Synthesis And Bioacitvity Study On2-Substituted-5’,6’,8’,9’-Tetarhydrospiro[Benzo[d]annulene-4,7’(1’H)-Inriidazolidine]-2,5-Dione

Today, a large number of natural nitrogen-containing heterocyclic compounds have widedistribution in nature， with the vigorous development of the life sciences, thenitrogen-containing heterocyclic compounds in the field of pharmaceuticals, pesticides, dyes,materials are increasingly being used. In the nitrogen-containing heterocyclic compounds,pentatomic heterocyclic plays an important role. Hydantoin and its derivatives are importantpentatomic heterocyclic compounds, Their structure contain two N atoms and two carbonylgroups. Hydantoin exists widely in the sprouts of tropical trees and seedings of Sugar beet.From beginning, hydantoin is applied in the research on the protein in living creatures. Withthe development of research, a series of hydantoin derivatives are found one by one, whichmake hydantoin and its derivatives more and more popular in lots of fields. Because of theunique biological activity of hydantoin derivatives and broad applications has receivedextensive attention in chemical researchers.Considering the special pharmacological action of hydantoin derivatives, eries tetral inhydantoin derivatives were synthesized refer to the research group experimental methods, andon that basis, the target compounds of containing benzocycloheptane structures were designedand synthesized.3,4-dimethyl-1-bromobenzene and5-bromothiophene-2-carboxaldehydewere respectively used as the initial raw material to synthesis the corresponding ketonesstructure intermediates, followed by ‘Bucherer-Bergs’ synthesis was used to obtain targetcompounds. The key intermediate and the ultimate objective product were confirmed by1HNMR,13C NMR and pharmacological activity was studied through mice ammonia inducedcough experiments.There are many kinds of ways to synthesize the molecular process,in the end wechoose the Bucherer-Bergs method. The Bucherer-Bergs synthesis applies the mostwidespread hydantoin derivative synthetic method at present, which has high productionrate,besides the operation is relatively simple. During the synthesis process of target compounds, when synthesis the key intermediate2-substituted-5,6,8,9-tetrahydro-benzo[d]cyclohepten-7-one, because of milder reaction conditions Suzuki reaction,2-butyl-5,6,8,9-tetrahy dro-benzo[d]cyclohepten-7-one and2-octyl-5,6,8,9-tetrahydro-benzo[d]cyclohepten-7-onecould be directly obtained by alkylation from2-bromo-5,6,8,9-tetrahydro-benzo[d]cyclohepten-7-one when R was butyl and octyl. During the synthesis process of tetrahydrobenzo [b]thiophene hydantoin derivatives, when synthesis the key intermediate5-substituted-2-thiophenecarboxaldehyde,5-phenyl-2-thiophenolaldehyde could be directly obtainedby arylation from5-bromo-thiophene-2-formaldehyde when R was phenyl. But when Rwas octyl, the better method was with1-octene as raw material and Heck reactionwas adopted,5-octyl-2-thiophene-carboxaldehyde could be directly obtained by alkylation from5-bromo-thiophene-2-formaldehyde.Finally,by studying the effects on ammonia water cough test of mice and pharmacologyactivity screening of hydantoin derivatives. Hydantoin derivatives could reduce ammoniaspray frequency cough in mice, and extend the cough incubation period, and show goodantitussive effect. Especially the benzocycloheptane hydantoin derivatives when R=C4H9-could show most obvious antitussive effect.Hydantoin compound as a new, broad-spectrum, and efficient disinfectant has beenwidely applied. And have a good prospect of application in the treatment of diabetes, kidneydisease, autoimmune diseases and blood disorders. Therefore,has far-reaching significance tothe study of the hydantoin compounds. In this article, hydantoin derivatives were designed andsynth-esized. This approach could provide a pharmacological basis for clinical treatment anddrug research and development of cough and asthma and chronic lung disease.