Synthesis Of New Non-peptide AngⅡ/AT1 Receptor Antagonists And Reserches On Related Methods

The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure. An alternate and more direct mode of selectively blocking the RAS is by antagonism of the effector hormone AT1 at the receptor level.As far as peptide analogs of antagonists are concerned, their usefulness as therapeutic agents and pharmacological tools has been hampered by their lack of oral absorption, short duration of action. The parallel discovery of losartan and eprosartan, potent and orally active nonpeptide Ang II antagonists, has stimulated the design of a large number of congeners. In this dissertation, we report a number of new non-peptide AT1 receptor antagonists originating from structural designs of terazole analogs of sartans compounds have been reported. We turned our attention to search for modification of the tetrazole ring, replacement of the tetrazole ring by imidazole rings and triazole rings and combination with benzimidazoles derivatives which have antagonistic activity for angiotensin II, designed and synthesized a series of Ang II antagonists contaning imidazole or traizole ring. It is primary for the following filtrations of antihypertensive agents, thereout, we wish to obtain antihypertensive drugs which have independent intellectual property right.In the design of precursor, it is benzimidazole rings that become nuclear parent, starting from methyl 4-methyl-3-aminobenzoate, via acylation, nitration, reduction, intramolecular cyclization and hydrolysis, then reacted with N-methyl-o-phenylenediamine hydrochloride and afford the corresponding precursor. In the following, we started from inexpensive 2-cyano-4'-methylbiphenyl. Firstly it was condensated with ethylenediamine and converted to imidazoline, then was oxidized to imidazole under mild conditions.