Potential antitumor agents. 14. 4-Substituted 2-formylpyridine thiosemicarbazones

A series of 4-substituted 2-formylpyridine thiosemicarbazones has been synthesized which contain a tertiary N at the 4 position. These materials were obtained by reacting 4-nitro-2-picoline N-oxide, either directly or after conversion to the corresponding 4-chloro derivative, with a variety of secondary amines. Rearrangement of the 4-substituted 2-picoline N-oxides with Ac2O yielded respective methyl acetates, which upon acid hydrolysis, MnO2 oxidation, and reaction with thiosemicarbazide resulted in the desired compounds. An alternate procedure which consisted of reacting 4-chloro-2-formylpyridine ethylene acetal with various amines, followed by hydrolysis and reaction with thiosemicarbazide, was also employed. Introduction of an alkyl group at the 3 position of the pyridine ring of 4-morpholino-2-formylpyridine thiosemicarbazone was achieved by utilizing 2,3-dimethyl-4-nitropyridine N-oxide; this material was converted to the corresponding 4-chloro derivative which was then subjected to nucleophilic substitution. 4-Morpholino-2-formylpyridine thiosemicarbazone was the most active antineoplastic agent of this series in mice bearing Sarcoma 180 ascites cells and was significantly superior to 5-hydroxy-2-formylpyridine thiosemicarbazone in this test system.