CYCLIC BENZAMIDES AS MIXED DOPAMINE D-2 SEROTONIN 5-HT2 RECEPTOR ANTAGONISTS - POTENTIAL ATYPICAL ANTIPSYCHOTIC AGENTS

A series of novel -(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl) c yclic amides was prepared and evaluated as potential antipsychotic age nts. The target compounds were examined in vitro for their binding aff inities to the dopamine D-2, serotonin 5-HT2, and serotonin 5-HT1a rec eptors and in vivo for their ability to antagonize the apomorphine-ind uced climbing response in mice. Derivatives that exhibited good D-2/5- HT2 selectivity in vitro and good potency in vivo were selected for fu rther evaluation in tests designed to assess their potential extrapyra midal side effect liability. Structural modifications discussed herein focus on the bicyclic amide subunit leading to the preparation of a v ariety of heterocyclic ring systems (i.e., phthalimide, isoindolinone, isoquinolinone, benzazepinone, indazolone, phthalazinone, 4-methyl ph thalazinone, benzisothiazolone 1,1-dioxide, benzotriazinone, homophtha limide, benzisothiazolone, phthalazinedione, quinazolinone, and satura ted phthalazinones). The potency and selectivity within this series wa s found to be dependent on ring size, nature of the covalent linking u nit, relative position of the functional groups, degree of unsaturatio n, and relative stereochemistry, In general, the cyclic benzamides exa mined in this investigation exhibited receptor binding activities indi cative of potential atypical antipsychotic agents. Several of these de rivatives possessed in vivo activities that suggest they would be usef ul in the treatment of schizophrenia and would have a low propensity t o induce extrapyramidal side effects. Two potent analogues were identi fied and selected for further evaluation: -(4-(1,2-benzisothiazol-3-yl )-1-piperazinyl)butyl) -1-isoindolinone (31) and butyl)-4a,5,6,7,8,8a- hexahydro-1(2H)-phthalazinone hydrochloride (52).