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