Synthesis and neuroleptic activity of a series of 1-[1-(benzo-1,4-dioxan-2-ylmethyl)-4-piperidinyl]benzimidazolone derivatives

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Abstract
A series of 1-[1-(benzo-1,4-dioxan-2-ylmethyl)-4-piperidinyl]benzimidazolones with various substituents in both aromatic rings have been synthesized and tested for neuroleptic activity (antiapomorphine effects and [3H]spiroperidol binding) as well as extrapyramidal effects (cataleptogenic effect). A strong dependence of activity on the 5-substituent in the benzimidazolone moiety could be demonstrated. Some compounds show a large split between the desired antiapomorphine and the undesired extrapyramidal effect. From these, 1-[1-(benzo-1,4-dioxan-2-ylmethyl)-4-piperidinyl]-5-chlorobenzimidazol-2-one hydrochloride (HR 723), 12, has been selected for further preclinical and toxicological profiling.