Design、synthesis And Antihistamine Activity Of Desloratadine Derivatives

Allergic diseases are human common disease. The mechanism of this diseaserelates to a kind of active substrate—histamine. Desloratadine, the active metaboliteof loratadine, which exhibited strong anti-allergic effects, fast action, no sedation andcardiac toxicity, had the trend to take the place of loratadine. However, clinical studyshowed that in low concentration, desloratadine can arose dry mouth, dizziness,headache due to the good affinity to M choline. Besides, desloratadine had cardiactoxicity in large dose.The aim of this paper is to modify desloratadine in order to acquire the targetcompounds. And then they will be progressed activity test to sieve the moreanti-histamine active and less side-effects compounds.Firstly, the synthesis of N-Hydroxyalkyl-4-piperidones was studied.N-Hydroxyalkyl-4-piperidones can be obtained from amino alcohols and methylacrylate through Michael reaction, followed by Dieckmann cyclization anddecarboxylation in the yield of21.9%~45.6%. The amount of sodium methoxide wasinvestigated in the Dieckmann cyclization and the best result was received under themolar ratio1:1.6of diadduct to sodium methoxide. The by-products through aldolcondensation and chloro substitution were separated and characterized in the processof synthesizing N-hydroxyhexyl-4-piperidone.Secondly, we saw hydroxypropyl desloratadine as the lead compound, designedand synthesized two kinds of desloratadine derivatives. They were hydroxyalkylderivatives with the carbon chain increasing and fluoro, chloro, bromacyl substitutionderivatives according the bioisosterism. Besides, desloratadine was acted as the leadcompound. We designed and synthesized a series of cyclic desloratadine derivatives.Finally, the antihistamine activity of four desloratadine derivatives was tested.The results showed that all of them had the antihistamine activity and hydroxypropyland fluopropyl desloratadine derivatives were better.