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(12) United States Patent (10) Patent No.: US 8,178,536 B2

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(12) United States Patent (10) Patent No.: US 8,178,536 B2 US008178536B2 (12) UnitedO States Patent (10) Patent No.: US 8,178,536 B2 Nunes et al. (45) Date of Patent: May 15, 2012 (54) SIRTUIN MODULATING COMPOUNDS 2004/0010033 A1 1/2004 Anderson et al. 2004.0034037 A1 2/2004 Harbeson et al. 2004/0044203 A1 3/2004 Wittman et al. (75) Inventors: Joseph J. Nunes, Andover, MA (US); 2004/0048843 A1 3/2004 Ting et al. Jill Milne, Brookline, MA (US); Jean 2004/0072760 A1 4/2004 Carboni et al. Bemis, Arlington, MA (US); Roger Xie, 2004/O142997 A1 7, 2004 Chen et al. Stably M. S. St. Vu, 2004/O1578452004/O152743 A1 8/2004 DohertySchoenafinger et al. et al. rlington, MA (US) Pui Yee Ng. 2004/0171073 Al 9, 2004 Neiland et al. Boston, MA (US); Jeremy S. Disch, 2004/O180905 A1 9, 2004 Munchhof Natick, MA (US); Thomas Salzmann, 2004/022O189 A1 11/2004 Sun et al. 2005.000984.0 A1 1/2005 Cui et al. Warren, NJ (US); David Armistead, 2005, OO65151 A1 3, 2005 Norcross Sudbury, MA (US) 2005, OO65,196 A1 3, 2005 Inaba et al. 2005/0085519 A1 4/2005 Rubinet al. (73) Assignee: Sirtris Pharmaceuticals, Inc., 2005. O197353 A1 9, 2005 Ritzeler et al. 2005/O197375 A1 9, 2005 Sircar et al. Cambridge, MA (US) 2005.0245513 A1 11/2005 Gallant et al. 2005/0266515 A1 12/2005 O'Brien et al. (*) Notice: Subject to any disclaimer, the term of this 2006, OO14756 A1 1/2006 Edwards et al. patent is extended or adjusted under 35 2006.0036098 A1 2/2006 Kim et al. U.S.C. 154(b) by 0 days. 2006, OO74O75 A1 4/2006 Hadida-Ruah et al. 2007/0O37809 A1 2/2007 Nunes et al. 2007/0O3781.0 A1 2/2007 Nunes et al. (21) Appl. No.: 12/955,663 2007, 0037827 A1 2/2007 Nunes et al. 2007/0O37865 A1 2/2007 Nunes et al. (22) Filed: Nov. 29, 2010 2009.0099.170 A1 4, 2009 Nunes et al. 2009, O163476 A1 6/2009 Milburn et al. (65) Prior Publication Data 2010/0168084 A1 7, 2010 Huber et al. US 2011 FO130387 A1 Jun. 2, 2011 FOREIGN PATENT DOCUMENTS O O AU 30932.89 9, 1989 Related U.S. Application Data DE 1 108 698 6, 1961 (62) Division of application No. 1 1/499,876, filed on Aug. P 28 92 3.28. 4, 2006, now Pat. No. 7,855,289. (Continued) (60) Provisional application No. 60/705,612, filed on Aug. 4, 2005, provisional application No. 60/741,783, filed OTHER PUBLICATIONS on Dec. 2, 2005, provisional application No. 60/779.370, filed on Mar. 3, 2006, provisional Bundgaard (Design and application of prodrugs. In A Textbook of application No. 60/792.276, filed on Apr. 14, 2006. DrugKubinyi Design (3D QSARand Development, in Drug Design: (1991), Ligand-Protein p. 113-191). Interactions and (51) Int. Cl Molecular Similarity, vol. 2-3, Springer, 1998, 800 pages) TOC and Aiki/50 2006.O1 pp. 243-244 provided.* ( .01) Wermuth, The Practice of Medicinal Chemsitry, 2d ed. (2003), 768 C07D 237/26 (2006.01) pages. CHS. 9-10 provided.* (52) U.S. Cl. ........................................ 514/249; 544/235 Pacholec et al. (J. Biol. Chem., 285(11), 8340-51).* (58) Field of Classification Search .................. 514/249; Bemis et al. (Bioorg. Med. Chem. Lett., 19 (2009), 2350-53).* 544/235 Parket al. (Toxicology Lett., 120 (2001), 281-91).* See application file for complete search history. (Continued) (56) References Cited Primary Examiner — Robert Havlin U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm — Ropes & Gray LLP 3,164,603 A 1/1965 McCafferty 3,503,929 A 3, 1970 Loudas (57) ABSTRACT 3,517,007 A 6, 1970 Kim et al. 3,712,888 A 1/1973 Kaempfen Provided herein are novel sirtuin-modulating compounds and 3,928,228 A 12/1975 Crounse methods of use thereof. The sirtuin-modulating compounds it's A 38. 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WO WO 2004/030625 4/2004 Elgemeie et al., “Synthesis of Benzimidazole Ketene N.S-Acetals WO WO 2004/033666 4/2004 and Their Reactions with Nucleophiles.” Synthetic Communications, WO WO 2004/0393.18 5, 2004 WO WO 2004/041277 5, 2004 33(4):555-62 (2003). WO WO 2004/062663 T 2004 Fekner et al., “Synthesis and Metalation of a Chiral, Pyridine WO WO 2004/069 160 8, 2004 Strapped, Cyclic Bis(benzimidazole) Ligand.” Organic Letters, WO WO 2004/084.813 10, 2004 6(6): 989-92 (2004). WO WO 2005/OO2552 1, 2005 Halluska et al., “In vitro and in vivo Antitumor Effects of the Dual WO WO 2005/025574 3, 2005 Insulin-Like Growth Factor-I/Insulin Receptor Inhibitor, WO WO 2005/043630 5, 2005 BMS-554417.” Cancer Research, 66(1):362-71 (2006). WO WO 2005, O77939 8, 2005 Huang et al., “Synthesis and Anticancer Evaluation of WO WO 2005,10O342 10/2005 Bis(Benzimidazoles), Bis(Benzoxazoles), and Benzothiazoles.” WO WO 2005,105798 11, 2005 Bioorganic & Medicinal Chemistry, 14:6106-19 (2006). WO WO 2006/O1828O 2, 2006 Jules et al., “Derivatives of 3-, 4-, and 5-Phenylsalicylamides,” J. Am. WO WO 2006/02O767 2, 2006 WO WO 2006/034833 4/2006 Pharma. Assoc., 45(5):277-281 (1956). WO WO 2006/050506 5, 2006 Kaeberlein et al., “Substrate-specific Activation of Sirtuins by WO WO 2006/053227 5, 2006 Resveratrol.” J. Biol. Chem., 280(17): 17038-45 (2005). WO WO 2006/094236 9, 2006 Katagiri et al., “Studies on Ketene and Its Derivatives. Part 1191). WO WO 2006/113458 10, 2006 Reactions of Haloketenes with 2-Arylideneaminopyridines,” J. WO WO 2007/019344 2, 2007 Hetero. Chem. 21:407-12 (1984). WO WO 2007/019346 2, 2007 Kubinyi, "3D QSAR in Drug Design Ligand-Protein Interactions and WO WO 2008/073451 6, 2008 Molecular Similarity.” Springer, 800 pages, 2-3:243-44 provided WO WO 2008, 106692 9, 2008 (1998). 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