title: Synthesis and antiulcer activity of 5,11-dihydro[1]benzoxepino[3,4-b]pyridines.
abstract: A series of substituted 5,11-dihydro[1]benzoxepino[3,4-b]pyridines was synthesized and evaluated for antiulcer activity in water immersion/restrained stress ulcer assay in rats. Structure-activity relationships are described. Most of the tested compounds exhibited low affinity to the muscarinic acetylcholine receptor. The molecular features for the best activities are the 2-(diethylamino)ethylenediamine group at the 5-position of the oxepin ring and an oxepin skeleton rather than a thiepin or a pyran skeleton. Methyl and chlorine substitution on the benzene ring reduced the activity. Compound 11, 5-[[2-(diethylamino)ethyl]amino]-5,11-dihydro[1]benzoxepino [3,4-b]pyridine trihydrochloride was selected for further evaluation. Synthesis and antiulcer activity of optically active 11 is described. There were no statistically significant differences between (+)-, (-)-, and (+/-)-11. Compound 11 showed weak antisecretory activity in pylorus-ligated rats. It is now under clinical evaluation as KW 5805.
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kumazawa
authors.forename: H
authors.initials: H
authors.lastname: Harakawa
authors.forename: H
authors.initials: H
authors.lastname: Obase
authors.forename: Y
authors.initials: Y
authors.lastname: Oiji
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: K
authors.initials: K
authors.lastname: Shuto
authors.forename: A
authors.initials: A
authors.lastname: Ishii
authors.forename: T
authors.initials: T
authors.lastname: Oka
authors.forename: N
authors.initials: N
authors.lastname: Nakamizo
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D001584:Benzoxepins / Q000138:chemical synthesis* / Q000627:therapeutic use; D005744:Gastric Acid / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000627:therapeutic use*; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism; D013312:Stress, Physiological / Q000150:complications; D013329:Structure-Activity Relationship; D014456:Ulcer / Q000188:drug therapy / Q000209:etiology
chemical_list: D000897:Anti-Ulcer Agents; D001584:Benzoxepins; D011725:Pyridines; D011976:Receptors, Muscarinic; C055432:KW 5805