Crystal structures and pharmacological activity of calcium channel antagonists: 2,6-dimethyl-3,5-dicarbomethoxy-4-(unsubstituted, 3-methyl-, 4-methyl-, 3-nitro-, 4-nitro-, and 2,4-dinitrophenyl)-1,4-dihydropyridine

Abstract

The molecular structures of 2,6-dimethyl-3,5-dicarbomethoxy-4-phenyl-1,4-dihydropyridine and the 3-methyl-, 4-methyl-, 3-nitro-, 4-nitro-, and 2,4-dinitrophenyl derivatives were determined by X-ray diffraction methods. The dihydropyridine ring in each of the compounds exists in a boat-type conformation. However, the degree of ring puckering varies among the compounds. The observed ring distortions were found to be influenced to a great extent by the position of the substituent in the 4-phenyl ring and the conformation about the interring bond. The distortion at the apical nitrogen of the dihydropyridine ring was found to be linearly related to that at the apical tetrahedral carbon. A correlation was observed between the pharmacological activities of this class of calcium channel antagonists, determined by their ability to inhibit the Ca2+-dependent muscarinic mechanical responses of guinea pig ileal longitudinal smooth muscle, and the magnitude of the 1,4-dihydropyridine ring puckering; the more active compounds exhibited the smallest degree of ring distortion from planarity.

Structure of a 4-phenyl-1,4-dihydropyridine derivative containing a nitrooxyalkyl ester at the 3-position

“…A large ring distortion is seen at C4 and N1. This feature is observed in other dihydropyridine derivatives (Fossheim et al, 1982;Tamazawa et al, 1986). Lorentz and polarization corrections were applied to the data.…”

Structures of two inactive nifedipine analog calcium channel antagonists: (I) C17H17N3O4 and (II) C19H20N2O6

“…Two (1)-C(2) 1.370 (3) C17HITN304 AND Clgn2oN206 constraining the orientation of the phenyl ring to lie close to the N(1)-C(4) vertical symmetry plane of the 1,4-DHP ring (Loev et al, 1974;Rodenkirchen, Bayer, Steiner, Bossert, Meyer &Moller, 1979). Diffraction studies (Triggle, Shefter & Triggle, 1980;Fossheim, Swarteng, Mostad, Romming, Shefter & Triggle, 1982) confirmed this intramolecular constraint and furthermore revealed that antagonist potency correlated more strongly with the degree of DHP ring flatness than with the degree of phenyl ring rotational coplanarity with the N(1)-C(4) DHP vertical symmetry plane. In such structures the DHP ring has a shallow boat conformation with N(1) and C(4) defining the stern and bow positions, the aryl group is situated above the bow of the boat in an axial or flagpole orientation with the ortho or meta substituent almost invariably positioned on the forward or bowsprit side of the phenyl ring.…”

Diethyl 2,6-dimethyl-4-p-tolyl-1,4-dihydropyridine-3,5-dicarboxylate

“…(1) Å and 0.151 (2) Å, respectively, from the plane defined by C8, C9, C10, and C11, and form the apexes of a boat-type conformation (Fossheim et al, 1982).…”

“…For ring conformations and ring puckering analysis, see: Boeyens (1978); Cremer & Pople (1975). For related 1,4-dihydropyridine structures, see : Fossheim et al (1982); Teng et al (2008); Bai et al (2009). For the stability of the temperature controller used in the data collection, see : Cosier & Glazer (1986).…”