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( 12 ) United States Patent US009963439B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 ,963 , 439 B2 Diaz et al. ( 45 ) Date of Patent: May 8 , 2018 ( 54 ) SPECIFIC INHIBITORS OF CYTOCHROME FOREIGN PATENT DOCUMENTS P450 26 RETINOIC ACID HYDROXYLASE CN 102503857 6 / 2012 (71 ) Applicants : University of Washington Through its EP 0722928 A1 7 /1996 Center for Commercialization , Seattle, (Continued ) WA (US ) ; UNIVERSITY OF MONTANA , Missoula , MT (US ) OTHER PUBLICATIONS (72 ) Inventors : Philippe Diaz , Missoula , MT (US ); Ohta (Biorganic and Medicinal Chemistry Letters ; 23 , 2013 , 81 -84 ; Nina Isoherranen , Seattle , WA (US ) ; available online Nov. 15 , 2012 ). * Brian Buttrick , Seattle , WA (US ) ; (Continued ) Nicolas Guilloteau , Missoula , MT ( US ) Primary Examiner — Pancham Bakshi ( 73 ) Assignees: University of Washington Through Its (74 ) Attorney , Agent, or Firm — McDonnell Boehnen Center For Commercialization , Hulbert & Berghoff LLP Seattle , WA (US ) ; University of ( 57 ) ABSTRACT Montana , Missoula , MT (US ) The present disclosure is generally directed to compositions ( * ) Notice : Subject to any disclaimer, the term of this and methods for treating diseases that are ameliorated by the inhibition ofCYP26 mediated retinoic acid metabolism . The patent is extended or adjusted under 35 compositions comprise compounds of formula ( I ) . A rep U . S . C . 154 ( b ) by 0 days . days . reid50000060307390 IB /345 nullsents aryl optionally sub stituted with one , two, three , or four groups that are each ( 21) Appl . No. : 14 /912 , 479 independently halogen , cyano , nitro , C1- 6 alkyl , C1- 6 haloalkyl, - NH2, — NH ( C . - C . alkyl) , - N ( C / - C alkyl) 2 , (22 ) PCT Filed : Aug. 20 , 2014 OH , C , - Cô alkoxy , and C . - C6 haloalkoxy ; X is a bond , CH , CHR — - C = CHR NR4 — , ( 86 ) PCT No. : PCT/ US2014 /051962 - N = O R4 , 04 , S4 , SO , S0 , - , C ( O ) - , or - C (NR4 ) — , or X is of formula ( a ), (b ) or ( c ) , $ 371 ( c ) ( 1 ) , wherein each n is independently 1 , 2 , or 3 ; each R4 is ( 2 ) Date : Feb . 17, 2016 independently hydrogen or C1- 6 alkyl; R is independently hydrogen , C1- 6 alkyl , or - OR " , where Rº is selected from ( 87 ) PCT Pub . No. : WO2015 / 026990 the group consisting of hydrogen , C1- 6 alkyl, C2- 6 alkenyl, C2- 6 alkynyL C3- 12 cycloalkyl, heterocyclyl, aryl , ary1C1- 6 PCT Pub . Date : Feb . 26 , 2015 alkyl, heteroaryl, or heteroary1C1- 6 alkyl; Y is C1- 6 alkylene , (65 ) Prior Publication Data C2- 6 alkenylene , or C2- 6 alkylylene moiety . US 2016 /0200703 A1 Jul. 14 , 2016 Related U . S . Application Data (60 ) Provisional application No . 61 / 867 ,892 , filed on Aug . 7 R 20 , 2013 . (51 ) Int . CI. C070 31730 ( 2006 .01 ) C07C 69 / 738 ( 2006 .01 ) (Continued ) mm (52 ) U . S . CI. CPC .. .. C07D 317 / 30 ( 2013 .01 ) ; C07C 57/ 50 ( 2013 .01 ) ; C07C 59 /54 ( 2013 .01 ) ; C07C 59 /72 (2013 .01 ) ; ( Continued ) ( 58 ) Field of Classification Search mi USPC .. .. .. .. .. .. .. .. .. 514 /440 , 444 , 445 , 452 See application file for complete search history . - (56 ) References Cited mu U . S . PATENT DOCUMENTS mu 4 ,814 , 454 A 3 / 1989 Misra 4 , 826 , 969 A 5 / 1989 Maignan et al. (Continued ) 53 Claims, 4 Drawing Sheets US 9 , 963, 439 B2 Page 2 (51 ) Int. Cl. Chandraratna, “ Rational design of receptor- selective retinoids, " C07C 323 /65 ( 2006 .01 ) Journal of the American Academy of Dermatology , vol. 39 , No. 4 , C07C 69 /616 ( 2006 .01 ) Suppl Pt 2 , pp . S124 - S128 , 1998 . Chapman , et al. , “ Use of captive spray ionization to increase C07C 69 /73 ( 2006 . 01 ) throughput of the data - independent acquisition technique C07C 69 / 734 ( 2006 . 01 ) PACIFIC , ” Rapid Communications in Mass Spectrometry , vol. 30 , C07D 339 / 06 ( 2006 . 01 ) No . 9 , pp . 1101 - 1107 , 2016 . C07C 317 / 44 ( 2006 .01 ) Charton , et al. , " Novel non -carboxylic acid retinoids: 1 , 2 , 4 C07C 323 /62 ( 2006 .01 ) Oxadiazol - 5 -one derivatives ,” Bioorganic & Medicinal Chemistry C07C 229 / 42 ( 2006 . 01) Letters , vol . 19 , 2 , pp . 489 - 492 , 2009 . C07C 229 / 44 ( 2006 .01 ) Chen , et al. , “ Biological effects and metabolism of 9 -cis -retinoic C07C 57 /50 (2006 .01 ) acid and its metabolite 9 , 13 - di -cis -retinoic acid in HaCaT C07C 59 /54 ( 2006 .01 ) keratinocytes in vitro : comparison with all - trans -retinoic acid , " C07C 59 / 72 ( 2006 .01 ) Archives of Dermatological Research , vol . 292 , No . 12 , pp . 612 620 , 2000 . C07C 59 /86 ( 2006 .01 ) Cheng , et al. , “ Voriconazole inhibition of vitamin A metabolism : are (52 ) U . S . CI. adverse events increased in cystic fibrosis patients ? ” Pediatric CPC . .. C07C 59 /86 ( 2013. 01 ) ; C07C 69 /616 Pulmonology , vol . 45 , No. 7 , pp . 661 - 666 , 2010 . (2013 .01 ) ; C07C 69 / 73 (2013 .01 ) ; C07C Chiba , et al. , “ Distinct retinoid X receptor- retinoic acid receptor 69 /734 ( 2013 .01 ) ; C07C 69 / 738 (2013 .01 ) ; heterodimers are differentially involved in the control of expression C07C 229 /42 ( 2013. 01 ) ; C07C 229 /44 of retinoid target genes in F9 embryonal carcinoma cells , " Molecu (2013 .01 ) ; C07C 317 /44 (2013 . 01 ) ; C07C lar and Cellular Biology, vol . 17 , No. 6 , pp . 3013 - 3020 , 1997 . 323 /62 ( 2013 .01 ) ; C07C 323 /65 ( 2013 .01 ) ; Christie , et al . , " Synthesis and evaluation of synthetic retinoid derivatives as inducers of stem cell differentiation , ” Organic & CO7D 339 /06 ( 2013 .01 ) ; C07C 2602 / 10 Biomolecular Chemistry , vol. 6 , No . 19 , pp . 3497 -3507 , 2008 . ( 2017 . 05 ) ; C07C 2602 / 28 ( 2017 . 05 ) ; C07C Chung , et al ., “ Role of retinoid signaling in the regulation of 2603/ 74 ( 2017. 05 ) spermatogenesis ," Cytogenetic and Genome Research , 105 ( 2 4 ) : 189 - 202 , 2004 . ( 56 ) References Cited Clarke , et al. , “ Retinoids: potential in cancer prevention and therapy ,” Expert Reviews in Molecular Medicine , vol . 6 , No . 25 , pp . U . S . PATENT DOCUMENTS 1 - 23 , 2004 . 4 ,829 , 080 A 5 / 1989 Maignan et al . Clugston et al ., “ Altered hepatic retinyl ester concentration and acyl 4 , 833 , 240 A 5 / 1989 Maignan et al . composition in response to alcohol consumption ,” Biochimica et 5 ,023 , 363 A 6 / 1991 Maignan et al . Biophysica Acta , vol . 1831 , No . 7 , pp . 1276 -1286 , 2013 . 5 , 128 ,479 A 7 / 1992 Janssen et al . Cordoba , et al. , “ Hypercalcemia due to an interaction of all - trans 5 , 556 , 844 A 9 / 1996 Reichert et al . retinoic acid (ATRA ) and itraconazole therapy for acute 6 , 258 , 775 B1 * 7 / 2001 Bernardon . C07C 45 / 46 424 / 70 . 1 promyelocytic leukemia successfully treated with zoledronic acid ,” 6 , 291 ,677 B1 9 / 2001 Vasudevan et al . European Journal of Clinical Pharmacology, vol. 64 , No . 10 , pp . 6 , 300 , 350 B1 10 / 2001 Belloni et al. 1031 - 1032 , 2008 . 6 , 653 ,322 B1 . 11 / 2003 Chambon et al . Cramer , et al. , “ ApoE - directed therapeutics rapidly clear beta 7 , 560, 589 B2 7 / 2009 Britton et al. amyloid and reverse deficits in AD mouse models , ” Science , vol. 7 , 569 , 601 B2 8 / 2009 Fang et al . 335 , No . 6075 , pp . 1503 - 1506 , 2012 . 7 ,964 , 639 B2 6 / 2011 DeLuca et al . Dawson , “ Treatment of progressive metastatic prostate cancer ," 2002 / 0049250 A1 4 / 2002 Maignan et al. Oncology , vol. 7 , No . 5 , pp . 17 - 24 , 1993 . 2006 /0122282 AL 6 / 2006 Leonard Dawson , et al ., “ An Adamantyl- Substituted Retinoid -Derived Mol 2010 /0330200 A1 * 12 / 2010 Carminati . .. .. .. .. A61K 31/ 192 ecule That Inhibits Cancer Cell Growth and Angiogenesis by 424 /649 Inducing Apoptosis and Binds to Small Heterodimer Partner 2013/ 0164663 A1* 6 / 2013 Hirose .. .. .. .. GOGG 15 /0142 Nuclear Receptor: Effects of Modifying Its Carboxylate Group on 430 / 56 Apoptosis , Proliferation , and Protein - Tyrosine Phosphatase Activ 2014 /0086909 A13 / 2014 Lu et al. ity ,” Journal of Medicinal Chemistry , vol . 50 , No . 11 , pp . 2622 2639 , 2007. FOREIGN PATENT DOCUMENTS Dawson , et al ., “ Apoptosis Induction in Cancer Cells by a Novel EP 0915823 A15 / 1999 Analogue of 6 - ( 3 - ( 1 - Adamantyl) - 4 -hydroxyphenyl ] - 2 EP 2612665 A1 7 / 2013 naphthalenecarboxylic Acid Lacking Retinoid Receptor Transcrip WO 200145664 A2 6 / 2001 tional Activation Activity , ” Cancer Research , vol. 61 , No . 12 , pp . WO 2005108338 A1 11 / 2005 4723 - 4730 , 2001 . WO 2008025965 A2 3 / 2008 Dawson , et al ., “ Correlation of Retinoid Binding Affinity to Retinoic WO 2008086942 A2 7 /2008 Acid Receptor a with Retinoid Inhibition of Growth of Estrogen WO 2011055843 A1 5 / 2011 Receptor- positive MCF - 7 Mammary Carcinoma Cells , ” Cancer WO 2013040227 A2 3 / 2013 Research , vol . 55 , No. 19 , pp . 4446 -4451 , 1995 . WO 2013071282 A1 5 / 2013 De Coster, et al ., “ Experimental studies with liarozole (R75251 ) : An WO 2013104399 A1 7 / 2013 antitumoral agent which inhibits retinoic acid breakdown, ” Journal WO 2014016507 AL 1 / 2014 of Steroid Biochemistry and Molecular Biology , vol . 43 , No. 1 - 3 , pp . 197 - 201 , 1992 . OTHER PUBLICATIONS Debruyne, et al. , “ Liarozole- a novel treatment approach for advanced prostate cancer : results of a large randomized trial versus CAS Registry No . 941688 -51 - 3 ( retrieved on SciFinder Aug . 2016 ) . cyproterone acetate . Liarozole Study Group , " Urology , vol . 52 , No . 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