This invention relates to novel thiazol-2-ylcarbamoylcarboxylic acids, esters and amides having utility in the prevention and treatment of peptic ulcers, particularly gastric ulcers.
A peptic ulcer is defined as circumscribed ulceration of the mucous membrane penetrating through the muscularis mucosa and occurring in areas bathed by acid and pepsin. Peptic ulcers most commonly are found along the lesser curvature of the stomach (gastric ulcers) and in the first few centimeters of the duodenum, known as the duodenal bulb (duodenal ulcers).
There is but limited understanding of the cause of peptic ulcers. While it is known that peptic ulcers are absent if the stomach does not secrete acid, nearly all humans secrete acid, so that it remains to be established why some develop ulcers and others do not. There appears to be a balance between ulcer-promoting factors, such as the excessive secretion of acid or pepsin, and the mucosal protective factors, such as mucus production, membrane barriers to permeability, or mucosal cell turnover time. This balance can be disturbed at a number of points and by many factors. Stress has been implicated as a commonly occurring precipitating factor, as has the administration of certain drugs, such as corticosteroids, phenylbutazone, and reserpine.
A variety of treatments for peptic ulcers have been developed. The treatment depends upon the severity of the ulcer and may range from dietary and medical (drug) treatment to surgery.
Treatment of gastric and duodenal ulcer is frequently designed to neutralize or decrease gastric acidity even though gastric acidity is usually normal in patients with gastric ulcer. Although there is no proof that antacids promote healing or prevent recurrence, there is general agreement that they give symptomatic relief. Antacids such as sodium bicarbonate and calcium carbonate are the most potent antacids, but they are absorbable and continuous use is prone to cause alkalosis or the so-called milk alkali syndrome. Symptoms are not distinctive and these complications can progress unrecognized to irreversible kidney damage. Aluminum hydroxide, which is nonabsorbable, is also commonly used as an antacid. However, phosphate depletion can occur from gastrointestinal binding of phosphate by aluminum--causing phosphorous blood levels to decrease and phosphorous resorption from bone to increase, reflected in weakness, malaise and anorexia. Bone demineralization can ultimately occur, if the diet does not provide adequate phosphorus. Aluminum hydroxide also causes constipation, and so is usually combined with magnesium hydroxide, also a nonabsorbable antacid, but also a cathartic. Even on low daily doses, patients can require careful titration to avoid one or the other of the aluminum/magnesium hydroxide side-effects of constipation or diarrhea. Anticholinergic drugs (e.g. belladonna, glycopyrrolate, isopropamide) are sometimes co-administered with antacids. The anticholinergic is given to delay emptying of the stomach and so prolong antacid retention. In higher doses, anticholinergic agents will also diminish basal secretion of acid. However such doses are usually accompanied by the undesirable side effects of dry mouth or blurred vision or both. More recently histamine H.sub.2 receptor blocking agents (e.g. cimetidine) have found clinical use in the treatment of gastric ulcers. These compounds block histamine H.sub.2 effects, including gastric acid secretion and thereby function in the treatment of ulcers. Drugs which function by means other than neutralization or inhibition of secretion of gastric acid have also been reported useful in the treatment of gastric ulcers. One such drug to have gained widespread attention is carbenoxolone sodium, the disodium salt of the hemisuccinate of glycyrrhetinic acid. It is reported to prevent formation of and to accelerate healing of gastric ulcers in animals, including humans. ["A Symposium on Carbenoxolone Sodium" J. M. Robson, F. M. Sullivan, Eds. (Butterworths, London, 1968) 263 pp.]. However, its use is accompanied by undesirable side effects, such as edema, diastolic hypertension or hypokalemia. It cannot be used where cardiovascular, pulmonary or renal reserves are inadequate.
The compounds of the present invention are a further example of a class of antiulcer agents which function in some manner to enhance the normal defense mechanism of the body, rather than to reduce normal body secretions. Many of the present compounds are homologous with known ethyl thiazol-2-ylcarbamoylcarboxylate, a compound reported to have antiallergic activity at a high parenteral dose, and no significant oral activity even at 200 mg./kg. [Sellstedt et al., J. Med. Chem. 18 (9), 926-933 (1975); see also U.S. Pat. No. 3,966,965]. The Sellstedt compound, however, is lacking in the antiulcer activity determined for the compounds of the present invention. Furthermore, unlike ethyl thiazol-2-ylcarbamoylcarboxylate, many of the compounds of the present invention also possess a significant level of oral antiallergy activity. Various 4-phenylthiazol-2-ylcarbamoylcarboxylic acids and esters have been recently reported to be useful as antiallergy agents, [European Patent Appln. 6,368 (Jan. 9, 1980); British Pat. No. 2,023,580 (Jan. 3, 1980)], while certain acylated 2-halothiazol-4-ylamines have been reported useful as antiulcer and hyposecretory agents (Crossley, U.S. Pat. No. 4,183,854).