GB982072A — Benzothiadiazine-1,1-dioxides and processes for their manufacture

USPTO Abstract

The invention comprises compounds of the formula <FORM:0982072/C2/1> and the tautomers and alkali-metal salts thereof wherein X represents halogen or trifluoromethyl in the 6- or 7-position, Y represents hydrogen or a halogen, methyl or trifluoromethyl substituent in the 6-, 7- or 8-position and R is a saturated aliphatic hydrocarbon group of not more than 6 carbon atoms, e.g. alkyl or cycloalkyl such as cyclopropyl; and their preparation by (a) heating a compound of the formula <FORM:0982072/C2/2> wherein Z is H, benzyl or a lower aliphatic hydrocarbon group, Q may be (H,H), (H, RCO-), (RCO-, RCO-) or RC(O.lower alkyl) = and T is H or R.CO-, provided that when Z is methyl or ethyl Q is not RC(O.lower alkyl) = and that when Q and T is hydrogen, the heating is effected in the presence of a lower saturated aliphatic monocarboxylic acid R.COOH, or an ester, anhydride, acid halide or ortho ester thereof, or an a -lower alkoxy-aldehyde diacetal; (b) heating an X,Y-substituted-2-sulphamyl aniline with an ortho ester of the formula R.C(O.lower alkyl)3 or an acid RCOOH or ester, anhydride or halide thereof; (c) dehydrogenating the corresponding 3,4 - dihydro - benzothiadiazine analogue by treatment with a mild oxidizing agent such as potassium permanganate; or (d) removing hydrogen halide from a corresponding 3,4-dihydro-benzothiadiazine analogue bearing an a -haloalkyl group in place of the alkyl group R. Sulphamylanilines of the formula II are made by treating an X,Y-substituted-o-chloronitrobenzene with thiourea and benzyl chloride to give the corresponding o-benzylthio-nitrobenzene, oxidizing with chlorine to the o-nitrobenzenesulphonyl chloride, reacting with ammonia to give the sulphonamide, reducing to the o-aminobenzenesulphonamide and acylating to introduce groups RCO- on the amino and/or sulphonamido nitrogen atom, or acylating the nitrobenzenesulphonamide followed by reduction to give products acylated on the sulphonamide group only. Alternatively an X,Y-substituted o-amino-benzenesulphonamide bearing a lower aliphatic hydrocarbon or a benzyl substituent on the sulphonamide nitrogen atom may be treated an ortho ester R(COC2H5)3 to form a corresponding sulphonamide bearing an a -alkoxyalkylidene-amino substituent, e.g. R.C(OC2H5) =, in the o-position. o - Diacylamino - benzenesulphonic acids bearing substituents X and Y, in which the acyl groups are of the formula RCO-, are prepared by reacting the appropriate 2-amino-benzenesulphonic acid (e.g. 2-amino-5-chloro-benzenesulphonic acid) with an acylating agent of the formula RCOCl, (RCO)2O or R COONa (e.g. acetic anhydride). Pharmaceutical preparations having blood pressure lowering activity comprise the above compounds of the invention and a carrier suitable for enteral or parenteral administration, for example in the form of tablets, capsules, suppositories, elixirs, emulsions or injectable preparations.