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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
Author(s) -
Chem JiWang,
Lin HuaMei,
Cheng FongChi,
Lo JirChun,
Lai NanYi,
Kao ChaiLin,
Usifoh Cyril O.
Publication year - 1998
Publication title -
journal of the chinese chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.329
H-Index - 45
eISSN - 2192-6549
pISSN - 0009-4536
DOI - 10.1002/jccs.199800121
Subject(s) - benzothiadiazine , chemistry , ring (chemistry) , benzothiadiazines , medicinal chemistry , angiotensin ii receptor antagonist , methanol , stereochemistry , angiotensin ii , angiotensin receptor , organic chemistry , receptor , pharmacology , medicine , biochemistry
In the course of our investigations on the development of cardiovascular agents, 3‐butyl‐2‐[2′‐(2 H ‐tetra z ol‐5‐yl)bipheny]‐4‐yl]methyl‐2 H ‐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 IC 50 values of 3.6 μM and 5.4 μM, respectively. Compound 10 (IC 50 = 87 nM) exhibited stronger binding affinity than compound 2 (IC 50 = 750 nM).