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

• Published in: Journal of medicinal chemistry 1981-11, Vol.24 (11), p.1300-1304
• Main Authors: Acheson, R. Morrin, Bite, Maris G, Kemp, John E. G
• Format: Article
• Language: English
• Subjects: Animals; Blood Pressure - drug effects; Bronchodilator Agents; Chemical Phenomena; Chemistry; Dogs; Epinephrine - analogs & derivatives; Epinephrine - chemical synthesis; Guinea Pigs; Heart Rate - drug effects; In Vitro Techniques; Myocardial Contraction - drug effects; Receptors, Dopamine - drug effects; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; Thiadiazoles - chemical synthesis; Thiadiazoles - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00143a008

Treatment of N,N'-dibenzyl-1,2-diaminobenzene (2) 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) four bicyclic catecholamine analogues 7a-d. Hydrogenolysis of 4 yielded the parent heterocycle 5 in the first practicable synthesis avoiding expensive sulfamide (Scheme I). The trifluoromethanesulfonamidoacetophenones 8m and 8p on similar elaboration gave triflanilide catecholamine analogues 14m, 14p,17m, and 17p (Scheme II). 4,4'Dimethoxybenzhydrylamine (15) is recommended for the regiospecific synthesis of primary amines from epoxides (Scheme II). Series 7,14, and 17 were inactive in animal 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 approximately equal to 4).