Synthesis and Evaluation of Antileukemic Activity of 5-Thienyl- or 5-(2-Furyl)-2,3-dihydro-6,7-bis(hydroxymethyl)-1H-pyrrolizine Bis(alkylcarbamates) and Derivates

Article abstract of DOI:10.1021/jm00122a028

Treatment of N-(2-furoyl)proline (1a) or N-thenoylprolines (1b, 1c) and N-(2-thenoyl)thiazolidine-4-carboxylic acid (1d) with acetic anhydride and dimethyl acetylenedicarboxylate gave 5-substituted derivatives of dimethyl 2,3-dihydro-1H-pyrrolizine-6,7-dicarboxylate (2a, 2b, 2c) and derivatives of dimethyl 5-(2-thienyl)pyrrolo<1,2-c>thiazole (2d).Reduction of 2 with lithium aluminum hydride gave the diols 3a, 3b, 3c, and 3d.These diols yielded the corresponding diacetates 4 by treatment with acetic anhydride.The bis(methylcarbamates) 5a, 5b, 5c, and 5d and bis(isopropylcarbamates) 6b and 6c are obtained with the appropiate isocyanates.The 1-substituted pyrrolizines were synthesized, the 1-acetoxy compounds 7b and 7c further transformed into 1-hydroxy (8b, 8c) and 1-oxo (9b, 9c) analogues.The action of hydrochloric acid on 1-acetoxy derivatives (7b, 7c) gave 3H-pyrrolizines (10b, 10c).Evaluation of antileukemic activity was investigated on the leukemia L1210 in vivo, on several bis(alkylcarbamates).The compounds 5c and 5d show good antileukemic activity comparable with the mitomycin.