Crystalline forms of a MCL-1 inhibitor, a process for their preparation and pharmaceutical compositions containing them

Patent metadata

Field	Value
Publication number	US-12129261-B2
Application number	US-201917295521-A
Country	US
Kind code	B2
Filing date	Dec 5, 2019
Priority date	Dec 6, 2018
Publication date	Oct 29, 2024
Grant date	Oct 29, 2024

Abstract

Crystalline forms of Compound A:

characterized by its X-ray powder diffraction diagram, solid-state 13 C NMR spectrum, MIR spectrum and Raman spectrum and pharmaceutical compositions containing it.

First claim

The invention claimed is:

1. A crystalline Form M of 2-{[5-{3-Chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl) propanoic acid (Compound A).

2. The crystalline Form M of Compound A according to claim 1 in substantially pure form.

3. The crystalline Form M of Compound A according to claim 1 , having an X-ray powder diffraction diagram which exhibits at least the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 8.94 and 18.24.

4. The crystalline Form M of Compound A according to claim 1 , having an X-ray powder diffraction diagram which exhibits at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 6.27; 8.94; 9.09; 12.16; 13.67; 14.75; 15.06; 16.97; 17.22; 17.44; 18.24; 19.16; 19.93; 20.91; and 25.88.

5. The crystalline Form M of Compound A according to claim 4 , having an X-ray powder diffraction diagram which exhibits the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±) 0.2°): 8.94; 13.67; 14.75; 17.22; and 18.24.

6. The crystalline Form M of Compound A according to claim 4 , having an X-ray powder diffraction diagram which exhibits the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 6.27; 8.94; 9.09; 12.16; 13.67; 14.75; 15.06; 16.97; 17.22; 17.44; 18.24; 19.16; 19.93; 20.91; and 25.88.

7. The crystalline Form M of Compound A according to claim 6 , having the following X-ray powder diffraction diagram, expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ±0.2°) and interplanar distance d (expressed in Å):

Angle 2-theta
Interplanar distance

Line No.
(degrees)
(Å)

1
6.27
14.10

2
8.94
9.89

3
9.09
9.73

4
12.16
7.28

5
13.67
6.48

6
14.75
6.00

7
15.06
5.88

8
16.97
5.22

9
17.22
5.15

10
17.44
5.08

11
18.24
4.86

12
19.16
4.63

13
19.93
4.45

14
20.91
4.25

15
25.88
3.44.

8. The crystalline Form M of Compound A according to claim 1 , having a solid-state 13 C CP/MAS NMR spectrum which exhibits the following peaks (expressed in ppm ±0.2 ppm): 175.1, 153.7, 134.8, 108.9, 71.4 and 35.1.

9. The crystalline Form M of Compound A according to claim 1 , having a solid-state 13 C CP/MAS NMR spectrum which exhibits the following peaks (expressed in ppm #0.2 ppm): 175.1, 168.5, 167.4, 164.6, 162.6, 157.5, 156.3, 153.7, 135.5, 134.8, 130.4, 129.9, 128.4, 126.8, 120.9, 119.9, 118.5, 116.9, 112.5, 111.1, 108.9, 78.7, 71.4, 54.9, 42.1, 35.1 and 18.2.

10. A pharmaceutical composition comprising as active ingredient the crystalline Form M of Compound A according to claim 1 in combination with one or more pharmaceutically acceptable carrier, glidant, diluent, excipient or stabilizer.

11. A method of reducing the symptoms of a condition selected from MCL-1 associated cancers, auto-immune diseases and diseases of the immune system in a subject need thereof, comprising administration of the crystalline Form M of Compound A according to claim 1 , alone or in combination with one or more pharmaceutically acceptable excipients.

12. The method according to claim 11 , wherein the cancer is selected from bladder cancer, brain cancer, breast cancer, cancer of the uterus, chronic lymphoid leukemias, colorectal cancer, esophagus cancer, liver cancer, lymphoblastic leukemias, acute myeloid leukemia, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer.

13. A process for the preparation of the crystalline Form M of Compound A according to claim 1 , wherein Compound A is crystallized in a solvent selected from toluene, 2-methyltetrahydrofuran, and a mixture of toluene and methyl tert-butyl ether.

14. The process according to claim 13 , wherein the Compound A, from which form M is crystallized, is crystalline Form A of Compound A.

15. The process according to claim 13 , wherein the concentration of Compound A in the solvent is between 5 to 15% m/m.

16. The process according to claim 13 , wherein the process produces a slurry, which slurry is dried between 20° C. and 80° C.

17. The process according to claim 13 , wherein the crystallization is seeded using 0.5% to 5% m/m of crystalline Form M of Compound A.

18. The process according to claim 17 , wherein the crystallization is seeded at a temperature between 20° C. and 60° C.

Assignees

• Servier Lab
• Vernalis R&D Ltd

Inventors

• De Baets Emilie
• Auvray Julien
• Lynch Michael
• Leblanc Nicolas

Classifications

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title