Crystalline forms of an androgen receptor modulator

• US 10,526,310 B2
• Filed: 04/15/2019
• Issued: 01/07/2020
• Est. Priority Date: 06/07/2012
• Status: Active Grant

• Current Assignee: Aragon Pharmaceuticals, Inc. (Johnson & Johnson)
• Original Assignee: Aragon Pharmaceuticals, Inc. (Johnson & Johnson)
• Inventors: Dilhas, Anna, Herbert, Mark R., Ouerfelli, Ouathek, Smith, Nicholas D.
• Primary Examiner(s): Morris, Patricia L
• Application Number:
  US16/384,002
• Publication Number:
  US 20190241539A1
• Time in Patent Office: 267 Days
• Field of Search: 546 15, 514278
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/28 Antiandrogens
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond

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.

Claims

1. A crystalline Form C 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 an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.3±

0.1°

2-Theta, 6.9±

0.1°

2-Theta, 9.1±

0.1°

2-Theta, 10.6±

0.1°

2-Theta, 13.8±

0.1°

2-Theta, and 26.4±

0.1°

2-Theta.

2. The crystalline Form C of claim 1 that is further characterized as exhibiting at least one of the following:

(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3;

(b) a DSC thermogram substantially similar to the one set forth in FIG. 12;

(c) a thermo-gravimetric analysis (TGA) thermogram substantially similar to the one set forth in FIG. 12;

(d) a DSC thermogram with a first endotherm having an onset temperature at about 118°

C. and second endotherm having an onset temperature at about 193°

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.

3. The crystalline Form C of claim 2, wherein the crystalline form is characterized as having properties (a), (b), (c), (d), and (e).

4. The crystalline Form C of claim 1, wherein the crystalline form is an isopropanol solvate.

5. A pharmaceutical composition comprising 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide and at least one additional ingredient selected from pharmaceutically acceptable carriers, diluents and excipients, in which the 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide in the composition comprises the crystalline Form C according to claim 1.

6. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is in a form formulated for oral administration to a mammal.

7. The pharmaceutical composition of claim 6, wherein the mammal is a human.

8. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is in an oral solid dosage form.

9. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition comprises about 0.5 mg to about 1000 mg of the crystalline Form C 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.

10. A method of treating prostate cancer in a mammal comprising administering the crystalline Form C 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.

11. A method of treating prostate cancer in a mammal comprising administering the pharmaceutical composition according to claim 5 to the mammal in need of such treatment.

12. The method of claim 10, wherein the prostate cancer is hormone sensitive prostate cancer or hormone refractory prostate cancer.

13. The method of claim 11, wherein the prostate cancer is hormone sensitive prostate cancer or hormone refractory prostate cancer.

14. The method of claim 10, wherein the mammal is a human.

15. The method of claim 11, wherein the mammal is a human.

16. The method of claim 12, wherein the mammal is a human.

17. The method of claim 13, wherein the mammal is a human.

18. The crystalline Form C of claim 1 that is further characterized as exhibiting an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3.

19. The crystalline Form C of claim 1 that is further characterized as exhibiting a DSC thermogram substantially similar to the one set forth in FIG. 12.

20. The crystalline Form C of claim 1 that is further characterized as exhibiting a thermo-gravimetric analysis (TGA) thermogram substantially similar to the one set forth in FIG. 12.

21. The crystalline Form C of claim 1 that is further characterized as exhibiting a DSC thermogram with a first endotherm having an onset temperature at about 118°

C. and second endotherm having an onset temperature at about 193°

C.