Design And Synthesis Of Sinomenine D-cyclazole Derivatives

Sinomenine is a kind of isoquinoline alkaloid,similar to morphine in structure,which is extracted from the rhizome of the traditional Chinese medicine Qingfengteng,and it has many biological activities.It is commonly used as a treatment for rheumatoid arthritis in Asian countries such as China and Japan.In addition,sinomenine has been used in sedation and analgesia,immunosuppression,neuroprotection,anti-drug dependence,anti-tumor and other aspects.Although sinomenine has good biological activity,its application prospects are dim due to its large dosage,poor epidermal permeability,short half-life and many other defects.In order to overcome these defects,in recent years,people have been devoted to the synthesis of new sinomenine derivatives to screen more effective drugs for rheumatoid arthritis.According to the results of some studies,most sinomenine derivatives are more effective than sinomenine and have fewer side effects.In order to obtain sinomenine derivatives with good therapeutic effect and less side effects,three series of sinomenine derivatives modified with D-cycloazole heterocyclic ring were designed and synthesized in this paper,which expanded the library of sinomenine derivatives and provided the research and design basis for potential drugs.The main research contents of this paper are as follows:1)The synthesis scheme of 1,3,4-oxadiazole sinomenine derivatives was designed.Using sinomenine hydrochloride as raw material,sinomenine matrix was formed by neutralization reaction,and then reacted with sinomenine by cyanide bromide to obtain17-demethyl-17-cyanosinomenine.Then,through the reaction of Huisgen 1,3-dipole cycloaddition with azide,1,2,3,4-tetrazolium sinomenine was obtained.Sixteen arylated oxadiazole-sinomenine derivatives were synthesized by Huisgen rearrangement reaction of 1,2,3,4-tetrazole-sinomenine with benzoyl chloride series compounds.Their structures were characterized by NMR,IR,MS and EA.2)The synthesis scheme of 1,2,3,4-tetrazolium sinomenine derivatives was designed.Using sinomenine hydrochloride as raw material,sinomenine matrix was formed by neutralization reaction,and then reacted with sinomenine by cyanide bromide to obtain17-demethyl-17-cyanosinomenine.Then,through the reaction of Huisgen 1,3-dipole cycloaddition with azide,1,2,3,4-tetrazolium sinomenine was obtained.Eighteen benzylated tetrazole-sinomenine derivatives were synthesized by substitution reaction of1,2,3,4-tetrazole-sinomenine with benzyl chloride series compounds.Their structures were characterized and analyzed by NMR,IR and MS.3)The synthesis scheme of 1,2,3-triazole-1,2,3,4-tetrazole-sinomenine derivatives was designed.Using sinomenine hydrochloride as raw material,sinomenine matrix was formed by neutralization reaction,and then reacted with sinomenine by cyanide bromide to obtain 17-demethyl-17-cyanosinomenine.1,2,3,4-tetrazolium sinomenine was obtained by Huisgen 1,3-dipole cycloaddition reaction with azide.1,2,3,4-tetrazole-sinomenine was substituted with 3-bromoproparyne to produce 1-propionate tetrazole-sinomenine.Sixteen benzyltriazole-tetrazole-sinomenine derivatives were synthesized by Huisgen1,3-dipole cycloaddition reaction with benzyl chloride series compounds and sodium azide.Their structures were characterized by NMR,IR and MS.There are many studies on the structural modification of sinomenine,but few reports on the structural modification of biheterocyclic,and the study on the modification of sinomenine with tetrazole has not been reported.In this paper,we developed new methods for the synthesis of three kinds of sinomenine derivatives,and provided 50 new D-cycloazole sinomenine derivatives,which enriched the library of sinomenine derivatives and provided a new method for the study of structural modification of sinomenine and other drugs.