R. Alajarin et al., SYNTHESIS, STRUCTURE, AND PHARMACOLOGICAL EVALUATION OF THE STEREOISOMERS OF FURNIDIPINE, Journal of medicinal chemistry, 38(15), 1995, pp. 2830-2841
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.