(Imidazo[1,2-a]pyrimidin-2-yl)phenylmethanones and related compounds as potential nonsedative anxiolytics

Several series of heterocyclic carboxylic esters were found to be active in the benzodiazepine receptor binding assay, a typical example being ethyl 7-ethyl-5-methoxyimidazo[1,2-a]quinoline-2-carboxylate (4b) with an IC50 of 150 nM. The corresponding phenylmethanone 5d was more potent with an IC50 of 14 nM and was orally active in animal models thought to predict anxiolytic effects. The synthesis of a large number of compounds resulted in the optimization of this activity in a series of (imidazo[1,2-a]pyrimidin-2-yl)phenylmethanones of which compounds 7e, 8b, 8h, 8j, and 8k were equipotent with chlordiazepoxide while exhibiting reduced anticonvulsant activity, little or no muscle relaxation, and negligible sedative effects.