Sila-biperiden undendo-Sila-biperiden: Synthesen, Kristallstrukturen und antimuscarinische Eigenschaften

doi:10.1016/0022-328X(94)88024-7

Journal of Organometallic Chemistry

Volume 466, Issues 1–2, 22 February 1994, Pages 15-27

https://doi.org/10.1016/0022-328X(94)88024-7 Get rights and content

Summary

Starting from trichloro(vinyl)silane (Cl₃SiCH=CH₂), the muscarinic antagonists sila- biperiden [rac-(SiRS,C2SR)-exo-2] andendo-sila-biperiden [rac-(SiRS,C2SR)-endo-2] were prepared by a seven-step synthesis. Both silanols are configurationally stable in inert organic solvents but undergo slow epimerization in aqueous solution (pH 7.4, 32°C) by inversion of the configuration at the silicon atom. The relative configurations of sila-biperiden andendo-sila- biperiden were determined by single-crystal X-ray diffraction. Both compounds form intermolecular O-H ⋯ N hydrogen bonds in the crystal leading to the formation of centrosymmetric dimers (sila-biperiden) and infinite chains (endo-sila-biperiden), respectively. Sila-biperiden is a silicon analogue (C/Si exchange) of the antiparkinsonian drug biperiden [rac-(CRS/C2SR)-exo-1]. In functional pharmacological experiments, as well as in radioligand competition studies, biperiden, sila-biperiden andendo-sila-biperiden behaved as simple competitive antagonists at muscarinic M1-, M2-, M3- and M4-receptors. The three compounds displayed the highest affinity for M1-receptors (pA₂ values: 8.72–8.80; pK_i values: 8.8–9.1), intermediate affinity for M4- and M3-receptors, and lowest affinity for M2-receptors (pA₂ values: 7.57–7.79; pK_i values: 7.7–7.8). The affinity profile (M1 ≫ M4 ≫ M3 ≫ M2) of biperiden, sila-biperiden andendo-sila-biperiden is qualitatively similar to that of the M1-selective muscarinic antagonist pirenzepine. The antimuscarinic properties of the C/Si analogues biperiden and sila-biperiden are almost identical.

Zusammenfassung

Die Antimuscarinica sila-biperiden [rac-(SiRS,C2SR)-exo-2] undendo-Sila-biperiden [rac-(SiRS,C2SR)-endo-2] wurden ausgehend von Trichlor(vinyl)silan (Cl₃SiCH= CH₂) durch eine siebenstufige Synthese dargestellt. Die beiden Silanole sind in inerten organischen Solvenzien konfigurationsstabil, unterliegen aber in wa¨sseriger Lo¨sung (pH 7.4, 32°C) einer Epimerisierung durch Inversion der Konfiguration am Silicium-Atom. Die relativen Konfigurationen von Sila-biperiden undendo- Sila-biperiden wurden durch Einkristall-Ro¨ntgenstrukturanalysen bestimmt. Beide Verbindungen bilden im Kristall intermolekulare O-H ⋯ N-Was-serstoff-Bru¨ckenbindungen aus, die zum Aufbau von zentrosynunetrischen Dimeren (Sila-biperiden) bzw. unendlichen Ketten (endo-Sila-biperiden) fu¨hren. Sila-biperiden ist ein Silicium-Analogon (C/Si-Austausch) des Antiparkinsonmittels Biperiden [rac-(CRS,C2SR)-exo-1]. Sowohl in funktionellen pharmakologischen Untersuchungen als auch in Radioligand-Kompetitionsex-perimenten erwiesen sich Biperiden, Sila-biperiden undendo-Sila-biperiden als rein kompetitive Antagonisten an muscarinischen M1-, M2-, M3- und M4-Rezeptoren. Alle drei Verbindungen zeiGten die ho¨chste Affinita¨t zu den M1-Rezeptoren (pA₂-Werte: 8.72–8.80; pK_i-Werte: 8.8–9.1), eine deutlich geringere Affinita¨t zu den M4- und M3-Rezeptoren und die niedrigste Affinita¨t zu den kardialen M2-Rezeptoren (pA₂-Werte: 7.57–7.79; pK_i-Werte: 7.7–7.8). Das Affinita¨tsprofil (M1 ≫ M4 ≫ M3 ≫ M2) von Biperiden, Sila-biperiden undendo-Sila-biperiden ist dem des M1-selektiven Antimuscarinicums Pirenzepin qualitativ sehra¨hnlich. Die antimuscarinischen Eigenschaften der C/Si-Analoga Biperiden und Sila-biperiden sind nahezu identisch.

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Sila-biperiden undendo-Sila-biperiden: Synthesen, Kristallstrukturen und antimuscarinische Eigenschaften

Summary

Zusammenfassung

Endeavour, New Series

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

J. Organomet. Chem.

Eur. J. Pharmacol.

Br. J. Pharmacol

Mol. Pharmacol.

Trends Pharmacol. Sci.

Z. Naturforsch.

Liebigs Ann. Chem.

Chem. Ber.

Liebigs Ann. Chem.

Arch. Pharm. (Weinheim)

Liebigs Ann. Chem.

Liebigs Ann. Chem.

Chem. Ber.