Crystalline FGFR4 inhibitor compound and uses thereof

Patent metadata

Field	Value
Publication number	US-11498916-B2
Application number	US-201916722838-A
Country	US
Kind code	B2
Filing date	Dec 20, 2019
Priority date	Apr 14, 2015
Publication date	Nov 15, 2022
Grant date	Nov 15, 2022

Abstract

A number of crystalline forms of N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-1-y1)phenyl)acrylamide are provided. These include a crystalline free base form, a crystalline monohydrochloride salt form, a crystalline dihydrochloride salt form, and a crystalline ethanesulfonate salt form. Methods of making and using crystalline compounds are also provided.

First claim

We claim:

1. A crystalline free base form of compound N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acrylamide, wherein the crystalline free base form compound exhibits at least the following X-ray powder diffraction peaks, 2θ° (±0.2): 10.3, 8.0, and 14.8.

2. The crystalline free base compound of claim 1 , wherein the crystalline free base form compound exhibits at least the following X-ray powder diffraction peaks, 2θ° (±0.2°): 10.3, 8.0, 14.8, 16.5, 21.8, and 17.1.

3. The crystalline free base compound of claim 2 , wherein the crystalline free base form compound exhibits at least the following X-ray powder diffraction peaks, 2θ° (±0.2°): 10.3, 8.0, 9.5, 14.8, 16.5, 17.1, 19.3, 21.8, 23.7, and 24.5.

4. The crystalline free base compound of claim 1 , wherein the crystalline free base form is characterized by a powder X-ray diffraction (PXRD) pattern substantially as shown in FIG. 5 .

5. The crystalline free base compound of claim 1 , wherein the crystalline free base form is characterized by a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 8 .

6. The crystalline free base compound of claim 1 , wherein the crystalline free base form is characterized by a 13C-NMR solid state spectrum substantially as shown in FIG. 10 .

7. The crystalline free base compound of claim 1 , wherein the crystalline free base form is characterized by a differential scanning calorimetry curve having a single endothermic peak at an onset temperature of 213.6° C. (±1° C.).

8. The crystalline compound of claim 1 , wherein the crystalline free base form is characterized by 13C-NMR (100 MHz, solid state) δ(ppm) values comprising 11.9, 31.1, 52.2, 54.8, 56.5, 88.6, 95.7, 106.2, 110.8, 112.3, 114.5, 123.0, 129.0, 130.3, 132.3, 132.9, 133.8, 149.9, 153.2, 154.8, 155.4, 160.0, 162.1, and 164.4.

9. The crystalline free base compound of claim 1 , wherein the crystalline free base form is characterized by a solubility of 5.2 mg/mL in 0.1 N HCl.

10. A pharmaceutical composition comprising the crystalline compound of claim 1 and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10 , wherein said composition is formulated for oral, intravenous or subcutaneous administration.

12. A method of treating hepatocellular carcinoma in a subject in need thereof comprising administering to said subject a treatment effective amount of the pharmaceutical composition of claim 10 .

13. The method of claim 12 , wherein said hepatocellular carcinoma has altered FGFR4 and/or FGF19 status.

14. The method of claim 13 , wherein said altered FGFR4 and/or FGF19 status comprises increased expression of FGFR4 and/or FGF19.

15. A method of treating hepatocellular carcinoma in a subject in need thereof, comprising:
detecting an altered FGFR4 and/or FGF19 status in a biological sample containing cells of said hepatocellular carcinoma, and if said hepatocellular carcinoma has said altered FGFR4 and/or FGF19 status,
administering the pharmaceutical composition of claim 10 to said subject in a treatment-effective amount.

16. The method of claim 15 , wherein said altered FGFR4 and/or FGF19 status comprises increased expression of FGFR4 and/or FGF19.

17. A method of treating rhabdomyosarcoma in a subject in need thereof comprising administering to said subject a treatment effective amount of the pharmaceutical composition of claim 10 .

18. The method of claim 17 , wherein said rhabdomyosarcoma is characterized by FGFR4 expression or overexpression.

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Moniz George
• Sanders Kristen
• Chanda Arani
• Yoshida Kenshi
• Hao Ming-Hong
• Reynolds Dominic
• Prajapati Sudeep
• Selvaraj Anand
• Satoh Takashi
• Wang John

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/506 Primary

  not condensed and containing further heterocyclic rings · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61K31/505 Primary

  Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim · CPC title