Crystalline forms of mesylate salt of pyridinyl amino pyrimidine derivative, preparation methods therefor, and applications thereof
View Patent ↗Forms I and II of the mesylate salt of the compound of formula (I), a preparation methods thereof, a pharmaceutical composition containing the crystal forms, and the use of the crystal forms in treating diseases mediated by activating and resistance mutations of EGFR, in particular cancer, in mammal, in particular in human. The crystal forms of the mesylate salt of the compound of formula (I) have good solubilities and high bioavailabilities in animals
1. Form I of the mesylate salt of N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxy)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide represented by formula (I), wherein Form I has characteristic peaks in X-ray powder diffraction pattern at the following diffraction angles (2θ values) of: 4.58°±0.2°, 14.08°±0.2°, 15.00°±0.2°, 16.40°±0.2°, 17.84°±0.2°, 18.30°±0.2°, 20.26°±0.2°, 21.10°±0.2°, 21.88°±0.2°, 22.66°±0.2°, 25.58°±0.2°, 26.78°±0.2°,
2. Form I according to claim 1 , which has an X-ray powder diffraction pattern that is substantially identical to that in FIG. 1 .
3. A method for preparing Form I according to claim 1 , comprising:
a) suspending the compound of formula (I) in a first solvent,
b) warming the mixture up to 20-70° C., and dropwisely adding a solution of methanesulfonic acid dissolved in a second solvent, and
c) crystallizing and filtering to give Form I.
4. A method for preparing Form I according to claim 1 , comprising:
a) suspending the compound of formula (I) in a first solvent,
b) warming the mixture up to 20-70° C., and dropwisely adding a solution of methanesulfonic acid dissolved in a second solvent,
c) adding dropwisely a third solvent, and
d) crystallizing and filtering to give Form I.
5. The method according to claim 3 , wherein the first solvent is water, ketone, cyclic ether or nitrile solvent, or a mixed solvent thereof and the second solvent is water, ketone, cyclic ether or nitrile solvent, or a mixed solvent thereof.
6. The method according to claim 5 , wherein the first solvent is a mixed solvent of water and ketone, cyclic ether or nitrile solvent; and the second solvent is ketone solvent, cyclic ether solvent or nitrile solvent, or a mixed solvent of water and ketone, cyclic ether or nitrile solvent.
7. The method according to claim 5 , wherein the ketone solvent comprises acetone, and the cyclic ether solvent comprises tetrahydrofuran or 1,4-dioxane, and the nitrile solvent comprises acetonitrile.
8. The method according to claim 3 , wherein in step b), warming the mixture up to 35-55° C.
9. The method according to claim 4 , wherein the third solvent is C 6-7 alkane, ether or ester solvent.
10. The method according to claim 9 , wherein the C 6-7 alkane solvent comprises n-heptane; and the ether solvent comprises methyl t-butyl ether; and the ester solvent comprises methyl formate, ethyl acetate, isopropyl acetate, propyl acetate or butyl acetate.
11. Form II of the mesylate salt of N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxy)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide represented by formula (I), wherein Form II has characteristic peaks in X-ray powder diffraction pattern at the following diffraction angles (2θ values) of: 6.94°±0.2°, 11.24°±0.2°, 11.94°±0.2°, 14.72°±0.2°, 18.74°±0.2°, 19.38°±0.2°, 20.22°±0.2°, 22.10°±0.2°, 22.92°±0.2°, 24.48°±0.2°, 25.14°±0.2°, 26.42°±0.2°,
12. Form II according to claim 11 , which has an X-ray powder diffraction pattern that is substantially identical to that in FIG. 2 .
13. A method for preparing Form II according to claim 11 , comprising dissolving Form I of the mesylate salt of the compound of formula (I) in alcohol solvent under heating, cooling, crystallizing, and filtering to give Form II.
14. The method according to claim 13 , wherein said alcohol solvent comprises methanol or ethanol.
15. A pharmaceutical composition, comprising the form according to claim 1 and a pharmaceutically acceptable carrier.
16. A method of treating a patient suffering from cancers, the method comprising administering to the patient the Form I according to claim 1 .
17. A pharmaceutical composition, comprising the form according to claim 11 and a pharmaceutically acceptable carrier.
18. A method of treating a patient suffering from cancers, the method comprising administering to the patient the Form II according to claim 11 .