Synthesis of 1,4-dihydro-2-phenyl-4,4-bis(4-pyridinylmethyl)-2H-isoquinolin-3-one and related compounds as acetylcholine release enhancers

Acetylcholine release enhancers may have therapeutic value in the treatment of Alzheimer's disease. A series of 1,4-dihydro-4,4-bis(pyridinylmethyl)-2H-isoquinolin-3-ones (2-13) was synthesized as analogs of the known acetylcholine-release enhancer linopirdine (1). Their cholinergic activity was measured as the enhancement of indirectly-elicited twitch tension of the mouse diaphragm. Among the target compounds, 2-phenyl-4,4-bis(4-pyridinylmethyl)-4H-isoquinoline-1,3-dione (2) and 7-bromo-1,4-dihydro-2-phenyl-4,4-bis(4-pyridinylmethyl)-2H-isoquinolin-3-one (11) were found to be more potent than 1.