Synthesis And Bioactivity Determination Of 2-(4-substituted-benzyloxy) Aryl-s-1,2,4-triazolo"1,5-a" Pyridine Derivatives

In year 1999,our Medicine Facility of Zhejiang University found that 2-(4-benzyloxy) phenyl - s-l,2,4-triazolo [l,5-a]pyridine, compounds ZA11 andZA18, have strong anti-tumor activity in human ovary.In this study we selected compound ZA11 as a leading compound. According to relevant references, we carried out our research work on the following aspects:1. Introducing an electron-withdrawing group of NOi or an electron-contributing group of OCH3 to ring D;2. Introducing one or more electron-contributing group, e.g.:OCH3 -OCH2O- or several halogens, to ring E;R1=OCH3;H;NO2R2=OCH3;H;2-Cl;2,4-2F;4-OCH3;3,4-2OCH3;2,3-2OCH3;3-OCH2O-43. Keeping the integrality of ring A.R1=HR2=H;2-CI;2,3-2OCH3The target compounds were designed and synthesised as following: 1. Preparation of N-aminating agentTaking alcohol and acetonitrile as raw material to give ethyl aceto-hydroxamate.Then this procedure compound was reacted with mesitylenesulfonyl chloride to give ethyl O-(mesitylenesulfonyl)-acetohydroxamate ,which was hydrolyzed by acid to result in the desired O-mesitylenesultonylhydroxylamine(MSH).2. Preparation of nitrilesTreatment of p- hydroxy benzaldehyde derivatives and benzylchloride derivatives as raw material to afford benzyloxy benzaldehyde derivatives,which was then oxidated by oxygen in the presence of copper powder to give nitriles.3. Condensationa-methylpyridine (or isoquinoline)reacted with MSH gave the correspounding ylid,which was then cyclied with nitriles to obtain target compounds.Eighteen compounds were designed and synthesized. Among them,sixteen compounds have not been reported yet. The structures of the target compounds were confirmed by IR and 'HNMR.The suppressing experiments of seventeen compounds have been done in vitro on HO-8910 tumor cell of human ovarian and Bel 7402 tumor cell of human liver. Among them,eight compounds(42i 42d 42j 42k 42c 42g 41r 41p) have strong suppressing activities. Their structure-activity relationships were studied as following:1. When ring E has been substituted with some electron-contributing group,the substitution of ring D with 3-OCH3 will weaken the suppressing activity,eg:the activity of compound 42j is stronger than 42f,42k is stronger than 42e,et al.2. When ring E has been substituted with some electron-withdrawing group or no substituting group,the substitution of ring D with 3-OCH3 will be benefit to the suppressing activity,eg:the activity of compound 42g is stronger than 42n,et al.3. Substituting ring D with eletron-withdrawing groups will weaken the activityWe also testified that these compounds can bring Bel 7402 tumor cell into death.