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.

Effects of KW-5805, a New Antiulcer Agent, on Experimental Gastric and Duodenal Ulcers, Gastric Mucosal Lesions by Necrotizing Agents and Gastric Acid Secretion

“…reported to be effective in the treatment of gastroduo denal ulcers by their antisecretory action mediated through blockade of muscarinic receptors or histamine H2-receptors and uptake inhibition of noradrenaline or serotonin (3,4,28,29). KW-5805, however, has a very weak musucarinic receptor binding (1/30 of pirenzepine) (13) and no effect on H2-receptors and noradrenaline up take (A. Ishii et al, unpublished data). The mode of the antisecretory action of KW-5805 is thus apparently differ ent from those of cimetidine and tricyclic antidepressants and may be mediated at least partly through its weak an timuscarinic action as compared to pirenzepine.…”

Centrally mediated inhibitory effect of 5-(2-(diethylamino)ethyl)amino-5,11-dihydro(1)benzoxepino(3,4-b)pyridine trihydrochloride (KW-5805) on gastric acid secretion in rats.

“…It has been reported that KW-5805 is an antiulcerogenic compound that acts on the defensive mechanisms (3), as its antisecre tory activity is weak in pylorus-ligated rats (1,2). However, the present results indicate that KW-5805 could inhibit gastric acid secretion through centrally mediated mecha nisms.…”

“…In addition, its affinity to the muscarinic receptor was low as compared with that of pirenzepine in the receptor binding assay (1). This compound showed weak antisecretory activity after i.d.…”

“…-5,1 5,11 -di hydro [1] benzoxepino [3,4-b]pyridine trihy drochloride (KW-5805) is a new tricyclic derivative that consists of pyridine, oxepin and benzene rings (Fig. 1).…”

“…Abstract-KVV-5805, 5-[2-(diethylamino)ethyl]amino-5,11-dihydro [1 ]benzoxepi no [3,4-b]pyridine trihydrochloride, is a new tricyclic compound with antiulcer activities. Its effect on stimulated gastric acid secretion was investigated in the perfused stomach of anesthetized rats.…”