Patent Evaluation: Novel Angiotensin II Antagonists

Summary

Novelty: New imidazole derivatives are disclosed as antihypertensives. They contain an imidazole substituted in all positions, except for one nitrogen.

Biology: An in vitro assay is described using rat liver membranes treated with radiolabeled [¹²⁵I] angiotensin II (A II) at 30 μM (IC₅₀ values in the 0.5 nM range). An additional assay using portal vein rings of male Wistar rats treated with 30nM A II indicates IC₅₀ values in the order of 0.1 nM. In vivo, an assay to measure arterial diastolic pressure in pentobarbital anaesthetized male Sprague-Dawley rats indicates IC₅₀ values of 22 μg/kg.

Chemistry: One hundred and forty-three examples are given using conventional methods for the preparation of the compounds. Characterization is by mp, ir, NMR and elemental analysis. The preferred compound is 2-butyl-4-(methylthio) 1-[[2′-(1H-tetrazol-5-yl) (1,1′-biphenyl)-4-yl]methyl] 1H-imidazole-5-carboxylic acid.