The Medicinal Chemistry of Bicyclic Systems Containing a NNN Bond

Abstract

Synthetic routes to, and properties of, 4-amino and 4(3H)-imino-1,2,3- benzotriazines are reviewed in detail in the Introduction. 4-(4-Cyanoanilino)-1,2,3-benzotriazine, when boiled in morpholine, afforded 3-[2-amino-N-(4-cyanopheny1)-benzimidoy1 ]-4-(4-cyanopheny1 imino) - 3,4-dihydro-1 ,2,3-benzotriazine in addition to the major product 2-amino- N2-(4-cya nopheny1)-NENL-oxydi ethylenebenzami dine. The yield of the former product increased when high boiling non-nucleophilic solvents were employed as the thermolysis medium. Decomposition of 3-[2-amino-N-(4-cyanopheny] )-benzimidoy1]-4-(4- cyanophenylimino)-3,4-dihydro-1 ,2,3-benzotriazine in hot acid alone yielded 4-(4-cyanoanilino)-2-phenylquinazoline, whereas incorporation of nucleophiles in to the hot acidic media afforded a series of 4-(4- cyanoanilino)-2-(2-substituted phenyl) quinazolines. These quinazolines were prepared by an unambiguous route from the appropriate 2-(2- substituted phenyl)-4-chloroquinazolines and 4-cyanoaniline. The tetracyclic triazine, 8-(4-cyanopheny1imino)-8H-quinazolino[3,2-c]- 1,2,3-benzotriazine, was prepared by the diazocyclisation of 2-(2- aminopheny 1 )-4-(4-cyanoanilino)quinazoline. 4-Anilino-1 ,2,3-benzotriazines and their precursor acyclic triazenes yielded 3-arylquinazolin-4(3H)-ones when heated in formamide. The chemistry of the antitumour 3-alkylimidazo[5,1-d]-1,2,3,5-tetrazin- 4(3H)-ones is comparable to that of benzotriazin-4(3H)-ones. The former series yielded 5-(3-alkyltriazen-1-y1)-imidazole-4-carboxamides when treated with cold aqueous sodium carbonate and afforded 5-aminoimidazole- 4-carboxamide when boiled in water. Nitration of 8-carbamoy1-3-alkylimidazotetrazinones yielded the corresponding 8-nitrocarboxamides and reaction with sodium nitrite in concentrated sulphuric acid yielded the corresponding 8-carboxylic acids. 5-Diazoimidazole-4-carboxamide generated by thermolysis of 8-carbamoy-]3l- (2-chloroethy1)imidazo[5,1,-d]-1,2,3,5-tetrazin-4(3H)-one in acetic acid or pyridine was trapped by reactive methylenic ketones, nitriles or esters to afford imidazo[5,l1-c]-1,2,4-triazines. Thermolytic decomposition of the 3-alkylimidazotetrazinones in methanol and ethanol yielded 2-azahypoxanthine and 5-amino-1-carboalkoxyimidazole- 4-carboxamide. In hydrazine hydrate, 3-(2-chloroethy] )imidazotetrazinone yielded 5-azidoimidazole-4-carboxamide, whereas the 3-alkyl analogues formed 5-amino-4-carbamoy1] imidazole-1-carbohydrazide.