Patent GB-1136686-A (GB)
Title: New sulphanilamide derivatives
IPC: C07D239/52
Filed: 1967-03-20
Abstract: 1,136,686. Sulphanilamides. J. R. GEIGY A.G. 20 March, 1967 [21 March, 1966], No. 12920/67. Heading C2C. The invention comprises compounds of general formula wherein R 1  is hydrogen, chlorine, C 1-3  alkyl, or C 1-2  alkoxy or alkylthio; R 2  is hydrogen, chlorine, C 1-3  alkyl, C 1-2  alkoxy or alkylthio, or cyclopropyl; R 3  is hydrogen, C 1-3  alkyl, C 1-2  alkoxy or cyclopropyl; one of R 2  and R 3  being cyclopropyl; and salts thereof; and their preparation by: (a) reaction of a compound of Formula II with one of Formula III (wherein X is NH 2  or a nitrogen-containing group convertible thereinto by hydrolysis or reduction, one of A 1  and A 2  is imino while the other represents a direct bond, Y and Z are reactive atoms or radicals which can be split off together) and, if necessary, converting the group X of the reaction product into NH 2 ; (b) reaction of a compound of Formula V with one of Formula VI, or an acetal, enol ether, enamine or ketal thereof (wherein R 1 <SP>1</SP> is hydrogen or C 1-3  alkyl, R 2 <SP>1</SP> is hydrogen, C 1-3  alkyl or cyclopropyl, X and R 3  are as above, one of R 2 <SP>1</SP> and R 3  being cyclopropyl), and if necesary, converting X in the reaction product to NH 2 , to give a compound of Formula I wherein R 1  and R 2  have the values of R 1 <SP>1</SP> and R 2 <SP>1</SP> respectively; and (c) reacting a compound of Formula V above with a dialkyl ester of cyclopropyl malonic acid or with an alkyl ester of a #-oxo-carboxylic acid of Formula VIII wherein R 2 <SP>1</SP> and R 3  are as above, one of them being cyclopropyl, to form a compound of Formula IX (wherein R 2 <SP>11</SP> is hydrogen, C 1-3  alkyl, cyclopropyl, or hydroxyl) and reacting this with an inorganic acid chloride to produce a compound of Formula I wherein R 1  and possibly R 2  is chlorine, and if necessary, converting the group X of the reaction product into NH 2 . Products of processes (a) and (c) wherein R 1  and/or R 2  is chlorine may be converted to the corresponding compounds in which R 1  and/or R 2  is hydrogen, alkoxy, or alkylthio. Any product may be converted into a salt. Pyrimidine compounds of Formula III wherein As is a direct bond, Z is alkylsulphonyl or chlorine and R 3  is cyclopropyl are made by condensing a cyclopropyl malonic acid dialkyl ester with thiourea followed by methylation, or with S-methyl isourea in either case to form 2-methylthio-5-cyclopropyl-pyrimidine-4,6-diol, which is then converted either to (a) the corresponding 4,6-dichloro or 4,6-dialkoxy compounds followed by oxidation of the 2-methylthio group to a methylsulphonyl group, or to (b) the corresponding 2,4,6-trichloro compound (via the 2,4,6-triol). Compounds of Formula III wherein A is a direct bond, Z is alkylsulphonyl or chlorine, and R 2  is cyclopropyl are made by condensing a #-oxo-#-cyclopropylpropionic acid ester optionally bearing an α-alkyl or alkoxy group with thiourea or an S-alkyl isourea to form a 2-mercapto- or 2- alkylthio-6-cyclopropyl-pyrimidin-4-ol optionally bearing a 5-alkyl or alkoxy group, which are converted into 2-chloro or 2-alkylsulphonyl compounds analogously to as described above. Compounds of Formula III wherein A 2  is a direct bond, Z is alkylsulphonyl or chlorine, one of R 2  and R 3  is cyclopropyl, the other and R 1  being hydrogen or alkyl, are made by condensing a compound of Formula VI above or an acetal, enol ether, enamine or ketal thereof with thiourea or an S-alkyl isourea to form a 2- mercapto or alkylthio- 5 or 6-cyclopropylpyrimidine optionally bearing an alkyl group at position 4 or 6 which is converted into a 2- alkylsulphonyl compound as described above, the 2-chloro compounds being obtained from the 2-mercapto compounds via the 2-hydroxy compounds. Compounds of Formula III wherein A 2  is imino and Z is hydrogen are prepared either by reacting 2-alkylsulphonyl pyrimidines described above with ammonia, or by reacting guanidine with alkyl esters of cyclopropyl malonic acid or #-oxo-#-cyclopropyl-propionic acid optionally bearing an α-alkyl or alkoxy group, to form a 2-amino- 5 or 6-cyclopropyl-pyrimidine-4-ol possibly with a 5-alkyl or alkoxy group, which is converted into the corresponding 4-chloro, 4- alkoxy, or 4-alkylthio compound. The preparation of compounds of Formula III wherein A 2  is imino and Z is nitro or cyano is also described. Diketones of Formula VI are prepared by reacting cyclopropyl methyl ketone with an ester of an alkane carboxylic acid. 1-Cyclopropyl-3-dimethylamino-prop-2-en-1-one is prepared from cyclopropyl methyl ketone and bisdimethylamino methoxymethane. Pharmaceutical compositions suitable for oral or parenteral administration in the treatment of infections by gram positive and gram negative bacteria comprise a compound of Formula I or acceptable salt thereof and at least one inert carrier.