Design And Synthesis Of An Analgesic Drug Based On Diarylmethylpiperazine

Opioid receptors are commoly referred to as ?,? and ? subtypes.Classic opioid analgesics like morphine selectively activate ? receptor with analgesic activity and the advantage of a wide spectrum of anti-pain through inhibiting the release of neurotransmitters.But it can cause respiratory depression,gastrointestinal motility inhibition,urination response inhibition,dependence,and addiction and other typical opioid side effects at the same time,which greatly subjects the clinical application.There has been increasing evidence that more and more people concern on the mixed?-? activity compounds.As the papers report,8 recptor can mediate the physiological effects of ?receptor,and meanwhile reduce respiratory depression and addiction and other side effects.Although,opioid receptor agonists are the main research field,the mixed agonist opioid are only partially overcome side effects.DPI-3290 is a mixed ?/?/? agonist,which produces analgesic potency between morphine and fentanyl,and significantly weakening respiratory depression and dependence relatively,increasing the security.Achievement of this research is as follows:1.According to the opioid receptor protein crysal X-ray structure,"messenger-address"and SAR of the lead compouds to designed three types of compouds:diarylmethylpiperazines,diarylmethenepiperidine and diarylmethyldiazabicyclo.2.Exploring the means of synthesis of those compounds.Applying the McMurry coupling reaction produced oleficin,then through the acidify,amide,and demethylation to make diarylmethenepiperidines.Diarylmethylpiperazines were preparaed by the followed four reactions in three steps,with arylaldehyde,chiral monoalkylated piperazine,benzotriaole and aryl Grignard to achieve stereoselective reaction.(1R,4R)-2-benzyl-2,5-diazabicyclo[2.2.1]heptane intermediate was prepared from natural trans-4-hydroxy-L-proline and undergo 2-racemization with the base,followed by an intramolecular aminolysis.Then through nuleophilic substitutin,acidify,amide and demethylation to get the diarylmethyldiazabicyclos.