Quinazolines. VIII. Synthesis of 1,3-diaminobenzo[f]quinazolines

Twenty-one 1,3-diaminobenzof]quinazolines ( 2 , R = H, alkyl, halogen, methoxy) were synthesized as planar tricyclic analogs of the antimalarial agent pyrimethamine ( 1 ). The synthetic methods included i) condensation of 1-cyano-2-naphthylamines with cyanamide in the presence of pyridine hydrochloride, ii) cyclization of N¹,N⁵-bis(2-naphthyl)biguanide hydrochlorides in diphenyl ether at 250°, iii) reaction of 2-naphthylamine hydrochlorides with excess sodium dicyanamide in boiling 1-octanol, and iv) selenium dioxide dehydrogenation of 1,3-diamino-5,6-dihydrobenzof]quinazolines. A number of new 2-naphthols and 2-naphthylamines were synthesized as intermediates. Substituent effects on the ultraviolet absorption spectra of 1,3-diamino-benzof]quinazolines were investigated and found to be additive. These compounds are of interest as inhibitors of dihydrofolate reductase and as potential antimalarial and antitumor agents.