G. Ermondi et al., Structural investigation of Ca2+ antagonists benzofurazanyl and benzofuroxanyl-1,4-dihydropyridines, J MOL STRUC, 523, 2000, pp. 149-162
The structure of Ca2+ channel blockers benzofurazanyl- and benzofuroxanyl-1
,4-dihydropyridines (1,4-DHPs) was investigated by an integrated NMR, X-ray
diffraction and molecular graphics study. H-1- and C-13-NMR showed that al
l the benzofuroxan derivatives exist in solution as tautomeric mixtures. De
lta G degrees and Delta G* for 4' reversible arrow 7' and 5' reversible arr
ow 7' benzofuroxanyl tautomeric equilibria were determined for the benzofur
oxan derivatives VI and VII. These figures are close to those observed for
other substituted benzofuroxans known from literature including DHP derivat
ives.
The conformational domain of all the compounds was analyzed, showing two se
ts of energetically accessible arrangements of the heterocyclic substructur
e with respect to C(4)H-DHP hydrogen, antiperiplanar and synperiplanar. Rot
americ preference in solution around the C(4)-C(4') bond in benzofurazanyl
derivative IV was sought by normalized transient Delta NOE spectra using in
teratomic distances derived from AM1 energy minimized structures. A synperi
planar fraction of ca. 75% was calculated, in keeping with results obtained
by Rovnyak for Nifedipine. Finally, the solid state preferred conformation
was assessed by X-ray analysis for 5'-benzofurazanyl (V) and 5'(6')-benzof
uroxanyl (VII) derivatives. The latter in the solid state prefers the 5'-fo
rm (VIIa). The pentatomic ring systems always lie on the same side of the C
(4)H-DHP hydrogen. This was also found to be the case for 4'-substituted de
rivatives and a large number of dihydropyridine derivatives. (C) 2000 Elsev
ier Science B.V. All rights reserved.