Synthesis and biological evaluation of 1-(1,2-benzisothiazol-3-yl)- and (1,2-benzisoxazol-3-yl)piperazine derivatives as potential antipsychotic agents

Abstract

Members of the series of title compounds were tested for potential antipsychotic activity in relevant receptor binding assays and behavioral screens. Structure-activity relationships within the series are discussed. Compound 24 (BMY 13859-1), a (1,2-benzisothiazol-3-yl)piperazine derivative, was selected for further study because of its potent and selective profile in primary CNS tests. It was active in the Sidman avoidance paradigm and blocked amphetamine-induced stereotyped behavior in dogs for up to 7 h. The compound's lack of typical neuroleptic-like effects in the rat catalepsy test and its failure to produce dopamine receptor supersensitivity following chronic administration indicate that it should not cause the movement disorders commonly associated with antipsychotic therapy. Although 24 has potent affinity for dopaminergic binding sites, its even greater affinity for serotonin receptors suggests that a serotonergic component may be relevant to its atypical profile. Compound 24 is currently undergoing clinical evaluation in schizophrenic patients.

Design, Synthesis, and Biological Evaluation of Conformationally Constrained Analogues of Naphthol AS-E as Inhibitors of CREB-Mediated Gene Transcription

“…Initially, it was envisioned that an S N Ar reaction between 4-chloroaniline and chloride 15 would deliver compound 4 . 20 Thus, a synthetic route depicted in Scheme 2 was designed. Hydroxamide 13 was prepared by condensing hydroxylamine with the methyl ester of acid 12 .…”

Biocatalytic synthesis of some chiral drug intermediates by oxidoreductases

“…Standards of compounds 1 and 2 were synthesized by the Chemical Process Research Department, Bristol-Myers Squibb Pharmaceutical Research Institute (New Brunswick, NJ) (22,23). (Table 1) were obtained from the American Type Culture Collection (Rockville, MD).…”

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

“…However, like many antipsychotic drugs its main therapeutic activity is probably due to its antagonistic action on dopamine receptors. The molecule comprises of a 1,2-benzisothiazole core, which is readily prepared from commercially available benzo[ d ]isothiazol-3(2 H )-one ( 369 ), a saccharin derivative [108]. The corresponding chloroimidate 370 formed by treatment of compound 369 with phosphoryl chloride is reacted with excess piperazine to afford intermediate 371 (Route A) [109].…”