Nitroimidazoles: Part IV. 1-Sulphonyl(carbamoyl/thiocarbamoyl 1-methyl-5-nitroimidazol-2-yl)-2-imidazolidiones

Abstract

Sulphone (5) is condensed with sodium salts of a variety of 1-sulphonyl (7), lrthiocarbamoyl (9) and 1-carbonyl (10)-2-imidazolidinones to give 3-(2-imidazolyl)imidazolidinones (12), (13) and (14) respectively, out of which l-methylsulphonyl-3-(l-methyl-5-nitro-imidazol-2-yl)-2-imidazolidinone (12a) is undergoing clinical trials as an antiamoebic-antitrichomonal agent. 15 and 16 are analogous imidazolidinones, while 17 and 18 are benzimidazolone derivatives. The reaction of 5 with the sodium salt of 2-imidazolidinone gives rise to the mono and bis-condensation products 21 and 22 respectively. Several other minor byproducts, 23-27 have been identified. 23,26 and 27 arise from 21. 24, a transformation product of 5 leads to the ether 25 by a displacement reaction. A second synthesis of 12a involves the nitration of imidazolylimidazolidinone (30) in the terminal step, with 30 becoming available from l-methyl-2-aminoimidazole (28) and chloroethyl isocyanate, and subsequent reaction of resultant 29 with methanesulphonyl chloride. The higher ring homologue, 33 of 12a is synthesised in poor yield from 5 and 1-methylsulphonylhexahydropyrimidinone. Treatment of 12a and 13a with KI in DMF leads to the isomeric 4-nitro derivatives 38a, b and desmethyl derivatives 37a, b. Treatment of 12a with triethyloxonium fluborate affords the quaternary isothiourea (35)whieh is hydrolysed to 36. Treatment of 12a and 13a with aqueous alkali leads to cleavage of imidazolidinone ring to form the ethylenediamines 31a and b. Position isomers 41 and 43 of 12a are respectively obtained by the reaction of l-methyl-4-nitro-5-chloro-(40)-, and l-methyl-5-nitro-4-chloro-(42)-imidazoles with 1-methylsulphonyl-ethylene urea. Treatment of the last compound with various reactive halides, e.g. 2-chlorobenzothiazole, yields several analogues 44a-i of 12a while niridazole (45) and methylsulphonyl chloride affords the nitrothiazole analogue 46.