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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The 3-and 4benzoylpiperidines and 3-benzoylpyrrolidines were prepared by the reaction of l-acetylisonipecotoyl or 1-acetylnipecotoyl chloride with a substituted aromatic compound under Friedel-Crafts conditions or by treatment of the cyanopiperidines and pyrrolidines with an arylmagnesium halide. Alkylation gave the I-substituted compounds which were evaluated as CNS depressants. The I-substituted 4(p-fluorobenzoyl)piperidines were the most active compounds, several of which were more potent than chlorpromazine, triperidol, or haloperidol in the fighting mouse assay.

Hydroxylamine and hydroxamic acid derivatives of a known nonsteroidal antiinflammatory dibenzoxepine series display both cyclooxygenase (CO) and 5-lipoxygenase (5-LO) inhibitory properties. Many of these new dual CO/5-LO inhibitors also exhibit potent topical antiinflammatory activity in the arachidonic acid-induced murine ear edema model. On the basis of their promising profile of in vitro and in vivo activities, hydroxamic acids 24h, 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-++ +methylpropanamide (HP 977), and 25, 3-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-hydroxy-N- methylpropanamide (P10294), were selected as developmental candidates for the topical treatment of inflammatory skin disorders.

Indolo[1,2‐c] quinazolines, indolo[1,2‐d] [1,4]benzodiazepines, indolo [1,2‐d] [1,4]benzodi‐azepin‐6‐ones and benzimidazo[1,2‐d] [1,4] benzodiazepin‐6‐ones were synthesized. In an acid medium, the indoloquinazolines were produced from 2‐(o‐aminophenyl)indole and acyl halides. However, in the presence of sodium acetate, the acylated amine was obtained and was cyclized to the indolobenzodiazepinones using sodium hydride. The syntheses are described in detail and characterization data are given.