Patent GB-831043-A (GB)
Title: Sulphonyl carbamides
Filed: 1958-02-18
Abstract: The invention comprises sulphonyl ureas of the formula <FORM:0831043/IV (b)/1> and alkali-metal, ammonium and organic amine salts thereof wherein W is an amino, acylamino or nitro group, X is chlorine, bromine, alkyl or alkoxy, Y is hydrogen, chlorine, bromine, alkyl or alkoxy and R is a saturated open-chain or cyclic hydrocarbon radical optionally interrupted by O or S atoms.  The compounds are prepared (1) by reacting a sulphonamide of the formula <FORM:0831043/IV (b)/2> (where W is an acylamino or a nitro group) preferably in the form of its sodium or potassium salt with an isocyanate RNCO or a compound convertible into the isocyanate under the reaction conditions such as carbamic halides, urethanes, N2-substituted ureas and their N1-acylated derivatives, wherein the N1-substituents are for example acetyl, propionyl, butyryl or benzoyl groups, followed by conversion of the nitro or acylamino group into an amino group by hydrolysis or reduction if desired; (2) by reacting an amine RNH2 with a benzenesulphonyl isocyanate <FORM:0831043/IV (b)/3> (where W is an acylamino or nitro group) or with a compound convertible into the sulphonyl isocyanate under the reaction conditions such as a sulphonyl urethane, sulphonyl thiourethane, sulphonyl carbamic halide or a sulphonyl urea or an N2-acylated derivative thereof, followed, if desired, by conversion of W into an amino group by hydrolysis or reduction; (3) by reacting a substituted isourea alkyl ether NH : C (O alkyl).NHR with the appropriate benzenesulphonyl halide (in which W is an acylamino or nitro group) and splitting the resulting benzenesulphonyl isourea ether into the sulphonyl urea and an alkyl halide by treatment with a hydrogen halide, followed, if desired, by conversion of W into an amino group by hydrolysis or reduction; (4) by treating a corresponding benzene sulphonyl guanidine or benzene sulphonyl thiourea by alkaline hydrolysis or by reduction respectively followed by conversion of W into an amino group by hydrolysis or reduction if desired; and (5) for the preparation of products containing one or two halogen atoms in the benzene ring, by direct halogenation of the corresponding benzenesulphonyl urea in which W is an acylamino or nitro group, followed by conversion of W into an amino by hydrolysis or reduction, if desired.  The products are used as oral anti-diabetic agents (see Group VI).  Examples describe the preparation of 4-aminobenzenesulphonyl ureas of the formula I in which X, Y and R respectively have the values 3-Br, H, n-butyl; 3-Br, 5-Br, n-butyl; 3-Cl, H, n-butyl; 3-Cl, 5-Cl, n-butyl; 3-methyl, H, n-butyl; 3-Br, H, g -methoxypropyl and 3-methyl, H, g -methoxypropyl; 3-aminobenzenesulphonyl ureas in which X, Y and R have the values 4-methyl, H, n-butyl; 4-methyl, H, g -methoxypropyl; 4-methyl, H, g -methoxybutyl; 4-methyl, H, cyclohexyl; 4-methyl, 5-methyl, n-butyl; 4-methyl, 5-methyl, g -methoxybutyl; 4 - Cl, H, n - butyl; 4 - methoxy, H, n - butyl; 4 - methoxy, H, cyclohexyl; 2 - methyl, H, g - methoxypropyl; 2 - methyl, H, g  - methoxybutyl; 2 - methyl, H, cyclohexyl; 4 - methyl, H, (2 - pentyl); 4 - methyl, H, cyclopentyl; 4 - methyl, H, tetrahydrofurfuryl; 4 - ethyl, H, n - butyl; 4 - ethyl, H, cyclohexyl; 6-methyl, H, n-butyl; 4-Cl, H, n-butyl and 4-methyl, H, g -methylthiopropyl and N1 - (2 - amino - 4 - methyl - benzenesulphonyl)-N2 - cyclohexyl - urea: the corresponding intermediate nitro or acylamino compounds such as the actylamino compounds (W = -NO2 or -NHCOCH3) of most of the above products are also prepared.  Urethanes used as starting materials in the above examples i.e. 3-acetylamino-4-methyl-4 - acetylamino - 3 - methyl -, 3 - nitro - 4, methyl -, 3:4 - dimethyl - 5 - amino - , 3-nitro - 4 - methoxy -, 2 - methyl - 3 - nitro -, 3-nitro - 4 - ethyl - and 3 - acetylamino - 6-methyl-, benzenesulphonyl urethane (ethyl esters) are made by treating the corresponding benzenesulphonamide with ethyl chloroformate.  Bis - (4 - acetylamino - 3 - bromo - benzenesulphonyl) urea is made by the action of phosgene on 4 - acetylamino - 3 - bromo - benzenesulphonamide and is converted into its g -methoxypropylamine salt.  N1 - (3 - nitro - 4 - chloro - benzenesulphonyl)-N2 - n - butylthiourea is made by the action of n-butyl isothiocyanate on 3-nitro-4-chlorobenzenesulphonamide.  N1 - (3 - methyl - 4 - acetylamino - benzenesulphonyl) - N2 - n - butyl - guanidine is made by the action of n - butyl guanidine on 3 - methyl - 4 - acetylamino - benzenesulphonyl chloride.  N1 - (3 - chloro - 4 - nitro - benzenesulphonyl) N2 - n - butyl isourea methyl ether is made by treating n-butyl urea with dimethyl sulphate and reacting the n-butyl isourea methyl ether methylsulphate obtained with 3-chloro-4-nitrobenzenesulphonyl chloride.  3 - Nitro - 4 - chlorobenzenesulphonyl isocyanate is made by the action of phosgene on 3-nitro-4-chlorobenzenesulphonamide.  2 - Acetylamino - 4 - methyl benzenesulphonamide is prepared by catalytic reduction of the 2-nitro-compound followed by acetylation.  3 - Keto - 6 - methyl - 3 : 4 - dihydro - benzothiadiazine - 1 : 1 - dioxide, cyclohexylamine salt is made by heating N1-(2-amino-4-methylbenzenesulphonyl)-N2-cyclohexyl urea to its melting point.  Specification 831,044 isreferred to.ALSO:Compositions for the treatment of diabetes comprise one or more benzenesulphonyl ureas of the formula (I) <FORM:0831043/VI/1> in which W is an amino, acylamino or nitro group, X is chlorine, bromine, alkyl or alkoxy, Y is hydrogen, chlorine, bromine, alkyl or alkoxy and R is a saturated open-chain or cyclic hydrocarbon radical which can be interrupted by oxygen and sulphur, or alkali or alkaline earth metal, ammonium or organic amine salts thereof (see Group IV (b)), in association with a pharmaceutical carrier. The preparations are preferably administered orally in the form of tablets, pills, lozenges or dragees or as emulsions or suspensions in water or unsweetened fruit juices, or in the form of powders filled into gelatine capsules.  In the preparation of tablets or other shaped or compressed preparations the sulphonyl urea may be mixed and milled with a solid pulverulent extending agent or the solid carrier may be impregnated with a suspension of the sulphonyl urea in water or a solution thereof in an organic solvent such as ethanol, methanol or acetone and the water or solvent then removed.  Suitable diluting agents include sugar, lacvulose, lactose, starch, bolus alba, gelatine, gum arabic, yeast extract, agar, tragacanth, methyl cellulose, pectin, stearic acid, talc and magnesium stearate. Tablets preferably contain 25 mg. to 50 mg. of the sulphonyl urea. The sulphonyl ureas may also be administered as suppositories in assocition with suitable vehicles such as cocoa butter.  In examples there are described, (32) tablets comprising N1 - (3 - bromo - sulphanilyl) - N2 - (n-butyl) urea, starch and magnesium stearate; (33) dragees comprising N1-(3 : 5-dichloro-sulphanilyl)-N2-(n-butyl) urea, starch and stearic acid, coated with sugar syrup and talc and sweetened and coloured as desired; (34) gelatine capsules containing N1-(4-methyl-3-aminobenzenesulphonyl) - N2 - (n - butyl) urea; (35) gelatine capsules containing N1-(3-bromo-sulphanilyl) - N2 - (g  - methoxypropyl) urea, starch, lactose and gum tragacanth; (37) a suspension containing N1 - (3 : 4 - dimethyl - 5 - amino - benzenesulphonyl) - N2 - (n - butyl) urea in an aqueous solution of sugar and methyl cellulose, flavoured and coloured as desired; and (38) suppositories containing N1-(3 - amino - 4 - chloro - benzenesulphonyl) - N2-(n-butyl) urea and a fatty ester or polyethylene glycol suppository base.  Specification 831,044 is referred to.