Synthesis and Cytotoxic Activity of Carboxamide Derivatives of Benzo[b][1,6]naphthyridines

The reaction of 4-dimethylaminomethylene-6-methyl-4H-pyrano[4,3-b]quinoline-1,3-dione (I) with a range of primary amines gave rise to a series of 2-substituted 6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acids, e.g., II. The derived 4-N-[2-(dimethylamino)ethyl]carboxamides, e.g., III, were tested for growth inhibitory properties against murine P388 leukemia, Lewis lung carcinoma (LLTC), and human Jurkat leukemia cell lines. Most compds. were potent cytotoxins, with some having IC50 values less than 10 nM. Five were tested in vivo against s.c. colon 38 tumors in mice, and a single dose (3.9 mg/kg) proved to be curative for the 2-Me and 2-(3,4-dimethoxyphenyl) derivs. in this refractory model.