(12) united states patent us 8,729,130 b2 (45) date of ...(12) united states patent holson et al....
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(12) United States Patent Holson et al.
US008729130B2
US 8,729,130 B2 May 20, 2014
(10) Patent N0.: (45) Date of Patent:
(54) METHODS OF USING NOVEL SOLID FORMS OF TACEDINALINE
(75) Inventors: Edward Holson, Newton, MA (US); Florence F. Wagner, Ashland, MA (U S); G. Patrick Stahly, West Lafayette, IN (Us)
(73) Assignee: The Broad Institute, Inc., Cambridge, MA (US)
( * ) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days.
(21) App1.No.: 13/620,761
(22) Filed: Sep. 15, 2012
(65) Prior Publication Data
US 2013/0150450 A1 Jun. 13, 2013
Related US. Application Data
(62) Division of application No. 13/174,780, ?led on Jul. 1, 2011, now abandoned.
(51) Int. Cl. A61K 31/167 (2006.01) C07C 237/40 (2006.01) A61P 25/28 (2006.01) A61P 25/00 (2006.01) A61P 25/18 (2006.01) A61P 25/22 (2006.01) A61P 25/30 (2006.01)
(52) US. Cl. USPC .......................... .. 514/616; 514/619; 564/157
(58) Field of Classi?cation Search None See application ?le for complete search history.
(56) References Cited
U.S. PATENT DOCUMENTS
5,137,918 A 8/1992 Weiershausen et a1. 6,469,058 B1 10/2002 Grove et a1.
2011/0224303 A1* 9/2011 Tsaiet a1. ................... .. 514/616 2013/0102677 A1* 4/2013 Holson et a1. ............... .. 514/616
FOREIGN PATENT DOCUMENTS
EP 1 273 296 B1 11/2003 W0 WO 2009/076234 A2 6/2009 W0 WO 2011/053876 A1 5/2011
OTHER PUBLICATIONS
Byrn, S. et al., “Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations”, Pharmaceutical Research, v01. 12, N0. 7, pp. 945-954 (1995). Gediya L.K., et al., “Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs 0r retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts”, Bioorganic &* Medicinal Chemistry 16, pp. 3352-3360 (2008). Liu, J. et al., “Study on the Synthesis of Anticancer Drug Tacedinaline”, Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing, China, pp. 343-344. Riva, L. et al., “Pharmacokinetics and Cerebrospinal Fluid Penetra tion of CI-994 (N-Acetyldinaline) in the Nonhuman Primate”, Clini cal Cancer Research, vol. 6, pp. 994-997 (2000). Thomas, M. et al., “Synthesis and biological evaluation of glucuronide prodrugs of the histone deacetylase inhibitor CI-994 for application in selective cancer chemotherapy”, Bioorganic & Medicinal Chemistry, 16, pp. 8109-8116 (2008). International Preliminary Report on Patentability, International Application No. PCT/US2011/042728, issued Jan. 8, 2013. Written Opinion, International Application No. PCT/US2011/ 042728, mailed Nov. 29, 2011.
* cited by examiner
Primary Examiner * Anna Pagonakis
(74) Attorney, Agent, or Firm * Vedder Price P.C.; Thomas J. Kowalski; Smitha B. Uthaman
(57) ABSTRACT
Novel solid forms of tacedinaline (4-(acetylamino)-N-(2 aminophenyl)benzamide), including crystalline tacedinaline Forms A, B, and D, a novel crystalline tacedinaline TFA salt, and amorphous tacedinaline, are disclosed. Pharmaceutical compositions comprising crystalline tacedinaline Forms A, B, and D, the novel crystalline tacedinaline TFA salt, and/or amorphous tacedinaline, and methods of treating various con ditions by administering those novel solid forms, are also disclosed.
7 Claims, 66 Drawing Sheets
U.S. Patent May 20, 2014 Sheet 1 0f 66 US 8,729,130 B2
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US 8,729,130 B2
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US. Patent May 20, 2014 Sheet 4 0f 66 US 8,729,130 B2
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US. Patent May 20, 2014 Sheet 5 0f 66 US 8,729,130 B2
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US 8,729,130 B2 Sheet 6 0f 66 May 20, 2014 US. Patent
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US 8,729,130 B2 Sheet 8 0f 66 May 20, 2014 US. Patent
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US. Patent May 20, 2014 Sheet 10 0f 66 US 8,729,130 B2
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US 8,729,130 B2
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US. Patent May 20, 2014 Sheet 14 0f 66 US 8,729,130 B2
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US. Patent May 20, 2014 Sheet 15 0f 66 US 8,729,130 B2
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US 8,729,130 B2 Sheet 16 0f 66 May 20, 2014 US. Patent
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US 8,729,130 B2 Sheet 17 0f 66 May 20, 2014 US. Patent
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US 8,729,130 B2 Sheet 18 0f 66 May 20, 2014 US. Patent
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May 20, 2014 Sheet 19 0f 66 US 8,729,130 B2
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