Patent GB-826921-A (GB)
Title: Natriuretic agents
IPC: C07D285/30
Filed: 1957-05-01
Abstract: The invention comprises thiadiazine compounds of the formula <FORM:0826921/IV (b)/1> or <FORM:0826921/IV (b)/2> and sodium and potassium salts thereof, in which R is hydrogen, halogen (e.g. Cl, Br or F), C1-5 alkyl, C1-5 alkoxy, nitro or amino, R1 is hydrogen, or C1-5 alkyl, and R2 is hydrogen, C1-5 alkyl or an aryl, aralkyl or aralkenyl group containing one benzene nucleus which optionally bears a C1-5 alkyl, C1-5 alkoxy or halogen substituent.  The compounds are prepared: (1) by heating a disulphamoyl aniline <FORM:0826921/IV (b)/3> with formic acid or ethyl formate, preferably at 100 DEG  to 150 DEG  C.; (2) by treating an N-acylaniline disulphonyl chloride <FORM:0826921/IV (b)/4> with ammonia, preferably aqueous or alcoholic ammonium hydroxide, and heating the resulting N - acylaniline - disulphonamide, preferably at 150 DEG  to 250 DEG  C., to cyclize it, or (3) by treating a compound of the formula <FORM:0826921/IV (b)/5> in which R11 is C1-5 alkyl, with formic acid or ethyl formate, chlorosulphonating the resulting benzothiadiazine - 1 : 1 - dioxide, for example 2 - methyl - 1 : 2 : 4 - benzothiadiazine - 1 : 1 - dioxide and reacting the resulting sulphonyl chloride with ammonia. The disulphamoyl aniline used as a starting material in (1) is made by reacting an aniline derivative C6H5.NHR*, wherein R* is hydrogen, C1-5 alkyl, acetyl or C3-6 alkanoyl and which optionally bears a further substituent R on the benzene ring, with chlorosulphonic acid in the presence of an alkali metal halide, e.g. sodium chloride, and treating with ammonia, e.g. aqueous or alcoholic ammonium hydroxide, to give the disulphonamide with simultaneous removal of any acyl group R*.  The acylaniline disulphonyl chloride used as a starting material in (2) is made by reacting an aniline derivative C6H5-NHR1, optionally bearing a substituent R in the benzene ring with chlorosulphonic acid in the presence of an alkali-metal halide, e.g. sodium chloride, and treating the resulting disulphonyl chloride with an acid chloride or anhydride derived from an alkanoic acid of not more than six carbon atoms or a mono-nuclear aryl, aralkyl or aralkenyl carboxylic acid R2COCl or (R2CO)2O.  The preparation of the intermediate compounds is described in Specifications 826,922, 826,923 and 826,924.  The benzothiadiazine compounds are used therapeutically as diuretic and natriuretic agents.  Examples describe the preparation of 7-sulphamoyl-1 : 2 : 4-benzothiadiazine - 1 : 1 - dioxide and its 6-chloro-, 6-bromo-, 6-methyl-, 6-methoxy-, 6-amino-, 6-nitro-, 2-methyl-, 6-chloro-3-methyl-, 6 - chloro - 3 - phenyl -, 6 - chloro - 3 - propyl -, 6 - chloro - 3 - amyl -, 6 - chloro - 4 - methyl and 6-fluoro-3-benzyl-derivatives and 6-sulphamoyl - 1 : 2 : 4 - benzothiadiazine - 1 : 1 - dioxide and its 7-chloro-derivative.ALSO:Pharmaceutical compositions having diuretic and natriuretic properties comprise compounds of the general formula <FORM:0826921/VI/1> in which R is hydrogen, halogen (e.g. Cl, Br or F), C1-5 alkyl, C1-5 alkoxy, nitro or amino, R1 is hydrogen or C1-5 alkyl and R2 is hydrogen, C1-5 alkyl or an aryl, aralkyl or aralkenyl group containing one benzene nucleus, optionally bearing a C1-5 alkyl, C1-5 alkoxy or halogen substituent (see Group IV (b)) and a solid or liquid pharmaceutical diluent.  The compositions may take the form of pills, tablets, capsules, solutions, dispersions or suspensions, e.g. in an aqueous medium, such as dilute alkali or polyethylene glycol solutions, and may be administered orally or by injection. An example describes the preparation of tablets comprising 6-chloro-7-sulphamyl-1 : 2 : 4-benzothiadiazine - 1 : 1 - dioxide. Specifications 826,922, 826,923 and 826,924 are referred to.