(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
Top Related