1-Oxa-3,8-diazaspiro[4.5]decan-2-one derivatives with a potent inhibitory effect on neural Ca-uptake and protecting action against TET-induced brain edema and memory and learning deficits

Summary A series of novel 1-oxa-3,8-diazaspiro[4.5]decan-2-one derivatives 8–71 were synthesized. Several representatives were examined for their in vitro inhibitory action on 45 Ca-uptake into cerebrocortical synaptosomes depolarized by potassium and veratrine and on triethyltin-induced brain edema. Of the compounds displaying most potent inhibitory action on veratrine-induced 45 Ca-uptake into cerebrocortical synaptosomes and outstanding protection against triethyltin chloride (TET) induced brain edema in rats, four were tested for their antihypoxic action and prevention of learning and memory deficits elicited by various agents (eg, electroshock, diazepam, scopolamine, carbon dioxide and normobaric hypoxia). In some of these tests the four compounds showed remarkable protecting/restoring activity. It is assumed that the beneficial effects of these compounds in brain edema formation are probably related to their actions on intracellular Ca 2+ -and Na + -movements. These cellular effects may also play role in their antiamnesic actions, but other mechanisms may also be involved. On the basis of results obtained in the tests used, the pharmacological profile of the novel 1-oxa-3,8-diazaspiro[4.5]decan-2-one derivatives seems to differ from that of known Ca 2+ -antagonists such as flunarizine or nimodipine and Na + -channel blocker, phenytoin. Out of the four most active compounds tested, one ( 44 ) was selected for further investigation and this compound is currently under preclinical development with the code name of RGH-2716 or TDN-345.