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Stilbene Analogs and Methods of Treating Cancer David Watt University of Kentucky, [email protected]

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Stilbene Analogs and Methods of Treating Cancer David Watt University of Kentucky, Dwatt@Uky.Edu University of Kentucky UKnowledge Pharmaceutical Sciences Faculty Patents Pharmaceutical Sciences 9-15-2015 Stilbene Analogs and Methods of Treating Cancer David Watt University of Kentucky, [email protected] Chunming Liu University of Kentucky, [email protected] Vitaliy M. Sviripa University of Kentucky, [email protected] Wen Zhang University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/ps_patents Part of the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Watt, David; Liu, Chunming; Sviripa, Vitaliy M.; and Zhang, Wen, "Stilbene Analogs and Methods of Treating Cancer" (2015). Pharmaceutical Sciences Faculty Patents. 39. https://uknowledge.uky.edu/ps_patents/39 This Patent is brought to you for free and open access by the Pharmaceutical Sciences at UKnowledge. It has been accepted for inclusion in Pharmaceutical Sciences Faculty Patents by an authorized administrator of UKnowledge. For more information, please contact [email protected]. 111111 1111111111111111111111111111111111111111111111111111111111111 US0091321 02B2 c12) United States Patent (10) Patent No.: US 9,132,102 B2 Watt et al. (45) Date of Patent: Sep.15,2015 (54) STILBENE ANALOGS AND METHODS OF (56) References Cited TREATING CANCER U.S. PATENT DOCUMENTS (71) Applicant: UNIVERSITY OF KENTUCKY 4,683,087 A 7/1987 Witiak eta!. RESEARCH FOUNDATION, 5,430,062 A 7/1995 Cushman eta!. Lexington, KY (US) 5,674,906 A 10/1997 Hatanaka eta!. 6,552,085 B2 4/2003 Inman et al. (72) Inventors: David Watt, Lexington, KY (US); 6,562,834 B2 5/2003 Bissery 6,790,869 B2 9/2004 Ghai eta!. Chunming Liu, Lexington, KY (US); 6,919,324 B2 7/2005 Chaplin et a!. Vitaliy M. Sviripa, Lexington, KY (US); 6,992,106 B2 112006 Morinaga et a!. Wen Zhang, Lexington, KY (US) 7,655,696 B2 212010 Morinaga eta!. 2003/0203908 A1 10/2003 Lowe (73) Assignee: UNIVERSITY OF KENTUCKY 2004/0147788 A1 7/2004 Savouret et al. 2005/0096384 A1 5/2005 Forman et al. RESEARCH FOUNDATION, 2006/0094716 A1 * 5/2006 Aissaoui eta!. ........... 514/232.5 Lexington, KY (US) 2007/0249647 A1 10/2007 Vander Jagt et al. 2008/0096973 A1 4/2008 Liou eta!. ( *) Notice: Subject to any disclaimer, the term of this 2008/0108840 A1 5/2008 Kung et a!. patent is extended or adjusted under 35 2008/0261982 A1 10/2008 Lee eta!. 2009/0136431 A1 5/2009 Srinivas et a!. U.S.C. 154(b) by 0 days. 2009/0221666 A1 9/2009 Pettit et a!. 2010/0056463 A1 3/2010 Raederstorff eta!. (21) Appl. No.: 14/192,616 2010/0119499 A1 5/2010 Kneller eta!. (22) Filed: Feb.27,2014 FOREIGN PATENT DOCUMENTS (65) Prior Publication Data CN 1143629 A 2/1997 CN 100482638 c 4/2009 US 2014/0249161 Al Sep. 4, 2014 JP 02-085828 A 3/1990 JP 05-249517 A 9/1993 wo 03/099763 A1 12/2003 wo 2008-070872 A1 6/2008 Related U.S. Application Data (62) Division of application No. 13/360,109, filed on Jan. OTHER PUBLICATIONS 27, 2012, now Pat. No. 8,664,273. Cancer definition in MedicineNet.com 2004.* (60) Provisional application No. 61/437,341, filed on Jan. "Adult Brain Tumors Treatment", National Cancer Institute, pp. 1-21 28, 2011, provisional application No. 61/439,118, (Jan. 24, 2013).* filed on Feb. 3, 2011. "Types of Brain Cancer" at http://www.cancercenter.com/brain-can­ cer/types-of-brain-cancer.cfm (Mar. 12, 20 13). * (51) Int. Cl. "Colorectal Cancer" at cancer.net (published Sep. 2012), pp. 1-2.* A61K 31103 (2006.01) "Types of Breast Cancer", published in breastcancer.org (Sep. 30, A61K 31144 (2006.01) 2012); p. 1.* C07C 211148 (2006.01) Stomach cancer-Mayoclinic.com-2012.* C07C 211152 (2006.01) Schafer eta!. Drug discovery Today 2008, 13 (21122), 913-916.* C07C 291104 (2006.01) Luo eta!. (Celll36, Mar. 6, 2009; 823-837).* Wang eta!. (BMC Cancer 2014, 14:196).* C07D233/64 (2006.01) International Search Report and the Written Opinion of the Interna­ C07D 2951073 (2006.01) tional Searching Authority issued in International Patent Application C07D 495104 (2006.01) No. PCT/US2012/022938 dated Aug. 3, 2012. G01N331574 (2006.01) (Continued) G01N33/58 (2006.01) C07C 39121 (2006.01) C07C 43123 (2006.01) Primary Examiner- Valerie Rodriguez-Garcia (52) U.S. Cl. CPC ................. A61K 31103 (2013.01); A61K 31144 (74) Attorney, Agent, or Firm- McDermott Will & Emery (2013.01); C07C 39121 (2013.01); C07C 43123 LLP (2013.01); C07C 211148 (2013.01); C07C 211152 (2013.01); C07C 291104 (2013.01); (57) ABSTRACT C07D 233164 (2013.01); C07D 2951073 (2013.01); C07D 495104 (2013.01); G01N Stilbene analogs and pharmaceutical compositions that are 33157484 (2013.01); G01N 331582 (2013.01); useful for the treatment of various cancers, including without GOJN 2800/52 (2013.01) limitation, colorectal cancer (CRC) and breast cancer are (58) Field of Classification Search disclosed. The halogenated stilbene analogs include nitrogen CPC .... C07C 211/52; C07C 291/04; C07C 39/21; heteroaryl groups and/or amino groups on the stilbene ring. C07C 43/23; C07D 233/64; C07D 295/073; C07D 495/04; A61K 31/03; A61K 31/44 See application file for complete search history. 7 Claims, 18 Drawing Sheets US 9,132,102 B2 Page 2 (56) References Cited Cantoni, G.L. et a!. "S-Adenosylmethionine; a new intermediate formed enzymatically from L-methionine and OTHER PUBLICATIONS adenosinetriphosphate." Received for Publication: Mar. 23, 1953. pp. 403-416. Mohammad, S. "A Quantum Mechanical Approach to the Theory of Cai, J. et a!. "Changes in S-Adenosylmethionine Synthetase in Cancer from Polynuclear Compounds". Molecular Pharmacology an Human Liver Cancer: Molecular Characterization and Significance." International Journal. Jan. 1985. vol. 27. pp. 148-155. Hepatology. vol. 24. No.5. pp. 1090-1097. 1996. Reid, E. "Carcinogenic Action of 2-Chloro-4- International Preliminary Report and Written Opinion issued in cor­ responding PCT Application No. PCT/US20 12/022938, mailed Aug. Dimethylaminostilbene, In Relation to (A) Possible Effects of 5, 2013. Growth Hormone, and (B) Composition ofLiver Cytoplasm". British Huang eta!.: J. Phys Chern. C 2007, 111, 10672-10681). Journal of Cancer. Mar. 1956. pp. 123-128. International Search Report and the Written Opinion of the Interna­ Gu, B. eta!. "Epithelial Stem Cells: An Epigenetic and Wnt-Centic tional Searching Authority issued in International Patent Application Perspective." Journal of Cellular Biochemistry. 110:1279-1287. No. PCT/US2012/022938 dated Jan. 27, 2012. 2010. Rimando, Agnes, eta!., "Biological/Chemopreventative Activity of Zhang, W. eta!. "Fluorinated N,N-Dialkylaminostilbenes for Wnt Stilbenes and their Effect on Colon Cancer", Planta Med, 2008, pp. Pathway Inhibition and Colon Cancer Repression." Journal of 1635-1643, Georg Thieme Verlag KG. Medicinal Chemistry. vol. 54. pp. 1288-1297.2011. Supplementary European Search Report EP 12 73 9698 dated May Hotchkiss, P. eta!. "Modification of the Surface Properties oflndium 26,2014. Tin Oxide with Benzylphosphonic Acids: A Joint Experimental and Tanvi S. Jani eta!., "Inhibition of methionine adenosyltransferase II Theoretical Study." Advanced Materials. vol. 21. pp. 4496-4501. induces FasL expression, Fas-DISC formation and caspase-8-depen­ 2009. dent apoptotic death in T leukemic cells", Cell Research (2009) vol. Ito, K. et a!. "Correlation Between the Expression of Methionine 19, No.3, pp. 358-369. Adenosyltransferase and the Stages of Human Colorectal Carci­ Chinese Office Action issued in Chinese Patent Application No. noma." Surgery Today. vol. 30. pp. 706-710. Mar. 24,2000. 201280013655.1 dated Sep. 22, 2014 w/English translation. Liu, Q. eta!. "The X Protein of Hepatitis B Virus Inhibits Apoptosis Notification of the Second Office Action, Chinese Patent Application in Hepatoma Cells through Enhancing the Methionine No. 201280013655.1 dated May 11, 2015 with full English transla­ Adenosyltransferase 2A Gene Expression and Reducing tion. S-Adenosylmethionine Production." Journal of Biological Chemis­ try. vol. 286. No. 19. pp. 17168-17180. May 13,2011. * cited by examiner U.S. Patent Sep.15,2015 Sheet 1 of 18 US 9,132,102 B2 OH OH HO HO OH OH OCH 3 2 OH FIG.l c (E)-ArCH=CHAr' 4 - b FIG. 2 U.S. Patent Sep.15,2015 Sheet 2 of 18 US 9,132,102 B2 y y X 4z X, Y =F 4cc X, Y =F 4aa X =F, Y =Cl 4dd X= F, Y = Cl 4bb X,Y = Cl 4ee X,Y =Cl F 4ff F FIG. 3 FIG.4 U.S. Patent Sep.15,2015 Sheet 3 of 18 US 9,132,102 B2 A 4a 4b 4c B c Axin2 Axin2 c-Myc c-Myc 13-catenln 13-catenin Actin Actin FIG.5 U.S. Patent Sep.15,2015 Sheet 4 of 18 US 9,132,102 B2 D E Axin2 Axin2 c-Myc c-Myc [:\-eaten in 13-catenin Actin Actin FIG. 5 Continued U.S. Patent Sep.15,2015 Sheet 5 of 18 US 9,132,102 B2 A N(CH3)2 N(CH3)2 N(CH3)2 F '-':: F F F :::,.._ ~ :;'/ :::,.._ :::,.._ 4m F 4n 40 F N(CH3)2 F F '-':: F :::,.._ :::,.._ :::,.._ ~ N(CH3)2 N(CH3)2 F 4p F 4r N(C2H5)2 N(CH3)2 N(CH3)2 F :::,.._ F :::,.._ F :::,.._ F 4t F N(CH3l2 N(CH3l2 N(CH3)2 F F '-':: Cl :::,.._ F :::,.._ :::,.._ ~ F F F 4v 4w 4x N(CH3)2 N(CH3)2 Cl '-':: F :::,.._ ~ Cl 4y F 5r 8 0 Cl) :!!! :::l .... 0 1: E ... c .... '<t '<t '<t '<t '<t ~ Axin2 c-Myc f"l-catenin Actin FIG.6 U.S.
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