Design, Synthesis And Biological Evaluations Of 4-aminopyridine Derivatives

Neurodegenerative diseases(ND)are a class of central nervous system diseases,whose common pathological feature is a large number of protein in memory neurons misfolding and aggregation,leading to progressive degeneration and even death of neurons.Large amount of studies have shown that a lot of CNS degenerative diseases were with abnormal activation of Rho kinase(ROCK).Hence,we speculate that ROCK can influence the occurrence and development of diseases from different aspects.4-Aminopyridine,a type of voltage-gated potassium channel blocker,which can promote transmitters release like ACh,NA and DA in the central nervous system,is frequently used in treatment of neurologic diseases in clinic such as multiple sclerosis and Alzheimer’s disease.This project includes two parts:1.A scalable and facile process for N-(pyridin-4-yl)piperazine-1-carboxamide hydrochloride,a novel Rho kinase inhibitor currently under investigation for the treatment of neurodegenerative diseases,was established.Strategy one used 4-aminopyridine as raw material,ethyl chloroformate as activator,1,4-dioxane as solvent and N-methylpyrrolidine as catalyst.Treatment with piperazine in autoclave shortened the reaction time.Change of molar ratio avoided the by-product.Strategy two used N,N’-Carbonyldiimidazole as activator,acetone as solvent,reacting with N-Boc-piperazine at room tempreture,followed by deprotection and salt-formation.The reaction condition of strategy two was mild with the purity above 99% and yield about 54%.The progress can offer kilogram product.2.Eight 4-aminopyridine derivatives were designed and synthezed with4-aminopyridine and N-(pyridin-4-yl)piperazine-1-carboxamide as the lead compounds.The rat PC12 mice pheochromocytoma cells of A53 T mutant ofα-synuclein were as an in vitro model in the biological experiments.Five compounds were evaluated.The vitro biological activitity results showed that compounds 11 and12 exhibit better significant activity than others.However,compounds except 14 can facilitate apoptosis.Therefore,they are believed to be potential candidate drug for tumor.