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

Abstract

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