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(12) United States Patent (10) Patent No.: US 8,466,166 B2 Koike Et Al

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(12) United States Patent (10) Patent No.: US 8,466,166 B2 Koike Et Al USOO8466 166B2 (12) United States Patent (10) Patent No.: US 8,466,166 B2 Koike et al. (45) Date of Patent: Jun. 18, 2013 (54) BENZIMIDAZOLE DERIVATIVES AS Sachs G. et al., “The Pharmacology of the Gastric Acid Pump: The SELECTIVE ACDPUMPINHIBITORS H*, K* ATPasel'', Annu. Rev. Pharmacol. Toxicol. 35:277-305 (1995). Pope A.J. et al., “Reversible Inhibitors of the Gastric H"/K"-Trans (75) Inventors: Hiroki Koike, Aichi-ken (JP); Mikio porting ATPase: a New Class of Anti-Secretory Agent”. Trends in Morita, Aichi-ken (JP) Pharmacological Sciences 14:323-325 (1993). Vakil N., “Review Article: New Pharmacological Agents for the (73) Assignee: Raqualia Pharma Inc., Aichi-Ken (JP) Treatment of Gastro-Oesophageal Reflux Disease'. Aliment Pharmacol Ther. 19:1041-1049 (2004). (*) Notice: Subject to any disclaimer, the term of this Kiljander T.O., “The Role of Proton Pump Inhibitors in the Manage patent is extended or adjusted under 35 ment of Gastroesophageal Reflux Disease-Related Asthma and U.S.C. 154(b) by 507 days. Chronic Cough'. The American Journal of Medicine I I5(3A):65S 71S (2003). (21) Appl. No.: 12/442,277 Yeo M. et al., “The Novel Acid Pump Antagonists for Anti-Secretory Actions With Their Peculiar Applications Beyond Acid Suppres (22) PCT Filed: Sep. 17, 2007 sion”.J. Clin. Biochem. Nutr; 38:1-8 (2006). Stahl P.H. et al., “Handbook of Pharmaceutical Salts: Properties, (86). PCT No.: PCT/B2007/002749 Selection, and Use', (Wiley-VCH. Weinheim, Germany, 2002), 4 pageS. S371 (c)(1), Haleblian J.K., "Characterization of Habits and Crystalline Modifi (2), (4) Date: Mar. 20, 2009 cation of Solids and Their Pharmaceutical Applications”, Journal of Pharmaceutical Sciences 64(8): 1269-1288 (1975). (87) PCT Pub. No.: WO2008/035195 Greene T.W. et al., “Protective Groups in Organic Synthesis', (John Wiley & Sons, 1999), pp. 17-247. PCT Pub. Date: Mar. 27, 2008 Sawamura M. et al., “The Asymmetric Aldol Reaction of Tosylmethyl Isocyanide and Aldehydes Catalyzed by Chiral Silver(I) (65) Prior Publication Data Complexes”. J. Org. Chem. 55:5935-5936 (1990). US 201O/OO48532 A1 Feb. 25, 2010 (Continued) Primary Examiner — Renee Claytor Related U.S. Application Data (74) Attorney, Agent, or Firm — Scully, Scott, Murphy & (60) Provisional application No. 60/826,442, filed on Sep. Presser, P.C. 21, 2006, provisional application No. 60/912.264, (57) ABSTRACT filed on Apr. 17, 2007. This invention relates to compounds of the formula (I): or a (51) Int. Cl. pharmaceutically acceptable salt thereof, wherein: R', R, A6 IK3I/44 (2006.01) R. R. A. and E are each as described herein or a pharmaceu A6 IK3I/445 (2006.01) tically acceptable salt, and compositions containing Such A6 IK3I/4I (2006.01) compounds and the method of treatment and the use, com (52) U.S. Cl. prising Such compounds for the treatment of a condition USPC ........... 514/279:514/292; 514/321; 514/326; mediated by acid pump antagonistic activity Such as, but not 514/337; 514/360 limited to, as gastrointestinal disease, gastroesophageal dis ease, gastroesophageal reflux disease (GERD), laryngopha (58) Field of Classification Search ryngeal reflux disease, peptic ulcer, gastric ulcer, duodenal USPC .................. 514/279, 292,321,326,337, 360 ulcer, NSAID-induced ulcers, gastritis, infection of Helico See application file for complete search history. bacter pylori, dyspepsia, functional dyspepsia, Zollitger-El (56) References Cited lison syndrome, non-erosive reflux disease (NERD), visceral pain, cancer, heartburn, nausea, esophagitis, dysphagia, U.S. PATENT DOCUMENTS hypersalivation, airway disorders or asthma. 6,106,864 A 8, 2000 Dolan et al. FOREIGN PATENT DOCUMENTS (I) O WO WO91f11172 8, 1991 WO WO94,025.18 2, 1994 RN N WO WO98,55148 12/1998 N WO WO99/40091 8, 1999 N R2 WO WOOO,35298 6, 2000 R4 WO WO 2004/054984 A1 T 2004 N WO WO 2004/0877O1 A1 10/2004 WO WO 2006/037759 A1 4/2006 E R1 WO WO 2006/10O255 A1 9, 2006 WO WO 2006,136552 A2 12/2006 OTHER PUBLICATIONS Hirschowitz B.I. et al., “Pharmacological Aspects of Acid Secretion'. Digestive Diseases and Sciences 40(2):3S-23S (1995). 8 Claims, No Drawings US 8,466,166 B2 Page 2 OTHER PUBLICATIONS Verma R.K. et al., "Current Status of Drug Delivery Technologies and Yang D. et al., “Local and Framework Stereochemical Markers in Future Directions'. Pharmaceutical Technology On-Line 25(2):1-14 Vibrational Circular Dichroism: 1.2- and 2,3-Dimethylaziridines', (2001). Firmin B.C. et al., “Transdermal Penetration Enhancers: Applica Canadian Journal of Chemistry 71:2028-2037 (1993). tions, Limitations, and Potential”, Journal of Pharmaceutical Sci Lee N.E. et al., “Asymmetric Hydrogenation of Enamines With a ences 88(10):955-958 (1999). Chiral Titanocene Catalyst”. J. Am. Chem. Soc. I 16:5985-5986 Keeling D.J. et al., "SCH 28080 is a Lumenally Acting K'-Site (1994). Inhibitor of the Gastric (H'+K")-ATPase'. Biochemical Pharmacol Greene T.W. et al., “Protective Groups in Organic Synthesis', pp. ogy 37(11):2231-2236 (1988). 369-453 (1999). Watanabe K. et al., “Stimulation of Gastric Acid Secretion by Remington's Pharmaceutical Sciences. 19' Edition (Mack Pub Progesterone Metabolites as Neuroactive Steroids in Anesthetized lishing Company, 1995). Rats'. J. Physiol. (Paris) 94:111-116 (2000). Liang A.C. et al., “Fast-Dissolving Intraoral Drug Delivery Sys Heidenhain R. “Ueber Die Absonderug Der Fundusdrisen Des tems'. Expert Opinion in Therapeutic Patents II (6):981-986 (2001). Magens”, Arch. Ges. Physiol. 19:148-167 (1879). "Pharmaceutical Dosage Forms: Tablets, vol. 1'', by H. Lieberman Zhou Z. et al., “Properties of HERG Channels Stably Expressed in and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247 HEK 293 Cells Studied at Physiological Temperature'. Biophysical 6918-X). Journal 74:230-241 (1998). US 8,466,166 B2 1. 2 BENZMDAZOLE DERVATIVES AS SELECTIVE ACDPUMPINHIBITORS (I) O BACKGROUND OF THE INVENTION RS N This invention relates to tricyclic compounds. These com 4 pounds have selective acid pump inhibitory activity. The R NX-R present invention also relates to a pharmaceutical composi tion, method of treatment and use, comprising the above E R1 derivatives for the treatment of disease conditions mediated 10 by acid pump modulating activity; in particular acid pump inhibitory activity. It has been well established that proton pump inhibitors or a pharmaceutically acceptable salt thereof, wherein; (PPIs) are prodrugs that undergo an acid-catalyzed chemical 15 R" represents a C-C alkyl group being unsubstituted or rearrangement that permits them to inhibit H/K"-ATPase by substituted with 1 to 2 substituents independently covalently binding to its Cystein residues (Sachs, G. et. al., Selected from the group consisting of a hydroxy group, a Digestive Diseases and Sciences, 1995, 40, 3S-23S: Sachs et C-C alkoxy group, a hydroxy-Substituted C-C, al., Annu Rev Pharmacol Toxicol, 1995, 35,277-305.). How cycloalkyl group, a hydroxy-C-C alkyl-substituted ever, unlike PPIs, acid pump antagonists inhibit acid secretion C-C cycloalkyl group, an aryl group, a hydroxy-Sub via reversible potassium-competitive inhibition of H/K"- stituted aryl group, a heteroaryl group and a halogen ATPase. SCH28080 is one of Such reversible inhibitors and Substituted heteroaryl group; has been studied extensively. Other newer agents (revapra R represents a hydrogen atom or a C-C alkyl group Zan, Soraprazan, AZD-0865 and CS-526) have entered in being unsubstituted or substituted with 1 to 2 substitu clinical trials confirming their efficacy in human (Pope, A.; 25 ents independently selected from the group consisting of Parsons, M., Trends in Pharmacological Sciences, 1993, 14, a hydroxy group and a C-C alkoxy group; 323-5; Vakil, N., Alimentary Pharmacology and Therapeu Rand R' independently represent a hydrogen atom, or a tics, 2004, 19, 1041-1049.). In general, acid pump antagonists C-C alkyl, C-C, cycloalkyl or heteroaryl group being are found to be useful for the treatment of a variety of dis unsubstituted or substituted with 1 to 3 substituents eases, including gastrointestinal disease, gastroesophageal 30 independently selected from the group consisting of a deuterium, a halogen atom, a hydroxy group, a C-C, disease, gastroesophageal reflux disease (GERD), laryn alkoxy group and a C-C, cycloalkyl group; or RandR gopharyngeal reflux disease, peptic ulcer, gastric ulcer, taken together with the nitrogen atom to which they are duodenal ulcer, non-steroidal anti-inflammatory drug attached form a 4 to 6 membered heterocyclic group (NSAID)-induced ulcers, gastritis, infection of Helicobacter 35 being unsubstituted or substituted with 1 to 2 substitu pylori, dyspepsia, functional dyspepsia, Zollinger-Ellison ents selected from the group consisting of a hydroxy syndrome, non-erosive reflux disease (NERD), visceral pain, group, an oxo group, a C-C alkyl group, a C-C acyl cancer, heartburn, nausea, esophagitis, dysphagia, hypersali group, and a hydroxy-C-C alkyl group; Vation, airway disorders or asthma (hereinafter, referred as A represents an aryl or heteroaryl group being unsubsti “APA Diseases: Kiljander, Toni O, American Journal of 40 tuted or substituted with 1 to 5 substituents indepen Medicine, 2003, 115 (Suppl. 3A), 65S-71S: Ki-Baik Hahmet dently selected from the group consisting of a halogen al., J. Clin. Biochem. Nutr., 2006, 38, (1), 1-8.). atom, a C-C alkyl group, a hydroxy-C-C alkyl group, WOO4/87701 refers to some compounds, such as tricyclic a C-C alkoxy-Substituted C-C alkyl group, benzimidazole derivatives, as acid pump antagonists. NRSO.R and CONR7R; There is a need to provide new acid pump antagonists that 45 R. R7 and Rindependently representahydrogenatom or are good drug candidates and address unmet needs by PPIs for a C-C alkyl group; treating diseases.
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