Crystal and molecular structures of pyridazinone cardiovascular agents

Abstract

The crystal and molecular structures of 11 6-substituted pyridazinone derivatives: 6-phenyl-3(2H)-pyridazinone-acetic acid (1/1) (1), 6-(4-aminophenyl)- 3(2H)-pyridazinone (2), 6-(4-aminophenyl)- 5-methyl-3(2H)-pyridazinone (3), 6-(4-acetamidophenyl)- 3(2H)-pyridazinone (4), 6-(4-acetamido-2- methoxyphenyl)-3(2H)-pyridazinone (5), 6-(2-aminophenyl)-3(2H)- pyridazinone (6), 6-phenyl-3(2H)- pyrazinone (7), 6-(4-aminophenyl)-4,5-dihydro- 3(2H)-pyridazinone (8), (R)-(-)-6[4-(3-bromopropionamido)phenyl]- 4,5-dihydro-5-methyl-3(2H)-pyridazinone (9), (R)-(-)-6-(4-ammoniophenyl)-4,5- dihydro-5-methyl-3(2H)-pyridazinone (-)-tartrate-dichloromethane-methanol (1/1/1) (10), 4,5-dihydro-6-methyl-3(2H)-pyridazinone (11) have been determined as part of a study to determine the relationship between their cardiovascular properties and molecular structure and dimensions. For the two optically resolved chiral derivatives (9) and (10) the absolute configuration has been determined.

The matching of electrostatic extrema: A useful method in drug design? A study of phosphodiesterase III inhibitors

“…Initial modelling and minimisation of the specific PDE III inhibitors showed that most of them had essentially planar conformations. This is in agreement with previous studies [14] which propose a generally flat topology for specific PDE III inhibitors, and the molecular geometry in the crystal of many inhibitors of phosphodiesterase III [15].…”

“…The best over!ay of the alternative conformation(with the acetyl group rotated in a trans conformation, to mimic SK&F95800), SK&F93741ac, matches different points and gives a comparable rmsd value, with only two moderate clashes. SK&F95800 is a better inhibitor than SK&F93741, despite the fact that it lacks a methyl group which is known to increase inhibitory activity [15]. Hence, it is not necessary to assume that SK&F93741 adopts the higher energy conformation, analogous to SK&F95800, in order to have an electrostatically favourable binding orientation.…”

Sugar-Derived Di- and Tetrahydropyridazinones: Synthesis of New Glycosidase Inhibitors

“…1); structural parameters agree with those of known dihydropyridazinone derivatives [30]. HÀC(2) resonated at much higher field than to HÀC(3).…”

Intermolecular N–H...O hydrogen bonds assisted by resonance. Heteroconjugated systems as hydrogen-bond-strengthening functional groups

“…Hydrogen-bond topology: hydrogen-bond connectivities represented by means of: (a) our notation described in the text; (b) EMIl notation (Etter et ai., 1990); (c) EMB notation but taking into account RAHB (Gilli et al, 1989). Mastropaolo, Camerman & Camerman (1991); (k) Ohms, Guth, Hellner, DannOhl & Schweig (1984); (/) Schmalle, H~ggi & Dubler (1988); (m) Prout et al (1994); (n) Ferretti, Bertolasi, Gilli & Borea (1985); (o) Boer (1972); (t7) Bradshaw, Guynn, Wood, Wilson, Dalley & Izatt (1987); (q) Lowe, Schwalbe & Williams (1987); (r) Low, Tollin, Brand & Wilson (1986); (s) Watt, Martin, Duchamp, Mizsak, Nielson & Prairie (1988); (t) Smith, Bobe, Minnetian, Hope & Yanuck (1985). In the remaining examples (7 and 35-39), N.--O distances are rather short (2.734-2.856,~,), although the C:O and NH moieties apparently belong to a O---C--C--NmH non-conjugated moiety.…”