Conformationally Constrained Butyrophenones. Synthesis and Evaluation as Antipsychotics

The present report provides a full and extended study of the chemistry and CNS pharmacology of cyclic aminobutyrophenones as neuroleptics. A series of more than fifty novel conformationally restricted aminobutyrophenones bearing 4-(6-fluorobenzisoxazol-3-yl)piperidine, 4-(4-fluorobenzoyl)piperidine, 4-phe-nylpiperazine, 4-(2-methoxyphenyl)piperazine, 4-(2-pyridyl)piperazine, or linear but-yro- phenone fragments have been prepared and evaluated as antipsychotic agents by in vitro assays of affinity for dopamine (D1, D2 and, in some cases, D4) and serotonin (5-HT2A, 5-HT2B and 5-HT2C) receptors, and by in vivo assays on antipsychotic potential and extrapyramidal side effects. The synthesized amino-butyrophenones are referred to as a-(2-aminoethyl) and b-(aminomethyl)-benzocycloalkanones in the benzene series, as well as a-(2-aminoethyl) and b-(amino methyl) heterocycloalkanones in the thiophene, furan, indole, carbazole and quinoline series. In all these series the conformation of the butyrophenone chain is constrained by its partial incorporation into a cycloalkanone ring fused to a benzene or heterocyclic ring. Most of the butyrophenones prepared are very active as atypical antipsychotic agents, and represent good candidates for a further development. Some butyrophenones bearing arylpiperazine moieties show selectivity at 5-HT2B 5-HT2C receptors.