Bicyclic nitrogen heterocyclic ethers and thioethers, and their

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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514307, 514309, 514310, 514311, 514312, 514313, 514314, 544 62, 544128, 544321, 544363, 548134, 548141, 548142, 548143, 548145, 548148, 548152, 548153, 548155, 548159, 548165, 548166, 548172, 548176, 548177, C07D21702, A61K 3144

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046329277

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to a class of bicyclic heterocyclic compounds characterized by an ether or thioether substituent on the bicyclic ring system and methods for the treatment of physiological disorders, including gastrointestinal disorders, such as peptic ulcer, in humans and other mammals.


REPORTED DEVELOPMENTS

Gastrointestinal hyperacid secretion, stomach and intestinal ulceration, and gastritis are major gastrointestinal disorders observed in the general adult populations of industrialized societies. Many factors, including the production of excess gastric acid and the weakening of the lining of the stomach and gastrointestinal tract against such acid are implicated as causes of these disorders. Traditional treatment of these disorders has involved the administration of antacids to neutralize the excess gastric acid and the administration of antisecretory drugs which generally reduce the production of all gastric secretions.
In the last few years, the treatment of gastrointestinal disorders such as peptic ulcer has changed to include the use of anti-secretory drugs which selectively block the production of gastric acid. These drugs are believed to interfere with the body's physiological pathway responsible for the production of gastric acid by blocking the action of histamine. Histamine production is induced in the body by a number of stimuli, including stress, allergic reaction, etc., and acts to increase gastric secretion, dilate blood vessels and stimulate smooth muscle tissue. Histamine is believed to function by way of interaction with histamine receptors in the body. The subdivision of these receptors into two groups, the H.sub.1 - and H.sub.2 -receptors, was proposed by Ash and Schild (Brit. J. Pharmacol. Chemother, 1966, 27, 427) and Black et al (Nature 1972, 236, 385). The H.sub.1 -receptor is involved in the bronchial and gastrointestinal smooth muscle stimulative action of histamine. Drugs which block this action are labelled "antihistamines" (e.g. mepyramine).
Black et al, cited above, described the group of substances which act at histamine receptors other than the H.sub.1 -receptor as H.sub.2 -receptor agonists/antagonists. Blocking the action of histamine at the H.sub.2 -receptors will selectively block histamine's stimulative action on gastric acid secretion and heart rate. Burimamide was the first clinically effective H.sub.2 -receptor antagonist inhibiting gastric secretion in man; but Burimamide's oral absorptivity is poor. Subsequent studies developed the orally active Metiamide, the side effects of which limited clinical use, and Cimetidine which has been marketed as an anti-ulcer drug. A number of classes of heterocyclic chemical compounds have been reported as H.sub.2 -receptor antagonists, for example, those disclosed in U.S. Pat. Nos. 4,104,381, 4,279,819, 4,323,566, and British published patent application GB 2067987A, the disclosures of which are incorporated by reference.
Another method for the prevention or treatment of gastric ulcer comprises the use of drugs which neither neutralize nor inhibit the secretion of gastric acid. These drugs constitute a class of anti-ulcer compounds which function to enhance the normal defense mechanisms of the body, rather than to reduce normal body secretions, and are described as "cytoprotective" agents. It has been proposed that such agents act to strengthen the mucosal lining of the gastrointestinal system by one or more mechanisms, thereby preventing any damage which could result from the action of strong gastric acid. Prostaglandins have been implicated in the mechanism of cytoprotection by a number of workers in the field. See, the discussion of cytoprotection in Robert, Andre, "Prostaglandins and Digestive Diseases", Advances in Prostaglandin and Thromboxane Research, Vol. 8 (Raven Press, N.Y. 1980), and Robert et al, "Cytoprotection by Prostaglandins in Rats", Gastroenterology, 77, 433-443 (1979), hereby incorporated by reference. Drugs, other than prostaglandins, which exhibit cytoprotective activity in

REFERENCES:
patent: 4520025 (1985-05-01), Campbell

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