(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

2' $5 340

310

l

22 DEGREE FIG. 1A | 190

| 160

40

=

I I I I I I I I I I I I I

LO LO LO LO LO LO |\ N N N N N

(D N 1125— 4275: 3825 33 29 24 20 1575 6075i 5625: 5175' 4725

US. Patent May 20, 2014 Sheet20f66

M

CPS 6250. 6750i 5250i 4750i 4250i 3750i 3250l 2750i 2250i 1750i 1250i 750i 250i 4.0

DEGREE

US 8,729,130 B2

FIICS. 1 E3

US. Patent May 20, 2014 Sheet 4 0f 66 US 8,729,130 B2

10 deg/min

TGA TEMPERATURE (00) FIG 3

US. Patent May 20, 2014 Sheet 5 0f 66 US 8,729,130 B2

310.6 °C

247.3 °C 0

DSC TEMPERATURE (°C) FIG 4

(ii/M) M011 iVEIH

US 8,729,130 B2 Sheet 6 0f 66 May 20, 2014 US. Patent

8 . who . 8 . 2 . Ow . m.“ . 2 2 . ? .2“ . Own . mm . Ow . ow . Ox . i . . . 3 3 3 .3: .2? EFF: ks

.00 n n n . "

Ir H n n n n 0 0 H n n n H 00 m m m m m

.0 6 H

...... ...... ....... ...... ? .... ...... ....... ...... .... ...... ...... ....... .._ ...... ...... ...... ...... ..

|||||||||||||||| I.

|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ._. I I v I I I I I I I ‘ I I I I I I I | r I I I I I I I . I I I I I I I 4 I I I I I . I v | I I I . I I A I I I I I I I I v I I I I I I I . | I I I I . I I . I I I I . I I I > I I | I I I I 1 I I I I I I I I v I I I I . I I 4 I I I I I I I I 1 I | I I I I I A I I I I I I I I 1 I I I I I I I . . . > I I I I I I I I . | I I I | I I.

|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| I. ||||||||||||||||||||||||||||||||| I.

c: ....... .m ...... +5.7" ....... ...9999999911111 ....... .._ .... ...6

m9991L666LL966m " C._ m. "1.076167167100009" " /_ "W n n n _

US 8,729,130 B2 Sheet 7 0f 66 May 20, 2014 US. Patent

mm .@_H_ 23 z . g _ @.@ _ ma _ o.» N.“ _ E _ E _ w.» _ orw _ pr _ Em _ g _ ma _ 0.0 _ Na _ g . Qm . Wm .09 . N9 . 12

|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| L. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 4| .l..1.ill-.417!!!-........_.........1...............ll...11......Ill-11.11.12:...._...1.1.1:...-21.1.1.4.......111.1........................_..1...-......................T

US 8,729,130 B2 Sheet 8 0f 66 May 20, 2014 US. Patent

8.3.0 .N E N.

.N E @

.NO

on .@_H_ 25% :

hm. mmhmmm

.m Em w.

we Ow we we

US. Patent

AU

May 20, 2014 Sheet 9 0f 66 US 8,729,130 B2

0.85 3: Diode Array _ Range: 8.6e+1

5.0e+1 §

0.0 0.50 1.00 1.50 2.00 2.50

3: Diode Array 1 0 210

- Range: 1.26

5.0e-1

|||||||||||||||||||||||||||||||||||||||||||||||||

0.50 1.00 1.50 2.00 2.50

2: Scan ES TIC

6.53e6 2.03

2.48 2.37 /

%

0.23 \

22 lIl|llll|llll|llll|llll|llll|llll|llll|llll|llll|

0.50 1.00 1.50 2.00 2.50

1:ScanES+ 0'86 TIC

8.58e7

2.22 4

0.50 1.00 1.50 2.00 2.50

FIG. 6 (PART1)

US. Patent May 20, 2014 Sheet 10 0f 66 US 8,729,130 B2

100 _ 268.0506 2: Scan ES 1.5236

- 239.0351

_ 315.0357 1112.2023 1371.3353

0 _ . / 333-9948 1030.7534 1299.4214

100 _ 270.1565 1; Scan ES+ 4.1957

_ 271.1475

272-1635 599.2233

' / 539.1547 303.2350 / 1105.7433 1249.1371

0 IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII m/Z 200 400 600 800 1000 1200 1400

FIG. 6 (PART 2)

US 8,729,130 B2

mmmoma QR 3% 0.8 gm Qmm QNN 0.9 0.3 0.2 0.2 E 3“

_

Sheet 11 0f 66 May 20, 2014

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

IE .45 .63 mo? ~08 TE .55 ~82 wow: .03 5:: ICE | 0%?

US. Patent

US 8,729,130 B2

m“ .wE mmmwma

Qmw QNN 6.2 0.9 0.2 0.2 E 3‘

_

Sheet 12 0f 66 May 20, 2014 US. Patent

US 8,729,130 B2 Sheet130f66 B4ay20,2014 US. Patent

@ .oE 2-5 wmmmgzzmi; OOON oomw

80m

8%

l o O. o

' l

O L!) O L!) N ‘—. F. O. o o o o

o m. o

wmqo NSC (an) 901

US. Patent May 20, 2014 Sheet 14 0f 66 US 8,729,130 B2

10 deg/min

0 )

TGA TEMPERATURE (°C FIG. 9

110 100 — 90 80 70

US. Patent May 20, 2014 Sheet 15 0f 66 US 8,729,130 B2

crimped pan, 10 deg C/min 3084°C 0

241.0 °C

DSC TEMPERATURE (00) FIG 10

US 8,729,130 B2 Sheet 16 0f 66 May 20, 2014 US. Patent

253 : Ono . who . 8 . 3 . Ow . mu . 0..” . mm . ? . 2N . Ow . ? . ow . mw . OK . Q.“ . Ohm . mm .8 . mo .2: .2: . 3;: . 2s

}}}}

08-..? ..... ...... ...... ...... ............ ...... ..... ..... ...... ...... ...... NIggmdQ/EU ...... ...... ..

82- ................................. .............................................. ............... ...... ...... ...... ...... ...... hv I ...... ...... ..

H H H H M H H H H H H .m M W ...... ...... ..

. w . IZ

US 8,729,130 B2 Sheet 17 0f 66 May 20, 2014 US. Patent

m: .0_H_ 253 z .E . g . 3 . E . 2 . E . E . m: . 3 . Aw . :w @w 3 3 g 2 3 3 0.2 . 2: i:

US 8,729,130 B2 Sheet 18 0f 66 May 20, 2014 US. Patent

2 2 Z N.N 2 him mN

o S .0_H_ 253 :

m Em

.w 2 i S“ m; EN we 3“ 3 E N.

1

US. Patent

AU

AU

May 20, 2014 Sheet 19 0f 66 US 8,729,130 B2

3: Diode Array 0'85 Range: 2.676e+1

2.0e+1 A 1.0 +1 6 0.17

/ |?||||||||||||||||||||||||||||||||||||||||||||||

0.50 1.00 1.50 2.00 2.50

0.85 3: Diode Array 4 0 1 210

' 6' Range: 4.662e-1

2.09-1

lll|llll|llll|l|ll|llll|llll|llll|llll|m 0.50 1.00 1.50 2.00 2.50

0.50 1 .00

FIG. 12 (PART 1)

1.50