Patent GB-791923-A (GB)
Title: New sulphonamides
Inventor: ROSE FRANCIS LESLIE
Filed: 1955-08-08
Abstract: The invention comprises sulphonamides of the general formula <FORM:0791923/IV (b)/1> wherein R is a hydrocarbon radical which may be substituted, x is 1 or 2, R1 is hydrogen or an alkyl radical of 1-4 carbon atoms, and the nucleus A may be further substituted, otherwise than by amino groups, with the proviso that when R is a methyl, a p-nitro- or p-aminophenyl radical R1 does not stand for hydrogen; and the manufacture thereof by (1) oxidation of compounds of the general formula <FORM:0791923/IV (b)/2> (e.g. with hydrogen peroxide), or (2) interaction of compounds of the general formula <FORM:0791923/IV (b)/3> wherein X is a halogen atom, with a compound of the formula NH2.R1 (both processes (1) and (2) may take place in the presence of an inert solvent and the reaction may be assisted and/or completed by the application of heat); also pharmaceutical compositions containing these products (see Group VI).  In examples, sulphonamides of the general formula, where x= 2, R1=H and R=ethyl-, n-propyl-, isopropyl-, n-butyl-, cyclohexyl-, 4-nitrobenzyl-, phenyl-, 4-chlorophenyl-, and 4-bromophenyl-; where x=2, R1=H, R=ethyl-, and the ring A is substituted as follows: 3-chloro-, 3-bromo-, 3 : 5-dibromo-, 3-methyl-, 3-bromo-5-methyl-, 3 : 5-dichloro-, 3 : 6-dichloro-; where x=2, R1=methyl, R=ethyl, and the ring A is substituted by 3-chloro-; and where x=2, R1=H, R=phenyl and A is substituted by 2-chloro-, are formed by oxidation of the corresponding thio-compounds as in process (1).  Similarly, examples are given of the preparation of compounds wherein x=1, R1=H, and R=isopropyl or n-propyl by the same process except that the heating period is shortened or the reaction takes place at 20-25 DEG  C.  In further examples, using process (2), sulphonamides wherein x=2, R1=H and R=isopropyl, or R=ethyl, with A substituted by 2-chloro-, are prepared by converting the corresponding sulphonylbenzene sulphonic acid to the acid chloride and reacting this with ammonia.  The Provisional Specification also refers to the preparation of compounds wherein x=2 by oxidation of corresponding compounds wherein x=1, by hydrogen peroxide.  Starting materials.  4 - R - Thiobenzenesulphonamides (wherein R=ethyl, n-propyl, isopropyl, n-butyl, cyclohexyl and 4-nitrobenzyl) are prepared by reacting diazotized 4-aminobenzene-sulphonic acid with potassium ethyl xanthate, alkylating or aralkylating the resulting mercapto benzene sulphonate, and converting this into the acid chloride and thence into the amide.  4 - Ethylthiobenzenesulphonamides (wherein the ring A is substituted by halogen and/or methyl) are prepared in a similar manner to that above but using the appropriately substituted 4-amino benzene sulphonic acid.  4 : 21 - Dichlorodiphenylsulphide - 41 - sulphonamide, as above, using 4-amino-3-chlorobenzenesulphonic acid and 4-nitrochlorobenzene, in place of the alkylating agent, and with subsequent reduction of the nitro group.  4-Chloro- and 4-bromo-diphenylsulphide-41-sulphonamides are prepared by reduction of 4-nitro-diphenylsulphide - 41 - sulphonamide, diazotization and replacement of the amino group by -Cl or -Br. 4 - n - and iso - propylsulphonylbenzene sulphonic acids, from the corresponding thiosulphonic acids, by oxidation with hydrogen peroxide.  2 - Chloro - 4 - ethylsulphonylbenzene sulphonic acid is prepared from ethyl-4-chlorophenyl-sulphone by nitration to give 2-chloro-5-ethylsulphonyl-1-nitrobenzene, converting this to sodium 4 - ethylsulphonyl - 2 - nitrobenzene sulphonate, with sodium sulphite, reducing this to the amino compound, diazotizing and replacing the amino group by Cl.ALSO:Pharmaceutical compositions (e.g. tablets, pills and dispersions) comprise, as active ingredients, one or more sulphonamides of the general formula <FORM:0791923/VI/1> (wherein R is a hydrocarbon radical which may be substituted, x is 1 or 2, R1 is hydrogen or an alkyl radical of one to four carbon atoms, and the nucleus A may be further substituted, otherwise than by amino groups, with the proviso that when R is a methyl, a p-nitro- or p-amino-phenyl radical R1 does not stand for hydrogen), mixed with one or more pharmaceutical excipients.  Tablets and pills may contain 5-90 per cent by weight of active ingredient or ingredients together with a diluent (e.g. calcium carbonate or lactose), a disintegrating agent (e.g. maize starch), a lubricating agent (e.g. stearic acid or magnesium stearate) and/or a granulating or binding agent (e.g. starch paste, gelatin solution or gum acacia), and aqueous dispersions may contain not less than 0.5-50 per cent by weight of active ingredient or ingredients in an aqueous medium together with a suspending or dispersing agent (e.g. sodium carboxymethyl cellulose) and/or a wetting agent (e.g. a polyethyleneoxycetanol). In examples: 3 - chloro - 4 - ethylsulphonylsulphonamide is mixed with maize starch and/or calcium carbonate and granulated by admixture with an aqueous solution of acacia, followed by compression into tablet form; 4-chloro-diphenyl-41-sulphonamide is ball milled with a pharmaceutical base comprising icing sugar, sodium carboxymethylcellulose solution, heptadecaethylene-oxycetanol and methyl- and propyl-p-hydroxybenzoates.