Studies On Synthesis Of Aminoacid Biphenyl Compounds And Evaluation Of Their Anti-Hypertension Effects

The angiotensinⅡ（AngⅡ）, a powerful vasoconstrictor, is the primary effector hormone of the Renin-Angiotemin-Aldosterone System （RAAS） which plays an important role in the regulation of blood pressure and electrolyte balance. In addition to vasoconstriction, the physiological actions of AngⅡand renal re-absorption of sodium were regulated. The inhibition of this system has been a fundamental target in the therapy of hypertension and congestive heart failure and other diseases.AngiotensinⅡreceptor antagonists are newest type antihypertensive drugs come into the market in recent years. AngⅡreceptor antagonists specially act on AngⅡreceptor. They display the profile of good oral bioavailability and potent activities with along duration of action and have been widely used. At present, there are many kinds of AngⅡreceptor antagonists, such as losartan, valsartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, etc. Most of this kind of drugs mainly developed from modification of losartan. Using valsaran as a lead structure and based on the valsartan’s structure-activities relationship （SAR）, with （5-oxo-1,2,4-oxadiaole-3-yl）biphenyl as a core, some kinds of side chains were linked, a series of new compounds were designed by the application of the principle of bioisosterism and hybrid approach in order to research the SAR of new compounds and the influence of these side chains.The synthesis methods of TAK-536 and valsartan were taken into account. One synthesis routine was established. As the primary material, 2-methoxybenzoic acid was transferred into 2-cyano-4’-methybiphenyl then reacted with amino acid ester. After a series of reactions the target compounds were obtained, including acylation, changing cyano compounds into amidoxyl compound, cyclization, cleavage of the protective groups, etc.We studied the alternative and cleavage of the protective groups of amino acids. The synthetic process is improved. As a result, the reaction yields were enhanced and the time of reaction was shortened.All the target compounds were synthesized while their structures were confirmed by ¹HNMR, ¹³CNMR and MS spectrum, etc. The preliminary pharmacological assays indicate that compound 1 have distinctive anti-hypertension effects and deserves further evaluation as new anti-hypertension drug candidate. The further evaluation of all the six compounds is under investigation.