A series of 3-[[(aryloxy)alkyl]piperidinyl]-1,2-benzisoxazoles was synthesized and evaluated as potential antipsychotic D2/5-HT2 antagonists. Most of these compounds showed potent antipsychotic-like activity in an apomorphine-induced climbing mouse paradigm, with many also showing preferential mesolimbic activity, as indicated by their weaker effects in an apomorphine-induced stereotypy model. In receptor binding assays, many displayed a moderate affinity for the D2 receptor coupled with a significantly greater affinity for the 5-HT2 receptor: a property that has been suggested as necessary for atypicality. From this series, compound 45, 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone (iloperidone, HP 873), was further evaluated in a battery of in vivo and in vitro assays. This compound showed a 300-fold greater potency in inhibition of climbing than in inhibition of stereotypy or induction of catalepsy, and when evaluated chronically in an electrophysiological model, 45 caused a depolarization blockade of dopamine neurons in the A10 area of the rat brain but not in the A9 area. Additionally, it showed positive activity in a social interaction paradigm, suggesting potential efficacy against asociality, a component of the negative symptoms of schizophrenia. In chronic ex vivo studies, 45, similar to clozapine, caused a down regulation of 5-HT2 receptors but had no effect on the number of D2 receptors. Compound 45 is currently undergoing clinical evaluation.

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cis‐l ,4 Butendiol (I) liefert das Trichloracetimidat (II), das thermisch zu ( III) umgelagert und anschließend mit Dibrom‐formaldoxim in die beiden Isoxazoline (IV) und (V) übergeführt werden kann.

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The synthesis of the novel benzo[c]pyrrolo[1,2,3‐ef][1,5]benzodiazepine ring system is described. This was achieved by cyclization of an appropriately substituted (7‐aminoindolin‐1‐yl)benzamide or benzoic acid. The resulting tetracyclic lactams were reacted with N‐methylpiperazine in the presence of titanium tetrachloride to provide derivatives which were tested for potential antipsychotic activity.