Synthesis, Toxicological, Pharmacological, and Bronchodilating Activity in vitro of some Xanthineacetic Acid Derivatives

The possibility of the preparation of some ester derivatives of dimethylxanthines from 1‐theobromine‐ and 7‐theophylline acetic acids and 7‐(2‐hydroxyethyl)‐theophylline by DCC/DMAP‐mediated esterification under mild conditions was studied. The structures of the compounds synthesized and by products isolated were demonstrated by microanalyses, UV‐, IR‐, and 1 H NMR data. Acute toxicity assessment of the compounds on mice showed that compounds 4, 5, 6 , and 7 are less toxic than aminophylline. A pharmacological study of the in vitro broncholytic effect (IC 50 and pD 2 values) of the derivatives and aminophylline showed that the new compound 4 (1,2,3,6‐tetrahydro‐1,3‐dimethyl‐2,6‐dioxo‐7 H ‐purine‐7‐acetic acid 2‐(1,2,3,6‐tetrahydro‐1,3‐dimethyl‐2,6‐dioxo‐7 H ‐purine‐7‐yl)ethyl ester) has a strong bronchodilating effect on serotonine‐ and acetylcholine‐induced spasm in guinea pig trachea. The same compound does not influence barbiturate — induced hypnosis and locomotor activity, unlike to the effect of the aminophylline, used as a reference substance.