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(12) United States Patent (10) Patent No.: US 9,175,018 B2 Elliott Et Al

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(12) United States Patent (10) Patent No.: US 9,175,018 B2 Elliott Et Al US009 1750 18B2 (12) United States Patent (10) Patent No.: US 9,175,018 B2 Elliott et al. (45) Date of Patent: Nov. 3, 2015 (54) BORONATE ESTER COMPOUNDS AND (56) References Cited PHARMACEUTICAL COMPOSITIONS THEREOF U.S. PATENT DOCUMENTS 4,499,082 A 2f1985 Shenviet al. (71) Applicant: Millennium Pharmaceuticals, Inc., 5,106,948 A 4, 1992 RE al. Cambridge, MA (US) 5,159,060 A 10, 1992 Kinder et al. 5,169,841 A 12/1992 Kleeman et al. (72) Inventors: Eric L. Elliott, Brighton, MA (US); Abu 5,242,9045,187,157 A 9,2f1993 1993 Kettner et al. J. Ferdous, Winchester, MA (US); 5,250,720 A 10/1993 Kettner et al. Michael J. Kaufman, Lexington, MA 5.492.900 A 2/1996 LaHann (US); Sonja A. Komar, Belmont, MA 3. A AE t tal (US); Debra L. Mazaik, Holliston, MA 5,780,454- ww. A 7/1998 Adamsabeque et et al. al. (US); Quentin J. Mccubbin, Belmont, 5,834,487. A 1 1/1998 Lumet al. MA (US); Phuong M. Nguyen, 5,837,531. A 1 1/1998 Dedieu et al. Cambridge, MA (US); Vaithianathan 5,935,944 A 8, 1999 LaHann Palaniappan,ppan, Andover,s MA (US);s 6,060,4625.990,083. A 1 5/20001/1999 IqbalGalemmo, et al. Jr. et al. Raymond D. Skwierczynski, Andover, 6,066,730 A 5, 2000 Adams et al. MA (US); Nobel T. Truong, Milford, '39. f 29s ST stal MA (US); Csanad M. Varga, Newton, 6,297.217J. W-1 B1 10/2001 Adamsul et et al. al. MA (US); Peter N. Zawaneh, 6,699,835 B2 3/2004 Plamondon et al. Cambridge, MA (US) 6,713,446 B2 3/2004 Gupta 6,781,000 B1 8, 2004 Wang et al. (*) Notice: Subject to any disclaimer, the term of this gigs R: 1 858 Eley patent is extended or adjusted under 35 7,109,323- - w B2 9/2006 Plamondonupta et al. U.S.C. 154(b) by 0 days. 7,223,745 B2 5/2007 Chatterjee et al. 7,442,830 B1 10/2008 Olhava et al. (21) Appl. No.: 14/449,328 7,687,662 B2 3/2010 Olhava et al. 8,003,819 B2 8/2011 Olhava et al. 8,859,504 B2 * 10/2014 Elliott et al. ................. 514, 19.3 (22) Filed: Aug. 1, 2014 2002/0188100 A1 12/2002 Plamondon et al. (65) Prior Publication Data (Continued) US 2014/0343314 A1 Nov. 20, 2014 FOREIGN PATENT DOCUMENTS AU 395.1389 A 3, 1990 O O EP 0092999 B1 4f1992 Related U.S. Application Data EP 2 178888 B1 4/2012 (60) Division- - - of application No. 13/667,164, filed O Nov. WOJP WO96,2002145848 1326.6 A1A 5, 20021996 2. 2012, OW Pat. No. 8,859,504, which is a WO WO96, 14857 A1 5, 1996 continuation of application No. 12/485,344, filed on WO WO 98.35691 A1 8/1998 Jun. 16, 2009, now abandoned. WO WO99, 15183 A1 4f1999 WO WO99,30707 A1 6, 1999 (60) Provisional application No. 61/211,499, filed on Mar. WO WOOO,57887 A1 10, 2000 31, 2009, provisional application No. 61/132,244, (Continued) filed on Jun. 17, 2008. OTHER PUBLICATIONS (51) Int. Cl. C07F 5/04 (2006.01) Berge. et al., J. Pharm. Sci., 1977, vol. 66, 1-19. C07F 5/02 (2006.01) (Continued) C07K 5/078 (2006.01) C07K5/06 (2006.01) CD7C 23.3/83 (2006.01) Primary Examiner — Rei-Tsang Shiao A6 IK3I/98 (2006.01) (74) Attorney, Agent, or Firm — Honigman Miller Schwartz A6 IK3 L/454 (2006.01) and Cohn LLP; Lucy X. Yang; Jonathan P. O'Brien A6 IK3I/69 (2006.01) (52) U.S. Cl. (57) ABSTRACT CPC ................. C07F5/04 (2013.01); A61 K31/198 (2013.01); A61 K3I/454 (2013.01); A61 K The present invention provides novel compounds useful as 31/69 (2013.01); C07C233/83 (2013.01); proteasome inhibitors. The invention also provides pharma C07F 5/025 (2013.01); C07K5/06139 ceutical compositions comprising the compounds of the (2013.01); C07K5/0619.1 (2013.01) invention and methods of using the compositions in the treat (58) Field of Classification Search ment of various diseases. USPC .......................................................... 558/288 See application file for complete search history. 40 Claims, 8 Drawing Sheets US 9,175,018 B2 Page 2 (56) References Cited Mullard, A., “Next-generation proteasome blockers promise safer cancer therapy'. Nature Medicine, vol. 18 No. 1, Jan. 2012, p. 7. U.S. PATENT DOCUMENTS Pachnis, V., et al., “The structure and expression of a novel gene activated in early mouse embryogenesis.” The EMBO Journal, Mar. 2004/0171556 A1 9, 2004 Purandare et al. 2005/0107307 A1 5, 2005 Bernadini et al. 1988, vol. 7, No. 3, pp. 673-681. 2005/0282742 A1 12/2005 Plamondon et al. Ruggeri, B., “The Development and Pharmacology of Proteasome 2006, OO84592 A1 4/2006 Boucher Inhibitors for the Management and Treatment of Cancer.” Advances 2006/025274.0 A1 11/2006 Johnson, Jr. et al. in Pharmacology, vol. 57, 2009, pp. 91-135. 2010.0081633 A1 4/2010 Fleming et al. Yoo-Warren, H. et al., “Two regulatory Domains Flank the Mouse 2010/0204180 A1 8, 2010 Olhava et al. H19 Gene'. Molecular and Cellular Biology, vol. 8, No. 11, 1988, pp. 2011/0245203 A1 10/2011 Fleming et al. 4707-4715. 2012/0041196 A1 2/2012 Bernardini Zhang, Y. et al., “Imprinting of human H19: allele-spedfic CpG methylation, loss of the active allele in Wilms tumor, and potential for FOREIGN PATENT DOCUMENTS somatic allele Switching”. Am. J. Hum. Genet., vol. 53, 1993, pp. WO WO 01/02424 A2 1, 2001 113-124. WO O2O5923 1, 2002 Opponent's Notice of Opposition in EP1660507 Opposition (Euro WO WO O2/O591.30 A1 8, 2002 pean Patent Office Date: May 4, 2010). WO WO O2/O591.31 A1 8, 2002 Proprietor's Response to the Notice of Opposition with Amended WO O3O33507 4/2003 Claims in EP1660507 Opposition (European Patent Office Date: Jan. WO WOO3,059898 A2 T 2003 17, 2011). WO 2005O16859 2, 2005 WO WO 2005/021558 A2 3, 2005 Summons to Attend Oral Proceedings with Annex in EP1680507 WO WO 2005/097809 A2 10/2005 Opposition (European Patent Office Date: Apr. 1, 2011). WO 2005111008 11, 2005 Proprietor's Submissions and Amendments in EP1660507 Opposi WO 2006052733 5, 2006 tion (European Patent Office Date: Sep. 7, 2011). WO WO 2007/005991 A1 1, 2007 Opponent's Reply to Proprietor's Sep. 5, 2011 Submission in WO 20070896.18 8, 2007 EP1660507 Opposition (European Patent Office Date: Sep. 19, WO 2009006473 1, 2009 WO WO 2009/020448 A1 2, 2009 2011). WO WO 2010/036357 A1 4/2010 Proprietor's Letters Regarding Oral Proceedings in EP1680507 WO WO 2011/1235O2 A1 10, 2011 Opposition (European Patent Office Date: Sep. 21, 2011). Oral Proceedings Minutes and Results in EP1660507 Opposition OTHER PUBLICATIONS (European Patent Office Date: Nov. 2, 2011). Opponent's Request for Correction of Minutes of Oral Proceedings Cancer (online), Retrieved on Jul. 6, 2007: MedlinePlus, a service of in EP1660507 Opposition (European Patent Office Date: Nov. 10, Medicine and the National Institutes of Health, Retrieved from the 2011). Internet, URL: http://www.nlm.nih.gov/medlineplus/cancer.html, 10 Proprietor's Request Regarding Minutes of Oral Proceedings in pageS. EP1660507 Opposition (European Patent Office Date: Nov. 29, Capitulo 28: Iiotilizacion, Farmacotecnia: teoria y practicatomo 3. 2011). 1982. MX, pp. 1038-1041. Correction of Minutes of Oral Proceedings in EP1660507 Opposition Dick. L.R., et al., “Building on bortezomib: second-generation (European Patent Office Date: Dec. 5, 2011). proteasome inhibitors as anti-cancer therapy'. Elsevier, Drug Dis Opponent's Letter Further to Proprietor's Representative's Letter covery Today, vol. 15, No. 5. Mar. 6, 2010, pp. 243-249. Dated Nov. 29, 2011 in EP1660507 Opposition (European Patent Office Date: Dec. 7, 2011). EP1880607 Opposition. Jan. 11, 2013, Proprietor's Submission, 10 Annex to Opposition Letter Dated Nov. 2, 2011 in EP1660507 Oppo pageS. sition (European Patent Office Date: Dec. 7, 2011). EP2178888 Opposition. Oct. 17, 2011, Summons to Attend Oral Interlocutory Decision in Opposition Proceedings in EP1660507 Proceedings with Annex, 3 pages. Opposition (European Patent Office Date: Dec. 14, 2011). EP2178888 Opposition, Dec. 30, 2011, Annex to Proprietor's Letter Proprietor's Notice of Appeal Against Decision of the Opposition dated Dec. 30, 2011, 3 pages. Division in EP1660507 Opposition (European Patent Office Date: EP2178888 Opposition. Dec. 30, 2011, Proprietor's Submission. 3 Feb. 23, 2012). pageS. Opponent's Notice of Appeal Against Decision of the Opposition EP2178888 Opposition, Apr. 4, 2013, Opponent's Submission, 25 Division in EP1660507 Opposition (European Patent Office Date: pageS. Feb. 23, 2012). Golub, T.R., et al., “Molecular Classification of Cancer: Class Dis Opponent's Statement of Grounds of Appeal in EP1660507 Opposi covery and Class Prediction by Gene Expression Monitoring.” Sci tion (European Patent Office Date: Apr. 23, 2012). ence, vol. 288, pp. 531-537 (Oct. 15, 1999). Proprietor's Submissions and Amendments in EP1680507 Opposi http://goldbookiupac.org/A00228.html. Retrieved from IUPAC, tion (European Patent Office Date: Apr. 24, 2012). Compendium of Chemical Terminology, 2nded. (the "Gold Book”). Opponent's Reply to Proprietor's Grounds of Appeal of Apr. 24, 2012 Compiled by A. D. McNaught and A. Wilkinson, Blackwell Scientific in EP1660507 Opposition (European Patent Office Date: Sep. 12, Publications. Oxford (1997), XML on-line corrected version: http:// 2012). goldbookiupac.org (2006-) created by M. Nic, J. Jirat, B. Kosata; Proprietor's Response to Opponent's Grounds of Appeal in updates compiled by A.
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