TOMMANNUUTTILIMINATIONUS009862693B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 , 862, 693 B2 Pietras et al. (45 ) Date of Patent : Jan . 9 , 2018 ( 54 ) COMPOUNDS AND METHODS OF ( 56 ) References Cited TREATING CANCER U . S . PATENT DOCUMENTS (71 ) Applicant : The Regents of the University of 4 , 574 ,123 A * 3 / 1986 Edwards . .. .. C07C 279/ 28 California , Oakland , CA (US ) 162 / 161 4 , 861, 760 A 8 / 1989 Mazuel et al. ( 72 ) Inventors : Richard J . Pietras , Los Angeles , CA 4 ,911 , 920 A 3 / 1990 Jani et al . (US ) ; Michael E . Jung, Los Angeles , 5 ,212 , 162 A 5 / 1993 Missel et al. CA (US ) ; Diana C . Marquez -Garban , 5 , 403 , 841 A 4 / 1995 Lang et al . 6 ,699 ,989 B1 * 3 / 2004 Shetty CO7D 215 / 56 Los Angeles, CA (US ) ; Gang Deng, 540 /474 Los Angeles, CA (US ) 7 , 285 ,681 B2 * 10 /2007 Moinet .. .. .. CO7D 295/ 215 564 /233 ( 73 ) Assignee : The Regents of the University of 7 ,671 , 019 B2 * 3 /2010 Tobia A61K 8 /44 California , Oaklnad , CA (US ) 514 / 1 . 1 8 , 853, 259 B2 10 /2014 Mylari Subject to any disclaimer, the term of this 2010 / 0087544 A1 4 / 2010 Kim et al. ( * ) Notice : 2011 /0196015 A1 8 / 2011 Kim et al . patent is extended or adjusted under 35 2011 / 0207810 Al 8 / 2011 Kim et al . U . S . C . 154 (b ) by 40 days. 2015 /0126518 Al 5 /2015 Kim et al . ( 21) Appl . No. : 14 /566 ,055 FOREIGN PATENT DOCUMENTS ( 22 ) Filed : Dec . 10 , 2014 WO WO - 96 /05309 A2 2 / 1996 WO WO - 96 /05309 A3 2 / 1996 (65 ) Prior Publication Data WO WO - 2011 /083998 A2 7 / 2011 WO WO - 2011 /083998 A3 7 / 2011 US 2015 /0158832 A1 Jun . 11, 2015 WO WO - 2011 / 147528 Al 12 / 2011 Related U . S . Application Data OTHER PUBLICATIONS (63 ) Continuation of application No . CAPLUS on STN , accession No . 2010 :923694 , Abstract of PCT/ US2013 /045250 , filed on Jun . 11, 2013 . CN101781273 Jul. 21 , 2010 . * Registry No . 793641 -52 - 8 , CAPLUS on STN , Dec . 7 , 2004. * (60 ) Provisional application No . 61/ 658 ,238 , filed on Jun . Alimova I . N . et al. (Mar . 15 , 2009) . “ Metformin inhibits breast 11 , 2012 . cancer cell growth , colony formation and induces cell cycle arrest in vitro , ” Cell Cycle 8 ( 6 ) : 909 - 915 . ( 51 ) Int. Cl. Berstein , L . M . ( Aug. 2010 ) . “ Modern approach to metabolic reha CO7D 295 /215 ( 2006 .01 ) bilitation of cancer patients : biguanides ( phenformin and CO7D 203 /20 ( 2006 .01 ) metformin ) and beyond ,” Future Oncol 6 ( 8 ) : 1313 - 23 . CO7D 211 / 16 ( 2006 . 01 ) Carey , L . A . et al . ( Jun . 7 , 2006 ). “ Race , breast cancer subtypes , and survival in the Carolina Breast Cancer Study ," JAMA 295 (21 ) : 2492 C07D 213 / 78 ( 2006 .01 ) 2502 . C07D 239 /28 ( 2006 . 01 ) Currie C . J . et al. ( Feb . 2012 , e - published Jan . 20 , 2012 ) . " Mortality C07D 401/ 12 ( 2006 . 01 ) after incident cancer in people with and without type 2 diabetes : A61K 31/ 155 ( 2006 . 01 ) impact of metformin on survival, ” Diabetes Care 35 ( 2 ): 299 - 304 . C07C 279 / 26 ( 2006 . 01 ) Dowling , R . J . et al . (Apr . 6 , 2011 ) . “ Understanding the benefit of metformin use in cancer treatment, ” BMC Med : 9 : 33 . A61K 31/ 4025 ( 2006 . 01 ) Dilman , V . M . et al . ( 1982 ) . “ Metabolic immunodepression and A61K 31 /445 ( 2006 .01 ) metabolic immunotherapy : an attempt of improvement in immuno A61K 31/ 4545 ( 2006 .01 ) logic response in breast cancer patients by correction of metabolic A61K 31/ 496 ( 2006 .01 ) disturbances , ” Oncology 39 ( 1 ) : 13 - 19 . A61K 31 /5377 ( 2006 .01 ) Evans , J . M . et al . (Jun . 4 , 2005 ) . " Metformin and reduced risk of cancer in diabetic patients , ” BMJ 330 ( 7503 ) :1304 - 1305 . C07C 279 / 22 ( 2006 .01 ) Foulkes, W . D . et al . (Nov . 11, 2010 ) . " Triple -negative breast can (52 ) U . S . CI. cer, " N Engl J Med . 363 ( 20 ) : 1938 - 1948 CPC . .. .. .. CO7D 295 /215 ( 2013 .01 ) ; A61K 31 / 155 International Search Report dated Nov . 1 , 2013 , for PCT Applica ( 2013 .01 ) ; A61K 31 /4025 ( 2013 .01 ) ; A61K tion No . PCT /US2013 /045250 , filed on Jun . 11 , 2013 , 4 pages . 31 /445 ( 2013 . 01 ) ; A61K 31/ 4545 ( 2013 .01 ) ; James , J. W . et al . (Sep . 1968 ) . “ The synthesis of some heterocyclic A61K 31/ 496 ( 2013 . 01 ) ; A61K 31 /5377 derivatives of biguanide with antibacterial activity , " J Med Chem (2013 . 01 ) ; C07C 279 / 22 ( 2013 . 01) ; C07C 11 ( 5 ): 942 - 945 . 279 / 26 ( 2013 .01 ) ; C07D 203 /20 ( 2013 . 01 ) ; (Continued ) CO7D 211/ 16 (2013 .01 ) ; C07D 213/ 78 Primary Examiner — Rebecca L Anderson ( 2013. 01 ) ; C07D 239 / 28 (2013 .01 ) ; C07D ( 74 ) Attorney , Agent, or Firm - Zachary L . Terranova ; 401 / 12 (2013 .01 ) Mintz , Levin , Cohn , Ferris , Glovsky and Popeo , P . C . ( 58 ) Field of Classification Search (57 ) ABSTRACT CPC .. .. CO7D 295 /215 ; C07D 203 / 20 ; CO7D Presented herein inter alia are novel compounds and meth 211710211 / 16 ; COLCO7D 213 / 78 ; CO7D 239 /28 ; CO7D 401/ 12 ods of using the same for the treatment of cancers . See application file for complete search history. 7 Claims, 10 Drawing Sheets US 9 , 862, 693 B2 Page 2 References Cited Kelarev, V . I . et al . (Sep . 1993 ) . “ Synthesis and properties of (56 ) derivatives of sym - triazines. 11 . Synthesis of 2 - amino - sym - triazines containing alkyl radicals , ” Chemistry of Heterocyclic Compounds OTHER PUBLICATIONS 29 ( 9 ) : 1087 - 1092 . Jiralerspong , S . et al. ( Jul. 10 , 2009 , e - published Jun . 1 , 2009 ) . Koh , M . et al. 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(May 2010 , e - published May 4 , 2010 ) . “ Metformin Kelarev, V . I. et al . (May 1988 ). “ Synthesis and properties of in cancer therapy : a new perspective for an old antidiabetic drug ? ” sym - triazine derivatives . 7 . Synthesis of pyridyl - substituted Mol Cancer Ther 9 ( 5 ) : 1092 - 1099 . 2 -amino - and 2 , 4 -diamino - sym -triazines , ” Chemistry of Heterocy Taubes, G . ( Jan . 6 , 2012 ) . " Cancer research . Unraveling the obesity clic Compounds 24 ( 5 ) :550 - 555 . cancer connection ,” Science 335 (6064 ): 28 , 30 - 32 . Kelarev , V . I. et al. (Sep . 1992) . " Synthesis and properties of Written Opinion dated Nov. 1 , 2013 , for PCT Application No . sym - triazine derivatives 9 . Synthesis of 2 - amino - and 2 , 4 -diamino PCT/ US2013 /045250 , filed on Jun . 11, 2013 , 7 pages. sym - triazines containing furan fragments ,” Chemistry of Heterocy clic Compounds 28 ( 9 ) : 1060 - 1065 . * cited by examiner U . S . 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