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Synthesis, NMR studies and conformational analysis of oxazolidine derivatives of the beta-adrenoreceptor antagonists metoprolol, atenolol and timolol

Authors
Publication Date
Keywords
  • Chemistry
  • Organic
  • Chemistry
  • Physical
  • Drug Delivery Systems
  • Improved Ocular Delivery
  • Crystal-Structure
  • Prodrug Type
  • Hydrolysis
  • Receptor
  • Esters
  • Lipophilicity
  • Pharmacology
  • Agonists
Disciplines
  • Computer Science

Abstract

Formaldehyde-derived oxazolidine derivatives 4-7 of the beta-adrenoreceptor antagonists metoprolol 1, atenolol 2 and timolol 3 have been synthesised. Conformational analysis of 1-3 and the oxazolidine derivatives 4-7 has been performed using H-1 NMR spectroscopy and computational methods. The H-1 NMR studies show that for the aryloxypropanolamine beta-adrenoreceptor antagonists there is a predominance of the conformer in which the amine group is approximately antiperiplanar or trans to the aryloxymethylene group. Both H-1 NMR data and theoretical studies indicate that the oxazolidine derivatives 4-7 and the aryloxypropanolamine beta-adrenoreceptor antagonists 1-3 adopt similar conformations around the beta-amino alcohol moiety. Thus, oxazolidine ring formation does not dramatically alter the preferred conformation adopted by the beta-amino alcohol moiety of 1-3. Oxazolidine derivatives of aryloxypropanolamine beta-adrenoreceptor antagonists may therefore be appropriate as prodrugs, or semi-rigid analogues, when greater lipophilicity is required for drug delivery.

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