# US 10,766,875 B2 · Crystalline forms of an androgen receptor modulator

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- Number: US 10,766,875 B2
- Document ID: US10766875B2
- Status: Granted
- Kind: B2
- Application number: 16/710,785
- Filed: 2019-12-11
- Published: 2020-04-16
- Granted: 2020-09-08
- Earliest claimed: 2012-06-07
- Assignees: Aragon Pharmaceuticals, Inc.; Sloan-Kettering Institute for Cancer Research
- Applicants: Aragon Pharmaceuticals, Inc.; Sloan-Kettering Institute For Cancer Research
- Inventors: Anna Dihas; Mark R. Herbert; Ouathek Ouerfelli; Nicholas D. Smith
- Web page: https://patentgrep.com/patent/US10766875B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/28: Antiandrogens
- A61P 13/08: of the prostate
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 33/00: Antiparasitic agents
- A61P 35/00: Antineoplastic agents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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

### Claim 1

A crystalline Form D 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 exhibiting at least one of:
(a) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.3±0.1° 2-Theta, 13.9±0.1° 2-Theta, 16.4±0.1° 2-Theta, 17.0±0.1° 2-Theta, 23.7±0.1° 2-Theta, and 24.8±0.1° 2-Theta; or
(b) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 4.

### Claim 2 (depends on 1)

The crystalline Form D of claim 1 that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.3±0.1° 2-Theta, 13.9±0.1° 2-Theta, 16.4±0.1° 2-Theta, 17.0±0.1° 2-Theta, 23.7±0.1° 2-Theta, and 24.8±0.1° 2-Theta.

### Claim 3 (depends on 1)

The crystalline Form D of claim 1 that is further characterized as exhibiting at least one of:
(a) a DSC thermogram substantially similar to the one set forth in FIG. 13;
(b) a thermo-gravimetric analysis (TGA) thermogram substantially similar to the one set forth in FIG. 13;
(c) a DSC thermogram with a first endotherm having an onset temperature at about 122° C. and second endotherm having an onset temperature at about 192° C.; or
(d) substantially the same X-ray powder diffraction (XRPD) pattern post storage at 40° C. and 75% RH for at least a week.

### Claim 4 (depends on 1)

The crystalline Form D of claim 1, further exhibiting a DSC thermogram with a first endotherm having an onset temperature at about 122° C.

### Claim 5 (depends on 3)

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

### Claim 6 (depends on 1)

The crystalline Form D of claim 1, wherein the crystalline form is a tert-butyl methyl ether (TBME) solvate.

### Claim 7 (depends on 1)

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 that is a pharmaceutically acceptable carrier, diluent, or excipient, 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 D according to claim 1.

### Claim 8 (depends on 7)

The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is in a form formulated for oral administration to a mammal.

### Claim 9 (depends on 8)

The pharmaceutical composition of claim 8, wherein the mammal is a human.

### Claim 10 (depends on 7)

The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is in an oral solid dosage form.

### Claim 11 (depends on 9)

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 D 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.

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 12)

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

### Claim 14 (depends on 12)

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

### Claim 15 (depends on 13)

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

### Claim 16 (depends on 7)

A method of treating prostate cancer in a mammal comprising administering the pharmaceutical composition according to claim 7 to the mammal in need of such treatment.

### Claim 17 (depends on 16)

The method of claim 16, wherein the prostate cancer is hormone sensitive prostate cancer or hormone refractory prostate cancer.

### Claim 18 (depends on 16)

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

### Claim 19 (depends on 17)

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