Antimitotic Agents: Synthesis of Imidazopyridin-6-ylcarbamates and Imidazopyridin-5-ylcarbamates

Article abstract of DOI:10.1021/jm00164a030

Cyclization of ethyl 5,6-diamino-4-hydrazinopyridin-2-ylcarbamate (10) with a mixture of CS2 and Et3N in dimethylacetamide gave mainly ethyl 1,4-diamino-2(3H)-thioxoimidazo<4,5-c>pyridin-6-ylcarbamate (15), whereas, in the absence of dimethylacetamide, a double cyclization gave mainly ethyl 5-amino-2(1H)-4-dithioxodiimidazo<4,5-b:5,4-c>pyridin-7-ylcarbamate (16).Cyclization of the benzylidenehydrazino derivative (6) of 10 with either CS2-Et3N or (EtO)3CH-HCl gave 1-(benzylideneamino)imidazo<4,5-c>pyridines 11 and 7 as major products and 7-(benzylidenehydrazino)imidazo<4,5-b>pyridines 12 and 8 as minor products.Dethiolation of 11 to give 7 and of 12 to give 8 was effected with excess Raney nickel in refluxing ethanol.The benzylidene group of 11 was removed with hydrazine in ethanolic HCl to give 15.This key compound was condensed with benzaldehydes to give 1-benzylideneamino derivatives (20,21) and alkylated with benzyl halides to give 2-benzylthio derivatives (24-26).In addition, cyclization of ethyl 5,6-diamino-4-(benzylidene-1-methylhydrazino)pyridin-2-ylcarbamate (30) with (EtO)3CH provided a method for the synthesis of an imidazo<4,5-b>pyridine (23) uncontaminated with isomeric products.The presence of an aryl group in both the imidazo<4,5-c>- and -<4,5-b>pyridines gave compounds that inhibited proliferation of growth and caused mitotic arrest against lymphoid leukemia L12010 at micromolar concentrations.However, the more active in vitro compounds (7, 8, 24-26) gave only borderline activity in mice against lymphocytic leukemia P388.