Tolebrutinib Form 2 of the following formula, wherein the XRPD pattern of Form 2 comprises at least four characteristic peaks at 2Θ values of 7.8°±0.2°, 12.0°±0.2°, 18.5°±0.2°, 18.8°±0.2 and 22.9°±0.2°.
The tolebrutinib Form 2 according to claim 1, wherein the XRPD pattern of Form 2 also comprises one or two or more characteristic peaks at 2Θ values of 11.1°±0.2°, 13.7°±0.2°, 16.2±02°, 23.9°±0.2° and 24.9°±0.2°.
The tolebrutinib Form 2 according to claim 1 or 2, wherein the XRPD pattern of Form 2 also comprises one or two or more characteristic peaks at 2Θ values of 13.3°±0.2°, 14.1°±0.2°, 20.3±0.2° and 21.7±0.2°.
The tolebrutinib Form 2 according to any one of claims 1 to 3, wherein the XRPD pattern of Form 2 comprises characteristic peaks at the following 2Θ values: 2θ±0.2° 7.8 11.1 12.0 13.3 13.7 16.2 18.5 18.8 19.3 20.3 20.9 21.5 21.7 22.9 23.9 24.9 26.4 27.9 29.0 30.4
The tolebrutinib Form 2 according to any one of claims 1 to 4, wherein the XRPD pattern of Form 2 is substantially as depicted in FIG. 14.
The tolebrutinib Form 2 according to any one of claims 1 to 5, wherein the DSC thermogram of Form 2 begins to show an endothermic peak at about 160-164°C.
The tolebrutinib Form 2 according to any one of claims 1 to 6, wherein the FT-IR spectrum of Form 2 comprises bands at wave numbers of 1699±2 cm -1 , 1229±2 cm -1 , 1486 cm -1 and 1507±2 cm -1 .
A method for preparing tolebrutinib Form 2 according to any one of claims 1 to 7, wherein the method is selected from any one of the following methods: 1) dispersing tolebrutinib in solvent 3 to form suspension, stirring at constant temperature, separating solids, and drying to obtain Form 2; wherein, the constant temperature stirring time is ≥ 12 hours, preferably 1-5 days; the constant temperature stirring temperature is ≥30°C, preferably 30-80°C, more preferably 40-70°C; the solvent 3 is selected from the single or mixed solvent of methyltert-butylether, n-heptane, 2-butanone, water, n-butyl acetate, diisopropyl ether, 2-butyl alcohol, dichloromethane and 1,4-dioxane; preferably, the solvent 3 is selected from a mixed solvent of 2-Butanone and water, and the mixed volume ratio is 1:1-1:10; or, it is selected from a mixed solvent of n-butyl acetate and dichloromethane, and the mixed volume ratio is 1 :1-1:10; 2) dissolving tolebrutinib in solvent 4 to form a solution, volatilizeing openly, and drying; wherein, the solvent 4 is selected from one or a mixture of toluene and methylcyclohexane; preferably, the solvent 4 is a mixed solvent of toluene and methylcyclohexane, and the solvent mixing ratio is 5:1-1:2; 3) putting tolebrutinib in a closed container containing solvent 5 for ≥ 1 day and dry to obtain Form 2; wherein, the solvent 5 is acetonitrile.
Tolebrutinib Form 1 of the following formula, wherein the XRPD pattern of Form1 has at least four characteristic peaks at 2Θ values of 10.4°±0.2°, 11.4°±0.2°, 20.6°±0.2°, 16.7°±0.2° and 22.7°±0.2°.
Tolebrutinib Form 1 according to claim 9, wherein the XRPD pattern of Form 1 has one or two or more characteristic peaks at 2Θ values of 4.2°±0.2°, 15.8°±0.2°, 17.9°±0.2°, 20.8°±0.2° and 24.8°±0.2°.
Tolebrutinib Form 1 according to claims 9 or 10, wherein the XRPD pattern of Form 1 has one or two or more characteristic peaks at 2Θ values of 10.9°±0.2°, 21.3°±0.2°, 23.5±0.2°, 25.3±0.2° and 25.7±0.2°.
Tolebrutinib Form 1 according to claims 9 to 11, wherein the XRPD pattern of the Form 1 comprises characteristic peaks at the following 2Θ values: 2θ±0.2° 4.2 10.4 10.9 11.4 15.8 16.7 17.9 20.3 20.6 20.8 21.0 21.3 22.7 23.5 23.7 24.8 25.3 25.7 26.9 27.2 27.4 31.1 35.5
Tolebrutinib Form 1 according to any one of claims 9 to 12, wherein the XRPD pattern of Form 1 is substantially as depicted in FIG. 7.
Tolebrutinib Form 1 according to any one of claims 9 to 13, wherein the DSC thermogram of Form 1 has an endothermic peak at about 126°C.
Tolebrutinib Form 1 according to any one of claims 9 to 14, wherein the FT-IR spectrum of Form 1 has bands at wavenumbers of 840.7±2 cm -1 , 978.3±2 cm -1 , 1472.3±2 cm -1 , and 1492.5±2 cm -1 .
The preparation method of tolebrutinib Form 1 according to any one of claims 9 to 15, wherein the method is selected from any one of the following methods: 1) dissolving tolebrutinib in solvent 1 to form a solution, volatilizing, recrystallizing, separating, and drying to obtain Form 1; wherein, the solvent 1 is acetone; preferably, the dissolving step is performed at room temperature; preferably, the volatilization is carried out at room temperature; 2) dissolving tolebrutinib in co-solvent to form a solution, stirring (1), adding anti-solvent, stirring (2), recrystallizing, separating, and drying to obtain Form 1; wherein, the co-solvent is selected from ethanol, acetone and tetrahydrofuran, as individual or mixed solvents; the anti-solvent is selected from a group consisting of water, n-heptane and n-hexane , and any mixture thereof, preferably a mixed solvent with water; the stirring (1) and stirring (2) are optional steps; preferably, the volume ratio of the anti-solvent to the co-solvent is no less than 0.1:1, more preferably, in the range of 1:1 to 8:1; preferably, the dissolving step is performed at room temperature; preferably, the stirring is performed at a certain temperature, and the certain temperature is no greater than 30°C; the stirring time is no less than 30min; 3) dissolving tolebrutinib in solvent 2 to form a suspension, stirring at room temperature, separating, and drying to obtain Form 1; wherein, the solvent 2 is selected from either ethanol or ethyl acetate, or a mixture thereof, preferably, the solvent is ethanol; the mass-volume ratio (mg/mL) of the tolebrutinib and solvent 2 is in the range of 20:1 to 100:1; preferably, the mass-to-volume ratio (mg/mL) of tolebrutinib and solvent 2 is in the range of 25: 1 to 50:1.
Amorphous form of tolebrutinib of the following formula, wherein the XRPD pattern of the amorphous form is characterized by having no diffraction peaks at 2Θ value within the range of 3 to 40°.
The amorphous of tolebrutinib according to claim 17, wherein the XRPD pattern of the amorphous form has a broad hump at 2Θ values within the range of 10 to 40°.
The amorphous form of tolebrutinib according to claim 17 or 18, wherein the XRPD pattern of the amorphous is substantially as depicted in FIG. 1.
The amorphous form of tolebrutinib according to any one of claims 17 to 19, wherein the FT-IR spectrum of the amorphous form has bands at wavenumbers of 1703±2cm -1 , 1440±2cm -1 , 788cm -1 and 753±2cm -1 .
The preparation method of the amorphous form of tolebrutinib according to any one of claims 17 to 20, wherein the method is selected from any one of the following methods: 1) dissolving tolebrutinib in a co-solvent, adding anti-solvent, stirring, precipitating solids, separating and drying; wherein, the co-solvent is either DMSO (dimethyl sulfoxide) or toluene, or their mixture thereof; the anti-solvent is selected from water or ether or their mixture thereof; preferably, the co-solvent is DMSO; the anti-solvent is water; preferably, the volume ratio of the co-solvent and the anti-solvent is in the range of 10: 1 to 1: 10, more preferably 1: 1; 2) dissolving tolebrutinib in solvent 6 at high temperature, filtering, stirring at low temperature, separating and drying; wherein, the solvent 6 is selected from one or more of the following mixed solvents: trifluoroethanol/water, isopropyl acetate/water, tetrahydrofuran/water, 1,4-dioxane/water, acetonitrile/water and chloroform/water; preferably, the solvent 6 is a mixed solvent of trifluoroethanol/water; preferably, the high temperature is in the range of 40°C to 80°C; preferably, the low temperature is no more than 10°C.
A pharmaceutical composition comprising one or more of tolebrutinib Form 2 according to any one of claims 1 to 7, or Tolebrutinib Form 1 according to any one of claims 9 to 15, or amorphous form of tolebrutinib according to any one of claims 17 to 20, or its combination thereof, and at least one pharmaceutically acceptable carrier.
Use of one or more of tolebrutinib Form 2 according to any one of claims 1 to 7, or Tolebrutinib Form 1 according to any one of claims 9 to 15, or amorphous form of tolebrutinib according to any one of claims 17 to 20,or its combination thereof, or the pharmaceutical composition thereof, for the preparation of medications for the treatment of BTK mediated diseases.
Use of one or more of tolebrutinib Form 2 according to any one of claims 1 to 7, or Tolebrutinib Form 1 according to any one of claims 9 to 15, or amorphous form of tolebrutinib according to any one of claims 17 to 20,or its combination thereof, for the preparation of medications for the treatment of cancer, autoimmune diseases, inflammatory diseases, and thromboembolic diseases.
A method of treating BTK mediated diseases, comprising administering to a patient an effective amount of one or more of tolebrutinib Form 2 according to any one of claims 1 to 7, or Tolebrutinib Form 1 according to any one of claims 9 to 15, or amorphous form of tolebrutinib according to any one of claims 17 to 20,or its combination thereof,,or a pharmaceutical composition thereof.
A method of treating cancer, autoimmune disease, inflammatory disease and thromboembolic disease, comprising administering to a patient in need thereof a therapeutically effective amount of one or more of tolebrutinib Form 2 according to any one of claims 1 to 7, or Tolebrutinib Form 1 according to any one of claims 9 to 15, or amorphous form of tolebrutinib according to any one of claims 17 to 20,or its combination thereof,, or a pharmaceutical composition thereof.
Tolebrutinib Form 2 according to any one of claims 1 to 7, or Tolebrutinib Form 1 according to any one of claims 9 to 15, or amorphous form of tolebrutinib according to any one of claims 17 to 20, or its combination thereof, or a combination thereof with other drugs, in combination with other drugs.
