Synthesis of 2-phenylthiazolidine derivatives as cardiotonic agents. III. Optically active isomers of N-methyl-2-(2-(2-(4-phenylpiperazino)ethoxy)phenyl)thiazolidine -3-carboxamides.

Optically active isomers of N-methy1-2-(2-(2-(4-phenylpiperazino)ethoxy)phenyl)thiazolidine3-carboxamides(( + )-2 and(-)-2) have been synthesized and tested for positive inotropic activity. The racemic thiocarboxamide((•})-3) was resolved into the enantiomers(( + )-3 and(•E)-3) via the Land D-N-(2-naphthylsulfonyl)prolyl derivatives ((+ )-4 and (-)-4). Conversion of the thiocarboxamides (( + )-3 and (-)-3) to the carboxamides (( + )-2 and (-)-2) was smoothly effected by treatment with the glycidic ester (7). The absolute stereochemistry of (-)-3 was determined to be 2S by X-ray crystallographic analysis. Hence, the absolute configuration of the carboxamide ((•E)-2) is 2S. On i.v. administration to anesthetized dogs, the enantiomers of 2 showed only a threefold difference in positive inotropic activity, with the levo isomer ((-)-2) being the more active . In the isolated cat heart muscle, the enantiomers were nearly equipotent to each other . Thus, no significant difference between the positive inotropic activities of the optical isomers of 2 was observed .