GB926038A - Sulphamoyl quinazolinones - Google Patents

Abstract

The invention comprises compounds of the formula: <FORM:0926038/IV(a)/1> in which R and R3 are hydrogen or C1-C6 alkyl radicals, R1 and R2 are hydrogen, C1-C6 alkyl radicals or aralkyl groups or R1 and R2 together are an oxygen atom and X is a halogen atom, e.g. Cl, Br or F or an alkyl or trihalomethyl, e.g. CF3, group, and comprises also the preparation of these compounds by (a) reacting an anthranilamide <FORM:0926038/IV(a)/2> in an acid medium with a carbonyl compound R1-CO-R2 or an acetal or ketal thereof and if desired alkylating any product in which R and/or R3 are hydrogen; (b) reducing a corresponding quinazolone having a double bond in the 1- or 2-position by means of an alkalimetal boron hydride, or (c) in the case when R1 and R2 together represent an oxygen atom, condensing an appropriate 4-substituted-5-sulphamoyl anthranilic acid or ester thereof with a thiourea R3NH.CS.NHR3 and oxidising the resulting 2-thio-1,2,3,4-tetrahydroquinazolinone-6-sulphonamide to replace the 2-thio-substituent by an oxygen atom. Other exemplified processes also include reaction of 4-chloro-5-sulphamoyl-anthranilic acid with urea or cyanic acid (giving a 2-ureido-4-chloro-5-suphamoyl-benzoic acid intermediate) or with propionaldehyde diethyl acetal and ammonia, ring closure of N-methyl-2-carbethoxyamino-4-chloro-5-sulphamoyl-benzamide, reaction of 4-chloro - 5 - sulphamoyl-anthranilamide with phosgene and reaction of ethyl 2-carbethoxyamino-4-chloro - 5 - sulphamoyl - benzoate with hydroxylamine, giving in each case a 2,4-dioxotetrahydroquinazoline. Intermediates 4-substituted- 5-sulphamoylanthranilic acids such as the 4-chloro-, 4-fluoro-and 4-bromocompounds are made by chlorosulphonating an N-acetyl-5-halo-toluidine, converting the 4-chlorosulphonyl-5-halo-acetyltoluidine obtained into the corresponding sulphonamide with ammonia; oxidising with permanganate to a 4-halo-5-sulphamoyl-acetylanthranilic acid which is then hydrolysed. The 4-trifluoromethyl-5-sulphamoyl-acetylanthranilic acid is made by a similar route. 4-Chloro-5-sulphamoyl- N-propionylanthranilic acid is made by the action of propionic anhydride on 4-chloro-5-sulphamoyl-anthranilic acid. 7-Substituted- 6-sulphamoyl-quinazolinones (used as starting materials in process (b) above) are made by treating a 4-substituted -5-sulphamoyl anthranilic acid or an N-acyl derivative thereof with an appropriate amide compound such as formamide, N-methylformamide, ethyl urethane, isobutyramide and N-methyl-acetamide. N-Methyl- 2-carbethoxyamino- 4-chloro-5-sulphamylbenzamide is made by treating 5-chlorotoluidine with ethyl chloroformate, chlorosulphonating the resulting N-carbethoxy-derivative and reacting with ammonia to form a 4-sulphamoyl-5-chloro N-carbethoxy-toluidine, oxidising to 2-carbethoxyamino-4-chloro - 5 - sulphamoyl - benzoi acid, treating with PCl5 and converting to the amide with methylamine. 4-Chloro- 5-sulphamoyl anthranilamide is made by treating 4-chloro-5-sulphamoylanthranilic acid with a chloroformic ester and then with ammonium hydroxide. Ethyl- 2-carbethoxyamino- 4-chloro- 5-sulphamoyl-benzoate is made by esterifying the free acid. The products of the invention are used pharmaceutically as diuretics.