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A series of 4,N-disubstituted 5-sulfamoylorthanilic acids was synthesized by nucleophilic substitution reactions starting either 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 (po), and in dogs orally and intravenously (iv), a number of highly active substances was found; the best had a threshold dose of 0.02 mg/kg po 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 in particular when they were located in the 4-position of the orthanilic acid molecule. The sulfanilic acid isomers corresponding to three of the most active compounds were synthesized and proved to be completely inactive in rats.

Bovine carbonic anhydrase B (CA) inhibitory effect of furosemide was established in two pH values at 26 degress. FFBu [N-furfuryl-4-chloro-5-(butoxymethylsulfamoyl)anthranilic acid] and FFMe [N-furfuryl-4-chloro-5-(methoxy-methylsulfamoyl)anthranilic acid], two of its alkoxymethyl derivatives, did not exert any CA inhibitory effect at those conditions but were found to inhibit the CA activity after their hydrolysis, which yielded the furosemide molecule. The CA inhibitory effect of furosemide was utilized for determining the kinetic rate constants for the hydrolysis of FFBu and FFMe at various pH and temperature levels. The hydrolysis rate constants of FFBu and FFMe were pH-independent in the pH range tested, and the temperature dependence for FFBu yielded an activation energy of 18 kcal/mol. It is pointed out that the hydrolysis rates of FFBu may be important for the explanation of its possible delayed diuretic effect.