1, 5-Benzoxathiepin Derivatives. II. Synthesis and Serotonin S2-Receptor-Blocking Activity of Aminoalkyl-Substituted 3, 4-Dihydro-2H-1, 5-benzoxathiepin-3-ols and Related Compounds

• Published in: Chemical & pharmaceutical bulletin Vol. 35; no. 5; pp. 1930 - 1952
• Main Authors: SUGIHARA, HIROSADA, MABUCHI, HIROSHI, HIRATA, MINORU, IMAMOTO, TETSUJI, KAWAMATSU, YUTAKA
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 1987; Maruzen; Japan Science and Technology Agency
• Subjects: 1, 5-benzoxathiepin derivative; 1, 5-benzoxathiepin derivative conformation; Adrenergic alpha-Antagonists - chemical synthesis; Adrenergic alpha-Antagonists - pharmacology; aminoalkyl-sub-stituted 3, 4-dihydro-2H-1, 5-benzoxathiepin-3-ol; Animals; Chemical Phenomena; Chemistry; CV-5197; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; In Vitro Techniques; Molecular Conformation; Organic chemistry; Preparations and properties; Rabbits; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - pharmacology; serotonin S2-receptor antagonist; seven-membered heterocycle; structure-activity relationship; Swine; Thiepins - chemical synthesis; Thiepins - pharmacology; Nitrogen heterocycle; Six membered ring; S2 receptor; Bicyclic compound; Aromatic compound; Infrared spectrum; NMR spectrum; Biological activity; Oxygen nitrogen heterocycle
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.35.1930

Novel 1, 5-benzoxathiepin derivatives, 3, 4-dihydro-2H-1, 5-benzoxathiepin-3-ols with an aminoalkyl group at the 2-, 3- or 4-position, were synthesized and evaluated for serotonin S2-receptor-blocking activity and adrenergic α1-receptor-blocking activity. Methyl 4-aminoalky1-3-hydroxy-3, 4-dihydro-2H-1, 5-benzoxathiepin-4-carboxylates showed significant S2-receptor-block-ing activities. Structure-activity relationships (including the results of a conformational study and skeletal modifications) were examined. In the series of 1, 5-benzoxathiepin, 1-benzoxepin and 1-benzothiepin derivatives, methyl cis-3-hydroxy-7-methoxy-4- [3- (4-phenyl -1-piperazinyl) propyl] -3, 4-dihydro-2H-1, 5-benzoxathiepin-4-carboxylatehydrochloride (CV-5197) showed the most potent and the most selective S2-receptor-blocking activity in the binding profile, and was chosen as a candidate for further pharmacological evaluation.