New anticancer agents: synthesis of 1,2-dihydropyrido[3,4-b]pyrazines (1-deaza-7,8-dihydropteridines)

• Published in: Journal of medicinal chemistry 1982-09, Vol.25 (9), p.1045-1050
• Main Authors: Temple, Carroll, Wheeler, Glynn P, Elliott, Robert D, Rose, Jerry D, Kussner, Conrad L, Comber, Robert N, Montgomery, John A
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Chemical Phenomena; Chemistry; Folic Acid Antagonists; Leukemia L1210 - drug therapy; Leukemia P388 - drug therapy; Mice; Mitosis - drug effects; Pyrazines - chemical synthesis; Pyrazines - pharmacology; Pyridines - chemical synthesis; Pyridines - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00351a008

Reaction of alpha-aminoacetophenone oximes (2) with ethyl 6-amino-4-chloro-5-nitropyridine-2-carbamate (1) gave ethyl 6-amino-5-nitro-4-[(2-oxo-2-phenylethyl)amino]pyridine-2-carbamate oximes (3), which were hydrolyzed under acidic conditions to give the corresponding ketones (4). Related pyridines substituted with a keto side chain were prepared from 1 and 1,3-diaminopropanone oximes and by oxidation of the side-chain hydroxy group of ethyl 6-amino-4- [[3-(N-methyl-N-phenylamino)-2-hydroxypropyl]amino]-5-nitropyridine-7- carbamates (6). Catalytic hydrogenation of the nitro group of 4 over Raney nickel in a large volume of ethanol gave the 1-deaza-7,8-dihydropteridines (7). Several of the oximes 3 were successfully hydrogenated to give 7 directly. The resulting 1-deaza-7,8-dihydropteridines showed potent cytotoxicity against cultured L1210 cells and significant anticancer activity against lymphocytic leukemia P-388 in mice. These biological activities are attributed to the accumulation of cells at mitosis.