Antitumour imidazotetrazines. Part 36.1 Conversion of 5-aminoimidazole-4-carboxamide to imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-ones and imidazo[1,5-a][1,3,5]triazin-4(3H)-ones related in structure to the antitumour agents temozolomide and mitozolomide

Abstract

Novel 3-substituted imidazo[5,1-d][1,2,3,5]tetrazinones 3 have been prepared by two routes: reaction of 5-diazoimidazole-4-carboxamide 2 and isocyanates, and nitrosative cyclisation of 5-amino-1-carbamoylimidazole-4-carboxamides 7. The latter cyclisations do not proceed efficiently when the 1-carbamoyl group bears an electron-donating alkyl group. 5-Amino-1-carbamoylimidazole-4-carboxamides 7 cyclise with triethyl orthoformate or triethyl orthobenzoate to yield imidazo[1,5-a][1,3,5]triazinones 15. A ¹H NMR study of the decomposition of 8-carbamoyl-3-ethylimidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one 3c in deuteriated phosphate buffer has shown that its ethylating capacity is attenuated by the unproductive generation of ethene. This observation explains why the ethylimidazotetrazine possesses weaker antitumour properties than the clinically-used congener temozolomide 3a.