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US008895596B2 (12) United States Patent (10) Patent No.: US 8,895,596 B2 Jiang et al. (45) Date of Patent: Nov. 25, 2014 (54) CYCLIC BENZMDAZOLE DERVATIVES (56) References Cited USEFUL AS ANT-DABETICAGENTS U.S. PATENT DOCUMENTS (75) Inventors: Jinlong Jiang, Scotch Plains, NJ (US); 5,596,025 A 1/1997 Oxman et al. Andrew J. Kassick, Scotch Plains, NJ 6,312,662 B1 11/2001 Erion et al. (US); Ahmet Kekec, Jersey City, NJ 6,489.476 B1 12/2002 Dang et al. (US); Iyassu K. Sebhat, Jersey City, NJ 7,098,220 B2 8, 2006 Rault et al. 7,268,145 B2 9, 2007 Matsumoto et al. (US) 2005, OO38068 A1 2/2005 Iyengar et al. 2005.0113283 A1 5/2005 Solow-Cordero et al. (73) Assignee: Merck Sharp & Dohme Corp, Rahway, 2005. O148643 A1 7/2005 Rui et al. NJ (US) 2005/O187277 A1 8/2005 Malti et al. 2005/0255415 A1 11/2005 Louwet et al. (*) Notice: Subject to any disclaimer, the term of this 2005/0272765 A1 12/2005 Feng et al. patent is extended or adjusted under 35 2006.0160872 A1 7/2006 Norman et al. 2006/0287356 Al 12/2006 Iyengaret al. U.S.C. 154(b) by 0 days. 2007, OO15665 A1 1/2007 Potluri et al. 2007/0O32529 A1 2/2007 Takagi et al. (21) Appl. No.: 13/578,302 2008. O1325O1 A1 6/2008 Sun et al. (22) PCT Fled: Feb. 21, 2011 FOREIGN PATENT DOCUMENTS (86) PCT NO.: PCT/US2011/025585 DE 33 16095 A1 11, 1983 EP O120403 A2 10, 1984 S371 (c)(1), EP O126030 A2 11, 1984 (2), (4) Date: Aug. 10, 2012 EP 0.128862 A2 12, 1984 EP O1295.06 A2 12, 1984 (87) PCT Pub. No.: WO2O11A106273 (Continued) PCT Pub. Date: Sep. 1, 2011 OTHER PUBLICATIONS (65) Prior Publication Data Janssens, et al. Document No. 110:212855, retrieved from CAPLUS, Jun. 10, 1989.* US 2012/0309736A1 Dec. 6, 2012 Janssens, et al. Document No. 108:21891, retrieved from CAPLUS, Jan. 23, 1988.* Related U.S. Application Data Cancer and Metastasis Reviews (1998), 17(1), 91-106.* Science (1999), vol. 286, 531-537.* (60) Provisional application No. 61/307,909, filed on Feb. Cancer online, retrieved on Jul. 6, 2007. Retrieved from the 25, 2010. internet, URL http://www.nlm.nih.gov/medlineplus/cancer.html>.* Cancer online, retrieved on Jul. 6, 2007. Retrieved from the (51) Int. C. internet, URL: http://en.wikipedia.orglwikilCancer.* CO7D 235/06 (2006.01) CO7D 235/26 (2006.01) (Continued) C07D 235/28 (2006.01) Primary Examiner — Shawquia Young C07D 235/30 (2006.01) (74) Attorney, Agent, or Firm — Baerbel R. Brown; A6 IK 45/06 (2006.01) Catherine D. Fitch A6 IK3I/366 (2006.01) A 6LX3/397 (2006.01) (57) ABSTRACT A6 IK3I/484 (2006.01) Novel compounds of the structural formula (I) are activators A6 IK3I/4985 (2006.01) of AMP-protein kinase and are useful in the treatment, pre CO7D 40/12 (2006.01) vention and suppression of diseases mediated by the AMPK A6 IK3I/442 (2006.01) activated protein kinase. The compounds of the present inven CO7D 403/2 (2006.01) tion are useful in the treatment of Type 2 diabetes, CO7D 405/2 (2006.01) hyperglycemia, metabolic syndrome, obesity, hypercholes (52) U.S. C. terolemia, and hypertension. CPC ............ C07D405/12 (2013.01); C07D 235/26 (2013.01); A61K 45/06 (2013.01); A61 K 31/366 (2013.01); A61 K3I/397 (2013.01); (I) A6 IK3I/4184 (2013.01); A61 K3I/4985 (2013.01); C07D 401/12 (2013.01); A61 K 3 1/44.12 (2013.01); C07D 403/12 (2013.01) N Y USPC ..................... 514/387: 548/304.4: 548/307.1; )-x- NZ 548/307.4 N (58) Field of Classification Search CPC. C07D 235/06; C07D 235/26: C07D 235/28; R4 R5 CO7D 235/30 USPC .................. 548/304.4, 307.1, 307.4: 514/387 See application file for complete search history. 23 Claims, No Drawings US 8,895,596 B2 Page 2 (56) References Cited WO 2009/O19504 A1 2/2009 WO 2009/100 130 A1 8, 2009 WO 2010/036613 A1 4/2010 FOREIGN PATENT DOCUMENTS WO 2010/047982 A1 4, 2010 WO 2010/051176 A1 5, 2010 EP O161219 A2 11, 1985 WO 2010/051206 A1 5, 2010 EP O161220 A2 11, 1985 WO 2011/106273 A1 9, 2011 EP O161222 A2 11, 1985 WO 2012,116145 A1 8, 2012 EP O560407 A1 9, 1993 EP O637585 A1 2/1995 OTHER PUBLICATIONS EP O655439 A2 5, 1995 Lan, “An efficient method to access 2-substituted GB 2099167 A 12/1982 benzimiclazoles...”. Tetrahedron Letters, 2008, vol. 49, pp. 1910 JP 6298731 A 10, 1994 1914. JP 9227854. A 9, 1997 Pangano, "Optimization of protein kinase CK2 inhibitors derived JP 2002141067 A 5, 2002 from . .”. J. Med. Chem, 2004, vol. 47, pp. 6239-6247. JP 200467629. 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The Int'l J. of Biochem & Cell Biol. 2005, vol. 37, pp. WO 99.43672 A1 9, 1999 2254-2259. WO 99.45O16 A2 9, 1999 Hardie, AMP-activated protein kinase as a drug target'. Annu. Rev. WO OO?O3997 A1 1/2000 Pharmacol. Toxicol. 2007, vol. 47, pp. 185-210 WO OO 14095 A1 3, 2000 vol. 47, pp. - . s WO OO,52015 A1 9, 2000 Musi, "AMP-activated protein kinase and type 2 diabetes'. Current WO 01.25238 A2 4, 2001 Med. Chem, 2006, vol. 13, pp. 583-589. WO O1, 53272 A1 T 2001 Kim, "Metformin inhibits hepatic gluconeogenesis . .”. Diabetes, WO O1,53291 A1 T 2001 2008, vol. 57, pp. 306–314. WO O2/40019 A1 5, 2002 Towler, AMP-activated protein kinase in metabolic control . Cir WO O2/O76454 A1 10, 2002 culation Res., 2007, vol. 100, pp. 328-341. WO O2/O92575 A1 11, 2002 Ofir, Increased glycogen stores due to gamma-AMPK overexpres WO 02/100833 A1 12/2002 sion . Biochem. Pharmacol., 2008, vol. 75, pp. 1482-1491. WO O3, 18061 A1 3, 2003 Hardie, “Role of Amp-activated protein kinase ... 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W. 38885 A: 3.399 Bergeron, R. et al., “Effect of 5-Aminoimidazole-4-Carboxamide-1- WO 2005/047266 A1 5, 2005 B-n-Ribofuranoside Infusion on InVivo Glucose and Lipid Metabo WO 2005/051298 A2 6, 2005 lism in Lean and Obese Zucker Rats', Diabetes, 2001, pp. 1076-, vol. WO 2005/051298 A3 6/2005 50. WO 2005,121132 A1 12/2005 Blazquez, C, et al., “The AMP-Activated Protein Kinase Is Involved WO 2006/018850 A2 2, 2006 in the Regulation of Ketone Body Production by Astrocytes”,Journal WO 2006/018850 A3 2, 2006 of Neurochemistry, 1999, pp. 1674-, vol. 73. WO 2006/030.031 A1 3, 2006 Buhl, E. S. et al., “Long-Term AICAR Administration Reduces meta W. 29: : A. 2.3. bolic Disturbances and Lowers Blood Pressure in Rats Displaying WO 2006/053342 A2 9, 2006 in the Insulin Resistance Syndrome', Diabetes, 2002, pp. W. 3:39: A: 23: Butler, A.E., et al., “B-Cell Deficit and Increased B-Cell Apoptosis in WO 2006/116412 A2 11/2006 Hijmans With Type 2 Diabetes', Diabetes, 2003, pp. 102-, vol. 52. 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  • I Regulations

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  • CPU0213, a Novel Endothelin Type a and Type B Receptor Antagonist, Protects Against Myocardial Ischemia/Reperfusion Injury in Rats

    CPU0213, a Novel Endothelin Type a and Type B Receptor Antagonist, Protects Against Myocardial Ischemia/Reperfusion Injury in Rats

    ISSN 0100-879X Volume 44 (11) 1070-1193 November 2011 BIOMEDICAL SCIENCES AND www.bjournal.com.br CLINICAL INVESTIGATION Braz J Med Biol Res, November 2011, Volume 44(11) 1148-1155 doi: 10.1590/S0100-879X2011007500119 CPU0213, a novel endothelin type A and type B receptor antagonist, protects against myocardial ischemia/reperfusion injury in rats Z.Y. Wang, W. Zhang, X.Z. Li, Y. Han, Y.P. Chen, Z. Liu, L.P. Xie, Y. Ji and X. Lu The Brazilian Journal of Medical and Biological Research is partially financed by Institutional Sponsors Explore High - Performance MS Orbitrap Technology In Proteomics & Metabolomics Campus Ribeirão Preto Faculdade de Medicina de Ribeirão Preto analiticaweb.com.br S C I E N T I F I C All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License Brazilian Journal of Medical and Biological Research (2011) 44: 1148-1155 ISSN 0100-879X CPU0213, a novel endothelin type A and type B receptor antagonist, protects against myocardial ischemia/reperfusion injury in rats Z.Y. Wang1, W. Zhang2, X.Z. Li2, Y. Han3, Y.P. Chen1, Z. Liu2, L.P. Xie2, Y. Ji2 and X. Lu1 1Department of Geriatrics, the Second Affiliated Hospital, 2Key Laboratory of Human Functional Genomics, Atherosclerosis Research Centre, 3Department of Geriatrics, the First Affiliated Hospital, Nanjing Medical University, Nanjing, China Abstract The efficacy of endothelin receptor antagonists in protecting against myocardial ischemia/reperfusion (I/R) injury is controversial, and the mechanisms remain unclear. The aim of this study was to investigate the effects of CPU0123, a novel endothelin type A and type B receptor antagonist, on myocardial I/R injury and to explore the mechanisms involved.