Crystalline forms of an androgen receptor modulator

Patent metadata

Field	Value
Publication number	US-9481663-B2
Application number	US-201314406520-A
Country	US
Kind code	B2
Filing date	Jun 4, 2013
Priority date	Jun 7, 2012
Publication date	Nov 1, 2016
Grant date	Nov 1, 2016

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 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.:

Crystal system
Monoclinic

Space group
P2 1 /c
a
17.7796(4) Å
α
 90°

b
12.9832(3) Å
β
100.897(2)°

c
18.4740(4) Å
γ
 90°

V
4187.57(16) Å 3

Z
8

Dc
1.515 g · cm −1

and optionally at least one of:
(d) a DSC thermogram substantially similar to the one set forth in FIG. 11 ;
(e) a thermo-gravimetric analysis (TGA) thermogram substantially similar to the one set forth in FIG. 11 ;
(f) a DSC thermogram with an endotherm having an onset temperature at about 194° C.;
(g) 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; or
(h) substantially the same X-ray powder diffraction (XRPD) pattern as (a) or (b) post storage at 25° C. and 92% RH for 12 days.

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.:

Crystal system
Monoclinic

Space group
P2 1 /c
a
17.7796(4) Å
α
 90°

b
12.9832(3) Å
β
100.897(2)°

c
18.4740(4) Å
γ
 90°

V
4187.57(16) Å 3

Z
8

Dc
1.515 g · cm −1

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

Assignees

• Aragon Pharmaceuticals Inc
• Sloan-Kettering Inst For Cancer Res

Inventors

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

Classifications

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P33/00

  Antiparasitic agents · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P5/28

  Antiandrogens · CPC title

• A61P13/08

  of the prostate · CPC title