Design And Synthesis Of Novel Angiotensin Ⅱ Receptor Antagonists

Hypertension,a medical condition in which the blood pressure is chronically elevated,is one of the risk factors for strokes,heart failure and renal failure,and also related with coronary heart disease and diabetes.It is defined as the blood pressure of an adult over 140/90mmHg by World Health Organization(WHO).The renin-angiotensin system(RAS) is recognized as a key element in blood pressure regulation and electrolyte/fluid homeostasis.Angiotensinogen from the liver is cleaved by the aspartyl protease renin to produce the decapeptide angiotensinⅠ(AngⅠ).Biologically inactive AngⅠis cleaved by the angiotensin-converting enzyme (ACE) to produce the endogenous octapeptide hormone angiotensinⅡ(AngⅡ). Once AngⅡbinds to its typeⅠreceptor,it subsequently activates several effector systems,such as phospholipases C,D,A2,adenyl cyclase,etc,to cause vasoconstriction and release of aldosterone,and thus blood pressure is elevated.To date,there are many kinds of anti-hypertensive drugs commercially available in the market such as diuretics,P-blokers,calcium blockers,angiotensin converting enzyme inhibitors(ACEI) and angiotensinⅡreceptor antagonists(or angiotensin receptor blockers,ARB).ARB is a novel antihypertensive agent targeted to RAS following the application of ACEI.Losartan,the first nonpeptide ARB,was approved to be used in clinics in 1994.By researching of the structure-activity relationship (SAR) and action mechanism,various angiotensinⅡreceptor blockers have been designed,synthesized and put into the clinical trials.Using Bali2005 and BMS-180560 as lead compounds,1,4-substituted indole compounds were designed according the theories of drug design such as SAR, hybridization and bioisosterism.Based on the previous researches on acidic group in our laboratory,biphenyl compounds containing fluorin substituted were also designed.Five target compounds have been designed and synthesized.As a crucial step, benzoyl chloride was employed to protect imino group of 4-methylindole in the synthesis of 1,4-substitued indole compounds.Then(4-(bromomethyl) -1H - indol -1- yl)(phenyl) methanone was successfully synthesized.Biphenyl compounds containing fluorin substiuent were synthesized using Suzuki coupling reaction as committed step to form the biphenyl C1-C1’ bond.During the synthesis,considerable efforts have been devoted to N-acylation,N-alkylation,Suzuki coupling reaction, benzyl bromination,cycloaddtion,removal of protective group.Mild synthetic methods with satisfied yield have been found.All the target compounds are novel and first synthesized in our laboratory.Their structures were characterized by NMR and MS.The pharmacological and toxicological studies are under investigation.