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.
Along with other developments, the history of pharmaceutical research in our laboratories shows a close connection with the history of diuretics. A few years after the discovery in 1919 that antibiotic mercury compounds display diuretic effects (1, 2), investigators at Hoechst developed Salyrgan as the reference compound of the "Mercurials" (3). About 30 years ago, these organometallic drugs were displaced by sulfonamide derivatives which produced long acting diuresis (4, 5, 6). In 1959, research ers at Hoechst discovered the first potent short acting high -ceiling diuretic with a benzenesulfonamide structure, furosemide (7). Another interesting development in the field of high-ceiling diuretics was the synthesis of the acylphenoxyacetic acid deriva tive, ethacrynic acid (8).Another significant contribution to the high-ceiling diuretics which emanated from research in our laboratories was the development of piretanide (Hoe 118) during the last few years (9).The present report will show the importance we attach to the long acting salidiuretics. When we first began our research into long acting diuretics, only the sulfonamide derivatives were known. At that time all commercial diuretics with a thiadiazidelike salidiuretic action could be derived from two general formu las, i.e., either from 3-sulfamoylsulfonamides (Structure 1) or from 3-sulfamoylbenzamides (Structure 2). Chlorthalidone (Compound 3) was an exception to this generalization (Scheme I).
Scheme I
3-Sulfamoylsulfonamides2 3-Sulfamoylbenzamides 3 Chlorthalidone 0-8412-0464-0/78/47-083-024$05.00/0
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