Salt or abexinostat, associated crystalline form, a process for their preparation and pharmaceutical compositions containing them

Patent metadata

Field	Value
Publication number	US-10150748-B2
Application number	US-201715405021-A
Country	US
Kind code	B2
Filing date	Jan 12, 2017
Priority date	Mar 4, 2013
Publication date	Dec 11, 2018
Grant date	Dec 11, 2018

Abstract

Abexinostat tosylate of formula (II):

and its crystalline form I characterized by its X-ray powder diffraction diagram, its Raman spectrum and its solid-state 13 C CP/MAS NMR spectrum.

Medicinal products containing the same which are useful in the treatment of cancer.

First claim

The invention claimed is:

1. A process for preparing crystalline form I of abexinostat tosylate, comprising crystallizing abexinostat in the presence of para-toluenesulfonic acid in a polar medium, wherein the polar medium is a binary mixture of isopropanol and water, wherein crystalline form I of abexinostat tosylate is characterized in that it has an X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2 theta, expressed in degrees±0.2°): 6.50, 9.94, 11.35, 14.08, 18.95, 21.08, and 27.05.

2. The process of claim 1 , wherein the polar medium is a 50/50 weight/weight mixture of isopropanol and water.

3. The process of claim 1 , wherein the polar medium is a 45/54 weight/weight mixture of isopropanol and water.

4. The process of claim 1 , further comprising seeding the crystallization with crystalline form I of abexinostat tosylate.

5. The process of claim 1 , wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it has an X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2 theta, expressed in degrees±0.2°): 6.50, 9.94, 11.35, 12.33, 14.08, 18.95, 19.96, 21.08, 22.82, 23.61, and 27.05.

6. The process of claim 1 , wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it has the following X-ray powder diffraction lines (Bragg's angle 2 theta, expressed in degrees±0.2°) and interreticular distance d (expressed in Å):

Line
Angle 2 theta
Interreticular Distance

No.
(degrees)
(Å)

1
6.50
13.581

2
9.94
8.894

3
11.35
7.789

4
12.33
7.173

5
14.08
6.285

6
18.95
4.683

7
19.61
4.526

8
19.96
4.449

9
21.08
4.215

10
22.82
3.897

11
23.61
3.768

12
27.05
3.296.

7. The process of claim 1 , wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it has a Raman spectrum having a peak at position 1608 cm −1 .

8. The process of claim 7 , wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it has a Raman spectrum having peaks at positions 940 cm −1 , 1088 cm −1 , 1132 cm −1 , 1242 cm −1 , 1360 cm −1 , and 1608 cm −1 .

9. The process of claim 1 , wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it has a solid-state 13 C CP/MAS NMR spectrum having the following peaks (expressed in ppm±0.2 ppm): 121.2 ppm, 122.1 ppm, 123.5 ppm 126.0 ppm, 126.8 ppm, 128.2 ppm, 128.9 ppm, 143.4 ppm, 144.6 ppm, 153.8 ppm, 159 ppm, 161.2 ppm and 162.1 ppm.

10. The process of claim 9 , wherein the crystallizing step results in forming Crystalline form I of abexinostat tosylate, characterized in that it has a solid-state 13 C CP/MAS NMR spectrum having the following peaks (expressed in ppm±0.2 ppm):

Peak
Chemical Shift

No.
(ppm)

1
162.1

2
161.2

3
159.0

4
153.8

5
144.6

6
143.4

7
128.9

8
128.2

9
126.8

10
126.0

11
123.5

12
122.1

13
121.3

14
65.9

15
50.6

16
46.9

17
45.0

18
21.9.

11. A pharmaceutical composition comprising crystalline form I of abexinostat tosylate, lactose monohydrate, and maize starch, wherein crystalline form I of abexinostat tosylate is characterized in that it has an X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2 theta, expressed in degrees±0.2°): 6.50, 9.94, 11.35,

Assignees

• Pharmacyclics Llc
• Pharmacyclics Llc

Inventors

• Pimont-Garro Anne
• Letellier Philippe

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07C309/30

  of six-membered aromatic rings substituted by alkyl groups · CPC title

• C07D307/85 Primary

  attached in position 2 · CPC title