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The enantiomers of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid [(+/-)-1, rebamipide, OPC-12759], a new antiulcer agent that enhances mucosal resistance, were synthesized from optically active alpha-amino acid derivatives of 2(1H)-quinolinone. The key intermediates, alpha-amino acid derivatives, were prepared by asymmetric synthesis and optical resolution. The (+)-1 was about 1.7 times as potent as the (-)-isomer in antiulcer activity against ethanol-induced gastric ulcers.

A series of 4-substituted 8-[(2-benzimidazolyl)sulfinylmethyl]-1,2,3,4-tetrahydroquinolin es was synthesized and examined for their (H+ + K+)adenosine triphosphatase (ATPase)-inhibitory and antisecretory activities against histamine-induced gastric acid secretion in rats. Many compounds tested were potent inhibitors of (H+ + K+)ATPase. Most compounds showed antisecretory activity. The antiulcer activity against water-immersion stress-induced gastric ulcer, aspirin-induced gastric ulcer and gastric necrosis induced by hydrochloric acid also were tested in the rat. Some of these compounds, in particular, 4-(N-allyl-N-methylamino)-1-ethyl-8-[(5-fluoro-6-methoxy-2-benzimidazoly l) sulfinylmethyl]-1-ethyl-1,2,3,4-tetrahydroquinoline (XVIIx) were found to have potent activity. The structure-activity relationships are discussed.

Many 1-substituted 4-(5-tetrazolyl)thio-1-butanones were synthesized and tested for antiulcer activity against acetic acid-induced gastric ulcer in rats. These compounds were prepared by the reaction of 5-mercaptotetrazoles and 4-halogeno-1-butanones. Among them, 1-cyclohexyl-4-(1-phenyl-5-tetrazolyl)thio-1-butanone (VIIIp) was found to have the most potent activity. The structure-activity relationships are discussed.

Many 8-[(2-benzimidazolyl)sulfinyl]-5,6,7,8-tetrahydroquinolines were synthesized and examined for their (H+ + K+) adenosine triphosphatase ATPase-inhibitory and antisecretory activities. These sulfinyl compounds could be considered to be rigid analogues of the 2-[(2-pyridyl)methylsulfinyl]benzimidazole class of antisecretory agents. All the compounds tested were potent inhibitors of (H+ + K+)ATPase. Most of the compounds also inhibited histamine-induced gastric acid secretion in rats. Among them, 8-[(5-fluoro-2-benzimidazolyl)sulfinyl]-3-methyl-5,6,7,8-tetrahydroqu inoline (XIVm) was found to have the most potent activity. The structure-activity relationships are discussed.

The healing process of acetic acid-induced gastric ulcers was studied for over 180 days after ulcerogen injection, and the effect of a new antiulcer agent, proamipide, was also assessed by histological measurements. In the control group, rapid reduction in the macroscopic ulcer index and increment in histological indices such as healing, regeneration of defective mucosa and proliferation of granulation tissue were observed from the 5th day to the 60th day after the ulcer induction followed by significant aggravation on the 120th and 140th day, suggesting the recurrence or relapse of gastric ulcers may occur at about 120 to 140 days after acetic acid administration. Proamipide (20 mg/kg/day, p.o.) decreased all of these indices significantly from those in the control group. This indicates that proamipide remarkably promotes the healing process in acetic acid-induced gastric ulcers, the regeneration of the injured mucosa and also the formation of granulation tissue. The glandular index in the surrounding areas of the regenerated mucosa was lower than that in the central part in the control animals and this difference was decreased by proamipide intake, suggesting an imbalance in the regenerated mucosa of the scar may have significant roles in the induction of the recurrence or relapse of gastric ulcers.

The antiulcer effects of OPC-12759, a novel antiulcer agent were compared with those of cetraxate in various experimental ulcer models and on gastric secretion in rats. OPC-12759 (0.3-30 mg/kg, b.i.d., p.o.) significantly accelerated the healing rate of acetic acid-induced gastric ulcer in a dose-dependent manner, while cetraxate did not. When administered orally at 0.3-30 mg/kg, b.i.d., for 7 days, pretreatment with OPC-12759 (0.3-30 mg/kg, b.i.d., p.o.) prevented the formation of acute gastric ulcers, induced by: restraint water immersion stress, aspirin, indomethacin, histamine, serotonin, platelet activating factor (PAF) and DDC. Cetraxate showed antiulcer activity against a part of the OPC-12759-positive gastric ulcer models. Given intraperitoneally at the single dosing range of 10-100 mg/kg, OPC-12759 inhibited the formation of these acute gastric ulcer models. OPC-12759 administered orally at 0.3-30 mg/kg, b.i.d., for 7 days did not inhibit basal gastric secretion in pylorus ligated rats. The results indicated that OPC-12759 possesses wide spectrum antiulcer activity as compared with cetraxate.

Many 8-[(2-benzimidazolyl)sulfinylmethyl]-1,2,3,4-tetrahydroquinolin e derivatives were synthesized and tested for their (H+ + K+)adenosine triphosphatase (ATPase)-inhibitory and antisecretory activities against histamine-induced gastric acid secretion in rats. These sulfinyl compounds were synthesized by the oxidation of the corresponding sulfides, which were obtained from the reaction of 8-chloromethyl-1,2,3,4-tetrahydroquinolines and 2-mercaptobenzimidazoles in the presence of potassium carbonate. All compounds tested were potent inhibitors of (H+ + K+)ATPase. Most of the compounds showed antisecretory activity. Among them, 8-[(2-benzimidazolyl)sulfinylmethyl]-1-ethyl-1,2,3,4-tetrahydro quinoline (IXa) was found to have the most potent activity. The structure-activity relationships are discussed.

OPC-12759, 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]-propionic acid, was studied for its efficacy to prevent the gastric mucosal damage induced by several necrotizing agents. Experiments were also performed to elucidate the mechanism of this mucosal protective activity. OPC-12759 dose dependently prevented the formation of mucosal necrosis induced by absolute ethanol, 0.2 N NaOH or 0.6 N HCl. PGE2 was also shown to prevent the gastric mucosal erosion induced by necrotizing agents. The mucosal protective effect of OPC-12759 was completely counteracted by pretreatment with indomethacin while that of PGE2 was not. In addition, OPC-12759 given alone increased the generation of gastric mucosal PGE2-like activity. OPC-12759 dose dependently reduced the volume, acid output and pepsin output of the gastric juice in pylorus-ligated rats. The inhibitory effect of OPC-12759 but not of cimetidine or atropine on gastric secretion was also abolished by concurrent administration of indomethacin. These findings suggest that the mucosal protective effect and antisecretory effect of OPC-12759 presumably result from enhancement of the generation of endogenous PGs.

A series of tetrazole alkanamides was synthesized and tested for antiulcer activity against acetic acid-induced gastric ulcer in rats. These compounds were prepared by the reaction of tetrazole alkanoic acids and various amines by the mixed anhydride method or acid chloride method. Among them, 3-[(1-ethyl-5-tetrazolyl)methylthio]propionamide (IIn) was found to have the most potent activity. The structure-activity relationships are discussed.