P-toluenesulfonate for MEK kinase inhibitor, and crystal form thereof and preparation method therefor

Patent metadata

Field	Value
Publication number	US-10118911-B2
Application number	US-201615559516-A
Country	US
Kind code	B2
Filing date	Mar 8, 2016
Priority date	Mar 27, 2015
Publication date	Nov 6, 2018
Grant date	Nov 6, 2018

Abstract

Disclosed are a p-toluenesulfonate of a MEK kinase inhibitor, and a crystal form thereof and a preparation method thereof. Specifically disclosed are a 2-((2-fluorine-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridine-3-group)oxygroup)-6-carbonyl-1,6-dihydropyridine-3-formamide p-toluenesulfonate (a compound represented by formula (I)), a crystal form I, and a preparation method thereof. The obtained crystal form I of the compound of formula (I) has good crystal form stability and chemical stability, and the crystallization solvent used has low toxicity and low residue, and is more suitable for use in clinical treatment.

First claim

What is claimed is:

1. A crystal form I of 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate of formula (I),

wherein the crystal has a characteristic X-ray powder diffraction spectrum comprising diffraction peaks at diffraction angles (2θ) of about 10.18, 17.13, 17.59, 21.51, and 21.88.

2. A method of preparing the crystal form I of the 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 1 comprising the following steps of:
(a) dissolving p-toluenesulfonic acid and 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide, or a crystal form or amorphous form of the 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate of formula (I) in an organic solvent or a mixed solvent of an organic solvent and water to precipitate a crystal, wherein the organic solvent is selected from the group consisting of alcohols, ketones, nitriles, ethers having 1 to 3 carbon atoms, and mixtures thereof; and
(b) filtering the crystal, then washing and drying it.

3. The method according to claim 2 , wherein the organic solvent in step (a) is selected from the group consisting of methanol, ethanol, isopropanol, and mixtures thereof; and the mixed solvent of the organic solvent and water is selected from the group consisting of methanol/water, ethanol/water, isopropanol/water, acetonitrile/water, acetone/water and tetrahydrofuran/water.

4. The method of claim 3 , wherein the single solvent is isopropanol and the mixed solvent is acetone/water.

5. The crystal form (I) of the 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 1 , further comprising diffraction peaks at diffraction angles 2θ of about 11.51, 12.34, 12.97, 13.72, 14.83, 15.76, 17.92, 18.50, 19.72, 20.03, 20.42, 21.04, 23.15, 24.14, 24.53, 24.77, 25.88 and 26.37.

6. The crystal form (I) of the 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 5 , wherein the crystal form has the following interplanar spacing (Å) at each of the indicated diffraction angles (2θ):

2θ(°)
Interplanar Spacing (Å)

10.18
8.68

11.51
7.68

12.34
7.17

12.97
6.82

13.72
6.45

14.83
5.97

15.76
5.62

17.13
5.17

17.59
5.04

17.92
4.95

18.50
4.79

19.72
4.50

20.03
4.43

20.42
4.35

21.04
4.22

21.51
4.13

21.88
4.06

23.15
3.84

24.14
3.68

24.53
3.63

24.77
3.59

25.88
3.44

26.37
3.38.

7. The crystal form (I) of the 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 1 , wherein a melting point of the crystal form is about 237° C.

8. The crystal form (I) of the 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 1 , wherein the crystal form has an X-ray powder diffraction spectrum as shown in FIG. 1 .

9. A pharmaceutical composition comprising the crystal form (I) of the 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 1 , and a pharmaceutically acceptable carrier.

10. A method of inhibiting MEK kinase in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 9 .

11. A method of treating melanoma in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 9 .

12. A pharmaceutical composition comprising the crystal form (I) of the 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 8 , and a pharmaceutically acceptable carrier.

13. A method of inhibiting MEK kinase in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 12 .

14. A method of treating melanoma in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 12 .

15. A method of inhibiting MEK kinase in a subject, the method comprising administering to the subject the crystal form (I) of the 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy

Assignees

• Jiangsu Hengrui Medicine Co

Inventors

• Wu Guaili
• Gao Xiaohui
• Bian Lin
• Jia Junlei

Classifications

• C07D213/82

  in position 3 · CPC title

• A61K31/4412

  having oxo groups directly attached to the heterocyclic ring · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title