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 derivatives

Abstract

Treatment of N-(2-furoyl)proline or N-thenoylprolines and N-(2-thenoyl)thiazolidine-4-carboxylic acid with acetic anhydride and dimethyl acetylenedicarboxylate gave 5-substituted derivatives of dimethyl 2,3-dihydro-1H-pyrrolizine-6,7-dicarboxylate and derivatives of dimethyl 5-(2-thienyl)pyrrolo[1,2-c]thiazole. 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 appropriate isocyanates. The 1-substituted pyrrolizines were synthesized, the 1-acetoxy compounds 7b and 7c further transformed into 1-hydroxy and 1-oxo analogues. The action of hydrochloric acid on 1-acetoxy derivatives gave 3H-pyrrolizines. 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.