Benzo- and pyrido-1,4-oxazepin-5-ones and -thiones: synthesis and structure-activity relationships of a new series of H1-antihistamines

• Published in: Journal of medicinal chemistry Vol. 32; no. 9; pp. 2178 - 2199
• Main Authors: Cale, Albert D, Gero, Thomas W, Walker, Kathleen R, Lo, Young S, Welstead, William J, Jaques, Larry W, Johnson, Ashby F, Leonard, Charles A, Nolan, Joseph C, Johnson, David N
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.09.1989
• Subjects: Animals; Azepines - chemical synthesis; Cats; Chemical Phenomena; Chemistry; Exact sciences and technology; Female; Guinea Pigs; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Histamine H1 Antagonists - chemical synthesis; Histamine H1 Antagonists - pharmacology; Hypnotics and Sedatives - pharmacology; Male; Molecular Conformation; Organic chemistry; Oxazepines - chemical synthesis; Oxazepines - pharmacology; Preparations and properties; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00129a026

A series of novel benzo- and pyrido-1,4-oxazepinones and -thiones which represents a new structural class of compounds possessing H1 antihistaminic activity was synthesized, and the SARs were evaluated. The antihistaminic activity was determined by blockade of histamine-induced lethality in guinea pigs. The sedative potential was determined by comparison of the EEG profiles of the compounds with those of known sedating and nonsedating antihistamines. Several of the compounds were shown to possess potent H1 antihistaminic activity and to be free of the cortical slowing with synchronized waves and spindling activity found in the EEG of sedative antihistamines. One compound, 2-[2-(dimethylamino)ethyl]-3,4-dihydro-4-methylpyrido[3,2-f]-1,4- oxazepine-5(2H)-thione (rocastine) is currently undergoing clinical evaluation as a nonsedating H1 antihistamine.