Studies in sulphonamides, sulphones and allied compounds

Abstract

Studies in Sulphonamides, Sulphones and Allied Compounds Part I – Introduction The present thesis consists of four parts. Introduction under Part I deals in brief with: (1) the history of sulphonamide chemotherapy, (2) the discovery and development of sulphonamide group of drugs, (3) chemistry of the more important sulphonamides, (4) classification of the sulphonamides, (5) correlation of physiological activity with chemical constitution, (6) mode of action of sulphonamides, (7) relation of chemical structure to chemotherapeutic activity.

Part I-B – Synthesis of benzene-1,4-disulphonamides In the vastly expanding field of sulphonamides, data on nuclear-substituted sulphonamides and on di- or polysulphonamides are meagre because such substituted sulphonamides have not been investigated particularly well from either the chemical or pharmacological side. Two very obvious reasons are: first, nuclear-substituted derivatives are somewhat more difficult to synthesise than are the nitrogen-substituted derivatives, and second, that the simple derivatives so far made have practically no activity. However, the conclusion should not be drawn that any substitution of the ring will destroy activity since 3,5-dimethyl sulphanilamide, aniline 3,5-disulphonamide, and o,p-di(p-amino benzene sulphonamido)isopropyl alcohol are said to possess activity. This would indicate that search for new therapeuticals may profitably be pursued in the field of disulphonamides with or without basic substituents in the nucleus. In this programme of work twenty-four unsubstituted disulphonamides of the general formula 1,4-C?H?(SO?–NHR)? where R is alkyl, aryl or heterocyclic residue have been prepared by the action of 1,4-benzene disulphonyl chloride on various amines.

Part II – Synthesis of benzene-1,4-disulphonic acid esters Carr and Brown have synthesised a number of p-alkoxy benzene sulphonic acid esters as possible local anaesthetics. With a view to studying the chemistry and pharmacological properties of disulphonic acid esters of the type x-O-SO?–p–SO?-O-x where x is aryl radical, benzene disulphonyl chloride has been reacted with eleven aromatic hydroxy compounds in acetone solution in presence of sodium carbonate or diethyl aniline. This part deals with the synthesis of eleven such esters. Their physical and chemical properties are also described.

Part III – Studies in Sulphones A – Introduction This deals with the discovery and development of sulphone series of drugs. The chemistry of the more important sulphones, probable mechanism of action of these drugs and the correlation of chemotherapeutic activity with chemical structure are also discussed. B – Azo dyes of 4-nitro-4'-amino diphenylsulphone Although the antistreptococcal activity of 4,4'-diaminodiphenyl sulphone was found to be approximately hundred times that of sulphanilamide and is probably the most active of all the antibacterial chemotherapeuticals which have been studied up till now with the single exception of penicillin, its toxicity precluded its practical application in chemotherapy. 4,4'-diaminodiphenyl sulphone has come into the forefront of chemotherapy as a possible cure of tuberculosis, leprosy and gas gangrene. But the toxic nature of this compound coupled with its high degree of specificity make the search for more effective and less toxic derivatives a promising field of investigation. With this end in view nine azo dyes of 4-nitro-4'-amino diphenyl sulphone have been prepared and detailed in this part.

Part IV – Schiff’s bases of 4,4'-diaminodiphenyl sulphide The high antibacterial activity of 4,4'-diaminodiphenyl sulphone and sulphanilamides has led to the belief that the molecular grouping essential for chemotherapeutic activity is the complex –SO?–NH–. Raiziss and his associates have shown that the therapeutic properties of 4,4'-diaminodiphenyl sulphide and its acetyl derivative compared favourably with that of sulphanilamide. This finding is not surprising when one views it in the light of the postulation of Fourneau and his associates that the molecular grouping essential for activity is –NH–SO?– complex. However, Raiziss has shown that 4,4'-diaminodiphenyl sulphide is more toxic for rabbits than sulphanilamide. With a view to obtaining substances similar in activity to 4,4'-diaminodiphenyl sulphide having more suitable physical properties but with less toxicity, nine Schiff’s bases of 4,4'-diaminodiphenyl sulphide have been prepared and detailed in this section. Their properties are also described. All the new compounds described in this thesis will be subjected to pharmacological examination at the earliest convenience.