Novel Synthesis Routes Based On Aryltriazenes For Deuterated Lodobenzene Derivatives And The Natural Products:Lipocarbazoles And Pharmacological Properties?synthesis Of Loperamide Hydrochloride Derivatives

There are three parts in this paper.For the first two parts,we have designed novel synthesis routes based on Aryltriazenes for a kind of important organic synthesis intermediates: 1-iodo-2-methyl-d3-benzene derivatives and the natural products : lipocarbazoles.In the last part,we made some research on the synthesis and pharmacological properties of the loperamide hydrochloride derivativesFirst,1-iodo-2-methyl-d3-benzene derivatives,as a kind of important organic synthesis intermediates,have an important role in drug development and the study in organic synthesis mechanisms.Currently,the Synthesis of this kind of compounds has been reported rarely.In this part we have designed a novel synthetic route,which is based on the Aryltriazenes to get a series of 1-iodo-2-methyl-d3-benzene derivatives.This new protocol showed wide substrate scope with respect to both electron-rich and electron-deficient Aryltriazenes.Also this method was characterized with high efficiency and good functional group tolerance.Second,We have designed a new synthesis route for the natural product lipocarbazoles.Lipocarbazoles is the secondry metabolites isolated from Tsukamurella pseudospumae Acta 1857,which is a series of new carbazole derivatives with long alkyl chain.Because of the compounds' small isolated amounts from natural sources,the synthesis of these compounds is of great significance.In this part,we planed to use a kind of Biaryltriazenes as the precursor to build lipocarbazoles' carbazole skeleton.when building the precursor,the mature Suzuki coupling method and Negishi coupling method haven't been unable to afford the desired product,the coupling reaction conditions still need further design and testing.Leukemia have been a widespread disease occurred in the world.In third part of the paper,we have found a class of targets that closely related to the occurrence and development of leukemia.Then,we intend to conduct a drug design through computer-aided drug design technology(CADD).First,with the use of CADD,we have initially established the pharmacophore model for leukemia.Second,through much virtual screening work for the pharmacophore model in the database containing approximately 900 existing clinical drugs,excitingly,we found antidiarrheal loperamide has potent inhibitory activity for the target,and the inhibition constant Ki is 19.8 ?M.Next,we designed a number of loperamide's structural modification sites.Finally,we conducted a corresponding chemical synthesis and got a series of loperamide derivatives,which will be in a new round of biological activity test,and the work is still in progress.