# US 10,118,911 B2 · P-toluenesulfonate for MEK kinase inhibitor, and crystal form thereof and preparation method therefor

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- Number: US 10,118,911 B2
- Document ID: US10118911B2
- Status: Granted
- Kind: B2
- Application number: 15/559,516
- Filed: 2016-03-08
- Published: 2018-05-03
- Granted: 2018-11-06
- Earliest claimed: 2015-03-27
- Assignees: Jiangsu Hengrui Medicine Co., Ltd.
- Applicants: Jiangsu Hengrui Medicine Co., Ltd.
- Inventors: Guaili Wu; Xiaohui Gao; Lin Bian; Junlei Jia
- Web page: https://patentgrep.com/patent/US10118911B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K 31/4412: having oxo groups directly attached to the heterocyclic ring
- A61P 35/00: Antineoplastic agents
- C07D 213/82: in position 3
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## 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.

## Claims

### Claim 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.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 2)

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.

### Claim 4 (depends on 3)

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

### Claim 5 (depends on 1)

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.

### Claim 6 (depends on 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 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.

### Claim 7 (depends on 1)

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.

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 1)

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.

### Claim 10 (depends on 9)

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

### Claim 11 (depends on 9)

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

### Claim 12 (depends on 8)

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.

### Claim 13 (depends on 12)

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

### Claim 14 (depends on 12)

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

### Claim 15 (depends on 1)

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)-6-oxo-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 1.

### Claim 16 (depends on 8)

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)-6-oxo-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 8.

### Claim 17 (depends on 1)

A method of treating melanoma in a subject in need thereof, 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)-6-oxo-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 1.

### Claim 18 (depends on 8)

A method of treating melanoma in a subject in need thereof, 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)-6-oxo-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 8.