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United States Patent (10) Patent No.: US 9.233,998 B2 Anderson Et Al

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United States Patent (10) Patent No.: US 9.233,998 B2 Anderson Et Al US009233998B2 (12) United States Patent (10) Patent No.: US 9.233,998 B2 Anderson et al. (45) Date of Patent: Jan. 12, 2016 (54) NATURAL PRODUCT ANALOGS INCLUDING 5,002,939 A 3, 1991 Streber AN ANTI-NFLAMMLATORY CYANOENONE 5,013,649 A 5/1991 Wang et al. .................. 435/69.1 PHARMACORE AND METHODS OF USE 5,064,823. A 1 1/1991 Lee et al. ...................... 514,198 5,401,838 A 3/1995 Chou ............................ 536,281 (75) Inventors: Eric Anderson, Houston, TX (US); 5,426,183 A 6, 1995 Kjell . 536,285.5 Gary L. Bolton, Ann Arbor, MI (US); 5,464,826 A 11, 1995 Grindey et al. ................. 514,50 Deborah A. Ferguson.g s Branchburg,2. NJ 5,521,294 A 5/1996 Wildfeur ....................... 536,187 (US); Xin Jiang, Dallas, TX (US); 5,597,124. A 1/1997 Kessel et al. .................... 241.30 5,603,958 A 2f1997 Morein et al. ... 424/489 Robert M. Kral, Jr., Grapevine, TX 5,606,048. A 2/1997 Chou et al. ......... 536,271.1 (US); Patrick M. O’Brien, Stockbridge, 5,629,295 A 5/1997 Denimno et al. ................ 514, 26 MI (US); Melean Visnick, Irving, TX 5,972,703 A 10/1999 Long et al. ..... 435/372 (US) 6,025,395 A 2/2000 Breitner et al. ............... 514/570 6,303,569 B1 10/2001 Greenwald et al. ............... 514/2 (73) Assignee: REATA PHARMACEUTICALS, 6,326,507 B1 12/2001 Gribble et al. ..... 558,415 INC. Irving, TX (US) 6,369,101 B1 4/2002 Carlson ....... ... 514,169 6,485,756 B1 1 1/2002 Aust et al. ...... ... 424,725 (*) Notice: Subject to any disclaimer, the term of this 6,552,075 B2 4/2003 Gribble et al. ... 514,522 patent is extended or adjusted under 35 6,642,217 B2 11/2003 Krasutsky et al. ............ 514,169 U.S.C. 154(b) by 0 days. 6,649,654 B1 1 1/2003 Karinet al. (Continued) (21) Appl. No.: 13/552,530 FOREIGN PATENT DOCUMENTS (22) Filed: Jul.18, 2012 CN 1687021 A 10/2005 (65) Prior Publication Data CN 102O7O697 5, 2010 US 2012/0283450 A1 Nov. 8, 2012 (Continued) OTHER PUBLICATIONS Related U.S. Application Data (63) Continuation of application No. 12/426,889, filed on Nguyen et al., “Synthesis of the 5-7-6 Core of Guanacastepenes. Apr. 20, 2009, now Pat. No. 8,258,329. Construction of C8 Quaternary Carbon via the Inversion of Stereochemistry.” Organic Letters, vol. 4. No. 22, pp. 3959-3962, (60) Provisional application No. 61/046,363, filed on Apr. 20O2.* 18, 2008. (Continued) (51) Int. Cl. CD7C 255/46 (2006.01) C07D 31 7/26 (2006.01) Primary Examiner — Barbara P Badio C07. 4I/00 (2006.01) (74) Attorney, Agent, or Firm — Parker Highlander PLLC C07D 31 1/74 (2006.01) CO7D 49.3/10 (2006.01) C07F 7/18 (2006.01) (57) ABSTRACT C07, 2L/00 (2006.01) CO7I 53/00 (2006.01) This invention provides novel compounds comprising the CO7I 71/00 (2006.01) following anti-inflammatory pharmacore: (52) U.S. Cl. CPC ........... C07J 41/0094 (2013.01); C07C 255/46 (2013.01); C07D 31 1/74 (2013.01); C07D 317/26 (2013.01); C07D493/10 (2013.01); C07F 7/1856 (2013.01); C07J 21/003 (2013.01); C07J 4 I/0055 (2013.01); C07J 53/001 (2013.01); C07J 71/0005 (2013.01); C07C 2101/16 (2013.01) (58) Field of Classification Search R R2 USPC ........................................... 558/440; 549/200 See application file for complete search history. wherein X, R and R are defined herein. Also provided are (56) References Cited pharmaceutical compositions, kits and articles of manufac ture comprising such compounds, methods and intermediates U.S. PATENT DOCUMENTS useful for making the compounds, and methods of using the 3,013,010 A 2f1957 Cardenas compounds and compositions. 2,875,201 A 2f1959 Johns .... 260,239.55 4,395,423. A 7, 1983 Neumann ... 424,304 4,808.614 A 2, 1989 Hertel ............................. 514/45 3 Claims, 24 Drawing Sheets US 9,233,998 B2 Page 2 (56) References Cited FOREIGN PATENT DOCUMENTS U.S. PATENT DOCUMENTS DE 10 2005041613 3, 2007 EP O 272 891 A2 6, 1988 6,689,787 B1 2, 2004 McKearn et al. ............. 514,275 EP O 329 348 B1 7, 1995 6,951,847 B2 10/2005 Gibson et al. .. 514,169 EP O 376 518 B1 11, 1995 6,974,801 B2 12/2005 Honda et al. .................... 514/25 EP O 576 230 B1 4f1996 6,991,814 B2 1/2006 Ray et al. ...................... 424,756 EP O 577 303 B1 10, 1997 7,053,119 B2 5, 2006 Karinet al. 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