5-Sulfamoylorthanilic acids, a sulfonamide series with salidiuretic activity

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Abstract
A series of 4,N-disubstituted 5-sulfamoylorthanilic acids was synthesized by nucleophilic substitution reactions starting from 2,4-dihalogeno-5-sulfamoylbenzenesulfonic acids or in most cases from phenyl 2,4-dihalogeno-5-sulfamoylbenzenesulfonates. The latter method is based on the relative stability of the phenoxysulfonyl group to nucleophiles, e.g., amines, phenols and thiols, and the possibility of smooth hydrolytic or hydrogenolytic cleavage as a final step, with formation of the SO3H group. On evaluation of these compounds for salidiuretic activity in rats orally (p.o.) and in dogs orally and i.v., a number of highly active substances was found; the best had a threshold dose of 0.02 mg/kg p.o. in dogs. The results are given in tables, and the structure-activity relationships within the series are discussed. Besides the known effect of the phenoxy radical, an outstanding activating effect was shown by the butylsulfonyl and cycloalkylsulfonyl radicals and by the N-methylanilino radical when they were located in the 4-position of the orthanilic acid molecule. The sulfanilic acid isomers corresponding to 3 of the most active compounds were synthesized and proved to be completely inactive in rats.

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