Antimitotic agents. Alterations at the 2,3-positions of ethyl (5-amino-1,2-dihydropyrido[3,4-b]pyrazin-7-yl)carbamates.
The reaction of ethyl (6-amino-4-chloro-5-nitropyridin-2-yl)carbamate (2) with alpha-amino ketone oximes gave 4-[(2-oxoethyl)amino]pyridine oximes 3, which were reductively cyclized to give a series of ethyl (1,2-dihydro-pyrido[3,4-b]pyrazin-7-yl)carbamates (6). In another approach, alpha-nitro ketones, alpha-oximino ketones, and alpha-nitro alcohols were reduced to give alpha-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.
Temple
C
C
Kettering-Meyer Laboratories, Southern Research Institute, Birmingham, Alabama 35255.
Rener
G A
GA
Comber
R N
RN
Waud
W R
WR
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D002219:Carbamates / Q000138:chemical synthesis* / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D011719:Pyrazines / Q000138:chemical synthesis* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002219:Carbamates; D011719:Pyrazines