X-ray investigations of nebivolol and its isomers

Tuchalski, Gisbert; Emmerling, Franziska; Gröger, Karsten; Hänsicke, André; Nagel, Thomas; Reck, G.

doi:10.1016/j.molstruc.2006.03.086

Cited by 12 publications

(20 citation statements)

References 7 publications

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“…The average C-N, C-C and C-O distances in the title compound ( Fig. 1) are in good agreement with those in other nebivolol derivatives (Peeters et al, 1993;Tuchalski et al, 2006). Figure 2 shows the packing in (I).…”

Section: Data Collectionsupporting

confidence: 76%

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L-Nebiviololinium chloride dihydrate

Tuchalski¹,

Hänsicke²,

Reck

et al. 2007

Acta Cryst E

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The hydrochloride salt of chiral l-nebivolol {systematic name: (+)−(R,S,S,S)-bis[2-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)-2-hydroxyethyl]ammonium chloride dihydrate}, C22H26F2NO4 +·Cl−·2H2O, was obtained by chiral liquid chromatography as a dihydrate. The pyran rings adopt half-chair conformations. Hydrogen bonds between the cation, anions and water molecules contribute to the formation of layers parallel to the ac plane.

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Section: Data Collectionsupporting

confidence: 76%

“…For related literature, see: Cini et al (1990); van Lommen et al (1990); Peeters et al (1993); Tuchalski et al (2006).…”

Section: Related Literaturementioning

confidence: 99%

L-Nebiviololinium chloride dihydrate

Tuchalski¹,

Hänsicke²,

Reck

et al. 2007

Acta Cryst E

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“…The stereochemical purity of all isomers is shown in Table 1; impurities of more than 1% were analyzed to exclude the existence of constitutional byproducts. Single crystals were prepared and the unit cells were investigated by X-ray crystallography, 12 additionally 1 H and 13 C NMR data confirmed the structures. The spatial orientation of all isomers was found to correlate with the four chirality centers and the crystallized compounds demonstrated definite differences in extension.…”

Section: The B-blocker Nebivololmentioning

confidence: 90%

Stereochemical comparison of nebivolol with other β‐blockers

Siebert

Hänsicke²,

Nagel³

2007

Chirality

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beta-Blockers are widely used in the treatment of cardiovascular disease and act by antagonizing the effects of adrenaline (epinephrine) and noradrenaline (norepinephrine) on beta-adrenergic receptors. All beta-blockers currently used in the treatment of cardiovascular disease contain at least one chiral center and, while most are marketed as racemates, their cardiac antihypertensive activity generally resides in the S-enantiomer. Nebivolol is a third generation beta-blocker that is highly selective for the beta(1)-adrenoceptor. The nebivolol molecule contains four chiral centers and is marketed as a racemate of (+)-nebivolol (SRRR-configuration) and (-)-nebivolol (RSSS-configuration). Nebivolol differs from all other beta-blockers with a hydroxypropanolamine substructure in that its cardiac antihypertensive activity resides in the R-enantiomer at the hydroxy group, whereas all other beta-blockers have antihypertensive activity in the S-enantiomer. Two of the four chiral centers in nebivolol are part of a ring structure and the increased rigidity of this structure may be related to nebivolol's divergence from the standard pharmacophore model of beta-blockers.

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“…[43][44][45][46] In analysis of series of isomers and related congeners, it is important to be able to examine related structures and their physicochemical properties. [40][41][42][69][70][71][72][90][91][92][93][94] The CSD as a repository for structural information is important for ancillary information such as melting points. [40][41][42][90][91][92][93][94] In designing series of compounds, the drive to obtain a high melting point isomer should be influenced by the choice of Cl or Br-derivatives over F or Me and with parasubstitutions where possible.…”

Section: Melting Point Analysis: 81-89 Comparisons With Related Seriesmentioning

confidence: 99%

At the Interface of Isomorphous Behavior in a 3 × 3 Isomer Grid of Monochlorobenzamides: Analyses of the Interaction Landscapes via Contact Enrichment Studies

Gallagher

Farrell

Hehir

et al. 2019

Crystal Growth & Design

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The physicochemical properties of a 33 isomer grid of mono-chlorobenzamides (Clxx) are reported with comprehensive studies of their crystal structures and interaction environments (Clx = para-/meta-/ortho-chlorobenzoyl and x = para-/meta-/orthoaminopyridine substitutions). The nine compound Clxx series was synthesised from the three p-/m-/o-chlorobenzoyl chlorides and three p-/m-/o-aminopyridine isomers using standard synthetic procedures. Clxx exhibits some similarities to the related Fxx and Brxx congeners e.g. the isomorphous behaviour of Clpp (para-Chloro-N'-(parapyridyl)benzamide) with several close relatives, and there are five isomorphous pairs of Clxx and Brxx crystal structures. Notably Clmp and Clpm both crystallise with Z'=4 in space group P but show important differences. The overall lack of isomers crystallising with solvate molecules is noteworthy, except for Clmm(H 2 O). In all Clxx crystal structures, strong N-H…N hydrogen bonds form, however, Clpo also crystallises as the unexpected Clpo_O polymorph with N-H…O=C intermolecular hydrogen bonding. The Clxo triad (with orthopyridines) exhibits the expected cyclic N-H…N dimer formation with R 2 2 (8) hydrogen bonded rings. The H C atom type, forming weak C-H…Cl hydrogen bonds, is the only favoured interaction partner of chlorine in Clxx. Conformational analyses (gas phase) together with crystal contact enrichment studies place Clxx in context and at the interface of hydrogen and halogen bonding interactions, though strong hydrogen bonding dominates. In Clxx the interaction energies with nearest neighbours are shown to contribute to most of the lattice electrostatic energies. The melting temperatures T m show correlation with both molecular symmetry (Carnelley's rule) and total electrostatic energy of the weak interactions; in addition, these T m values can be well predicted from a linear fit combining both descriptors. In Clxx, N-H…N hydrogen bonds dominate, largely in the absence of solvates, and with five Clxx forming isomorphous pairs with Brxx analogues; Clpp being isomorphous with several close benzamide relatives. Analysis of T m reveals correlations involving both symmetry and electrostatic energies.

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X-ray investigations of nebivolol and its isomers

Cited by 12 publications

References 7 publications

L-Nebiviololinium chloride dihydrate

L-Nebiviololinium chloride dihydrate

Stereochemical comparison of nebivolol with other β‐blockers

At the Interface of Isomorphous Behavior in a 3 × 3 Isomer Grid of Monochlorobenzamides: Analyses of the Interaction Landscapes via Contact Enrichment Studies

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