Crystalline form of a proteasome inhibitor

Patent metadata

Field	Value
Publication number	US-10072029-B2
Application number	US-201615550132-A
Country	US
Kind code	B2
Filing date	Feb 10, 2016
Priority date	Feb 11, 2015
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

Abstract

The present disclosure relates to a novel crystalline form of a proteasome inhibitor, and to the processes for the preparation thereof. The novel crystalline form according to the disclosure may be used in the preparation of pharmaceutical compositions for the treatment of cancer.

First claim

We claim:

1. A crystalline form comprising N,N′,N″-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediyl)]]tris(2,5-dichlorobenzamide) having the structure of Formula (1b):

2. The crystalline form according to claim 1 , wherein the crystalline form is crystalline Pattern B comprising an X-ray powder diffraction pattern having characteristic peaks expressed in degrees two-theta at approximately 5.79±0.20, 10.63±0.20, 16.06±0.20, and 23.58±0.20.

3. The crystalline form according to claim 1 , wherein the crystalline form is crystalline Pattern B comprising an X-ray powder diffraction pattern having characteristic peaks expressed in degrees two-theta at approximately 5.79±0.20, 10.63±0.20, 16.06±0.20, 17.12±0.20, 17.93±0.20, 19.69±0.20, 23.58±0.20, 24.17±0.20 and 24.93±0.20.

4. The crystalline form according to claim 1 , wherein the crystalline form is crystalline Pattern B comprising an X-ray powder diffraction pattern having a reference peak expressed in degrees two-theta at 5.79±0.20, and having peaks in degrees two-theta angles of 4.84, 10.27, 17.79 relative to the reference peak.

5. The crystalline form according to claim 1 , wherein the crystalline form is crystalline Pattern B comprising an X-ray powder diffraction pattern having a reference peak expressed in degrees two-theta at 5.79±0.20, and having peaks in degrees two-theta angles of 4.84, 10.27, 11.33, 12.14, 13.90, 17.79, 18.38, 19.14 relative to the reference peak.

6. The crystalline form according to claim 1 , wherein the crystalline form is crystalline Pattern B comprising an X-ray powder diffraction pattern having characteristic peaks expressed in degrees two-theta at approximately:

Angles (°2θ) ± 0.20
Intensity (%)

5.79
100

6.98
18

9.46
13

9.89
33

10.63
70

11.40
16

12.41
13

13.96
32

14.13
29

14.38
16

16.06
75

16.73
27

17.12
68

17.53
23

17.93
61

18.58
28

19.26
20

19.69
68

20.05
25

20.65
18

21.37
24

21.99
33

22.59
11

23.58
80

24.17
67

24.33
32

24.93
39

25.26
15

26.11
12

26.54
13

26.92
11

28.12
11

28.46
11

29.36
11

29.59
10.

7. The crystalline form according to claim 1 , having a DSC profile characterized by an endothermic transition at about 123.4° C.

8. The crystalline form according to claim 1 , having a DSC profile characterized by an endothermic transition at about 120° C. to about 125° C.

9. The crystalline form according to claim 8 , having a DSC profile characterized by an endothermic transition of about 123.0° C.

10. The crystalline form according to claim 1 , having a TGA profile losing about 1.9% weight up to 150° C. at a temperature rate of 10° C. per minute, and decomposition at about 272±5° C.

11. The crystalline form according to claim 1 , wherein the crystalline form is a monohydrate.

12. A method for the preparation of the crystalline form according to claim 1 , wherein the crystalline form is crystalline Pattern B, comprising:
(a) adding a non-crystalline solid comprising a compound of Formula (Ib) to a solvent or solvent mixture

(b) stirring the resulting mixture for a sufficient amount of time to form crystalline Pattern B; and optionally
(c) isolating crystalline Pattern B.

13. The method according to claim 12 , wherein the solvent or solvent mixture is acetone/water (1:3), DMF/water (1:2), iso-propyl acetate, or THF/water (1:10).

14. A method for the preparation of the crystalline form according to claim 1 , wherein the crystalline form is crystalline Pattern B, comprising:
(a

Assignees

• Millennium Pharm Inc

Inventors

• Langston Marianne
• Mazaik Debra
• Elliott Eric
• Peterson Anton
• Andres Patricia
• Teng Jing

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K31/69

  Boron compounds · CPC title

• A61P19/00

  Drugs for skeletal disorders · CPC title