Structural investigation of Ca2+ antagonists benzofurazanyl and benzofuroxanyl-1,4-dihydropyridines

Citation
G. Ermondi et al., Structural investigation of Ca2+ antagonists benzofurazanyl and benzofuroxanyl-1,4-dihydropyridines, J MOL STRUC, 523, 2000, pp. 149-162
Citations number
22
Categorie Soggetti
Physical Chemistry/Chemical Physics
Journal title
JOURNAL OF MOLECULAR STRUCTURE
ISSN journal
00222860 → ACNP
Volume
523
Year of publication
2000
Pages
149 - 162
Database
ISI
SICI code
0022-2860(20000502)523:<149:SIOCAB>2.0.ZU;2-Q
Abstract
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.