Crystals of alkynyl-containing compound, salt and solvate thereof, preparation method, and applications
The invention discloses the crystal form, preparation method and application of an alkynyl compound, its salt and solvent compound. The invention specifically discloses 3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl) benzamide crystal form I and 3-((1H-pyrazolo [3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl) benzamide fumarate crystal form II. The crystal form of the invention has good stability and has important value for drug optimization and development.
1 . A crystal form of 3-((1H-pyrazolo[3,4-b]pyridin-5-yl) ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) phenyl) benzamide, which has characteristic XRPD diagram peaks at the following positions represented by 2θ angles: 9.498±0.2°, 12.293±0.2°, 13.045±0.2°, 15.899±0.2°, 16.199±0.2°, 18.183±0.2°, 18.327±0.2°, 21.755±0.2°, 22.362=0.2°, and 25.690±0.2°.
2 . The crystal form of claim 1 , which has characteristic XRPD diagram peaks at the following positions represented by 2θ angles: 8.968±0.2°, 9.498±0.2°, 12.293=0.2°, 13.045±0.2°, 15.899±0.2°, 16.199=0.2°, 16.533=0.2°, 16.908±0.2°, 18.183=0.2°, 18.327±0.2°, 20.042=0.2°, 20.271=0.2°, 21.755±0.2°, 22.362=0.2°, and 25.690=0.2°.
3 . The crystal form of claim 1 , which exhibits a weight loss of 0.15% at 200° C., as determined by thermogravimetric analysis; or exhibits a thermal absorption peak at 235° C., as determined by differential scanning calorimetry (DSC).
4 . A method for preparing the crystal form of claim 1 , comprising the step of crystallizing 3-((1H-pyrazole[3,4-b]pyridine-5-substituted) ethynyl)-4-methyl-n-(4-((4-methylpiperazine-1-substituted) methyl)-3-(trifluoromethyl) phenyl) benzamide in an organic solvent, wherein the organic solvent is one or more of C 1 -C 10 alkane, C 1 -C 4 alcohol, ether, nitrile, ketone, ester or DMSO.
5 . The method of claim 4 , wherein
the crystallization is performed by suspension stirring, room temperature stirring, heating and cooling crystallization, solvent volatilization or anti-solvent addition;
the organic solvent is one or more of heptane, methanol, ethanol, isopropanol, methyl tert-butyl ether, acetonitrile, acetone, 2-butanone, ethyl acetate, isopropyl acetate or dimethyl sulfoxide;
the mass/volume ratio of the 3-((1H-pyrazolo[3,4-b]pyridin-5-yl) ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) phenyl) benzamide to the organic solvent is from 1/1 g/mL to 1/5 g/mL;
the crystallization temperature is from 20° C. to 50° C.; or
the crystallization time is from 1 hour to 36 hours.
6 . The method of claim 4 , wherein the crystallization comprises the addition of an anti-solvent, wherein the anti-solvent is one or more of water, alcohol or nitrile;
wherein the water is distilled water, deionized water, purified water, tap water or mineral water;
wherein the alcohol is isopropanol;
wherein the nitrile is acetonitrile; or
wherein the mass/volume ratio of the 3-((1H-pyrazolo[3,4-b]pyridin-5-yl) ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) phenyl) benzamide to the anti-solvent is from 1/2 g/mL to 1/25 g/mL.
7 . A pharmaceutical composition comprising the crystal form of claim 1 and a pharmaceutically acceptable excipient.
8 . A method of treating or preventing cancer, comprising administering the crystal form of claim 1 to a subject having the cancer.