Design And Synthesis Of VLX600 And Its Related Analogues

In this paper,the iron chelators were illustrated in detail.A synthetic route of VLX600 was improved.7-Methyl isatin?2?was synthesized via Sandmeyer reaction from o-toluidine,then 2 reacted with thiosemicarbazide in water with beta cyclodextrin??-CD?as catalyst to give 3.When the reaction of 3 with hydrazine hydrate in isopropanol was finished,4 was separated by filtration.Then 4 was subjected to condensation with 2-acetylpyridine in the presence of acetic acid to afford VLX600.The chemical structures of VLX600 was confirmed by MS,¹H-NMR and ¹³C-NMR.VLX600 was selected as the lead compound and referenced the structural features of CaspseactivatorPAC-1.Accordingtothetheoryofbioisosterism,5H-[1,2,4]triazolino[5,6-b]indolewas replaced by 5,10-dihydropyridine[2',3':5,6]pyrazine[2,3-e][1,2,4]triazine.Various substituted arylhydrazon were incorporated into the C-3position and different substituents were introduced into the N-6 position of skeleton by the theoryofScaffoldhopping.Aseriesof3-arylhydrazonyl-5-substituted-5,10-dihydropyridine[2',3':5,6]pyrazine[2,3-e][1,2,4]triazinederivatives which add up to 44 new compounds were designed and synthesized.The synthetic route of VLX600 analogue was designed according to the analogy.2-chloro-3-nitropyridine is used as starting materials,substituted with various amines to give 2-substituted amino-3-nitropyridine compound ZB-B.Then,through nitro reduction reaction and oxalic acid cyclization reaction give compound ZB-C.Using phosphorus oxychloride as chloro reagent to obtain intermediate ZB-D.It is cyclized with thiosemicarbazide to give to intermediate ZB-E.Then substitution reaction occurs with hydrazine hydrate,and finally a condensation reaction occurs with aryl aldehyde or aryl ethyl ketone to obtain a series of VLX600 analogue.The structures of VLX600 analogue were identified by¹H-NMR,some of them were confirmed by¹³C-NMR.