Crystalline forms of an androgen receptor modulator

• US 9,481,663 B2
• Filed: 06/04/2013
• Issued: 11/01/2016
• Est. Priority Date: 06/07/2012
• Status: Active Grant

• Current Assignee: Aragon Pharmaceuticals, Inc. (Johnson & Johnson), Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Original Assignee: Aragon Pharmaceuticals, Inc. (Johnson & Johnson), Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Inventors: Dilhas, Anna, Herbert, Mark R, Ouerfelli, Ouathek, Smith, Nicholas D
• Primary Examiner(s): Morris, Patricia L
• Application Number:
  US14/406,520
• Publication Number:
  US 20150133481A1
• Time in Patent Office: 1,246 Days
• Field of Search: 546/15, 514/278
• US Class Current: 1/1
• 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 B 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 is characterized as having at least one of:

(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 2;

(b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 12.1±

0.1°

2-Theta, 16.0±

0.1°

2-Theta, 16.7±

0.1°

2-Theta, 20.1±

0.1°

2-Theta, 20.3±

0.1°

2-Theta;

(c) unit cell parameters substantially equal to the following at −

173°

C.;

2. The crystalline form of claim 1, wherein the crystalline form has an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 2.

3. The crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 12.1±

0.1°

2-Theta, 16.0±

0.1°

2-Theta, 16.7±

0.1°

2-Theta, 20.1±

0.1°

2-Theta, 20.3±

0.1°

2-Theta.

4. The crystalline form of claim 1, wherein the crystalline form has unit cell parameters substantially equal to the following at −

173°

C.;

5. The crystalline form of claim 1, wherein the crystalline form has a DSC thermogram substantially similar to the one set forth in FIG. 11.

6. The crystalline form of claim 1, wherein the crystalline form has a thermo-gravimetric analysis (TGA) thermogram substantially similar to the one set forth in FIG. 11.

7. The crystalline form of claim 1, wherein the crystalline form has a DSC thermogram with an endotherm having an onset temperature at about 194°

C.

8. The crystalline form of claim 1, wherein the crystalline form has substantially the same X-ray powder diffraction (XRPD) pattern as (a) or (b) post storage at 40°

C. and 75% RH for at least a week.

9. The crystalline form of claim 1, wherein the crystalline form has substantially the same X-ray powder diffraction (MOD) pattern as (a) or (b) post storage at 25°

C. and 92% RH for 12 days.

10. The crystalline form of claim 1, wherein the crystalline form that is characterized as having properties (a), (b), (c), (d), (e), (f), (g), and (h).

11. The crystalline form of claim 1, wherein the crystalline form was obtained from water, ethyl acetate, tert-butyl methyl ether (TBME), toluene, isopropylacetate, or methyl ethyl ketone (MEK).

12. The crystalline form of claim 1, wherein the crystalline form is unsolvated.

13. 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 B according to claim 1.

14. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition is in a form suitable for oral administration to a mammal.

15. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is in an oral solid dosage form.

16. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition comprises about 0.5 mg to about 1000 mg of crystalline Form B 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.

17. A method of treating prostate cancer in a mammal comprising administering the pharmaceutical composition according to claim 13 to a 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 pharmaceutical composition of claim 14, wherein the mammal is a human patient.

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

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