Studies on 1, 2, 4‐Benzothiadiazine 1, 1‐Dioxide IX.1 Synthesis and Pharmacological Evaluation of 1, 2, 4‐Benzothiadiazine 1, 1‐Dioxide Biphenyl Tetrazoles as Angiotensin II Antagonists

Abstract

AbstractIn the course of our investigations on the development of cardiovascular agents, 3‐butyl‐2‐[2′‐(2H‐tetrazol‐5‐yl)bipheny]‐4‐yl]methyl‐2H‐1, 2, 4‐benzothiadiazine 1, 1‐dioxide (2) was considered as a potential angiotensin II antagonist on the basis of bioisosteric replacement of the quinazoline ring of compound 1 with a 1, 2, 4‐benzothiadiazine 1, 1‐dioxide ring system. Alkylation of 6 with 4 afforded 7 and 8 in 24% and 28% yields, respectively. An attempt to remove the trityl group of compounds 7 and 8 under acidic condition gave the ring opened products 9 and 11 in 28% and 36% yields, respectively. However, compounds 2 and 10 were obtained in 46% and 85% yields when compounds 7 and 8 were refluxed in methanol. Preliminary assays of compounds 9 and 11 against angiotensin II receptors revealed weak activity with IC50 values of 3.6 μM and 5.4 μM, respectively. Compound 10 (IC50 = 87 nM) exhibited stronger binding affinity than compound 2 (IC50 = 750 nM).