SYNTHESIS, STRUCTURE, AND PHARMACOLOGICAL EVALUATION OF THE STEREOISOMERS OF FURNIDIPINE

The synthesis and pharmacological activities of the four stereoisomers of methyl tetrahydrofuran-2-ylmethyl 1,4-dihydropyridine-3,5-dicarbox ylate(furnidipine) are reported. The four isomers were synthesized by a modified Hantzsch synthesis by reaction of (-)- or (+)-tetrahydrofur an-2-ylmethyl 3-aminocrotonate and methyl 2-[(2'-nitrophenyl)methylene ]acetoacetate or, alternatively, by re action of (-)- or (+)-tetrahydr ofuran-2-ylmethyl 2-[(2'-nitrophenyl)methylene]acetoacetate and methyl 3-aminocrotonate. The 1:1 diastereomeric mixtures thus obtained were separated by chromatography, using poly(D-phenylglycine) as the chiral stationary phase. The enantiomeric purity of the stereoisomers was de termined by a high-performance liquid chromatography-chiral stationary phase technique (HPLC-CSP). Attempts to obtain crystals of a single s tereoisomer failed in different solvents, while methanol crystallizati on of the product obtained from (+)-tetrahydrofuran-2-ylmethyl 2-[(2'- nitrophenyl)methylene]acetoacetate and methyl 3-aminocrotonate yielded good-quality crystals of the most insoluble racemate which proved to be a mixture of the (SS)/(RR) enantiomers by X-ray crystallography. Co nformational analysis of the stereoisomers, assuming rotation of the a ryl substituent and ester groups, shows small energy differences (abou t 4 kcal . mol(-1)) between the most and the least favorable conformat ions. Binding studies were performed using [H-3]isradipine as a refere nce ligand. The results showed stereospecificity of the furnidipine is omers in brain, ileum, and cardiac tissues, the (SS)- and (SR)-isomers clearly being more potent than their (RR)- and (RS)-enantiomers. The (SS)- and (SR)-isomers were also more selective on cerebral tissue whe n compared with ileal and cardiac preparations.