Crystalline forms of an androgen receptor modulator

Patent metadata

Field	Value
Publication number	US-12018008-B2
Application number	US-202117158806-A
Country	US
Kind code	B2
Filing date	Jan 26, 2021
Priority date	Jun 7, 2012
Publication date	Jun 25, 2024
Grant date	Jun 25, 2024

Abstract

Described herein are amorphous and crystalline forms of the androgen receptor modulator 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide. Also described are pharmaceutical compositions suitable for administration to a mammal that include the androgen receptor modulator, and methods of using the androgen receptor modulator, alone and in combination with other compounds, for treating diseases or conditions that are associated with androgen receptor activity.

First claim

What is claimed is:

1. A crystalline Form F of 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.6±0.1° 2-Theta, 6.1±0.1° 2-Theta, 14.3±0.1° 2-Theta, 21.6±0.1° 2-Theta, 22.4±0.1° 2-Theta, 23.3±0.1° 2-Theta, and 25.5±0.1° 2-Theta.

2. The crystalline Form F of claim 1 that is further characterized as exhibiting at least one of:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 6 ;
(b) a DSC thermogram substantially similar to the one set forth in FIG. 15 ;
(c) a thermo-gravimetric analysis (TGA) thermogram substantially similar to the one set forth in FIG. 15 ; or
(d) a DSC thermogram with an endotherm having an onset temperature at about 113° C.

3. A crystalline Form G of 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.0±0.1° 2-Theta, 10.3±0.1° 2-Theta, 14.1±0.1° 2-Theta, 15.2±0.1° 2-Theta, and 23.6±0.1° 2-Theta.

4. The crystalline Form G of claim 3 that is further characterized as exhibiting at least one of:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 7 ;
(b) unit cell parameters substantially equal to the following at −173° C.:

Crystal system
Monoclinic

Space group
Cc
a
18.613(2)Å
α
90°

b
16.9728(14)Å
β
91.328(8)°

c
 7.8214(7)Å,
γ
90°

V
2470 2(4)Å 3

Z
4

Dc
1.488 g · cm −1

(c) a DSC thermogram substantially similar to the one set forth in FIG. 16 ;
(d) a DSC thermogram with a first endotherm having an onset temperature at about 101° C. and second endotherm having an onset temperature at about 190° C.; or
(e) substantially the same X-ray powder diffraction (XRPD) pattern post storage at 40° C. and 75% RH for at least a week.

5. The crystalline Form G of claim 3 , wherein the crystalline form is a 2-methoxyethanol solvate.

6. A crystalline Form J of 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.6±0.1° 2-Theta, 19.3±0.1° 2-Theta, 20.8±0.1° 2-Theta, 24.3±0.1° 2-Theta, and 27.6±0.1° 2-Theta.

7. The crystalline Form J of claim 6 that is further characterized as exhibiting at least one of:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 10 ;
(b) a DSC thermogram substantially similar to the one set forth in FIG. 18 ;
(c) a thermo-gravimetric analysis (TGA) thermogram substantially similar to the one set forth in FIG. 18 ; or
(d) a DSC thermogram with a first endotherm having an onset temperature at about 104° C. and second endotherm having an onset temperature at about 193° C.

8. The crystalline Form J of claim 6 , wherein the crystalline form is an acetone solvate.

9. A pharmaceutical composition comprising the crystalline Form F of 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide according to claim 1 , and at least one additional ingredient that is a pharmaceutically acceptable carrier, diluent, or excipient.

10. The pharmaceutical composition according to claim 9 , wherein the pharmaceutical composition is in a form formulated for oral administration to a mammal.

11. The pharmaceutical composition of claim 10 , wherein the mammal is a human.

12. The pharmaceutical composition according to claim 10 , wherein the pharmaceutical composition is in an oral solid dosage form.

13. The pharmaceutical composition according to claim 9 , wherein the pharmaceutical composition comprises a unit dosage form containing about 0.5 mg to about 1000 mg of the crystalline Form F of 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide.

14. A method of treating prostate cancer in a mammal comprising administering the crystalline Form F of 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide according to claim 1 to the mammal in need of such treatment.

15. The method of claim 14 , wherein the prostate cancer is hormone sensitive prostate cancer or hormone refractory prostate cancer.

16. The method of claim 15 , wherein the mammal is a human.

17. A method of treating prostate cancer in a mammal comprising administering the pharmaceutical composition according to claim 9 to the mammal in need of such treatment.

18. The method of claim 17 , wherein the prostate cancer is hormone sensitive prostate cancer or hormone refractory prostate cancer.

19. The method of claim 18 , wherein the mammal is a human.

20. A pharmaceutical composition comprising the crystalline Form G of 4-[7-(6- cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N- methylbenzamide according to claim 3 , and at least one additional ingredient that is a pharmaceutically acceptable carrier, diluent, or excipient.

21. The pharmaceutical composition according to claim 20 , wherein the pharmaceutical composition is in a form formulated for oral administration to a mammal.

22. The pharmaceutical composition of claim 21 , wherein the mammal is a human.

23. The pharmaceutical composition according to claim 21 , wherein the pharmaceutical composition is in an oral solid dosage form.

24. The pharmaceutical composition according to claim 20 , wherein the pharmaceutical composition comprises a unit dosage form containing about 0.5 mg to about 1000 mg of the crystalline Form G of 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbe

Assignees

• Aragon Pharmaceuticals Inc
• Sloan Kettering Inst Cancer Res

Inventors

• Dilhas Anna
• Herbert Mark R
• Ouerfelli Ouathek
• Smith Nicholas D

Classifications

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/4184 Primary

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• A61P5/28

  Antiandrogens · CPC title