Studies On The Synthesis And Antimyocardial Ischemia Evaluation Of The Ivabradine Analogues As Antianginal Agents

Myocardial ischemia disease such as angina is a high attack-rate of coronary artery disease.At present,medication has been the main method to cure myocardial ischemia in clinic.I_f inhibitor has been developed as a new kind of antimyocardial ischemia drug in recent years,and Ivabradine is a representative drug of I_f inhibitor in clinic.This article summarized the research progresses on the drugs of anti-angina, especially the research progresses on the synthesis of I_f inhibitor.On the base of the research,nine compound as Ivabradine analogues were designed,synthesized,and evaluated for their antimyocardial ischemia activities.The main contents of this paper are as follws:1.In this paper,2-Bromo-4,5-dimethoxyhydrocinnamonitrile was synthesized in two different routes.It was synthesized from vertraldethyde,via bromination, condensation with cyanocetic acid,reduction,decarboxylation to give 2-Bromo-4, 5-dimethoxycinnamonitrile;It was synthesized from vertraldethyde,via bromination,condensation with acetonitrile and reduction to give 2-Bromo-4,5-dimethoxycinnamonitrile, which has never been reported in any article,and 2-Bromo-4,5-dimethoxycinnamonitrile is a new compund.Then 1-Cyano-4,5-dimethoxybenzocyclobutene was obtained in the ring closing reaction by NaNH₂ in anhydrous liquid NH₃2.7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one is an important intermediate in this synthetic route.After comparing the four routes in literatures,this synthetic route was chosed and improved as:3,4-Dimethoxy-phenylacetic acid as starting material,after reaction with SOCl₂,acylation with aminoacetaldehyde dimethyl acetal,then ring closing reaction to give the important intermediate 7,8-Dimethoxy-1,3- dihydro-2H- 3-benzazepin-2-one.It is suitable for large-scale preparation.3.In the proccess of designing the target compounds,the two molecules of Ivabradine and Ranolazine applied in clinic were dissected and hybrided.In the end the frame segment benzazepin-2-one was preserved,piperazine ring and acylamide bond was introduced.Then the main molecule frame was decorated with different groups,to give series of Ivabradine analogues.The Structural modification of compounds included two aspects:changing the substituted groups on the aromatic ring and changing the connecting way between the aromatic ring and piperazine.The substituted groups on the aromatic ring was methoxy, chloride,methyl,fluoride,nitro ect.Chloroacetyl chloride and carbonyl group were used in connection.Therefore,nine target compounds and one intermediate were synthezied,and confirmed by IR,¹HNMR and EI-MS.4.The target compounds was synthesized from 7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one, via reaction with 1-bromo-3-chloropropane,connection with piperazine ring to give 1,3-Dihydro-7,8-dimethoxy-3-[3-(1-piperazinyl) propyl]-2H-3-Benzazepin-2-one as the common intermediate.Then the common intermediate reacted with six N-Aryl-2-Chloroacetamide to give compound 1-6;reacted with three Benzoyl chloride to give compound 7-9.5.The nine compounds synthezied in this paper were evaluated for vasorelaxant activity against 40 mmol.L^-1 KCl and 1.8 mmol·L^-1 CaCl₂,inducing constraction of rat aorta in vitro.The preliminary data suggested that the target compounds showed some vasorelaxant activity and heart rate-reducing activity at 10μM concentration.The activities of compounds(7-9) are stronger than compounds (1-6),easpeciallly the inhibition of compound 8 is 52.6%.The data applied by BL-410 test system showed that the nine compound had different inhibition on the heart rate in rats in the dosage of 5 mg/kg,the reduction to the heart rate of compound 1 is 32.3%.Further biological evaluation and structural modification are on the way.