Urinary metabolites of timolol from humans and laboratory animals. Syntheses and .beta.-adrenergic blocking activities

Publisher Website
Google Scholar
Abstract
Syntheses are reported for 3 metabolites (2-4) of timolol (1) [used to treat hypertension and angina pectoris] formed by oxidative metabolism of the morpholine ring. GLC-MS [mass spectroscopy] comparisons are presented which establish that the 2 metabolites whose structures were previously in question are identical with their synthetic counterparts 2 and 3. In 2, metabolic oxidation of the 4-morpholinyl group of 1 has occurred at the C next to O to give the 2-hydroxy-4-morpholinyl moiety, but in 3, the morpholine of 1 was oxidized 1 step further and then ring opened to produce the N-(2-hydroxyethyl) glycine substitutent. Biological testing of synthetic samples of the 3 major metabolites from human urine indicated that only 4, in which the morpholine moiety was degraded to a 2-hydroxyethylamino group, had significant .beta.-adrenergic blocking activity (1/7 that of timolol in anesthetized dogs).