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A series of N-substituted-3and -4-benzenedisuIfonamides (Tables I and II) have been prepared by the reaction between 3-and 4-sulfamylbenzenesulfonyl chloride and amines, respectively. A number of other synthetic methods were not successful. The anticonvulsant and carbonic anhydrase inhibitory properties of these compounds are listed in Tables III-VII. Some show greater anticonvulsant activity than either acetazolamide or ethoxzolamide. The N-substituted-4-benzenedisulfonamides are more potent anticonvulsant agents than the N-substituted-3-benzenedisulfonamides. Within the N-substituted-4-benzenedisulfonamide series, bulky or polar substituents (Ri, R2) decrease anticonvulsant activity. A correlation between in vivo inhibition of brain carbonic anhydrase and anticonvulsant activity is suggested.Within the past few years a considerable body of literature has appeared relating to the clinical usefulness of a wide variety of benzene and heterocyclic sulfonamides. Some of these, such as the 1,2,4-benzothiadiazine-1,1-dioxides and 1,3-benzenedisulfonamides, are potent diuretic agents.2-8 Other sulfonamides, such as acetazolamide,9 ethoxzolamide,10 dichlorphenamide,11 and methazolamide,12 which were originally developed as diuretic agents, are used now either in the treatment of glaucoma or epilepsy. The diuretic, antiglaucoma and anticonvulsant activities of these latter drugs result from their inhibiting the enzyme carbonic anhydrase4-613-17 in the renal tubules, ciliary body of the eye18•19 and brain,20•21 respectively. The more effective 1,2,4-benzothiadiazine-l, 1-dioxides have largely replaced the carbonic anhydrase inhibitors as diuretic agents.A series of X-substituted benzenedisulfonamides was prepared during the course of a search for prototype sulfonamides. This report is a structure-anticonvulsant activity study of these compounds, inasmuch as their diuretic activity has already been shown(1) A.

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