Crystalline forms of an androgen receptor modulator

Patent metadata

Field	Value
Publication number	US-9994545-B2
Application number	US-201615262522-A
Country	US
Kind code	B2
Filing date	Sep 12, 2016
Priority date	Jun 7, 2012
Publication date	Jun 12, 2018
Grant date	Jun 12, 2018

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 A 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:
(a) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.8±0.1° 2-Theta, 7.1±0.1° 2-Theta, 14.2±0.1° 2-Theta, 16.3±0.1° 2-Theta, and 20.1±0.1° 2-Theta; or
(b) unit cell parameters substantially equal to the following at −173° C.:

Crystal system
Orthorhombic

Space group
P2(1)2(1)2
a
 16.3429(3) Å
α
90°

b
 37.7298(7) Å
β
90°

c
7.23410(10) Å
γ
90°

V
4460.65(13) Å3

Z
8

Dc
1.446 g · cm −1

and optionally:
(c) a DSC thermogram with an endotherm having an onset temperature at about 108-120° C. and a peak at about 133-135° C.

2. The crystalline Form A of claim 1 that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.8±0.1° 2-Theta, 7.1±0.1° 2-Theta, 14.2±0.1° 2-Theta, 16.3±0.1° 2-Theta, and 20.1±0.1° 2-Theta.

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

4. The crystalline Form A of claim 1 , wherein the crystalline form has unit cell parameters substantially equal to the following at −173° C.:

Crystal system
Orthorhombic

Space group
P2(1)2(1)2
a
 16.3429(3) Å
α
90°

b
 37.7298(7) Å
β
90°

c
7.23410(10) Å
γ
90°

V
4460.65(13) Å3

Z
8

Dc
1.446 g · cm −1 .

5. The crystalline Form A of claim 1 , wherein the crystalline form exhibits substantially the same X-ray powder diffraction (XRPD) pattern post storage at 40° C. and 75% RH for at least a week.

6. The crystalline Form A of claim 1 , wherein the crystalline form exhibits a DSC thermogram with an endotherm having an onset temperature at about 108-120° C. and a peak at about 133-135° C.

7. The crystalline Form A of claim 1 , wherein the crystalline form exhibits a DSC thermogram substantially similar to the one set forth in FIG. 19 .

8. The crystalline Form A of claim 1 , wherein the crystalline form is characterized as exhibiting properties (a), (b), and (c).

9. The crystalline Form A of claim 1 , wherein the crystalline form was obtained from ethanol, tetrahydrofuran (THF), dichloromethane, acetone, methanol, nitromethane, water, THF-water mixture, or dioxane-water mixture.

10. The crystalline Form A of claim 1 , wherein the crystalline form was obtained from ethanol.

11. The crystalline Form A of claim 1 , wherein the crystalline form is solvated by ethanol, acetone, or methanol.

12. The crystalline Form A of claim 1 , wherein the crystalline form is an ethanol solvate.

13. The crystalline Form A of claim 1 , wherein the crystalline form is a hydrate.

14. The crystalline Form A of claim 1 , wherein the crystalline form is a solvated hydrate.

15. 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 A of claim 1 .

16. The pharmaceutical composition according to claim 15 , wherein the pharmaceutical composition is in a form formulated for oral administration to a mammal.

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

18. The pharmaceutical composition according to claim 15 , wherein the pharmaceutical composition comprises about 0.5 mg to about 1000 mg of the crystalline Form A 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.

19. A method of treating prostate cancer in a mammal comprising administering the crystalline Form A 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 a mammal in need of such treatment.

20. A method of treating prostate cancer in a mammal comprising administering the pharmaceutical composition according to claim 15 to a mammal in need of such treatment.

21. The method of claim 19 , wherein the prostate cancer is hormone sensitive prostate cancer or hormone refractory prostate cancer.

Assignees

• Aragon Pharmaceuticals Inc
• Sloan Kettering Inst Cancer Res

Inventors

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

Classifications

• A61P33/00

  Antiparasitic agents · CPC title

• A61P5/28

  Antiandrogens · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P13/08

  of the prostate · CPC title