A deuterium isotope effect on the inhibition of gastric secretion by N,N-dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)ure a. Synthesis of metabolites

Article abstract of DOI:10.1021/jm00365a020

The use of isotopic substitution to retard the oxidative metabolism of the gastric antisecretory agent N,N-dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)ure a (1) and improve its antisecretory potency was examined. The pyridine ring methyl hydrogens of 1 were replaced with either deuterium or fluorine. The hexadeuterated analogue was found to be ~2.1 times more potent than the protio form (1) as an inhibitor of gastric acid secretion stimulated by gastrin tetrapeptide. The hexafluoro analogue was 0.4 times as potent as 1. A useful pyridine ring synthesis was developed to prepare the metabolites of 1, (4-hydroxymethyl) and (6-hydroxymethyl), and the hexafluoro analogue. These syntheses involved the condensation of 1,3-diketones with an appropriately N-substituted amidinoacetate.