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(12) United States Patent (10) Patent No.: US 7,776,873 B2 Hahm Et Al

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(12) United States Patent (10) Patent No.: US 7,776,873 B2 Hahm Et Al USOO7776873B2 (12) United States Patent (10) Patent No.: US 7,776,873 B2 Hahm et al. (45) Date of Patent: Aug. 17, 2010 (54) METHOD FORTREATING DAMAGE TO Konturek, P.C., Journal of Physiology and Pharmacology, (1997), GASTRCMUCOSA 48(1), pp. 9-42 (Abstract).* “Peptic Ulcer Disease.” Curr. Probl. Surgery, vol. 42: 346-454, Jun. 2005. (75) Inventors: Ki-Baik Hahm, Seongnam-si (KR): G. Glavin, et al.: “Experimental gastric mucousal injury: laboratory Dong-Kyu Kim, Suwon-si (KR); models reveal mechanisms of pathogenesis and new therapeutic Mi-Sun Kwak, Gunpo-si (KR); strategies.” The FASEB Journal, vol. 6, pp. 825-831, Feb. 1992. Sang-Aun Joo, Seoul (KR): K. Jain, et al.: “Recent advances in proton pump inhibitors and Byoung-Seok Moon, Uiwang-si (KR); management of acid-peptic disorders. Bioorg. Med. Chem, vol. 15, Geun-Seog Song. Anyang-si (KR) pp. 1181-1205, 2007. Y. Tsukimi, et al.: “Recent Advances in Gastrointestinal (73) Assignee: Yuhan Corporation, Seoul (KR) Pathophysiology: Role of Heat Shock Proteins in Mucosal Defense and Ulcer Healing.” Biol. Pharm. Bull., vol. 24. No. 1, pp. 1-9, Jan. (*) Notice: Subject to any disclaimer, the term of this 2001. patent is extended or adjusted under 35 S. Okabe, et al.: "An Overview of Acetic Acid Ulcer Models: The U.S.C. 154(b) by 134 days. History and State of the Art of Peptic Ulcer Research.” Biol. Pharm. Bull., vol. 28, No. 8, pp. 1321-1341, Aug. 2005. K. Tokuhara, et al.: “Rebamipide, anti-gastric ulcer drug, up-regu (21) Appl. No.: 11/604,269 lates the induction of iNOS in proinflammatory cytokine-stimulated hepatocytes.” Nitric Oxide, vol. 18, pp. 28-36, 2008. (22) Filed: Nov. 27, 2006 R. Utley: “Effect of cimetidine and omeprazole on aspirin- and taurocholate-induced gastric mucosal damage in the rat. Gut, vol. (65) Prior Publication Data 26, pp. 770-775, 1985. US 2007/O129391 A1 Jun. 7, 2007 T. Arakawa, et al.: “Rebamipide, Novel Prostaglandin-Inducer, Accelerates Healing and Reduces Relapse of Acetic Acid-Induced (30) Foreign Application Priority Data Rat Gastric Ulcer: Comparison with Cimetidine.” Digestive Diseases and Sciences, vol. 40, No. 11, pp. 2469-2472, Nov. 1995. Dec. 1, 2005 (KR) ...................... 10-2005-O116567 K. Murakami, et al.: “Rebamipide Attenuates Indomethacin-Induced Gastric Mucosal Lesion Formation by Inhibiting Activation of (51) Int. Cl. Leukocytes in Rats.” Digestive Diseases and Sciences, vol. 42, No. 2, A63/56 (2006.01) pp. 319-325, Feb. 1997. S. Watanabe, et al.: “Effects of rebamipide on bile acid-induced (52) U.S. Cl. ...................................................... 514/275 inhibition of gastric epithelial repair in a rabbit cell culture model.” (58) Field of Classification Search ....................... None Aliment. Pharmacol. Ther. vol. 10, pp. 927-932, 1996. See application file for complete search history. * cited by examiner (56) References Cited Primary Examiner Phyllis G. Spivack U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm Rothwell, Figg, Ernst & 2005/0249811 A1* 11/2005 Plachetka ................... 424,472 Manbeck, P.C. FOREIGN PATENT DOCUMENTS (57) ABSTRACT WO WO96,05177 A1 2, 1996 Provided is a method for treating damage to the gastric WO WO97,42186 A1 11, 1997 mucosa with a cytoprotective agent, comprising administer WO WO98, 18784 A1 5, 1998 ing to a human in need thereof a pharmaceutical composition comprising an effective amount for treating damage to gastric OTHER PUBLICATIONS mucosa of a pharmaceutically acceptable salt of revaprazan as the cytoprotective agent, and a pharmaceutically accept Antiulcer drug revaprazan, http://www.manufacturingchemist. com/story.asp?storyCode=30005&sectioncode=81, Dec. 1, 2004.* able carrier. Revaprazan or its salt has an excellent treatment Sorbera et al., Drugs of the Future (2004), 29(5), 455-459.* effect for gastrointestinal mucosal damage by potentiating a Johansson, C. Scandinavian Journal of Gastroenterology, 22(S128) defensive factor in the gastrointestinal mucosa, simulta (1987), pp. 24-31 (Abstract).* neously with acting as an acid pump antagonist. Tarnawski, et al., Scandinavian Journal of Gastroenterology, 25(174), (1990), pp. 9-14 (Abstract).* 21 Claims, 5 Drawing Sheets U.S. Patent Aug. 17, 2010 Sheet 1 of 5 US 7,776,873 B2 FIG. 1 5O.O SS 4O.O t 3O,O to 20.O 3 10.0 O.O. L. i H. pylori (48h) s Rebanipide (50M) -- Revaprazan (50M) s FIG. 2 : 10 5 EtOH (200mM) - s -- Rehamipide (M) 50 Revaprazan (JM) AP m 50 U.S. Patent Aug. 17, 2010 Sheet 2 of 5 US 7,776,873 B2 FIG. 3A 40mg/kg Indomethacin 10mg/kg Revaprazan -- 40mg/kg Indomethacin FIG. 3B EtOH 10mg/kg Revaprazan -- EtOH U.S. Patent Aug. 17, 2010 Sheet 3 of 5 US 7,776,873 B2 FIG. 4 H. pylori Revaprazan (M) FIG. 5 Probe alone H. pylor (1 h) r s Rebarnipide (50M) - - - - Revaprazan (25pM) - - - - NF-kB U.S. Patent Aug. 17, 2010 Sheet 4 of 5 US 7,776,873 B2 FIG. 6 Sulindac (100pM, 8h) s -- Rebamipide (50p M) qo - -- Revaprazan (25pM) - a as as as see GAPDH FIG. 7 - 5 1 O 25 Revaprazan (uM) Indomethacin (0.5 M) as a-tubulin U.S. Patent Aug. 17, 2010 Sheet 5 of 5 US 7,776,873 B2 Control 5mgg Omeprazole + 30mg/kg. Rehampide + (40 mg/kg Indomethacine, 12hrs) 40mg/kg Indomethacine 40mgg Indomethacine - a cars.-- 5mggRevaprazant 10 mgg Revaprazant 40mgg indomethacine 40 mg/kg Indomethacine FIG. 9 (mgglindomethacine, 8hrs) US 7,776,873 B2 1. 2 METHOD FOR TREATING DAMAGE TO have found that revaprazan or its salt has a cytoprotective GASTRICMUCOSA activity in the gastrointestinal tracts, beyond proton pump inhibitory activity. Such surprising findings Suggest that CROSS-REFERENCE TO RELATED PATENT revaprazan or its salt has not only the effect of inhibiting the APPLICATION 5 secretion of the gastric acid (an offensive factor), but also the gastrointestinal cytoprotective effect of potentiating a defen This application claims priority from Korean Patent Appli sive factor. cation No. 10-2005-0116567, filed on Dec. 1, 2005, in the Therefore, the present invention provides a composition Korean Intellectual Property Office, the disclosure of which is for preventing or treating damages of the mucosa in the gas incorporated herein in its entirety by reference. 10 trointestinal tracts, comprising revaprazan or its salt. FIELD OF THE INVENTION BRIEF DESCRIPTION OF THE DRAWINGS The present invention relates to a composition for prevent The above and other features and advantages of the present ing or treating damages of the mucosa in the gastrointestinal 15 invention will become more apparent by describing in detail tracts, comprising revaprazan or its salt. exemplary embodiments thereof with reference to the attached drawings in which: DESCRIPTION OF THE RELATED ART FIG. 1 shows MTT assay results for the inhibitory effect of Revaprazan, known by the chemical name, 5,6-dimethyl revaprazan on cell death due to Helicobacter pylori (H. 2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahy pylori)-induced gastrointestinal mucosal damage; droisoquinolin-2-yl)pyrimidine, is a compound represented FIG. 2 shows MTT assay results for the inhibitory effect of by Formula 1 below, and is available as an acid addition salt revaprazan on cell death due to ethanol-induced gastrointes (e.g., revaprazan hydrochloride) PCT Publication No. tinal mucosal damage; WO96/05177. FIGS. 3A and 3B are images showing the cytoprotective 25 effect of revaprazan against in vivo gastrointestinal damage: FIG. 4 is a Western blot image showing an inhibitory effect <Formula 1 > of revaprazan on H. pylori-induced ERK (extracellular sig nal-regulated kinase) activation; FIG. 5 is Electrophoretic Mobility Shift Assay (EMSA) 30 results showing an inhibitory effect of revaprazan on H. pylori-induced NF-kB activation; FIG. 6 is RT-PCR results showing an effect of revaprazan on the activity of pro-angiogenic growth factors; FIG. 7 is a Western blot image showing an effect of 35 revaprazan on the activity of heat-shock proteins; FIG. 8 is a comparative image showing the preventive effects for gastric mucosal lesions with the treatment of rebamipide, omeprazole, and revaprazan prior to indometha cin administration; and 40 FIG.9 is a comparative image showing the treatment effect co of revaprazan for gastric mucosal lesions after indomethacin Revaprazanor its salt binds reversibly to a H/K" exchange administration. site of proton pumps (H/K ATPase) existing in gastric pari etal cells to competitively inhibit the secretion of H" into the DETAILED DESCRIPTION OF THE INVENTION gastric lumen. Revaprazan or its salt binds to a specific site of 45 the H/K" ATPase to block the transport of H and acid The present invention provides a composition for prevent secretion into the gastric lumen, thereby raising intragastric ing or treating damages of the mucosa in the gastrointestinal pH. Unlike irreversible proton pump inhibitors such as ome tracts, comprising revaprazan or its salt and a pharmaceuti prazole, revaprazan or its salt is not affected by gastric acid cally acceptable carrier. activation of the drug or gastric acid secretion of the proton 50 In accordance with one aspect of the present invention, pumps. Based on the mechanism of revaprazan or its salt that there is provided a method for preventing or treating damage is different from that of irreversible proton pump inhibitors to the gastric mucosa comprising administering to a human in Such as omeprazole, revaprazan or its salt is classified as an need thereof a pharmaceutical composition comprising an Acid Pump Antagonist (APA). effective amount for preventing or treating damage to gastric Meanwhile, gastrointestinal disorders
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