Synthesis and neuroleptic activity of 3-(1-substituted-4-piperidinyl)-1,2-benzisoxazoles

• Published in: Journal of medicinal chemistry 1985-06, Vol.28 (6), p.761-769
• Main Authors: Strupczewski, Joseph T, Allen, Richard C, Gardner, Beth Ann, Schmid, Blaine L, Stache, Ulrich, Glamkowski, Edward J, Jones, Michael C, Ellis, Daniel B, Huger, Francis P, Dunn, Robert W
• Format: Article
• Language: English
• Subjects: Animals; Antipsychotic Agents - chemical synthesis; Antipsychotic Agents - pharmacology; Chemistry; Corpus Striatum - metabolism; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; In Vitro Techniques; Isoxazoles - chemical synthesis; Isoxazoles - pharmacology; Male; Mice; Motor Activity; Organic chemistry; Oxazoles - chemical synthesis; Piperidines - chemical synthesis; Piperidines - pharmacology; Preparations and properties; Spiperone - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00383a012

The synthesis of a series of 3-(1-substituted-4-piperidinyl)-1,2-benzisoxazoles is described. The neuroleptic activity of the series was evaluated by utilizing the climbing mice assay and inhibition of [3H]spiroperidol binding. Structure-activity relationships were studied by variation of the substituent on the benzisoxazole ring with concomitant variation of four different 1-piperidinyl substituents. Maximum neuroleptic activity was realized when there was a 6-fluoro substituent on the benzisoxazole ring. The 1-piperidinyl substituent appeared less significant, although in most cases, the (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl group imparted maximum potency. The most potent compound in both assays was 6-fluoro-3-[1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl]-4-piperidinyl]-1,2-benzisoxazole (11b).