Synthesis of potential anticancer agents. Pyrido[4,3-b][1,4]oxazines and pyrido[4,3-b][1,4]thiazines

• Published in: Journal of medicinal chemistry 1983-11, Vol.26 (11), p.1614-1619
• Main Authors: Temple, Carroll, Wheeler, Glynn P, Comber, Robert N, Elliott, Robert D, Montgomery, John A
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Chemistry; Drug Evaluation, Preclinical; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Indicators and Reagents; Leukemia L1210 - physiopathology; Leukemia P388 - drug therapy; Magnetic Resonance Spectroscopy; Mice; Mitotic Index - drug effects; Organic chemistry; Oxazines - chemical synthesis; Oxazines - therapeutic use; Preparations and properties; Pyridines - chemical synthesis; Pyridines - therapeutic use; Structure-Activity Relationship; Thiazines - chemical synthesis; Thiazines - therapeutic use
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00365a012

Hydrolysis of the chloro group of ethyl (6-amino-4-chloro-5-nitropyridin-2-yl)carbamate (3) with formic acid gave the corresponding 4-hydroxypyridine 4. Catalytic hydrogenation of the nitro group of 4 gave the 5-amino-4-hydroxypyridine 5, which was reacted with alpha-halo ketones in acetic acid at room temperature to give a series of 3- and 2,3-substituted ethyl (5-amino-2H-pyrido[4,3-b][1,4]oxazin-7-yl)carbamates 8. Treatment of 8 with hot concentrated hydrochloric acid regenerated the pyridine synthon 5. In the reaction of 3 with thioacetate, the product underwent hydrolysis and air-oxidation to give the corresponding disulfide 6. Simultaneous reduction of both the nitro group and disulfide linkage of 6 gave the 5-amino-4-mercaptopyridine 7, which was reacted with alpha-halo ketones either in acetic acid at room temperature or in a mixture of ethanol and water at reflux to give a series of 3-, 2,3-, and 2,2,3-substituted ethyl (5-amino-2H-pyridol[4,3-b][1,4]thiazin-7-yl)carbamates 9. The effects of these pyridooxazines and pyridothiazines upon the proliferation and the mitotic index of cultured L1210 cells and upon the survival of mice bearing P388 leukemia were determined.