WO2022194160A1 - Forme solide de fisogatinib et son procédé de préparation - Google Patents

Forme solide de fisogatinib et son procédé de préparation Download PDF

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WO2022194160A1
WO2022194160A1 PCT/CN2022/080989 CN2022080989W WO2022194160A1 WO 2022194160 A1 WO2022194160 A1 WO 2022194160A1 CN 2022080989 W CN2022080989 W CN 2022080989W WO 2022194160 A1 WO2022194160 A1 WO 2022194160A1
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crystal
salt
crystal form
solid
salt crystal
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PCT/CN2022/080989
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English (en)
Chinese (zh)
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彭欢
张良
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上海启晟合研医药科技有限公司
上海创诺医药集团有限公司
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Priority claimed from CN202110279921.6A external-priority patent/CN113045554A/zh
Priority claimed from CN202110624546.4A external-priority patent/CN115433171A/zh
Application filed by 上海启晟合研医药科技有限公司, 上海创诺医药集团有限公司 filed Critical 上海启晟合研医药科技有限公司
Publication of WO2022194160A1 publication Critical patent/WO2022194160A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl ) amino) tetrahydro-2H-pyran-4-yl) acrylamide crystal form, salt crystal form or co-crystal and preparation method thereof.
  • FGFR4 is an oncogenic driver in patients with locally advanced or metastatic hepatocellular carcinoma (HCC).
  • HCC locally advanced or metastatic hepatocellular carcinoma
  • FGF19 can activate FGFR4, thereby promoting hepatocyte proliferation and regulating intrahepatic bile acid balance.
  • About 30% of HCC patients have abnormal activation of FGF19/FGFR4 signaling pathway.
  • Fisotinib (BLU-554) is an investigational potent and highly selective fibroblast growth factor receptor-4 (FGFR4) inhibitor developed by Blueprint Medicines for the treatment of FGFR4-driven advanced HCC.
  • the drug is not yet on the market, and its phase I clinical trial data show that fisotinib as a single agent has demonstrated clinical efficacy and good tolerability in patients with locally advanced or metastatic hepatocellular carcinoma (HCC) with a history of multiple treatments.
  • the drug can stimulate T cells to infiltrate the tumor microenvironment, suggesting that its combination with an anti-PD-L1 inhibitor may show stronger efficacy in patients with FGFR4-driven advanced HCC.
  • fisotinib (BLU-554) is N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline) -2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide, the chemical formula is C 24 H 24 Cl 2 N 4 O 4 , the molecular weight is 503.38, and its molecular structure is as follows:
  • Patent WO2015061572 reports the compound of formula (I). According to the research of the present inventors, the amorphous form of the compound has poor solubility in water, and is less than 1 mg/mL at 50°C. Poor solubility results in slow drug absorption and low bioavailability. Drug co-crystals and salts are effective means to improve drug solubility.
  • the object of the present invention is to provide a solid form of fisotinib, a compound of formula (I), to meet the needs of drug research and industrial production.
  • Another object of the present invention is to provide a method for preparing a solid form of fisotinib with high stability.
  • a first aspect of the present invention provides a solid form of a compound as shown in formula (I),
  • the salt crystal form or co-crystal XM-IV of fisotinib with hydrochloric acid or,
  • Salt crystal form or co-crystal XM-V of fisotinib and stearic acid
  • the solid form is crystal form I
  • the X-ray powder diffraction pattern of the crystal form I includes 3 or more 2 ⁇ values selected from the following group: 5.9° ⁇ 0.2 °, 8.2° ⁇ 0.2°, 12.0° ⁇ 0.2°, 20.1° ⁇ 0.2°, 23.8° ⁇ 0.2°.
  • the solid form is crystal form II
  • the X-ray powder diffraction pattern of the crystal form I includes 3 or more 2 ⁇ values selected from the following group: 4.2° ⁇ 0.2 °, 16.7° ⁇ 0.2°, 20.9° ⁇ 0.2°, 23.0° ⁇ 0.2°, 29.7° ⁇ 0.2°.
  • the crystalline form I has one or more characteristics selected from the group consisting of:
  • the XRPD pattern of the crystal form I comprises 6 or more 2 ⁇ values selected from the group consisting of 5.9° ⁇ 0.2°, 8.2° ⁇ 0.2°, 10.3° ⁇ 0.2°, 10.6° ⁇ 0.2°, 10.9 ° ⁇ 0.2°, 11.7° ⁇ 0.2°, 12.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.9° ⁇ 0.2°, 16.5° ⁇ 0.2°, 17.4° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.1° ⁇ 0.2°, 19.0° ⁇ 0.2°, 20.1° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.4° ⁇ 0.2°, 22.2° ⁇ 0.2°, 23.1° ⁇ 0.2°, 23.8° ⁇ 0.2°, 24.9° ⁇ 0.2° , 26.6° ⁇ 0.2°, 27.5° ⁇ 0.2°, 28.3° ⁇ 0.2°, 29.1° ⁇ 0.2°, 31.4° ⁇ 0.2°.
  • the crystal form I has a DSC diagram as shown in Figure 3;
  • the crystal form I has a 1 H NMR spectrum substantially as shown in FIG. 4 .
  • the crystal form II has one or more features selected from the group consisting of:
  • the XRPD pattern of the crystal form II includes 6 or more 2 ⁇ values selected from the following group: 4.2° ⁇ 0.2°, 8.4° ⁇ 0.2°, 11.6° ⁇ 0.2°, 12.2° ⁇ 0.2°, 14.5 ° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.7° ⁇ 0.2°, 20.9° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.0° ⁇ 0.2°, 25.9° ⁇ 0.2°, 29.7° ⁇ 0.2°, 30.5° ⁇ 0.2°, 33.7° ⁇ 0.2°.
  • the crystal form II has an XRPD pattern substantially as shown in Figure 9;
  • the crystal form II has a TGA diagram substantially as shown in Figure 10;
  • the crystal form II has a DSC chart as shown in FIG. 11 ;
  • the crystal form II has a 1 H NMR spectrum substantially as shown in FIG. 12 .
  • the solid form is salt crystal form or co-crystal XM-I.
  • the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-I comprises the following 2 ⁇ values: 3.2° ⁇ 0.2°; and at least 2 2 ⁇ values selected from the following group: 8.7° ⁇ 0.2°, 9.8° ⁇ 0.2°, 11.8° ⁇ 0.2°, 23.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-I further has one or more 2 ⁇ values selected from the following group: 5.6° ⁇ 0.2°, 6.5° ⁇ 0.2°, 11.4° ⁇ 0.2°, 13.1° ⁇ 0.2°, 15.0° ⁇ 0.2°.
  • the differential scanning calorimetry analysis of the salt crystal form or co-crystal XM-I has an endothermic peak in the range of 200°C to 210°C.
  • the salt crystal form or co-crystal XM-I loses about 15 wt% at 150°C-250°C.
  • the salt crystal form or co-crystal XM-I has XRPD data substantially as shown in Table 11.
  • the salt crystal form or co-crystal XM-I has an XRPD spectrum substantially as shown in FIG. 17 .
  • the salt crystal form or co-crystal XM-I has a TGA spectrum substantially as shown in FIG. 18 .
  • the salt crystal form or co-crystal XM-I has a DSC spectrum substantially as shown in FIG. 19 .
  • the salt crystal form or co-crystal XM-I has a 1 H NMR spectrum substantially as shown in FIG. 20 .
  • the solid form is salt crystal form or co-crystal XM-II.
  • the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-II includes 3 or more, preferably 4 or more, more preferably 5 , 2 ⁇ values selected from the following group: 8.3° ⁇ 0.2°, 12.5° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.0° ⁇ 0.2°, 24.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-II also has one or more 2 ⁇ values selected from the following group: 4.1° ⁇ 0.2°, 5.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 19.9° ⁇ 0.2°, 21.6° ⁇ 0.2°.
  • the differential scanning calorimetry analysis of the salt crystal form or co-crystal XM-II has an endothermic peak in the ranges of 195°C-205°C and 330°C-340°C respectively.
  • the salt crystal form or co-crystal XM-II loses about 10% in weight at 100°C-220°C.
  • the salt crystal form or co-crystal XM-II has XRPD data substantially as shown in Table 12.
  • the salt crystal form or co-crystal XM-II has an XRPD spectrum substantially as shown in FIG. 21 .
  • the salt crystal form or co-crystal XM-II has a TGA spectrum substantially as shown in Figure 22.
  • the salt crystal form or co-crystal XM-II has a DSC spectrum substantially as shown in FIG. 23 .
  • the salt crystal form or co-crystal XM-II has a 1H NMR spectrum substantially as shown in FIG. 24 .
  • the solid form is salt crystal form or co-crystal XM-III.
  • the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-III includes 3 or more, preferably 4 or more, more preferably 5 2 ⁇ values selected from the following group: 5.1° ⁇ 0.2°, 8.1° ⁇ 0.2°, 10.2° ⁇ 0.2°, 13.1° ⁇ 0.2°, 20.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-III further has one or more 2 ⁇ values selected from the following group: 7.2° ⁇ 0.2°, 11.7° ⁇ 0.2°, 17.6° ⁇ 0.2°, 21.2° ⁇ 0.2°, 25.2° ⁇ 0.2°.
  • the salt crystal form or co-crystal XM-III has XRPD data substantially as shown in Table 13.
  • the salt crystal form or co-crystal XM-III has an XRPD spectrum substantially as shown in FIG. 25 .
  • the salt crystal form or co-crystal XM-III has a TGA spectrum substantially as shown in FIG. 26 .
  • the salt crystal form or co-crystal XM-III has a DSC spectrum substantially as shown in FIG. 27 .
  • the salt crystal form or co-crystal XM-III has a 1H NMR spectrum substantially as shown in FIG. 28 .
  • the solid form is salt crystal form or co-crystal XM-IV.
  • the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-IV includes 3 or more, preferably 4 or more, more preferably 5 , 2 ⁇ values selected from the following group: 3.6° ⁇ 0.2°, 5.4° ⁇ 0.2°, 9.8° ⁇ 0.2°, 21.8° ⁇ 0.2°, 25.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-IV further has one or more 2 ⁇ values selected from the following group: 5.0° ⁇ 0.2°, 13.2° ⁇ 0.2°, 13.8° ⁇ 0.2°, 17.5° ⁇ 0.2°, 19.8° ⁇ 0.2°.
  • the salt crystal form or co-crystal XM-IV has XRPD data substantially as shown in Table 14.
  • the salt crystal form or co-crystal XM-IV has an XRPD spectrum substantially as shown in FIG. 29 .
  • the solid form is salt crystal form or co-crystal XM-V.
  • the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-V includes 2 ⁇ values selected from the group consisting of: 5.7° ⁇ 0.2°, and at least 1, preferably 2 One or three 2 ⁇ values selected from the group consisting of: 3.8° ⁇ 0.2°, 9.5° ⁇ 0.2°, 24.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-V further has one or more 2 ⁇ values selected from the following group: 7.6° ⁇ 0.2°, 13.3° ⁇ 0.2°, 23.1° ⁇ 0.2°.
  • the differential scanning calorimetry analysis of the salt crystal form or eutectic XM-V has an endothermic peak in the ranges of 60°C-70°C and 210°C-220°C respectively.
  • the salt crystal form or eutectic XM-V loses about 4% weight at 25°C-150°C, and loses about 15% weight at 150°C-250°C.
  • the salt crystal form or co-crystal XM-V has XRPD data substantially as shown in Table 15.
  • the salt crystal form or co-crystal XM-V has an XRPD spectrum substantially as shown in FIG. 30 .
  • the salt crystal form or co-crystal XM-V has a TGA spectrum substantially as shown in FIG. 31 .
  • the salt crystal form or co-crystal XM-V has a DSC spectrum substantially as shown in FIG. 32 .
  • the X-ray powder diffraction is measured under the condition of CuK ⁇ radiation.
  • a second aspect of the present invention provides a method for preparing a solid form of fisotinib as described in the first aspect of the present invention
  • the seventh solvent includes an alcohol-based solvent, a ketone-based solvent, an amide-based solvent, an ester-based solvent, an ether-based solvent, a nitrile-based solvent, water, or a combination thereof. in,
  • the alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, or a combination thereof.
  • the ketone solvent is selected from the group consisting of acetone, 2-butanone, N-methylpyrrolidone, or a combination thereof.
  • the amide solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof.
  • the ester solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, n-propyl acetate, tert-butyl acetate, or a combination thereof.
  • the ether solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof.
  • the nitrile solvent is selected from the group consisting of acetonitrile.
  • the eighth solvent includes hydrocarbons, ethers, water, or a combination thereof.
  • the hydrocarbon solvent is selected from the group consisting of nitromethane, n-heptane, cyclohexane, methylcyclohexane, toluene, or a combination thereof.
  • the ester solvent is selected from the group consisting of diethyl ether, methyl tert-butyl ether, petroleum ether, or a combination thereof.
  • the solid is processed to obtain the crystal form, wherein the processing includes vacuum drying.
  • step (a) further includes a stirring step.
  • step (b) includes volatilizing the mixture at room temperature to separate out the solid form of fisotinib.
  • step (b) includes rinsing the solid with water or ether after collecting the solid.
  • the fisotinib raw material is the amorphous form of fisotinib.
  • the first solvent is selected from the group consisting of alcohol solvents, ketone solvents, aromatic hydrocarbon solvents, water, or a combination thereof.
  • the first dispersion formed by the fisotinib and the first solvent is a crystal slurry or a suspension.
  • the alcohol solvent is a C1-C4 alcohol solvent; preferably, the alcohol solvent is selected from methanol, ethanol, isopropanol, n-propanol, or a combination thereof.
  • the ketone solvent is a C2-C6 ketone solvent; preferably, the ketone solvent is selected from: acetone, 2-butanone, methyl isobutyl ketone, N-methylpyrrolidone, or a combination thereof.
  • the aromatic hydrocarbon solvent is selected from the group consisting of benzene and toluene.
  • step (a) the volume (mL)/mass (mg) ratio of the first solvent to the fisotinib raw material is 1:(20-40).
  • step (a) the reaction temperature is 16-23°C.
  • step (a) the stirring time is selected from 0.5-6d.
  • step (a) the stirring time is 5d.
  • step (a) the stirring time is 1 d.
  • step (b) the collecting includes filtering.
  • the rinsing solvent is selected from water or diethyl ether.
  • step (a) when the solid form is salt crystal form or co-crystal XM-I, step (a) includes:
  • the second solvent is selected from: an alcohol solvent, water or a combination thereof.
  • the alcohol solvent is a C1-C4 alcohol solvent; preferably, the alcohol solvent is selected from methanol, ethanol, isopropanol, n-propanol, or a combination thereof.
  • the alcoholic solvent is isopropanol.
  • step (ii) the stirring is performed at room temperature.
  • step (ii) stirring is performed for 5 days.
  • the volume (mL)/mass (mg) ratio of the second solvent to the fisotinib raw material is 1:(10-20).
  • the mass ratio of the maleic acid to the fisotinib raw material is 1:(1-10).
  • step (a) when the solid form is salt crystal form or co-crystal XM-II, step (a) includes:
  • the third solvent is selected from the group consisting of ketone solvents, water or a combination thereof.
  • the ketone solvent is acetone.
  • step (a) when the solid form is salt crystal form or co-crystal XM-III, step (a) includes:
  • the fourth solvent is selected from the group consisting of alcohol solvents, water, or a combination thereof.
  • the alcohol solvent is a C1-C4 alcohol solvent; preferably, the alcohol solvent is selected from methanol, ethanol, isopropanol, n-propanol, or a combination thereof.
  • the alcoholic solvent is isopropanol.
  • the volume (mL)/mass (mg) ratio of the fourth solvent to the fisotinib raw material is 1:(10-20).
  • step (a) when the solid form is salt crystal form or co-crystal XM-IV, step (a) includes:
  • the fifth solvent is selected from the group consisting of aromatic hydrocarbon solvents.
  • the fifth solvent is toluene.
  • the volume (mL)/mass (mg) ratio of the fifth solvent to the fisotinib raw material is 1:(20-40).
  • step (a) when the solid form is salt crystal form or co-crystal XM-V, step (a) includes:
  • the sixth solvent is selected from the group consisting of aromatic hydrocarbon solvents.
  • the sixth solvent is toluene.
  • the volume (mL)/mass (mg) ratio of the sixth solvent to the fisotinib raw material is 1:(20-40).
  • the mass ratio of the stearic acid and fisotinib raw material is 1:(1-5).
  • the rinsing solvent is diethyl ether.
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) the solid form of fisotinib as the active ingredient in the first aspect of the present invention; and (b) pharmaceutically acceptable accepted vector.
  • the dosage form of the pharmaceutical composition or preparation is selected from the group consisting of powder, capsule, granule, tablet, pill or injection.
  • the pharmaceutical composition is used to treat patients with FGFR4-driven locally advanced or metastatic hepatocellular carcinoma (HCC).
  • HCC locally advanced or metastatic hepatocellular carcinoma
  • the fourth aspect of the present invention provides a use of the pharmaceutical composition according to the third aspect to prepare a medicament for treating patients with FGFR4-driven locally advanced or metastatic hepatocellular carcinoma (HCC).
  • HCC metastatic hepatocellular carcinoma
  • the fifth aspect of the present invention provides the use of the solid form according to the first aspect, the use comprising: 1) preparing a compound of formula (I) or a salt thereof; 2) preparing a compound for the treatment of FGFR4-driven locally advanced or Drugs for patients with metastatic hepatocellular carcinoma (HCC).
  • HCC metastatic hepatocellular carcinoma
  • Fig. 1 is the XRPD pattern of the crystal form I of the present invention.
  • Figure 2 is a TGA diagram of the crystal form I of the present invention.
  • Figure 3 is the DSC chart of the crystal form I of the present invention.
  • Figure 4 is the 1H NMR spectrum of the crystal form I of the present invention.
  • Fig. 5 is the XRPD comparison chart of the crystal form I of the present invention placed at 25°C/60%RH and 40°C/75%RH for one month (from bottom to top in the figure are before placing and placing at 25°C/60%RH, Figure after one month at 40°C/75% RH).
  • Figure 6 is a DVS diagram of the crystal form I of the present invention.
  • Figure 9 is an XRPD pattern of the crystal form II of the present invention.
  • Figure 10 is a TGA diagram of the crystal form II of the present invention.
  • Figure 11 is a DSC chart of the crystal form II of the present invention.
  • Figure 12 is the 1H NMR spectrum of the crystal form II of the present invention.
  • Figure 13 is the XRPD comparison chart of the crystal form II of the present invention placed at 25°C/60%RH and 40°C/75%RH for one month (from bottom to top in the figure are before placing and placing at 25°C/60%RH, Figure after one month at 40°C/75% RH).
  • Figure 14 is a DVS diagram of the crystal form II of the present invention.
  • Figure 15 is the XRPD pattern of the crystal form II of the present invention before and after the DVS test (the bottom picture is the XRPD pattern of the sample before the DVS test, and the top picture is the XRPD pattern of the sample after the DVS test)
  • the XRPD pattern of the crystal form II of the present invention before and after grinding (the bottom picture is the XRPD pattern of the sample before grinding, and the top picture is the XRPD pattern of the sample after grinding).
  • Figure 17 is the XRPD pattern of salt crystal form or co-crystal XM-I of the present invention.
  • Figure 18 is a TGA diagram of the salt crystal form or co-crystal XM-I of the present invention.
  • Figure 19 is the DSC chart of the salt crystal form or co-crystal XM-I of the present invention.
  • Figure 20 is the 1 H NMR spectrum of the salt crystal form or co-crystal XM-I of the present invention.
  • Figure 21 is the XRPD pattern of the salt crystal form or co-crystal XM-II of the present invention.
  • Figure 22 is a TGA diagram of the salt crystal form or co-crystal XM-II of the present invention.
  • Figure 23 is the DSC chart of the salt crystal form or co-crystal XM-II of the present invention.
  • Figure 24 is the 1 H NMR spectrum of the salt crystal form or co-crystal XM-II of the present invention.
  • Figure 25 is the XRPD pattern of the salt crystal form or co-crystal XM-III of the present invention.
  • Figure 26 is a TGA diagram of the salt crystal form or co-crystal XM-III of the present invention.
  • Figure 27 is the DSC chart of the salt crystal form or co-crystal XM-III of the present invention.
  • Figure 28 is the 1 H NMR spectrum of the salt crystal form or co-crystal XM-III of the present invention.
  • Figure 29 is the XRPD pattern of salt crystal form or co-crystal XM-IV of the present invention.
  • Figure 30 is the XRPD pattern of salt crystal form or co-crystal XM-V of the present invention.
  • Figure 31 is a TGA diagram of the salt crystal form or co-crystal XM-V of the present invention.
  • Figure 32 is a DSC chart of the salt crystal form or co-crystal XM-V of the present invention.
  • the inventors After long-term and in-depth research, the inventors provided a crystal form I and crystal form II of the compound of formula (I) fisotinib, as well as salt crystal form or co-crystal-salt crystal form or co-crystal XM-I , XM-II, XM-III, XM-IV and XM-V.
  • the 7 solid forms of fisotinib have at least the following aspects: stability, solubility, hygroscopicity, tableting stability, mechanical stability, fluidity, process developability, formulation development, purification, and powder processing performance. advantage on the one hand. Based on the above findings, the inventors have completed the present invention.
  • starting material for the compound of formula (I) refers to the amorphous (form) and/or various crystalline forms of the compound of formula (I), including the various crystalline and amorphous forms mentioned herein , the crystalline form or amorphous form mentioned in various documents or patents, published or unpublished.
  • the method of adding the solvent or solution is direct pouring or uniform addition, and the like.
  • room temperature generally refers to 4-30°C, preferably 20 ⁇ 5°C.
  • slow addition includes, but is not limited to, dropwise addition, slow addition along the container wall, and the like.
  • the solid form of the compound represented by the formula (I) includes the solid form of the compound represented by the formula (I) or its salt, preferably a crystalline form, preferably including the crystalline form of the compound represented by the formula (I), the formula (I) ), the salt crystal form or co-crystal formed by the compound represented by ) and an acid, wherein the acid is preferably maleic acid, sulfuric acid, hydrochloric acid or stearic acid.
  • Fisotinib crystalline form Fisotinib salt crystalline form or co-crystal
  • crystalline forms of the present invention refer to Form I and Form II, salt forms or co-crystal XM-I, salt form or co-crystal XM-II, salt form as described herein Or co-crystal XM-III, salt form or co-crystal XM-IV and salt form or co-crystal XM-V.
  • the salt crystal form or co-crystal XM-I and XM-II are the crystal form or co-crystal formed by fisotinib and maleic acid
  • the salt crystal form or co-crystal XM-III is the crystal form formed by fisotinib and sulfuric acid.
  • the salt crystal form or co-crystal XM-I is the crystal form or co-crystal formed by fisotinib and maleic acid, and its XRPD pattern includes 3 or more (preferably 6 or more) selected from 2 ⁇ values of the next group: 3.2° ⁇ 0.2°, 5.6° ⁇ 0.2°, 6.5° ⁇ 0.2°, 8.7° ⁇ 0.2°, 9.8° ⁇ 0.2°, 11.4° ⁇ 0.2°, 11.8° ⁇ 0.2°, 13.1° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.0° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.6° ⁇ 0.2°, 23.1° ⁇ 0.2°.
  • the salt crystal form or co-crystal XM-I has an XRPD pattern substantially as shown in FIG. 17 .
  • the salt crystal form or co-crystal XM-I has a TGA diagram substantially as shown in FIG. 18 .
  • the salt crystal form or co-crystal XM-I has a DSC pattern substantially as shown in FIG. 19 .
  • the salt crystal form or co-crystal XM-I has a 1H NMR spectrum substantially as shown in FIG. 20 .
  • the salt crystal form or co-crystal XM-II is the crystal form or co-crystal formed by fisotinib and maleic acid, and its XRPD diagram includes 3 or more (preferably 6 or more) selections.
  • 2 ⁇ values from the next group 4.1° ⁇ 0.2°, 5.9° ⁇ 0.2°, 8.3° ⁇ 0.2°, 12.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.5 ° ⁇ 0.2°, 18.0° ⁇ 0.2°, 19.9° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.7° ⁇ 0.2°, 24.6° ⁇ 0.2°, 25.0° ⁇ 0.2°, 26.1° ⁇ 0.2°, 27.7° ⁇ 0.2°, 29.7° ⁇ 0.2°.
  • the salt crystal form or co-crystal XM-II has an XRPD pattern substantially as shown in Figure 21;
  • the salt crystal form or co-crystal XM-II has a TGA diagram substantially as shown in FIG. 22 ;
  • the salt crystal form or co-crystal XM-II has a DSC chart substantially as shown in Figure 23;
  • the salt crystal form or co-crystal XM-II has a 1H NMR spectrum substantially as shown in FIG. 24 .
  • Salt crystal form or co-crystal XM-III is a crystal form or co-crystal formed by fisotinib and sulfuric acid, and its XRPD pattern includes 6 or more 2 ⁇ values selected from the following group: 5.1° ⁇ 0.2°, 7.2° ⁇ 0.2°, 8.1° ⁇ 0.2°, 10.2° ⁇ 0.2°, 11.7° ⁇ 0.2°, 13.1° ⁇ 0.2°, 15.0° ⁇ 0.2°, 16.2° ⁇ 0.2°, 17.6° ⁇ 0.2°, 19.5° ⁇ 0.2 °, 20.4° ⁇ 0.2°, 21.2° ⁇ 0.2°, 25.2° ⁇ 0.2°, 26.3° ⁇ 0.2°;
  • the salt crystal form or co-crystal XM-III has an XRPD pattern substantially as shown in Figure 25;
  • the salt crystal form or co-crystal XM-III has a TGA diagram substantially as shown in Figure 26;
  • the salt crystal form or co-crystal XM-III has a DSC chart substantially as shown in Figure 27;
  • the salt crystal form or co-crystal XM-III has a 1 H NMR spectrum substantially as shown in FIG. 28 .
  • Salt crystal form or co-crystal XM-IV is the crystal form or co-crystal formed by fisotinib and hydrochloric acid, and its XRPD pattern includes 6 or more 2 ⁇ values selected from the following group: 3.6° ⁇ 0.2°, 5.0° ⁇ 0.2°, 5.4° ⁇ 0.2°, 9.8° ⁇ 0.2°, 13.2° ⁇ 0.2°, 13.8° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.8° ⁇ 0.2 °, 20.8° ⁇ 0.2°, 21.8° ⁇ 0.2°, 24.1° ⁇ 0.2°, 25.1° ⁇ 0.2°, 26.4° ⁇ 0.2°.
  • the salt crystal form or co-crystal XM-IV has an XRPD pattern substantially as shown in FIG. 29 .
  • Salt crystal form or co-crystal XM-V is a crystal form or co-crystal formed by fisotinib and stearic acid, and its XRPD pattern includes 6 or more 2 ⁇ values selected from the following group: 3.8° ⁇ 0.2°, 5.7 ° ⁇ 0.2°, 7.6° ⁇ 0.2°, 9.5° ⁇ 0.2°, 13.3° ⁇ 0.2°, 23.1° ⁇ 0.2°, 24.6° ⁇ 0.2°;
  • the salt crystal form or co-crystal XM-V has an XRPD pattern substantially as shown in Figure 30;
  • the salt crystal form or co-crystal XM-V has a TGA diagram substantially as shown in FIG. 31 ;
  • the salt crystal form or co-crystal XM-V has a DSC pattern substantially as shown in FIG. 32 .
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a solid form of fisotinib as described in the present invention, and optionally, one or more pharmaceutically acceptable carriers, excipients Excipients, adjuvants, excipients and/or diluents.
  • the auxiliary materials are, for example, odorants, flavoring agents, sweeteners, and the like.
  • the pharmaceutical composition provided by the present invention preferably contains 1-99% by weight of active ingredients, and the preferred ratio is that the compound of formula I as an active ingredient accounts for 65wt% to 99wt% of the total weight, and the rest is pharmaceutically acceptable carrier, diluent or solution or saline solution.
  • the compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in suitable solid or liquid carriers or diluents Neutralize in suitable sterile equipment for injection or instillation.
  • Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field.
  • the unit measurement of the formulation contains 1 mg-700 mg of the compound of general formula I, preferably, the unit measurement of the formulation contains 25 mg-300 mg of the compound of general formula I.
  • the compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, by oral, nasal, dermal, pulmonary, or gastrointestinal routes of administration. Most preferred is oral administration.
  • the most preferred daily dose is 50-1400 mg/kg body weight in a single dose, or 25-700 mg/kg body weight in divided doses. Regardless of the method of administration, the optimal dose for an individual will depend on the specific treatment. It is common to start with a small dose and gradually increase the dose until the most suitable dose is found.
  • the pharmaceutical composition of the present invention can be used for the treatment of patients with FGFR4-driven locally advanced or metastatic hepatocellular carcinoma (HCC), and when used for treatment, the solid form of the present invention or the fexotite prepared from the solid form of the present invention Ni (amorphous) can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • HCC locally advanced or metastatic hepatocellular carcinoma
  • the drying method is a conventional drying method in the field.
  • drying in the embodiments of the present invention refers to vacuum drying or normal pressure drying in a conventional drying oven.
  • drying is performed for 0.1 to 50h or 1 to 30h.
  • compositions and methods of administration are provided.
  • the present invention Solid form or fisotinib (amorphous) prepared from the solid form of the present invention and a pharmaceutical combination containing the solid form of the present invention or fisotinib (amorphous) prepared from the solid form of the present invention as the main active ingredient
  • the drug can be used to treat and/or prevent cancer or tumors such as metastatic hepatocellular carcinoma.
  • the solid form of the present invention or the filsotinib (amorphous form) prepared from the solid form of the present invention can be used to prepare the treatment or prevention of cancer or tumor (such as metastatic hepatocellular carcinoma), and the drug can be prepared by methods commonly used in the art. be made of.
  • the pharmaceutical composition of the present invention comprises the solid form of the present invention or fisotinib (amorphous) prepared from the solid form of the present invention within a safe and effective amount, and a pharmaceutically acceptable excipient or carrier.
  • the "safe and effective amount” refers to the amount of the compound (or solid form or amorphous form) sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the crystal form/dose of the present invention, more preferably, 10-200 mg of the crystal form/dose of the present invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • the mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms of the polymorphs of the present invention for topical administration include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the solid forms of the present invention or fisotinib (amorphous) prepared from the solid forms of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the solid form of the present invention or fisotinib (amorphous) prepared from the solid form of the present invention is suitable for a mammal (eg, a human) in need of treatment, wherein the dosage at the time of administration
  • a pharmaceutically effective dose for a person with a body weight of 60 kg, the daily dose is usually 1-2000 mg, preferably 20-500 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the crystal form stability and mechanical stability of the present invention are good.
  • the crystal form of the present invention has good crystal form stability, can reduce the risk of changing the dissolution rate and bioavailability due to the change of the crystal form of the drug, is beneficial to the crystal form control in the crystallization and preparation process, and is also beneficial to Production and storage of products.
  • the crystal form of Form I and Form II did not change before and after grinding, indicating that their mechanical stability is good, which can reduce the risk of crystal transformation caused by crushing the API during the preparation process.
  • the crystal form of the present invention has low hygroscopicity. Under the condition of 40%RH ⁇ 80%RH, the weight gain of crystal form I and crystal form II is 0.7% and 2.2%, respectively, and has low hygroscopicity. Therefore, the crystal form of the present invention does not have strict requirements on packaging and storage conditions, and does not require special drying conditions in the preparation process, which simplifies the preparation and post-treatment processes of the medicine, is beneficial to industrial production, and significantly reduces the production, transportation and storage of medicines. the cost of.
  • the solvent used in the preparation process of the crystal form of the present invention can be selected as a low-toxic or non-toxic solvent, and the preparation method is a conventional, industrially-produced crystallization method, and the particle size, crystal habit can be controlled by controlling the process parameters. And crystal form, etc., and then obtain stable and high-quality products.
  • the solvents used in the present invention are all analytically pure, and the water content is about 0.1%.
  • the compounds of formula (I) used as raw materials in the examples were all purchased. All test methods of the present invention are general methods, and the test parameters are as follows:
  • X-ray powder diffractometer Bruker D2 Phaser X-ray powder diffractometer; radiation source Cu Generator kv: 30kv; Generator mA: 10mA; initial 2 ⁇ : 2.000°, scanning range: 2.0000-35.000°, scanning step size 0.02°, scanning speed 0.1s/step.
  • Thermogravimetric analysis (TGA) instrument TGA55 of TA company in the United States; heating rate: 10° C./min; nitrogen flow rate: 40 mL/min.
  • DSC Differential scanning calorimetry
  • Hydrogen nuclear magnetic resonance data ( 1 H NMR) were obtained from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. 2 mg of the sample was weighed, dissolved in 0.6 mL of deuterated dimethyl sulfoxide, filtered, and the filtrate was added to a NMR tube for testing.
  • Dynamic Moisture Sorption (DVS) Instrument TA Q5000 SA from TA Company, USA; Temperature: 25°C; Nitrogen Flow Rate: 50mL/min; Mass Change per Unit Time: 0.002%/min; Relative Humidity Range: 0%RH ⁇ 90% RH.
  • the drying method is a conventional drying method in the field.
  • drying in the embodiments of the present invention refers to vacuum drying or normal pressure drying in a conventional drying oven.
  • drying is performed for 0.1 to 50h or 1 to 30h.
  • the solid forms of the present invention or fisotinib (amorphous) prepared from the solid forms of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the crystal form I and the crystal form II prepared by the present invention were placed openly for 30 days under different conditions respectively, XRPD detection was performed on the crystal forms before and after placement, and the XRPD patterns of the crystal forms before and after placement were compared.
  • the specific placement conditions and the results after placement are shown in Table 8.
  • the crystal forms I and II provided by the present invention have low hygroscopicity; from the XRPD results, it can be seen that the crystal forms of the crystal forms I and II do not change before and after the DVS test. It can be seen that the crystal form I and the crystal form II of the present invention have the ability to withstand high humidity environment.
  • the obtained solid is tested by XRPD, and the result is shown in Figure 21, and the spectrum data is shown in Table 12; the obtained solid is tested by TGA, and its spectrum is shown in Figure 22; the obtained solid is tested by DSC, and its spectrum is shown in Figure 23.
  • the obtained solid was tested by 1 H NMR, and its spectrum is shown in Figure 24.
  • the obtained solid was tested by XRPD, and the results were shown in Figure 25, and the spectrum data were shown in Table 13; the obtained solid was tested by TGA, and its spectrum was shown in Figure 26; the obtained solid was tested by DSC, and its spectrum was shown in Figure 27. The obtained solid was tested by 1 H NMR, and its spectrum is shown in Figure 28.
  • the obtained solid was tested by XRPD, and the results were shown in Figure 30, and the spectrum data were shown in Table 15; the obtained solid was tested by TGA, and its spectrum was shown in Figure 31; the obtained solid was tested by DSC, and its spectrum was shown in Figure 32. Show.

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Abstract

La présente invention concerne une forme solide de fisogatinib et son procédé de préparation. En particulier, la présente invention concerne une forme solide d'un composé tel que représenté dans la formule I, la forme solide comprenant une forme cristalline I, une forme cristalline II, une forme cristalline de sel ou un eutectique XM-I, une forme cristalline de sel ou un eutectique XM-II, une forme cristalline de sel ou un eutectique XM-III, une forme cristalline de sel ou un cristal eutectique XM-IV, ou une forme cristalline de sel ou un eutectique XM-V. Par comparaison avec les composés de fisogatinib existants, la forme solide selon la présente invention a une meilleure stabilité.
PCT/CN2022/080989 2021-03-16 2022-03-15 Forme solide de fisogatinib et son procédé de préparation WO2022194160A1 (fr)

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CN202110279921.6A CN113045554A (zh) 2021-03-16 2021-03-16 一种非索替尼晶型及其制备方法
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CN202110624546.4A CN115433171A (zh) 2021-06-04 2021-06-04 非索替尼固体形式及其制备方法
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070054916A1 (en) * 2004-10-01 2007-03-08 Amgen Inc. Aryl nitrogen-containing bicyclic compounds and methods of use
CN104540809A (zh) * 2012-07-11 2015-04-22 蓝印药品公司 成纤维细胞生长因子受体的抑制剂
CN105658642A (zh) * 2013-10-25 2016-06-08 蓝图药品公司 纤维母细胞生长因子受体抑制剂
CN113045554A (zh) * 2021-03-16 2021-06-29 上海希迈医药科技有限公司 一种非索替尼晶型及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070054916A1 (en) * 2004-10-01 2007-03-08 Amgen Inc. Aryl nitrogen-containing bicyclic compounds and methods of use
CN104540809A (zh) * 2012-07-11 2015-04-22 蓝印药品公司 成纤维细胞生长因子受体的抑制剂
CN105658642A (zh) * 2013-10-25 2016-06-08 蓝图药品公司 纤维母细胞生长因子受体抑制剂
CN113045554A (zh) * 2021-03-16 2021-06-29 上海希迈医药科技有限公司 一种非索替尼晶型及其制备方法

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