SYNTHESIS, NMR-STUDIES AND CONFORMATIONAL-ANALYSIS OF OXAZOLIDINE DERIVATIVES OF THE BETA-ADRENORECEPTOR ANTAGONISTS METOPROLOL, ATENOLOL AND TIMOLOL

Formaldehyde-derived oxazolidine derivatives 4-7 of the beta-adrenorec eptor antagonists metoprolol 1, atenolol 2 and timolol 3 have been syn thesised. Conformational analysis of 1-3 and the oxazolidine derivativ es 4-7 has been performed using H-1 NMR spectroscopy and computational methods. The H-1 NMR studies show that for the aryloxypropanolamine b eta-adrenoreceptor antagonists there is a predominance of the conforme r 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 aryloxypropanol amine 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 aryloxyp ropanolamine beta-adrenoreceptor antagonists may therefore be appropri ate as prodrugs, or semi-rigid analogues, when greater lipophilicity i s required for drug delivery.