Patent Evaluation: 1-Azabicycloalkanes containing ether or thioether side-chains as muscarinic agonists

Summary

Novelty: 1-Azabicycloalkane-based compounds are disclosed which exhibit muscarinic agonist activity. These are potentially useful in the symptomatic alleviation of cognitive disorders such as Alzheimer's disease, and as cognitive enhancers.

Biology: The muscarinic cholinergic agonist activity of the compounds is indicated by enhancement of polyphosphoinositide turnover in CHO cells and by a shift in GTP binding parameters in membrane preparations. Competition binding data in rat cerbral cortex membranes against [³H]-NET-647 indicate that selected compounds have K_i values in the range of 80–220 nM.

Chemistry: Synthesis of the compounds is by conventional methods, exemplified in sixty-two cases. A specifically claimed compound is 3-(2-propynyl)oxymethyl-1-azabicyclo[2.2.2]-octane.

Structure: