SYNTHESIS OF HYDROXY-SUBSTITUTED AZA-ANALOGS OF ANTITUMOR ANTHRAPYRAZOLES

Synthetic routes have been developed which lead to ring-hydroxylated a za-analogues of antitumor anthrapyrazoles, namely, 2,5-bis[(aminoalkyl )amino] substituted 10-hydroxyindazolo[3,4-fg] isoquinolin-6(2H)ones 1 and 7-hydroxyindazolo[4,3-gh]isoquinolin-6(2H)-ones 2. The regiospeci fic synthesis of 6,9-dihalo-4-hydroxybenz[g]isoquinolines 3 and 4 has been accomplished. Intermediate 3 was constructed in a multistep proce ss involving Diels-Alder chemistry of benzoylacrylates whereas 4 was a ssembled using Ni(II) mediated coupling of methyl 3-chloro-5-methoxyis onicotinate (15b) with the organic zinc reagent 18 derived from 2-fluo ro-5-chlorobenzyl bromide (17). After protection of the hydroxy group with a p-methoxybenzyl moiety, the different nucleofugacities of the l eaving groups present in 10 and 20 allowed sequential displacements by substituted hydrazines and amines, respectively, to lead to the desir ed p-methoxybenzyl protected analogues 12 and 22. Deprotection led to the side arm modified compounds 1 and 2. The displacements of 21a and 21b with N,N-dimethylethylenediamine also led to the tri[(aminoalkyl)a mino]substituted analogues 23a and 23b, respectively, which arose from further SNAr substitutions of the p-methoxybenzyloxy group.