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. 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