Synthesis, toxicological, pharmacological assessment, and in vitro bronchodilating activity of some 7-theophyllinylacetyloxyglycols.

The synthesis of four ester derivatives of 7-theophylline-acetic acid and glycols by DCC/DMAP-mediated esterification under mild conditions was studied. The structures of the synthesized compounds were proved by microanalyses, UV-, IR-, and 1H-NMR data. Acute toxicity assessment of the compounds in mice showed that compounds 2a-d are less toxic than aminophylline. It was shown by in vivo experiments that 2a-d had depressive action on CNS (increasing of hexobarbital sleeping time and decreasing of spontaneous locomotor activity), and they did not influence to a statistically significant extent the normal 24 hour diuresis of rats (except 2c). The results of cardiovascular screening in rats show that compounds 2a and 2c decreased the heart rate of rats. A pharmacological study of the in vitro broncholytic effect (IC50 and pD2 values) of the derivatives and aminophylline showed that 2c exhibited good broncholytic effect in vitro especially in acetylcholine and serotonin induced guinea pig tracheal contraction. It was demonstrated that compounds 2b,c exerted a stronger inhibitory effect on the enzymic activity of phosphodiesterase in concentration 2 x 10(-3) M than aminophylline.