Study On Synthesis Of 4?,16?-Diazocyclic Steroidal Neuromuscular Blockers

Neuromuscular blocking agents have the effect of skeletal muscle relaxation and can be widely used as an auxiliary drug for surgical anesthesia in endotracheal intubation.The marketed non-depolarizing neuromuscular blockers focus on steroidal drugs and benzyl isoquinoline drugs,which have the advantage of being reversed by anticholinesterase drugs,but generally have the disadvantages of slow onset,long duration of action,cardiovascular side effects and so on.Currently,steroid neuromuscular blockers on the market basically contain two acetylcholine-like structural units distributed at A-ring and D-ring,Among them,the acetylcholine structural unit of ring A may be the cause of some side effects of the drug,Therefore,the reconstruction of ring A pharmacophore can not only maintain the efficacy,but also provide an opportunity to alleviate the adverse reactions.In this paper,A synthetic route is designed to modify the acetylcholine structure of steroid neuromuscular blockers'A ring,This route has the advantages of simple operation,friendly reagent and universal application.Androstenedione was used as starting material in the experiment,Tetrahydropyrrole,piperidine and morpholine were used as the site 4 and site 16 substituent groups,A series of 4?,16?-dinitrogen heterocyclic steroids were synthesized by eight-step reaction.The structures of the synthesized compounds were confirmed by ¹H NMR and ¹³C NMR.At the same time,3?,17?-di?acetoxyl?-4?-?1-piperidine?-16?-?4-morpholine?-5?-androstene-16N-methy l iodide crystals were cultured,and their structure was further confirmed by means of crystal diffraction.The 4?,16?-diazocyclic steroidal compounds synthesized through this route conform to the structure-activity relationship of neuromuscular blockers,and can provide an important reference for the design and development of such drugs.