperidine Opioid Receptor Mixed Agonists

Opioid receptors(OR)are commonly referred to as ?(MOR),?(DOR)and ?(KOR)subtypes.Opioids are clinically important drug for treating pain by acting on the opioid receptors.Opioid receptors drugs resulting in not only desired strong antinociceptive effect,but also severe side effects,such as respiratory depression,addiction and tolerance.As evidences of counterbalancing between OR subtype activation have been accumulated recently,OR dual agonists emerged as a potential choice to reduce side effects,but were found only partially effective.Based on the preliminary test compound such as DPI-3290,We hypothesized previously that ?/?/?-triple activation would eliminate most of the opioid-like side effects while enhancing analgesia.Herein,we propose to Design and Synthesis of Diarylaminopiperidine Opioid Receptor Mixed Agonists.Base on the study of QSAR of benzhydrylpiperazine-like OR agonists,a series of compounds are obtained from 4-piperidone via Buchwald-Hartwig amination and reductive amination reactions.After the optimization of the reaction conditions and operation,a practical synthesis of benzhydrylpiperazine opioid receptor agonist DPI-3290 was developed by a key step which is a 4-component 3-stage cascade reaction.We can prepare DPI-3290 by large scale.stabilizing foundation of Pharmacological activity for our experimental group.C-glycosides are an important class of carbohydrate analogues with applications as potent pharmaceutical compounds.We have developed the method of transition metal-catalyzed synthesis of C-Aryl glycosides cross-coupling reaction of Grignard reagent with D-bromo glucose.