Acidic epinephrine analogs derived from 1H,3H-2,1,3-benzothiadiazole 2,2-dioxide and from trifluoromethanesulfonanilide. New synthesis of 1H,3H-2,1,3-benzothiadiazole 2,2-dioxide

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Abstract
Treatment of N,N''-dibenzyl-1,2-diaminobenzene successively with thionyl chloride and then m-chloroperbenzoic acid gave N,N''-dibenzyl-1H,3H-2,1,3-benzothiadiazole 2,2-dioxide (4) which gave (via routes analogous to standard epinephrine syntheses) 4 bicyclic catecholamine analogs. Hydrogenolysis of 4 yielded the parent heterocycle in the 1st practicable synthesis, avoiding expensive sulfamide (Scheme I). The trifluoromethanesulfonamidoacetophenones on similar elaboration gave triflanilide catecholamine analog (Scheme II). 4,4''-Dimethoxybenzhydrylamine is recommended for the regiospecific synthesis of primary amines from epoxides (Scheme II). The series were inactive in dog and guinea pig cardiovascular screens. Selected compounds were also screened in bronchodilator and in in vitro dopamine-, clonidine- and prazosin-receptor binding assays as appropriate; again no activity was observed. Steric, lipophilicity and acidity factors are discussed, and the inactivity is ascribed to the high acidity of both systems (pKa .apprxeq. 4).