ANTITUMOR IMIDAZOTETRAZINES - PART 36 - 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 ANTITUMOR AGENTS TEMOZOLOMIDE AND MITOZOLOMIDE

Novel 3-substituted imidazo[5,1-d][1,2,3,5]tetrazinones 3 have been pr epared by two routes: reaction of 5-diazoimidazole-4-carboxamide 2 and isocyanates, and nitrosative cyclisation of 5-amino-1-carbamoylimidaz ole-4-carboxamides 7. The latter cyclisations do not proceed efficient ly when the l-carbamoyl group bears an electron-donating alkyl group. 5-Amino-1-carbamoylimidazole-4-carboxamides 7 cyclise with triethyl or thoformate or triethyl orthobenzoate to yield imidazo[1,5-a][1,3,5]tri azinones 15, A H-1 NMR study of the decomposition of l-3-ethylimidazo[ 5,1-d][1,2,3,5]tetrazin-4(3H)-one 3c in deuteriated phosphate buffer h as shown that its ethylating capacity is attenuated by the unproductiv e generation of ethene. This observation explains why the ethylimidazo tetrazine possesses weaker antitumour properties than the clinically-u sed congener temozolomide 3a.