Study On The Synthetic Methods Of Anti-heart Failure Drug Omecamtiv Mecarbil

Heart failure(HF)is a common human disease with high morbidity.Its five-year survival rate is the similar to malignant tumor.There are many kinds of traditional anti-heart failure medicines in clinic,but all have their own corresponding limitations.Despite advances in therapy,HF patients continue to be at markedly increased risk for hospitalization and premature death in the last years.In addition,HF patients experience one of the lowest quality of life amongst chronic diseases.The cost of caring for HF patients also places an enormous burden on health care systems.Thus,novel therapies that can improve the natural history of HF patients are urgently needed.Cardiac contractions rely on a kind of contractile proteins including myosin proteins and actin proteins.Myosin proteins have two biological roles.First it has ATP enzyme activity that cleaves ATP and releases chemical energy.Second it has the ability to bind actin proteins.Cardiac myosin proteins can transform the released chemical energy into kinetic energy of muscle contraction.Advances in our understanding of underlying pathophysiologic mechanisms have given rise to a new therapie for treating the growing HF population,direct activator of cardiac myosin.Omecamtiv mecarbil,a small-molecule,selective,cardiac myosin activator is the most advanced exemplar of this novel mechanistic class.Omecamtiv mecarbil can increase cardiac contractility without changes in cardiac myocyte calcium homeostasis,which aim to increase myocardial contraction time,improve myocardial function.Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.Omecamtiv mecarbil(1),4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylic acid methyl ester,is developed by Cytokinetics company in the United States for left ventricular systolic heart failure.Omecamtiv mecarbil is studied in phase III clinical fields currently as a new mechanism which is directly activating cardiac myosin to exert anti-heart failure.Objectives:The study is aimed to establish the synthetic methods of Omecamtiv mecarbil,to optimize the reaction conditions and to obtain the target compounds.It is also aimed to establish the analysis methods of target compounds.Methods:Synthetic route of Omecamtiv mecarbil is settled by accessing to relevant literature and experiment design.Methyl 2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzoate(4)was synthesized from methyl3-amino-2-fluorobenzoate(2)as the starting material by successively condensed with phenyl chloroformate and 2-methyl-5-aminopyridine,then it was subjected to reduction and chlorinated to give 1-(3-(chloromethyl)-2-fluorophenyl)-3-(6-methylpyridin-3-yl)urea(6).Omecamtiv mecarbil was synthesized from 6 and methyl piperazine-1-carboxylate by nucleophilic substitution.The structures of intermediates and target products were comfirmed by melting point,mass specrum(MS)and nuclear magnetic(NMR).Finally,high performance liquid chromatography(HPLC)method was used for the chemical purity determination of Omecamtiv mecarbil.Results:By using the designed synthetic routes,the target compound Omecamtiv mecarbil was obtained successfully with an overall yield of 39.4%(based on compound 2).Omecamtiv mecarbil:white crystal solid,mp177.5～178.8°C,purity 99.4%.The structure was comfirmed by MS,~1H NMR.Conclusion:In this paper,using 3-amino-2-fluorobenzoic acid as the starting material,the target product Omecamtiv mecarbil was obtained by 6steps.The synthetic strategies were also optimized.The new route has the advantages of easy and cheap reagents,mild reaction conditions,simple work-up,stable yield.The study provides a new idea and important reference for development and production of Omecamtiv mecarbil in the future.