Antimitotic Agents. Alterations at the 2,3-Positions of Ethyl (5-Amino-1,2-dihydropyridopyrazin-7-yl)carbamates

Article abstract of DOI:10.1021/jm00115a005

The reaction of ethyl (6-amino-4-chloro-5-nitropyridin-2-yl)carbamate (2) with α-amino ketone oximes gave 4-<(2-oxoethyl)amino>pyridine oximes 3, which were reductively cyclized to give a series of ethyl (1,2-dihydropyrido<3,4-b>pyrazin-7-yl)carbamates (6).In another approach, α-nitro ketones, α-oximino ketones, and α-nitro alcohols were reduced to give α-amino alcohols, which were reacted with 2 to give 4-<(2-hydroxyethyl)amino>pyridines (5).Oxidation of these alcohols with the chromium trioxide-pyridine reagent gave the corresponding ketones (4), which were also reductively cyclized to give 6.Structure-activity relationship studies indicated that alterations at the 2- and 3-positions of the pyrazine ring of 6 had a significant effect on cytotoxicity and the inhibition of mitosis in cultured lymphoid leukemia L1210 cells.Compounds that exhibited in vitro cytotoxicities at less than 1 nM showed the same level of in vivo activity, whereas the less potent compounds showed wide variations in their in vivo activity.