Studies On Design And Synthesis Of Nonpeptide Angiotensin â…¡ Receptor Antagonists Fluorin Biphenyl Compounds

The cardiovascular disease is the serious disease that harms for people’s health. It is the main reason that causes population death. The hypertension that gets sick for the most common cardiovascular disease has become the first cause of death of our country inhabitant. It affects the quality of life seriously. Thus the preventing and controlling of hypertension was important.Renin-angiotensin system （RAS）, in which angiotensin II （Ang II） is a key hormone, plays an important role in regulation of blood pressure and electrolyte homeostasis. Angiotensionogen from liver is cleaved by renin to produce biologically inactive angiotensin I , which is converted to highly active Ang II by angiotensin-converting enzyme（ACE）. There are at least four Ang II receptor subtypes. The AT₁ subtype appears to mediate virtually all of the well-defined actions, such as vasoconstriction and aldosterone release that lead to increase in blood pressure.Nonpeptide Ang II receptor antagonists have developed as antihypertensive agents, which bind specially to Ang II receptor AT₁ and display the profile of good oral bioavailability and potent activity with a long duration of action. The first orally active, nonpeptide, Ang II receptor antagonist Losartan （Cozaar）, opened an exciting new phase for the treatment of hypertension. Based on the Losartan’s SAR, a series of new compounds were designed by the application of principle of bioisosterism and hybrid approach etc. Using Valsartan as a lead structure, with （5-oxo-1,2,4-oxadiaole-3-yl） biphenyl as a core, some kinds of side chains were linked. Based characterized by HNMR, MS, IR and microanalysis or high resolution MS. The compounds are potential antihypertensive.In the foundation of previous works, synthetic method of new sartan’s was explored. Fluorobenzoic acid as the core, north-irbesartan, north-losartan and north-valsartan as the hydrophobe area, the new compounds were designed in order to find some new information about effect and structures.The efficient synthesis of target compounds was obtained starting from 1-bromo-4-methylbenzene. The strategy of the target compounds was cut off from the middle of the two benzene rings, and the key step was accomplished through Suzuki Coupling reaction. It’s worth to mention that most of the intermediates were synthesized for the first time. All the target compounds were synthesized while their structures were confirmed by HNMR, MS, etc. The preliminary pharmacological assays indicate that compound 1 has distinctive anti-hypertension drug candidate. The further evaluation of all the six compounds is under investigation.