Preparation and Anticonvulsant Activity of N-Substituted Benzenedisulfonamides

Abstract

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.

Discovery of Novel Antitumor Sulfonamides Targeting G1 Phase of the Cell Cycle

“…4-Sulfamoylbenzenesulfonyl Chloride (28). Prepared from sulfanilamide and obtained as a pale-yellow solid in 66% yield: R f 0.50 (1:1 EtOAc/hexane); MS (FAB + ) m / e 256 (MH + ).…”

“…For the synthesis of 25 − 27 , sulfonyl chlorides 28 − 30 were prepared according to general procedures as shown in Scheme .

3

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“…Compound 13 was reduced with Zn/HCl to give amine 14, which was further transformed to 15 through the condensation reaction with methanesulfonyl chloride. A chlorine atom was introduced into the For the synthesis of 25-27, sulfonyl chlorides 28-30 were prepared according to general procedures 24 as shown in Scheme 3.…”

Cerebrovasodilatation through selective inhibition of the enzyme carbonic anhydrase. 1. Substituted benzenedisulfonamides

“…Comparison of compound 19 with 18 shows that anticonvulsant activity was more than doubled. However, moving the chlorine to position 3 (20) was not advantageous, and disubstitution as in 22,23, 25, and 39 abolished all anticonvulsant activity. Replacement of 2-C1 by 2-CF3, 21 and 38, also led to loss of anticonvulsant activity even at doses of 100 mg/kg.…”

“…Holland et al subsequently extended this reaction to sulfanilamide and obtained 4-sulfamoylbenzenesulfonyl chloride in good yield. 20 In a similar manner the anilines 1-6 (Scheme I) were diazotized to yield the appropriately substituted sulfonyl chlorides 7a-f from which the requisite disulfonamides (Table I) were obtained after reaction with various amines. The aniline 4 is novel and was prepared from 3,5-dimethylacetanilide by straightforward chlorosulfonation and amination followed by hydrolysis.…”