Studies on 1,2,4-benzothiadiazine 1,1-dioxide - IX. Synthesis and pharmacological evaluation of 1,2,4-benzothiadiazine 1,1-dioxide biphenyl tetrazoles as angiotensin II antagonists

In the course of our investigations on the development of cardiovascular agents, 3-butyl-2-[2'-(2H-tetrazol-5-yl)biphenyl-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 mu M and 5.4 mu M, respectively. Compound 10 (IC50 = 87 nM) exhibited stronger binding affinity than compound 2 (IC50 = 750 nM).