WO2019042383A1 - Crystalline forms of galunisertib, preparation method therefor, and use thereof - Google Patents

Crystalline forms of galunisertib, preparation method therefor, and use thereof Download PDF

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WO2019042383A1
WO2019042383A1 PCT/CN2018/103414 CN2018103414W WO2019042383A1 WO 2019042383 A1 WO2019042383 A1 WO 2019042383A1 CN 2018103414 W CN2018103414 W CN 2018103414W WO 2019042383 A1 WO2019042383 A1 WO 2019042383A1
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crystal form
ray powder
powder diffraction
diffraction pattern
crystalline form
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PCT/CN2018/103414
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French (fr)
Chinese (zh)
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陈敏华
张炎锋
高慧
陈宇浩
张晓宇
刘佳佳
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苏州科睿思制药有限公司
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to the field of pharmaceutical crystal technology. Specifically, it relates to a crystal form of Galunisertib, a preparation method thereof and use thereof.
  • TGF- ⁇ Transforming growth factor- ⁇
  • TGF- ⁇ Transforming growth factor- ⁇
  • the increased expression of TGF- ⁇ is closely related to the progression of various tumors, which can promote tumor growth, suppress the immune system and enhance tumors. Diffusion ability.
  • Galunisertib (LY-2157299) is a TGF-beta receptor kinase inhibitor developed by Lilly, which has the potential to treat myelodysplastic syndromes and solid tumors. Its chemical name is 2-(6-methyl-pyridine -2-yl)-3-[6-amido-quinolin-4-yl]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (hereinafter referred to as "compound (I) "), its structure is as follows:
  • a crystalline form is a different solid form formed by a different arrangement of a compound molecule or an atom in a lattice space.
  • a crystalline form of a drug refers to a solid drug in which a pharmacodynamic component exists in a specific crystalline form, and a drug polymorph refers to the presence or absence of two or two drugs. More than one different crystal form.
  • a monohydrate crystal form of Galunisertib (designated "Crystal Form 1" in the present invention) is currently disclosed in the patent document WO2007018818A1.
  • the inventors of the present application found the crystal form of Galunisertib during the research: crystal-free L, solvate crystal form H and crystal form N.
  • the novel crystal form of Galunisertib provided by the present invention has stability, melting point, solubility, dissolution in vitro and in vivo, moisture permeability, bioavailability, adhesion, compressibility, fluidity and processing.
  • the crystal type has a higher content of active ingredients at the same quality, which provides a new and better choice for the development of drugs containing Galunisertib, which is of great significance.
  • the main object of the present invention is to provide a novel crystal form of Galunisertib and a preparation method thereof.
  • the present invention provides a novel crystalline form of Galunisertib, designated as Form L.
  • the crystalline form L provided by the present invention is an anhydride.
  • the X-ray powder diffraction pattern of the Form L has characteristic peaks at diffraction angles 2 ⁇ of 12.7° ⁇ 0.2°, 22.6° ⁇ 0.2°, and 8.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form L has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ of 24.1° ⁇ 0.2°, 16.7° ⁇ 0.2°, and 18.3° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the crystal form L has a characteristic peak at a diffraction angle 2 ⁇ of 24.1° ⁇ 0.2°, 16.7° ⁇ 0.2°, and 18.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form L has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ of 15.7° ⁇ 0.2°, 19.1° ⁇ 0.2°, and 28.9° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the crystal form L has a characteristic peak at a diffraction angle 2 ⁇ of 15.7° ⁇ 0.2°, 19.1° ⁇ 0.2°, and 28.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form L is 12.7° ⁇ 0.2°, 22.6° ⁇ 0.2°, 8.6° ⁇ 0.2°, 24.1° ⁇ 0.2° at the diffraction angle 2 ⁇ , Any 3, or 4, or 5, or 6, or 7 of 16.7 ° ⁇ 0.2 °, 18.3 ° ⁇ 0.2 °, 15.7 ° ⁇ 0.2 °, 19.1 ° ⁇ 0.2 °, 28.9 ° ⁇ 0.2 ° , or 8 or 9 has characteristic peaks.
  • the X-ray powder diffraction pattern of Form L is substantially as shown in FIG.
  • the present invention also provides a method for preparing the crystal form L, which comprises heating the acetylacetone solvate to a temperature of from 130 ° C to 155 ° C at a rate of 2 to 20 ° C/min, and staying for 2 to Form L was obtained in 10 min.
  • the acetylacetone solvate is Form D of the invention, and the heating rate is 2-10 ° C/min.
  • Form D provides a new crystalline form of Galunisertib, designated as Form D.
  • Form D provided by the present invention is an acetylacetone solvate.
  • the X-ray powder diffraction pattern of Form D is substantially as shown in FIG.
  • the present invention also provides a preparation method of the crystal form D, which comprises adding a Galunisertib free base to an acetylacetone solvent, stirring at a temperature of 50 ° C to 100 ° C, centrifuging and drying to obtain a crystal form. D.
  • the stirring temperature is 80 °C.
  • the crystal form L of the present invention has a higher solubility than the prior art. Particularly in FaSSIF, FeSSIF, H 2 O, the solubility is four times that of the prior art crystal form 1.
  • Higher solubility is beneficial to increase the speed and extent of absorption of the drug in the human body, so that the drug can exert a better therapeutic effect; in addition, higher solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the drug's Side effects and improve the safety of the drug.
  • the crystal form L provided by the present invention has good physical and chemical stability.
  • the crystalline form L drug substance is placed at 25 ° C / 60% RH, 40 ° C / 75% RH, 60 ° C / 75% RH, the crystal form does not change for at least 7 weeks, and is placed at 80 ° C for at least 1 week.
  • the type has not changed, and the chemical purity is above 99%, and the purity remains basically unchanged during storage.
  • Form L has good physical and chemical stability, ensuring consistent controllable quality of the drug substance and preparation, and maximally reducing the toxicity of the drug due to crystal form change, and ensuring the efficacy of the drug.
  • the present invention provides a novel crystalline form of Galunisertib, designated as Form H.
  • the crystalline form H provided by the present invention is an acetic acid solvate having a molar ratio of Galunisertib to acetic acid of 1:2.
  • the X-ray powder diffraction pattern of the Form H has characteristic peaks at diffraction angles 2 ⁇ of 25.2° ⁇ 0.2°, 15.5° ⁇ 0.2°, and 6.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form H has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ of 12.3° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 22.6° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the Form H has a characteristic peak at a diffraction angle 2 ⁇ of 12.3° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 22.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form H has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ of 13.6° ⁇ 0.2°, 24.2° ⁇ 0.2°, and 26.6° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the Form H has a characteristic peak at a diffraction angle 2 ⁇ of 13.6° ⁇ 0.2°, 24.2° ⁇ 0.2°, and 26.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form H is 25.2° ⁇ 0.2°, 15.5° ⁇ 0.2°, 6.5° ⁇ 0.2°, 12.3° ⁇ 0.2° at the diffraction angle 2 ⁇ , Any of 18.0° ⁇ 0.2°, 22.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 24.2° ⁇ 0.2°, 26.6° ⁇ 0.2°, 11.3° ⁇ 0.2°, 18.7° ⁇ 0.2°, 22.9° ⁇ 0.2° There are characteristic peaks at 3, or 4, or 5, or 6, or 7, or 8, or 9 or 10, or 11 or 12 .
  • the X-ray powder diffraction pattern of Form H is substantially as shown in FIG.
  • the present invention also provides a preparation method of the crystal form H, which comprises adding a Galunisertib free base to acetic acid or a mixed solvent of acetic acid and an alkane solvent at a temperature of 40 ° C to 80 ° C. The mixture was stirred, and the precipitate was centrifuged and dried to obtain Form H.
  • the stirring temperature is 50 ° C
  • the alkane is n-heptane.
  • the crystalline form H of the present invention has a higher solubility than the prior art. Particularly in H 2 O, the solubility is 35 times that of the prior art crystal form 1.
  • Higher solubility is beneficial to increase the speed and extent of absorption of the drug in the human body, so that the drug can exert a better therapeutic effect; in addition, higher solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the drug's Side effects and improve the safety of the drug.
  • the present invention provides a novel crystalline form of Galunisertib, designated as Form N.
  • the crystal form N provided by the present invention is an acetic acid solvate, and the molar ratio of the Galunisertib compound to acetic acid is 1:1.
  • the X-ray powder diffraction pattern of the Form N has characteristic peaks at diffraction angles 2 ⁇ of 16.1° ⁇ 0.2°, 12.1° ⁇ 0.2°, and 7.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form N has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ of 26.4° ⁇ 0.2°, 23.3° ⁇ 0.2°, and 27.0° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the Form N has a characteristic peak at a diffraction angle 2 ⁇ of 26.4° ⁇ 0.2°, 23.3° ⁇ 0.2°, and 27.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form N has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ of 18.4° ⁇ 0.2°, 14.9° ⁇ 0.2°, 28.2° ⁇ 0.2°; Preferably, the X-ray powder diffraction pattern of the Form N has a characteristic peak at a diffraction angle 2 ⁇ of 18.4° ⁇ 0.2°, 14.9° ⁇ 0.2°, 28.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form N is 16.1° ⁇ 0.2°, 12.1° ⁇ 0.2°, 7.4° ⁇ 0.2°, 26.4° ⁇ 0.2° at the diffraction angle 2 ⁇ , Any 3, or 4, or 5, or 6, or 7 of 23.3 ° ⁇ 0.2 °, 27.0 ° ⁇ 0.2 °, 18.4 ° ⁇ 0.2 °, 14.9 ° ⁇ 0.2 °, 28.2 ° ⁇ 0.2 ° , or 8 or 9 has characteristic peaks.
  • the X-ray powder diffraction pattern of Form N is substantially as shown in FIG.
  • Form C is heated to a temperature of from 140 ° C to 145 ° C at a rate of 5 to 20 ° C / min in a closed environment, and is allowed to stand for 1 to 5 minutes to obtain Form N.
  • the heating rate is 10 ° C / min
  • the heating temperature is 142 ° C
  • the residence time is 2 min.
  • the crystal form N provided by the present invention has good physical and chemical stability.
  • the Form N drug substance is placed at 25 ° C / 60% RH, the crystal form does not change for at least 5 weeks, and the chemical purity is above 99%, and the purity remains substantially unchanged during storage.
  • Form N has good physicochemical stability, ensuring consistent controllable quality of the drug substance and preparation, and maximally reducing the toxicity of the drug due to crystal form change, ensuring the efficacy of the drug.
  • the crystal form N of the present invention has a higher solubility than the prior art. Particularly in H 2 O, the solubility is 24 times that of the prior art crystal form 1.
  • Higher solubility is beneficial to increase the speed and extent of absorption of the drug in the human body, so that the drug can exert a better therapeutic effect; in addition, higher solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the drug's Side effects and improve the safety of the drug.
  • the present invention provides a novel crystalline form of Galunisertib, designated Form E.
  • Form E provided by the present invention is a 2-hexanone solvate.
  • the X-ray powder diffraction pattern of Form E is substantially as shown in FIG.
  • the present invention also provides a preparation method of the crystal form E, which comprises adding a Galunisertib free base to a 2-hexanone solvent, and stirring at a temperature of 50 ° C to 100 ° C to precipitate The product was centrifuged and dried to obtain crystal form E.
  • the stirring temperature is 80 °C.
  • crystal or “crystal form” refers to the characterization by the X-ray diffraction pattern shown.
  • Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the “stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the "drying" can be carried out at room temperature or higher. Dry at room temperature to 60 ° C, or to 40 ° C, or to 50 ° C.
  • the drying time can be from 2 to 48 hours, or overnight. Drying is carried out in a fume hood, a forced air oven or a vacuum oven.
  • Form L, Form H, and Form N of the present invention are pure, substantially free of any other crystalline form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and prophylactically effective amount of Form L of the present invention, Form H and Form N, or any mixture thereof, and a pharmaceutically acceptable carrier, diluted Agent or excipient.
  • the present invention provides the use of crystal form L, Form H and Form N of Galunisertib or any mixture thereof in the preparation of a TGF- ⁇ receptor kinase inhibitor drug.
  • the present invention provides the use of crystal form L, Form H and Form N of Galunisertib or any mixture thereof in the preparation of a medicament for treating myelodysplastic syndrome.
  • the present invention provides the use of Form L, Form H and Form N of Galunisertib, or any mixture thereof, for the preparation of a medicament for the treatment of solid tumors.
  • the crystal form L, the crystal form H and the crystal form N of the Galunisertib provided by the present invention have stability, melting point, solubility, in vitro and in vivo dissolution, wettability, bioavailability, adhesion, compressibility, fluidity and processability, There is an advantage in at least one of purification, preparation and the like, in particular, low moisture permeability, high solubility, good stability, uniform particle size, and the crystal-free type provided by the present invention compared to the prior art crystal form 1.
  • the active ingredient content is higher at the same quality. It is very important to provide new and better choices for drug development with Galunisertib.
  • Figure 1 is an XRPD pattern of Form D.
  • Figure 2 is a DSC diagram of Form D.
  • Figure 3 is a TGA diagram of Form D.
  • Figure 1 is a 1 H NMR chart of Form D.
  • Figure 5 is an XRPD pattern of Form E.
  • Figure 6 is a DSC diagram of Form E.
  • Figure 7 is a TGA diagram of Form E.
  • Figure 1 is a 1 H NMR chart of Form E.
  • Figure 9 is an XRPD pattern of Form L.
  • Figure 10 is a DSC diagram of Form L.
  • Figure 11 is a TGA diagram of Form L.
  • Figure 1 is a 1 H NMR chart of Form L.
  • Figure 13 is an XRPD pattern of Form H.
  • Figure 14 is a DSC chart of Form H.
  • Figure 15 is a TGA diagram of Form H.
  • Figure 16 is a 1 H NMR chart of Form H.
  • Figure 17 is an XRPD pattern of Form N.
  • Figure 18 is a DSC diagram of Form N.
  • Figure 19 is a TGA diagram of Form N.
  • Figure 1 is a 1 H NMR chart of Form N.
  • Figure 21 XRPD comparison of the stability of crystal form L (XRPD from top to bottom, XRPD, 7 weeks after 25 ° C / 60% RH, and 7 weeks at 40 ° C / 75% RH) After XRPD, XRPD after 7 weeks at 60 ° C / 75% RH, and XRPD after 1 week at 80 ° C).
  • Figure 22 is a comparison of XRPD of Form N stability (from top to bottom, starting XRPD, XRPD after 5 weeks at 25 ° C / 60% RH).
  • the X-ray powder diffraction pattern of the present invention was collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the DSC map of the present invention was acquired on a TA Q2000.
  • the method parameters of the DSC according to the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
  • HPLC high performance liquid chromatography
  • DAD diode array detector
  • the elution gradient is as follows:
  • the Galunisertib starting material used in the following examples can be prepared according to the method described in the prior art WO2007018818A1, and the prepared Galunisertib raw material is a monohydrate crystalline form.
  • the first endothermic peak begins to appear at 149 ° C
  • the second endothermic peak begins at 187 ° C
  • the third endothermic peak begins to appear at 248 ° C.
  • Figure 2 shows.
  • thermogravimetric analysis when heated to 180 ° C, it had a mass loss of 11.8%, and its TGA is shown in FIG.
  • the crystal form D is an acetylacetone solvate in which the molar ratio of the Galunisertib compound to acetylacetone is 1:0.5, wherein the acetylacetone has two isomers of a keto form and an enol form.
  • Form D 6 mg was weighed and subjected to a heating test on a DSC instrument.
  • the sample was capped but not compacted, heated to 150 ° C at 10 ° C / min, and left for 5 min to obtain a solid.
  • the obtained solid was a crystalline form L, and its X-ray powder diffraction data is shown in Table 3, and its XRPD pattern is shown in FIG.
  • the first endothermic peak begins to appear at 186 ° C, followed by an exothermic peak, and a second endothermic peak begins to appear at 248 ° C.
  • the DSC chart is shown in FIG. When subjected to thermogravimetric analysis, it had a mass loss of 2.8% when heated to 150 ° C, and its TGA pattern is shown in FIG.
  • Simulated gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release. The effect of the solubility tested in such media is closer to that in the human environment.
  • the crystal form L of the present invention and 30 mg of WO2007018818A1 crystal form 1 were respectively dissolved in 2 mL of SGF, 2 mL of FaSSIF, 2 mL of FeSSIF and 2 mL of water to prepare a saturated solution, and after 0.25 hours of equilibration, the saturated solution was tested by high performance liquid chromatography.
  • the content of the sample (mg/mL), the results are shown in Table 4.
  • Form L has higher solubility in SGF, FaSSIF, FeSSIF and water than prior art Form 1, especially in FaSSIF, FeSSIF, H 2 O, crystal form.
  • the solubility of L is about four times that of WO2007018818A1 Form 1.
  • the crystal form L can be stable for at least 7 weeks at 25 ° C / 60% RH, 40 ° C / 75% RH, 60 ° C / 75% RH, and stable for at least 1 week at 80 ° C, crystal form and chemistry.
  • the purity remains basically unchanged, and the crystal form L has good physical and chemical stability.
  • the first endothermic peak begins to appear at 143 ° C, followed by a second endothermic peak at 157 ° C, and a third endothermic peak at 245 ° C, DSC As shown in Figure 14.
  • thermogravimetric analysis when heated to 160 ° C, it had a mass loss of 24.4%, and its TGA chart is shown in FIG.
  • the crystal form H liquid hydrogen spectrum nucleus is shown in Fig. 16.
  • the crystal form H is an acetic acid solvate in which the molar ratio of the Galunisertib compound to acetic acid is 1:2.
  • Simulated gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release. The effect of the solubility tested in such media is closer to that in the human environment.
  • the crystal form H of the present invention and 30 mg of WO2007018818A1 crystal form 1 were respectively dissolved in 2 mL of SGF, 2 mL of FaSSIF, 2 mL of FeSSIF and 2 mL of water to prepare a saturated solution, and after 0.25 hours of equilibration, the saturated solution was tested by high performance liquid chromatography.
  • the content of the sample (mg/mL), the results are shown in Table 7.
  • Form H 6 mg was weighed and subjected to a heating test on a DSC instrument, and the lid was heated to 142 ° C at 10 ° C / min for 2 min to obtain a solid.
  • the obtained solid was a crystalline form N, and its X-ray powder diffraction data is shown in Table 8, and its XRPD pattern is shown in FIG.
  • the first endothermic peak begins to appear when heated to 145 ° C
  • a second endothermic peak begins to appear when heated to 247 ° C.
  • the DSC is shown in FIG.
  • thermogravimetric analysis when heated to 180 ° C, it had a mass loss of 13.2%, and its TGA is shown in FIG.
  • the liquid hydrogen spectrum nucleus is shown in Fig. 20.
  • the crystal form N is an acetic acid solvate in which the molar ratio of the Galunisertib compound to acetic acid is 1:1.
  • Simulated gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release. The effect of the solubility tested in such media is closer to that in the human environment.
  • the crystal form N of the present invention and 30 mg of WO2007018818A1 crystal form 1 were respectively dissolved in 2 mL of SGF, 2 mL of FaSSIF, 2 mL of FeSSIF and 2 mL of water to prepare a saturated solution, and after 0.25 hours of equilibration, the saturated solution was tested by high performance liquid chromatography.
  • the content of the sample (mg/mL), the results are shown in Table 10.
  • Form N has higher solubility in SGF, FaSSIF, FeSSIF and water than in the prior art Form 1, especially in water, the solubility of Form N is about 24 times that of the prior art Form 1.

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Abstract

The present invention relates to a crystalline form L, a crystalline form H, and a crystalline form N of galunisertib, a preparation method therefor, and a use thereof, a pharmaceutical composition containing the crystalline forms, and a use of the crystalline forms for preparing a pharmaceutical preparation for the treatment of myelodysplastic syndrome. The crystalline form L, the crystalline form H, and the crystalline form N provided by the present invention have one or more improved characteristics over those in the prior art and are of great value for future optimization and development of the drug.

Description

Galunisertib的晶型及其制备方法和用途Crystal form of Galunisertib and preparation method and use thereof 技术领域Technical field
本发明涉及药物晶体技术领域。具体而言，涉及Galunisertib的晶型及其制备方法和用途。The invention relates to the field of pharmaceutical crystal technology. Specifically, it relates to a crystal form of Galunisertib, a preparation method thereof and use thereof.
背景技术Background technique
转化生长因子-β(TGF-β)是具有多种肿瘤支撑作用的多效性细胞因子，TGF-β的表达增加与多种肿瘤的进展密切相关，能够促进肿瘤生长、抑制免疫系统和增强肿瘤扩散能力。Transforming growth factor-β (TGF-β) is a pleiotropic cytokine with multiple tumor supporting effects. The increased expression of TGF-β is closely related to the progression of various tumors, which can promote tumor growth, suppress the immune system and enhance tumors. Diffusion ability.
Galunisertib(LY-2157299)是由礼来开发的一种TGF-β受体激酶抑制剂，具有治疗骨髓增生异常综合征和实体瘤的潜力，其化学名称为：2-(6-甲基-吡啶-2-基)-3-[6-酰氨基-喹啉-4-基]-5，6-二氢-4H-吡咯并[1，2-b]吡唑(以下称“化合物(I)”)，其结构如下：Galunisertib (LY-2157299) is a TGF-beta receptor kinase inhibitor developed by Lilly, which has the potential to treat myelodysplastic syndromes and solid tumors. Its chemical name is 2-(6-methyl-pyridine -2-yl)-3-[6-amido-quinolin-4-yl]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (hereinafter referred to as "compound (I) "), its structure is as follows:
Figure PCTCN2018103414-appb-000001
Figure PCTCN2018103414-appb-000001
化合物(I)Compound (I)
晶型是化合物分子或原子在晶格空间排列不同而形成的不同固体形态，晶型药物是指药效成分以特定晶型状态存在的固体药物，药物多晶型是指药物存在两种或两种以上的不同晶型。A crystalline form is a different solid form formed by a different arrangement of a compound molecule or an atom in a lattice space. A crystalline form of a drug refers to a solid drug in which a pharmacodynamic component exists in a specific crystalline form, and a drug polymorph refers to the presence or absence of two or two drugs. More than one different crystal form.
由于不同晶型的药物可能会影响其在体内的溶出、吸收，进而可能在一定程度上影响药物的临床疗效和安全性；特别是对一些难溶性口服固体或半固体药物，晶型的影响会更大。因此，在研制固体口服制剂时，对晶型的研究有利于选择一种在临床治疗上有意义且稳定可控的晶型。从药物质量监管的角度看，药物晶型必然是药物研究、检测和监管的重要内容，也是药物质量控制的重要内容。Because different crystal forms of the drug may affect its dissolution and absorption in the body, which may affect the clinical efficacy and safety of the drug to some extent; especially for some poorly soluble oral solid or semi-solid drugs, the effect of crystal form will Bigger. Therefore, in the development of solid oral formulations, the study of crystalline forms facilitates the selection of a crystalline form that is clinically therapeutically meaningful and stable and controllable. From the perspective of drug quality supervision, drug crystal form must be an important part of drug research, detection and supervision, and an important part of drug quality control.
目前仅有专利文献WO2007018818A1中公开了Galunisertib的一个一水合物晶型(本发明中命名为“晶型1”)。本申请发明人在研究过程中发现Galunisertib的晶型：无水晶型L，溶剂合物晶型H和晶型N。不同于WO2007018818A1中的晶型1，本发明提供的Galunisertib的新晶型，其在稳定性、熔点、溶解度、体内外溶出、引湿性、生物有效性、黏附性、可 压性、流动性以及加工性能、提纯作用、制剂生产等方面中的至少一方面上存在优势，特别是引湿性低、溶解度高、稳定性好、粒径均一，且相对于现有技术晶型1，本发明提供的无水晶型在同等质量下有效成分含量更高，为含Galunisertib的药物开发提供了新的更好的选择，具有非常重要的意义。A monohydrate crystal form of Galunisertib (designated "Crystal Form 1" in the present invention) is currently disclosed in the patent document WO2007018818A1. The inventors of the present application found the crystal form of Galunisertib during the research: crystal-free L, solvate crystal form H and crystal form N. Different from Form 1 in WO2007018818A1, the novel crystal form of Galunisertib provided by the present invention has stability, melting point, solubility, dissolution in vitro and in vivo, moisture permeability, bioavailability, adhesion, compressibility, fluidity and processing. There are advantages in at least one of performance, purification, formulation production and the like, in particular, low wettability, high solubility, good stability, uniform particle size, and no relative to the prior art crystal form 1. The crystal type has a higher content of active ingredients at the same quality, which provides a new and better choice for the development of drugs containing Galunisertib, which is of great significance.
发明内容Summary of the invention
本发明主要目的是提供Galunisertib的新晶型及其制备方法。The main object of the present invention is to provide a novel crystal form of Galunisertib and a preparation method thereof.
根据本发明的目的，本发明提供Galunisertib的新晶型，命名为晶型L。本发明提供的晶型L是无水物。In accordance with the purpose of the present invention, the present invention provides a novel crystalline form of Galunisertib, designated as Form L. The crystalline form L provided by the present invention is an anhydride.
一方面，使用Cu-Kα辐射，所述晶型L的X射线粉末衍射图在衍射角2θ为12.7°±0.2°、22.6°±0.2°、8.6°±0.2°处有特征峰。In one aspect, using Cu-Kα radiation, the X-ray powder diffraction pattern of the Form L has characteristic peaks at diffraction angles 2θ of 12.7°±0.2°, 22.6°±0.2°, and 8.6°±0.2°.
进一步地，所述晶型L的X射线粉末衍射图在衍射角2θ为24.1°±0.2°、16.7°±0.2°、18.3°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型L的X射线粉末衍射图在衍射角2θ为24.1°±0.2°、16.7°±0.2°、18.3°±0.2°处有特征峰。Further, the X-ray powder diffraction pattern of the crystal form L has a characteristic peak at one or two or three points in the diffraction angle 2θ of 24.1°±0.2°, 16.7°±0.2°, and 18.3°±0.2°; Preferably, the X-ray powder diffraction pattern of the crystal form L has a characteristic peak at a diffraction angle 2θ of 24.1°±0.2°, 16.7°±0.2°, and 18.3°±0.2°.
进一步地，所述晶型L的X射线粉末衍射图在衍射角2θ为15.7°±0.2°、19.1°±0.2°、28.9°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型L的X射线粉末衍射图在衍射角2θ为15.7°±0.2°、19.1°±0.2°、28.9°±0.2°处有特征峰。Further, the X-ray powder diffraction pattern of the crystal form L has a characteristic peak at one or two or three points in the diffraction angle 2θ of 15.7°±0.2°, 19.1°±0.2°, and 28.9°±0.2°; Preferably, the X-ray powder diffraction pattern of the crystal form L has a characteristic peak at a diffraction angle 2θ of 15.7°±0.2°, 19.1°±0.2°, and 28.9°±0.2°.
另一方面，使用Cu-Kα辐射，所述晶型L的X射线粉末衍射图在衍射角2θ为12.7°±0.2°、22.6°±0.2°、8.6°±0.2°、24.1°±0.2°、16.7°±0.2°、18.3°±0.2°、15.7°±0.2°、19.1°±0.2°、28.9°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form L is 12.7°±0.2°, 22.6°±0.2°, 8.6°±0.2°, 24.1°±0.2° at the diffraction angle 2θ, Any 3, or 4, or 5, or 6, or 7 of 16.7 ° ± 0.2 °, 18.3 ° ± 0.2 °, 15.7 ° ± 0.2 °, 19.1 ° ± 0.2 °, 28.9 ° ± 0.2 ° , or 8 or 9 has characteristic peaks.
非限制性地，所述晶型L的X射线粉末衍射图基本如图9所示。Without limitation, the X-ray powder diffraction pattern of Form L is substantially as shown in FIG.
根据本发明的目的，本发明还提供所述晶型L的制备方法，所述制备方法包括：将乙酰丙酮溶剂合物以2-20℃/min速率加热至130℃～155℃，停留2～10min得到晶型L。According to the object of the present invention, the present invention also provides a method for preparing the crystal form L, which comprises heating the acetylacetone solvate to a temperature of from 130 ° C to 155 ° C at a rate of 2 to 20 ° C/min, and staying for 2 to Form L was obtained in 10 min.
优选地，所述乙酰丙酮溶剂合物为本发明晶型D，所述加热速率为2-10℃/min。Preferably, the acetylacetone solvate is Form D of the invention, and the heating rate is 2-10 ° C/min.
进一步地，本发明提供Galunisertib的新晶型，命名为晶型D。本发明提供的晶型D是乙酰丙酮溶剂合物。Further, the present invention provides a new crystalline form of Galunisertib, designated as Form D. Form D provided by the present invention is an acetylacetone solvate.
非限制性地，所述晶型D的X射线粉末衍射图基本如图1所示。Without limitation, the X-ray powder diffraction pattern of Form D is substantially as shown in FIG.
更进一步地，本发明还提供所述晶型D的制备方法，所述制备方法包括：将Galunisertib游离碱加入到乙酰丙酮溶剂中，在50℃-100℃温度下搅拌，离心、干燥得到晶型D。Further, the present invention also provides a preparation method of the crystal form D, which comprises adding a Galunisertib free base to an acetylacetone solvent, stirring at a temperature of 50 ° C to 100 ° C, centrifuging and drying to obtain a crystal form. D.
优选的，所述搅拌温度为80℃。Preferably, the stirring temperature is 80 °C.
本发明提供的晶型L具有以下有益效果：The crystal form L provided by the present invention has the following beneficial effects:
(1)与现有技术相比，本发明晶型L具有较高的溶解度。特别是在FaSSIF、FeSSIF、H 2O中，溶解度是现有技术晶型1的4倍。 (1) The crystal form L of the present invention has a higher solubility than the prior art. Particularly in FaSSIF, FeSSIF, H 2 O, the solubility is four times that of the prior art crystal form 1.
更高的溶解度有利于提高药物在人体内被吸收的速度和程度，使药物发挥更好的治疗作用；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。Higher solubility is beneficial to increase the speed and extent of absorption of the drug in the human body, so that the drug can exert a better therapeutic effect; in addition, higher solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the drug's Side effects and improve the safety of the drug.
(2)本发明提供的晶型L物理、化学稳定性好。晶型L原料药在25℃/60％RH、40℃/75％RH、60℃/75％RH条件下放置，至少7周晶型未发生变化，在80℃条件下放置，至少1周晶型未发生变化，且化学纯度在99％以上，储存过程中纯度基本保持不变。(2) The crystal form L provided by the present invention has good physical and chemical stability. The crystalline form L drug substance is placed at 25 ° C / 60% RH, 40 ° C / 75% RH, 60 ° C / 75% RH, the crystal form does not change for at least 7 weeks, and is placed at 80 ° C for at least 1 week. The type has not changed, and the chemical purity is above 99%, and the purity remains basically unchanged during storage.
晶型的转变会导致药物的吸收发生变化，影响药物的毒副作用，尤其是在毒性靶器官中的浓度变化，直接影响药物的毒副作用。晶型L具有良好的物理化学稳定性，保证原料药和制剂质量一致可控，最大可能地减少药物由于晶型改变引起的毒性增加，保证药物疗效发挥。The transformation of the crystal form will lead to changes in the absorption of the drug, affecting the toxic side effects of the drug, especially the concentration change in the toxic target organ, directly affecting the toxic side effects of the drug. Form L has good physical and chemical stability, ensuring consistent controllable quality of the drug substance and preparation, and maximally reducing the toxicity of the drug due to crystal form change, and ensuring the efficacy of the drug.
根据本发明的目的，本发明提供Galunisertib的新晶型，命名为晶型H。本发明提供的晶型H是乙酸溶剂合物，Galunisertib与乙酸的摩尔比为1:2。In accordance with the purpose of the present invention, the present invention provides a novel crystalline form of Galunisertib, designated as Form H. The crystalline form H provided by the present invention is an acetic acid solvate having a molar ratio of Galunisertib to acetic acid of 1:2.
一方面，使用Cu-Kα辐射，所述晶型H的X射线粉末衍射图在衍射角2θ为25.2°±0.2°、15.5°±0.2°、6.5°±0.2°处有特征峰。In one aspect, using Cu-Kα radiation, the X-ray powder diffraction pattern of the Form H has characteristic peaks at diffraction angles 2θ of 25.2°±0.2°, 15.5°±0.2°, and 6.5°±0.2°.
进一步的，所述晶型H的X射线粉末衍射图在衍射角2θ为12.3°±0.2°、18.0°±0.2°、22.6°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型H的X射线粉末衍射图在衍射角2θ为12.3°±0.2°、18.0°±0.2°、22.6°±0.2°处有特征峰。Further, the X-ray powder diffraction pattern of the Form H has a characteristic peak at one or two or three points in the diffraction angle 2θ of 12.3°±0.2°, 18.0°±0.2°, and 22.6°±0.2°; Preferably, the X-ray powder diffraction pattern of the Form H has a characteristic peak at a diffraction angle 2θ of 12.3°±0.2°, 18.0°±0.2°, and 22.6°±0.2°.
进一步的，所述晶型H的X射线粉末衍射图在衍射角2θ为13.6°±0.2°、24.2°±0.2°、26.6°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型H的X射线粉末衍射图在衍射角2θ为13.6°±0.2°、24.2°±0.2°、26.6°±0.2°处有特征峰。Further, the X-ray powder diffraction pattern of the Form H has a characteristic peak at one or two or three points in the diffraction angle 2θ of 13.6°±0.2°, 24.2°±0.2°, and 26.6°±0.2°; Preferably, the X-ray powder diffraction pattern of the Form H has a characteristic peak at a diffraction angle 2θ of 13.6°±0.2°, 24.2°±0.2°, and 26.6°±0.2°.
另一方面，使用Cu-Kα辐射，所述晶型H的X射线粉末衍射图在衍射角2θ为25.2°±0.2°、15.5°±0.2°、6.5°±0.2°、12.3°±0.2°、18.0°±0.2°、22.6°±0.2°、13.6°±0.2°、24.2°±0.2°、26.6°±0.2°、11.3°±0.2°、18.7°±0.2°、22.9°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处或10处、或11处、或12处有特征峰。On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the Form H is 25.2°±0.2°, 15.5°±0.2°, 6.5°±0.2°, 12.3°±0.2° at the diffraction angle 2θ, Any of 18.0°±0.2°, 22.6°±0.2°, 13.6°±0.2°, 24.2°±0.2°, 26.6°±0.2°, 11.3°±0.2°, 18.7°±0.2°, 22.9°±0.2° There are characteristic peaks at 3, or 4, or 5, or 6, or 7, or 8, or 9 or 10, or 11 or 12 .
非限制性地，所述晶型H的X射线粉末衍射图基本如图13所示。Without limitation, the X-ray powder diffraction pattern of Form H is substantially as shown in FIG.
根据本发明的目的，本发明还提供所述晶型H的制备方法，所述制备方法包括：将Galunisertib游离碱加入到乙酸或者乙酸和烷烃类溶剂的混合溶剂中，在40℃-80℃温度下搅拌，将析出物离心、干燥得到晶型H。According to the object of the present invention, the present invention also provides a preparation method of the crystal form H, which comprises adding a Galunisertib free base to acetic acid or a mixed solvent of acetic acid and an alkane solvent at a temperature of 40 ° C to 80 ° C. The mixture was stirred, and the precipitate was centrifuged and dried to obtain Form H.
优选的，所述搅拌温度为50℃，所述烷烃类为正庚烷。Preferably, the stirring temperature is 50 ° C, and the alkane is n-heptane.
本发明提供的晶型H具有以下有益效果：The crystal form H provided by the present invention has the following beneficial effects:
与现有技术相比，本发明晶型H具有较高的溶解度。特别是在H 2O中，溶解度是现有技术晶型1的35倍。 The crystalline form H of the present invention has a higher solubility than the prior art. Particularly in H 2 O, the solubility is 35 times that of the prior art crystal form 1.
更高的溶解度有利于提高药物在人体内被吸收的速度和程度，使药物发挥更好的治疗作用；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。Higher solubility is beneficial to increase the speed and extent of absorption of the drug in the human body, so that the drug can exert a better therapeutic effect; in addition, higher solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the drug's Side effects and improve the safety of the drug.
根据本发明的目的，本发明提供Galunisertib的新晶型，命名为晶型N。本发明提供的晶型N是乙酸溶剂合物，Galunisertib化合物与乙酸的摩尔比为1:1。In accordance with the purpose of the present invention, the present invention provides a novel crystalline form of Galunisertib, designated as Form N. The crystal form N provided by the present invention is an acetic acid solvate, and the molar ratio of the Galunisertib compound to acetic acid is 1:1.
一方面，使用Cu-Kα辐射，所述晶型N的X射线粉末衍射图在衍射角2θ为16.1°±0.2°、12.1°±0.2°、7.4°±0.2°处有特征峰。In one aspect, using Cu-Kα radiation, the X-ray powder diffraction pattern of the Form N has characteristic peaks at diffraction angles 2θ of 16.1°±0.2°, 12.1°±0.2°, and 7.4°±0.2°.
进一步的，所述晶型N的X射线粉末衍射图在衍射角2θ为26.4°±0.2°、23.3°±0.2°、27.0°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型N的X射线粉末衍射图在衍射角2θ为26.4°±0.2°、23.3°±0.2°、27.0°±0.2°处有特征峰。Further, the X-ray powder diffraction pattern of the Form N has a characteristic peak at one or two or three points in the diffraction angle 2θ of 26.4°±0.2°, 23.3°±0.2°, and 27.0°±0.2°; Preferably, the X-ray powder diffraction pattern of the Form N has a characteristic peak at a diffraction angle 2θ of 26.4°±0.2°, 23.3°±0.2°, and 27.0°±0.2°.
进一步的，所述晶型N的X射线粉末衍射图在衍射角2θ为18.4°±0.2°、14.9°±0.2°、28.2°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型N的X射线粉末衍射图在衍射角2θ为18.4°±0.2°、14.9°±0.2°、28.2°±0.2°处有特征峰。Further, the X-ray powder diffraction pattern of the Form N has a characteristic peak at one or two or three points in the diffraction angle 2θ of 18.4°±0.2°, 14.9°±0.2°, 28.2°±0.2°; Preferably, the X-ray powder diffraction pattern of the Form N has a characteristic peak at a diffraction angle 2θ of 18.4°±0.2°, 14.9°±0.2°, 28.2°±0.2°.
另一方面，使用Cu-Kα辐射，所述晶型N的X射线粉末衍射图在衍射角2θ为16.1°±0.2°、12.1°±0.2°、7.4°±0.2°、26.4°±0.2°、23.3°±0.2°、27.0°±0.2°、18.4°±0.2°、14.9°±0.2°、28.2°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N is 16.1°±0.2°, 12.1°±0.2°, 7.4°±0.2°, 26.4°±0.2° at the diffraction angle 2θ, Any 3, or 4, or 5, or 6, or 7 of 23.3 ° ± 0.2 °, 27.0 ° ± 0.2 °, 18.4 ° ± 0.2 °, 14.9 ° ± 0.2 °, 28.2 ° ± 0.2 ° , or 8 or 9 has characteristic peaks.
非限制性地，所述晶型N的X射线粉末衍射图基本如图17所示。Without limitation, the X-ray powder diffraction pattern of Form N is substantially as shown in FIG.
将晶型H在密闭环境下以5～20℃/min速率加热至140℃～145℃，停留1～5min得到晶型N。Form C is heated to a temperature of from 140 ° C to 145 ° C at a rate of 5 to 20 ° C / min in a closed environment, and is allowed to stand for 1 to 5 minutes to obtain Form N.
优选的，所述加热速率为10℃/min，所述加热温度为142℃，所述停留时间为2min。Preferably, the heating rate is 10 ° C / min, the heating temperature is 142 ° C, and the residence time is 2 min.
本发明提供的晶型N具有以下有益效果：The crystal form N provided by the present invention has the following beneficial effects:
(1)本发明提供的晶型N物理、化学稳定性好。晶型N原料药在25℃/60％RH条件下放置，至少5周晶型未发生变化，且化学纯度在99％以上，储存过程中纯度基本保持不变。(1) The crystal form N provided by the present invention has good physical and chemical stability. The Form N drug substance is placed at 25 ° C / 60% RH, the crystal form does not change for at least 5 weeks, and the chemical purity is above 99%, and the purity remains substantially unchanged during storage.
晶型的转变会导致药物的吸收发生变化，影响药物的毒副作用，尤其是在毒性靶器官中的浓度变化，直接影响药物的毒副作用。晶型N具有良好的物理化学稳定性，保证原料药和制剂质量一致可控，最大可能地减少药物由于晶型改变引起的毒性增加，保证药物疗效发挥。The transformation of the crystal form will lead to changes in the absorption of the drug, affecting the toxic side effects of the drug, especially the concentration change in the toxic target organ, directly affecting the toxic side effects of the drug. Form N has good physicochemical stability, ensuring consistent controllable quality of the drug substance and preparation, and maximally reducing the toxicity of the drug due to crystal form change, ensuring the efficacy of the drug.
(2)与现有技术相比，本发明晶型N具有较高的溶解度。特别是在H 2O中，溶解度是现有技术晶型1的24倍。 (2) The crystal form N of the present invention has a higher solubility than the prior art. Particularly in H 2 O, the solubility is 24 times that of the prior art crystal form 1.
更高的溶解度有利于提高药物在人体内被吸收的速度和程度，使药物发挥更好的治疗作 用；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。Higher solubility is beneficial to increase the speed and extent of absorption of the drug in the human body, so that the drug can exert a better therapeutic effect; in addition, higher solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the drug's Side effects and improve the safety of the drug.
根据本发明的目的，本发明提供Galunisertib的新晶型，命名为晶型E。本发明提供的晶型E是2-已酮溶剂合物。In accordance with the purpose of the present invention, the present invention provides a novel crystalline form of Galunisertib, designated Form E. Form E provided by the present invention is a 2-hexanone solvate.
非限制性地，所述晶型E的X射线粉末衍射图基本如图5所示。Without limitation, the X-ray powder diffraction pattern of Form E is substantially as shown in FIG.
根据本发明的目的，本发明还提供所述晶型E的制备方法，所述制备方法包括：将Galunisertib游离碱加入到2-已酮溶剂中，在50℃-100℃温度下搅拌，将析出物离心、干燥得到晶型E。According to the object of the present invention, the present invention also provides a preparation method of the crystal form E, which comprises adding a Galunisertib free base to a 2-hexanone solvent, and stirring at a temperature of 50 ° C to 100 ° C to precipitate The product was centrifuged and dried to obtain crystal form E.
优选的，所述搅拌温度为80℃。Preferably, the stirring temperature is 80 °C.
本发明中，“晶体”或“晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X-射线衍射图不必和这里所指的例子中的X射线衍射图完全一致。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。In the present invention, "crystal" or "crystal form" refers to the characterization by the X-ray diffraction pattern shown. Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal. The peak intensities shown here are illustrative and not for absolute comparison. In addition, the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ±0.2° is usually allowed. In addition, due to experimental factors such as sample height, the overall offset of the peak angle is caused, and a certain offset is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray diffraction pattern of one crystal form in the present invention need not be identical to the X-ray diffraction pattern in the examples referred to herein. Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention. One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50～1800转/分钟，优选300～900转/分钟。The "stirring" is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
所述“干燥”可以在室温或更高的温度下进行。干燥温度室温至60℃，或者到40℃，或者到50℃。干燥时间可以为2～48小时，或者过夜。干燥在通风橱、鼓风烘箱或真空烘箱里进行。The "drying" can be carried out at room temperature or higher. Dry at room temperature to 60 ° C, or to 40 ° C, or to 50 ° C. The drying time can be from 2 to 48 hours, or overnight. Drying is carried out in a fume hood, a forced air oven or a vacuum oven.
在一些实施方案中，本发明的晶型L、晶型H和晶型N是纯的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。In some embodiments, Form L, Form H, and Form N of the present invention are pure, substantially free of any other crystalline form. In the present invention, "substantially free" when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
本发明提供一种药用组合物，所述药用组合物包含治疗和预防有效量的本发明晶型L、 晶型H和晶型N或它们的任意混合以及药学上可接受的载体、稀释剂或赋形剂。The present invention provides a pharmaceutical composition comprising a therapeutically and prophylactically effective amount of Form L of the present invention, Form H and Form N, or any mixture thereof, and a pharmaceutically acceptable carrier, diluted Agent or excipient.
进一步地，本发明提供Galunisertib的晶型L、晶型H和晶型N或它们的任意混合，在制备TGF-β受体激酶抑制剂药物中的用途。Further, the present invention provides the use of crystal form L, Form H and Form N of Galunisertib or any mixture thereof in the preparation of a TGF-β receptor kinase inhibitor drug.
进一步地，本发明提供Galunisertib的晶型L、晶型H和晶型N或它们的任意混合，在制备治疗骨髓增生异常综合症的药物中的用途。Further, the present invention provides the use of crystal form L, Form H and Form N of Galunisertib or any mixture thereof in the preparation of a medicament for treating myelodysplastic syndrome.
进一步地，本发明提供Galunisertib的晶型L、晶型H和晶型N或它们的任意混合，在制备治疗实体瘤的药物中的用途。Further, the present invention provides the use of Form L, Form H and Form N of Galunisertib, or any mixture thereof, for the preparation of a medicament for the treatment of solid tumors.
本发明提供的Galunisertib的晶型L、晶型H和晶型N，在稳定性、熔点、溶解度、体内外溶出、引湿性、生物有效性、黏附性、可压性、流动性以及加工性能、提纯作用、制剂生产等方面中的至少一方面上存在优势，特别是引湿性低、溶解度高、稳定性好、粒径均一，且相对于现有技术晶型1，本发明提供的无水晶型在同等质量下有效成分含量更高。为含Galunisertib的药物开发提供了新的更好的选择，具有非常重要的意义。The crystal form L, the crystal form H and the crystal form N of the Galunisertib provided by the present invention have stability, melting point, solubility, in vitro and in vivo dissolution, wettability, bioavailability, adhesion, compressibility, fluidity and processability, There is an advantage in at least one of purification, preparation and the like, in particular, low moisture permeability, high solubility, good stability, uniform particle size, and the crystal-free type provided by the present invention compared to the prior art crystal form 1. The active ingredient content is higher at the same quality. It is very important to provide new and better choices for drug development with Galunisertib.
附图说明DRAWINGS
图1晶型D的XRPD图。Figure 1 is an XRPD pattern of Form D.
图2晶型D的DSC图。Figure 2 is a DSC diagram of Form D.
图3晶型D的TGA图。Figure 3 is a TGA diagram of Form D.
图4晶型D的 1H NMR图。 Figure 1 is a 1 H NMR chart of Form D.
图5晶型E的XRPD图。Figure 5 is an XRPD pattern of Form E.
图6晶型E的DSC图。Figure 6 is a DSC diagram of Form E.
图7晶型E的TGA图。Figure 7 is a TGA diagram of Form E.
图8晶型E的 1H NMR图。 Figure 1 is a 1 H NMR chart of Form E.
图9晶型L的XRPD图。Figure 9 is an XRPD pattern of Form L.
图10晶型L的DSC图。Figure 10 is a DSC diagram of Form L.
图11晶型L的TGA图。Figure 11 is a TGA diagram of Form L.
图12晶型L的 1H NMR图。 Figure 1 is a 1 H NMR chart of Form L.
图13晶型H的XRPD图。Figure 13 is an XRPD pattern of Form H.
图14晶型H的DSC图。Figure 14 is a DSC chart of Form H.
图15晶型H的TGA图。Figure 15 is a TGA diagram of Form H.
图16晶型H的 1H NMR图。 Figure 16 is a 1 H NMR chart of Form H.
图17晶型N的XRPD图。Figure 17 is an XRPD pattern of Form N.
图18晶型N的DSC图。Figure 18 is a DSC diagram of Form N.
图19晶型N的TGA图。Figure 19 is a TGA diagram of Form N.
图20晶型N的 1H NMR图。 Figure 1 is a 1 H NMR chart of Form N.
图21晶型L稳定性的XRPD对比图(从上至下分别为起始XRPD、在25℃/60％RH条件下放置7周后的XRPD、在40℃/75％RH条件下放置7周后的XRPD、在60℃/75％RH条件下放置7周后的XRPD、在80℃条件下放置1周后的XRPD)。Figure 21 XRPD comparison of the stability of crystal form L (XRPD from top to bottom, XRPD, 7 weeks after 25 ° C / 60% RH, and 7 weeks at 40 ° C / 75% RH) After XRPD, XRPD after 7 weeks at 60 ° C / 75% RH, and XRPD after 1 week at 80 ° C).
图22晶型N稳定性的XRPD对比图(从上至下分别为起始XRPD、在25℃/60％RH条件下放置5周后的XRPD)。Figure 22 is a comparison of XRPD of Form N stability (from top to bottom, starting XRPD, XRPD after 5 weeks at 25 ° C / 60% RH).
具体实施方式Detailed ways
本发明进一步参考以下实施例限定，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。The invention is further defined by the following examples which describe in detail the preparation and use of the crystalline forms of the invention. It will be apparent to those skilled in the art that many changes in the materials and methods can be practiced without departing from the scope of the invention.
采集数据所用的仪器及方法：Instruments and methods used to collect data:
本发明中所用到的缩写的解释如下：The abbreviations used in the present invention are explained as follows:
XRPD：X射线粉末衍射XRPD: X-ray powder diffraction
DSC：差示扫描量热分析DSC: Differential Scanning Calorimetry
TGA：热重分析TGA: Thermogravimetric Analysis
1H NMR：核磁共振氢谱 1 H NMR: Nuclear Magnetic Resonance Spectroscopy
HPLC：高效液相色谱HPLC: high performance liquid chromatography
本发明所述的X射线粉末衍射图在Bruker D2PHASER X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：The X-ray powder diffraction pattern of the present invention was collected on a Bruker D2 PHASER X-ray powder diffractometer. The method parameters of the X-ray powder diffraction described in the present invention are as follows:
X射线光源：Cu,KαX-ray source: Cu, Kα
Figure PCTCN2018103414-appb-000002
1.54060；
Figure PCTCN2018103414-appb-000003
1.54439
Figure PCTCN2018103414-appb-000002
1.54060;
Figure PCTCN2018103414-appb-000003
1.54439
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：30仟伏特(kV)Voltage: 30 volts (kV)
电流：10毫安培(mA)Current: 10 milliamperes (mA)
扫描范围：自3.0至40.0度Scan range: from 3.0 to 40.0 degrees
本发明所述的DSC图在TA Q2000上采集。本发明所述的DSC的方法参数如下：The DSC map of the present invention was acquired on a TA Q2000. The method parameters of the DSC according to the present invention are as follows:
扫描速率：10℃/minScan rate: 10 ° C / min
保护气体：氮气Protective gas: nitrogen
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：The thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500. The method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
扫描速率：10℃/minScan rate: 10 ° C / min
保护气体：氮气Protective gas: nitrogen
核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL的溶液。 Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
本发明中高效液相色谱(HPLC)数据采自于安捷伦1260，所用检测器为二极管阵列检测器(DAD)。本发明有关物质的HPLC方法参数如下：The high performance liquid chromatography (HPLC) data of the present invention was taken from the Agilent 1260, and the detector used was a diode array detector (DAD). The HPLC method parameters of the substances related to the present invention are as follows:
1、色谱柱：Waters XBridge 150*4.6mm，5μm1. Column: Waters XBridge 150*4.6mm, 5μm
2、流动相：A：2mmol/L庚烷磺酸钠水溶液，pH3.02. Mobile phase: A: 2mmol/L sodium heptanesulfonate solution, pH3.0
B：乙腈溶液B: acetonitrile solution
洗脱梯度如下：The elution gradient is as follows:
Time(min)Time(min) ％B%B
0.00.0 1010
20.020.0 4040
40.040.0 8080
45.045.0 8080
46.046.0 1010
55.055.0 1010
3、流速：1mL/min3. Flow rate: 1mL/min
4、进样量：5μl4, injection volume: 5μl
5、检测波长：220nm5, detection wavelength: 220nm
6、柱温：40℃6, column temperature: 40 ° C
7、稀释剂：50％乙腈7. Thinner: 50% acetonitrile
除非特殊说明，以下实施例均在室温条件下操作。The following examples were operated at room temperature unless otherwise stated.
以下实施例中所使用的Galunisertib原料可根据现有技术WO2007018818A1文献所记载的方法制备获得，制备得到的Galunisertib原料为一水合物晶型。The Galunisertib starting material used in the following examples can be prepared according to the method described in the prior art WO2007018818A1, and the prepared Galunisertib raw material is a monohydrate crystalline form.
实施例1：晶型D的制备Example 1: Preparation of Form D
称取201.2mg Galunisertib游离碱放入3mL玻璃小瓶中，加入1.2mL的乙酰丙酮溶剂形成悬浊液，置于80℃下搅拌4天，离心得到固体，置于50℃鼓风干燥2小时。经检测，本实施例得到固体为晶型D，其X射线粉末衍射数据如表1所示，XRPD图如图1所示。201.2 mg of Galunisertib free base was weighed into a 3 mL glass vial, and 1.2 mL of acetylacetone solvent was added to form a suspension, which was stirred at 80 ° C for 4 days, centrifuged to obtain a solid, and blast dried at 50 ° C for 2 hours. Upon examination, the solid obtained in this example was crystalline form D, the X-ray powder diffraction data thereof is shown in Table 1, and the XRPD pattern is shown in FIG.
当进行差示扫描量热分析时，加热至149℃开始出现第一个吸热峰，在187℃开始出现第二个吸热峰，在248℃开始出现第三个吸热峰，其DSC如图2所示。当进行热重分析 时，加热至180℃时，具有11.8％的质量损失，其TGA如图3所示。When performing differential scanning calorimetry, the first endothermic peak begins to appear at 149 ° C, the second endothermic peak begins at 187 ° C, and the third endothermic peak begins to appear at 248 ° C. Figure 2 shows. When subjected to thermogravimetric analysis, when heated to 180 ° C, it had a mass loss of 11.8%, and its TGA is shown in FIG.
晶型D液态氢谱核磁如图4，核磁数据如下： 1H NMR(400MHz,DMSO)δ8.88(d,J＝4.5Hz,1H),8.26(d,J＝1.6Hz,1H),8.13(dd,J＝8.8,1.9Hz,1H),8.05(d,J＝8.7Hz,2H),7.58(dd,J＝7.0,6.0Hz,2H),7.42(d,J＝4.4Hz,1H),7.36(s,1H),6.97–6.88(m,1H),4.31(t,J＝7.2Hz,2H),2.83(s,2H),2.70–2.59(m,2H),2.14-2.03(d,3H),1.75(s,3H)。根据核磁数据可知，晶型D为乙酰丙酮溶剂合物，其中Galunisertib化合物与乙酰丙酮的摩尔比为1:0.5，其中乙酰丙酮具有酮式和烯醇式两种异构体。 Form D liquid hydrogen spectrum nuclear magnetic Figure 4, nuclear magnetic data as follows: 1 H NMR (400MHz, DMSO) δ8.88 (d, J = 4.5Hz, 1H), 8.26 (d, J = 1.6Hz, 1H), 8.13 (dd, J = 8.8, 1.9 Hz, 1H), 8.05 (d, J = 8.7 Hz, 2H), 7.58 (dd, J = 7.0, 6.0 Hz, 2H), 7.42 (d, J = 4.4 Hz, 1H) , 7.36(s,1H), 6.97–6.88(m,1H), 4.31(t,J=7.2Hz,2H),2.83(s,2H), 2.70–2.59(m,2H),2.14-2.03(d , 3H), 1.75 (s, 3H). According to the nuclear magnetic data, the crystal form D is an acetylacetone solvate in which the molar ratio of the Galunisertib compound to acetylacetone is 1:0.5, wherein the acetylacetone has two isomers of a keto form and an enol form.
表1Table 1
2theta2theta d间隔d interval 强度％strength%
8.618.61 10.0710.07 6.896.89
9.939.93 8.908.90 15.7615.76
10.5510.55 8.398.39 34.1134.11
11.1411.14 7.947.94 100.00100.00
12.9112.91 6.866.86 27.4927.49
14.3914.39 6.156.15 5.205.20
15.4015.40 5.755.75 8.028.02
15.5615.56 5.695.69 17.5717.57
16.4716.47 5.385.38 74.9574.95
17.0117.01 5.215.21 2.932.93
17.6217.62 5.035.03 7.727.72
18.8218.82 4.724.72 31.6931.69
19.1619.16 4.634.63 9.289.28
19.7119.71 4.504.50 18.2818.28
20.0720.07 4.424.42 64.3464.34
20.5020.50 4.334.33 3.203.20
21.5421.54 4.134.13 6.166.16
21.8521.85 4.074.07 3.913.91
22.2322.23 4.004.00 7.687.68
22.6122.61 3.933.93 10.8510.85
23.3823.38 3.803.80 2.712.71
23.8023.80 3.743.74 19.6619.66
24.5024.50 3.633.63 5.405.40
24.7624.76 3.603.60 49.5749.57
25.6725.67 3.473.47 55.1555.15
26.1026.10 3.413.41 32.5132.51
26.6326.63 3.353.35 2.522.52
27.0827.08 3.293.29 5.785.78
27.7327.73 3.223.22 17.3917.39
28.8528.85 3.103.10 9.109.10
29.4429.44 3.033.03 2.252.25
30.3530.35 2.952.95 4.124.12
31.0131.01 2.882.88 13.2413.24
33.1233.12 2.702.70 2.172.17
33.5933.59 2.672.67 2.642.64
34.8534.85 2.572.57 1.231.23
36.3736.37 2.472.47 5.025.02
38.2838.28 2.352.35 1.661.66
39.0339.03 2.312.31 1.241.24
39.4639.46 2.282.28 1.171.17
实施例2：晶型E的制备Example 2: Preparation of Form E
称取201.5mg Galunisertib游离碱放入3mL玻璃小瓶中，加入1.2mL的2-己酮溶剂形成悬浊液，置于80℃下搅拌4天，离心得到固体，置于50℃鼓风干燥2小时。经检测，本实施例得到固体为晶型E，其X射线粉末衍射数据如表2所示，其XRPD图如图5所示。当进行差示扫描量热分析时，加热至136℃开始出现第一个吸热峰，在183℃开始出现第二个吸热峰，在248℃开始出现第三个吸热峰，其DSC图如图6。当进行热重分析时，加热至160℃时，具有11.5％的质量损失，其TGA如附图7所示。Weigh 201.5 mg of Galunisertib free base into a 3 mL glass vial, add 1.2 mL of 2-hexanone solvent to form a suspension, stir at 80 ° C for 4 days, centrifuge to obtain a solid, and blast dry at 50 ° C for 2 hours. . Upon examination, the solid obtained in this example was crystalline form E, and its X-ray powder diffraction data is shown in Table 2, and its XRPD pattern is shown in FIG. When performing differential scanning calorimetry, the first endothermic peak begins to appear at 136 °C, the second endothermic peak begins at 183 °C, and the third endothermic peak begins at 248 °C. As shown in Figure 6. When subjected to thermogravimetric analysis, when heated to 160 ° C, it had a mass loss of 11.5%, and its TGA is as shown in FIG.
晶型E液态氢谱核磁如图8，核磁数据如下： 1H NMR(400MHz,DMSO)δ8.88(d,J＝4.4Hz,1H),8.25(s,1H),8.13(dd,J＝8.8,1.7Hz,1H),8.05(d,J＝8.7Hz,2H),7.59(d,J＝4.2Hz,2H),7.42(d,J＝4.4Hz,1H),7.36(s,1H),6.97–6.88(m,1H),4.31(t,J＝7.1Hz,2H),2.83(s,2H),2.70–2.59(m,2H),2.41(t,J＝7.3Hz,1H),2.07(s,1.5H),1.75(s,3H),1.43(dq,J＝15.1,7.4Hz,1H),1.24(dt,J＝14.8,7.4Hz,1H),0.85(t,J＝7.3Hz,1.5H).根据核磁数据可知，晶型E为2-己酮溶剂合物，其中Galunisertib化合物与2-己酮的摩尔比为1:0.5。 Crystalline E liquid hydrogen spectroscopy nucleus is shown in Figure 8. The NMR data is as follows: 1 H NMR (400 MHz, DMSO) δ 8.88 (d, J = 4.4 Hz, 1H), 8.25 (s, 1H), 8.13 (dd, J = 8.8, 1.7 Hz, 1H), 8.05 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 4.2 Hz, 2H), 7.42 (d, J = 4.4 Hz, 1H), 7.36 (s, 1H) , 6.97–6.88 (m, 1H), 4.31 (t, J = 7.1 Hz, 2H), 2.83 (s, 2H), 2.70–2.59 (m, 2H), 2.41 (t, J = 7.3 Hz, 1H), 2.07 (s, 1.5H), 1.75 (s, 3H), 1.43 (dq, J = 15.1, 7.4 Hz, 1H), 1.24 (dt, J = 14.8, 7.4 Hz, 1H), 0.85 (t, J = 7.3) Hz, 1.5H). According to the nuclear magnetic data, the crystal form E is a 2-hexanone solvate in which the molar ratio of the Galunisertib compound to 2-hexanone is 1:0.5.
表2Table 2
2theta2theta d间隔d interval 强度％strength%
8.338.33 10.6210.62 13.0213.02
9.019.01 9.819.81 4.004.00
9.979.97 8.878.87 7.097.09
10.7710.77 8.218.21 100.00100.00
12.3312.33 7.187.18 17.2017.20
14.1114.11 6.286.28 3.543.54
14.8114.81 5.985.98 1.241.24
15.5115.51 5.715.71 5.405.40
16.0316.03 5.535.53 2.282.28
16.6916.69 5.315.31 60.3760.37
16.9516.95 5.235.23 7.387.38
17.4417.44 5.095.09 4.014.01
17.7117.71 5.015.01 2.722.72
18.4318.43 4.814.81 25.2325.23
18.6718.67 4.754.75 15.8915.89
18.8718.87 4.704.70 5.715.71
19.9619.96 4.454.45 29.5629.56
20.1020.10 4.424.42 18.0618.06
20.9920.99 4.234.23 11.6411.64
21.6121.61 4.114.11 10.7510.75
21.9621.96 4.054.05 4.744.74
22.7722.77 3.913.91 5.205.20
23.4623.46 3.793.79 35.7435.74
23.8523.85 3.733.73 16.0016.00
24.4724.47 3.643.64 3.203.20
24.9524.95 3.573.57 29.9429.94
25.3225.32 3.523.52 37.2537.25
26.3626.36 3.383.38 18.7918.79
27.2727.27 3.273.27 9.499.49
27.7327.73 3.223.22 4.364.36
28.5228.52 3.133.13 1.351.35
30.5430.54 2.932.93 10.4110.41
32.0932.09 2.792.79 3.423.42
33.0133.01 2.712.71 2.062.06
33.8833.88 2.652.65 1.481.48
34.6834.68 2.592.59 0.830.83
35.7835.78 2.512.51 2.942.94
36.5936.59 2.462.46 1.551.55
37.9837.98 2.372.37 1.341.34
实施例3：晶型L的制备Example 3: Preparation of Form L
称取6mg晶型D在DSC仪器上进行加热实验，样品加盖但不压实，以10℃/min加热至150℃，停留5min，得到固体。经检测，所得固体为晶型晶型L，其X射线粉末衍射数据如表3，其XRPD图如图9所示。当进行差式扫描量热分析时，加热至186℃开始出现第一个吸热峰，随后出现一个放热峰，在248℃开始出现第二个吸热峰，其DSC图如图10。当进行热重分析时，加热至150℃时，具有2.8％的质量损失，其TGA图如图11。6 mg of Form D was weighed and subjected to a heating test on a DSC instrument. The sample was capped but not compacted, heated to 150 ° C at 10 ° C / min, and left for 5 min to obtain a solid. Upon examination, the obtained solid was a crystalline form L, and its X-ray powder diffraction data is shown in Table 3, and its XRPD pattern is shown in FIG. When performing differential scanning calorimetry, the first endothermic peak begins to appear at 186 ° C, followed by an exothermic peak, and a second endothermic peak begins to appear at 248 ° C. The DSC chart is shown in FIG. When subjected to thermogravimetric analysis, it had a mass loss of 2.8% when heated to 150 ° C, and its TGA pattern is shown in FIG.
晶型L液态氢谱核磁如附图12，核磁数据如下： 1H NMR(400MHz,DMSO)δ8.87(d,J＝4.4Hz,1H),8.25(s,1H),8.14–8.09(m,1H),8.04(d,J＝8.8Hz,2H),7.61–7.55(m,2H),7.41(d,J＝4.4Hz,1H),7.35(s,1H),6.96–6.90(m,1H),4.31(t,J＝7.1Hz,2H),2.83(s,2H),2.64(dd,J＝14.2,6.9Hz,2H),1.74(s,3H)。 Form L liquid hydrogen spectrum nucleus as shown in Figure 12, the nuclear magnetic data is as follows: 1 H NMR (400 MHz, DMSO) δ 8.87 (d, J = 4.4 Hz, 1H), 8.25 (s, 1H), 8.14 - 8.09 (m , 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.61 - 7.55 (m, 2H), 7.41 (d, J = 4.4 Hz, 1H), 7.35 (s, 1H), 6.96 - 6.90 (m, 1H), 4.31 (t, J = 7.1 Hz, 2H), 2.83 (s, 2H), 2.64 (dd, J = 14.2, 6.9 Hz, 2H), 1.74 (s, 3H).
表3table 3
2theta2theta d间隔d interval 强度％strength%
8.588.58 10.3110.31 47.2547.25
9.229.22 9.599.59 14.1914.19
10.2910.29 8.608.60 16.2316.23
11.6411.64 7.607.60 8.718.71
12.7012.70 6.976.97 100.00100.00
13.8413.84 6.406.40 2.662.66
14.6314.63 6.066.06 6.836.83
15.3115.31 5.795.79 3.743.74
15.6715.67 5.655.65 24.6424.64
16.4916.49 5.385.38 18.2318.23
16.7416.74 5.295.29 38.6138.61
17.3317.33 5.125.12 8.328.32
18.3118.31 4.844.84 28.3628.36
19.0919.09 4.654.65 18.1918.19
20.9820.98 4.244.24 11.5511.55
21.9921.99 4.044.04 16.6016.60
22.6422.64 3.933.93 84.7584.75
23.0823.08 3.853.85 21.3421.34
23.7123.71 3.753.75 23.0823.08
24.0724.07 3.703.70 46.4246.42
25.2025.20 3.533.53 10.3210.32
25.6325.63 3.483.48 14.2014.20
26.2426.24 3.403.40 11.2311.23
27.3227.32 3.263.26 5.825.82
28.8528.85 3.103.10 17.1917.19
30.6230.62 2.922.92 16.9116.91
实施例4：晶型L的溶解度Example 4: Solubility of Form L
模拟胃肠道液体例如SGF(模拟胃液)、FaSSIF(模拟禁食状态肠液)、FeSSIF(模拟喂食状态肠液)属于生物相关介质，此类介质能更好地反映胃肠道生理环境对药物释放产生的影响，在此类介质中测试的溶解度与人体环境中的溶解度更加接近。Simulated gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release. The effect of the solubility tested in such media is closer to that in the human environment.
取本发明的晶型L及WO2007018818A1晶型1各30mg分别溶于2mL的SGF、2mL的FaSSIF、2mL的FeSSIF及2mL的水配制成饱和溶液，平衡0.25小时后用高效液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表4所示。The crystal form L of the present invention and 30 mg of WO2007018818A1 crystal form 1 were respectively dissolved in 2 mL of SGF, 2 mL of FaSSIF, 2 mL of FeSSIF and 2 mL of water to prepare a saturated solution, and after 0.25 hours of equilibration, the saturated solution was tested by high performance liquid chromatography. The content of the sample (mg/mL), the results are shown in Table 4.
表4Table 4
Figure PCTCN2018103414-appb-000004
Figure PCTCN2018103414-appb-000004
结果表明，平衡1小时和4小时后，晶型L在SGF、FaSSIF、FeSSIF及水中均比现有技术晶型1具有更高的溶解度，特别是在FaSSIF、FeSSIF、H 2O中，晶型L的溶解度约是WO2007018818A1晶型1的4倍。 The results show that after 1 hour and 4 hours of equilibrium, Form L has higher solubility in SGF, FaSSIF, FeSSIF and water than prior art Form 1, especially in FaSSIF, FeSSIF, H 2 O, crystal form. The solubility of L is about four times that of WO2007018818A1 Form 1.
实施例5：晶型L的稳定性Example 5: Stability of Form L
称取本发明制备得到的晶型L各5mg，分别放置在25℃/60％RH、40℃/75％RH、60℃/75％RH、80℃条件下放置，采用HPLC和XRPD法测定晶型与纯度的变化。结果如表5所 示，XRPD对比图如图21所示。5 mg of each of the crystal forms L prepared by the present invention were weighed and placed at 25 ° C / 60% RH, 40 ° C / 75% RH, 60 ° C / 75% RH, 80 ° C, and the crystal was determined by HPLC and XRPD. Type and purity changes. The results are shown in Table 5, and the XRPD comparison chart is shown in Fig. 21.
表5table 5
Figure PCTCN2018103414-appb-000005
Figure PCTCN2018103414-appb-000005
结果表明，晶型L在25℃/60％RH、40℃/75％RH、60℃/75％RH条件下至少可稳定7周，在80℃条件下至少可稳定1周，晶型与化学纯度基本保持不变，晶型L具有较好的物理化学稳定性。The results show that the crystal form L can be stable for at least 7 weeks at 25 ° C / 60% RH, 40 ° C / 75% RH, 60 ° C / 75% RH, and stable for at least 1 week at 80 ° C, crystal form and chemistry. The purity remains basically unchanged, and the crystal form L has good physical and chemical stability.
实施例6：晶型H的制备Example 6: Preparation of Form H
称取202.5mg Galunisertib游离碱放入20mL玻璃小瓶中，加入5mL乙酸与正庚烷体积比为1:9的混合溶剂形成悬浊液，置于50℃下搅拌4天，离心得到固体，置于50℃鼓风干燥2小时。经检测，本实施例得到固体为晶型H，其X射线粉末衍射数据如表6所示。其XRPD图如图13所示。Weigh 202.5 mg of Galunisertib free base into a 20 mL glass vial, add 5 mL of a mixed solvent of acetic acid and n-heptane in a volume ratio of 1:9 to form a suspension, stir at 50 ° C for 4 days, centrifuge to obtain a solid, and place Dry at 50 ° C for 2 hours. Upon examination, the solid obtained in this example was crystalline form H, and its X-ray powder diffraction data is shown in Table 6. Its XRPD diagram is shown in Figure 13.
当进行差示扫描量热分析时，加热至143℃开始出现第一个吸热峰，随后在157℃开始出现第二个吸热峰，在245℃开始出现第三个吸热峰，其DSC如图14所示。当进行热重分析时，加热至160℃时，具有24.4％的质量损失，其TGA图如图15所示。When performing differential scanning calorimetry, the first endothermic peak begins to appear at 143 ° C, followed by a second endothermic peak at 157 ° C, and a third endothermic peak at 245 ° C, DSC As shown in Figure 14. When subjected to thermogravimetric analysis, when heated to 160 ° C, it had a mass loss of 24.4%, and its TGA chart is shown in FIG.
晶型H液态氢谱核磁如图16，核磁数据如下： 1H NMR(400MHz,DMSO)δ8.88(d,J＝4.4Hz,1H),8.25(d,J＝1.6Hz,1H),8.12(dd,J＝8.8,1.8Hz,1H),8.05(d,J＝8.7Hz,2H),7.59(d,J＝4.7Hz,2H),7.42(d,J＝4.4Hz,1H),7.36(s,1H),6.96–6.89(m,1H),4.31(t,J＝7.2Hz,2H),2.83(s,2H),2.64(dt,J＝14.6,7.3Hz,2H),1.91(s,6H),1.75(s,3H)。根据核磁数据可知，晶型H为乙酸溶剂合物，其中Galunisertib化合物与乙酸的摩尔比为1:2。 The crystal form H liquid hydrogen spectrum nucleus is shown in Fig. 16. The nuclear magnetic data is as follows: 1 H NMR (400 MHz, DMSO) δ 8.88 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.12 (dd, J = 8.8, 1.8 Hz, 1H), 8.05 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 4.7 Hz, 2H), 7.42 (d, J = 4.4 Hz, 1H), 7.36 (s, 1H), 6.96 - 6.89 (m, 1H), 4.31 (t, J = 7.2 Hz, 2H), 2.83 (s, 2H), 2.64 (dt, J = 14.6, 7.3 Hz, 2H), 1.91 ( s, 6H), 1.75 (s, 3H). According to the nuclear magnetic data, the crystal form H is an acetic acid solvate in which the molar ratio of the Galunisertib compound to acetic acid is 1:2.
表6Table 6
2theta2theta d间隔d interval 强度％strength%
6.516.51 13.5713.57 91.6491.64
7.797.79 11.3411.34 2.772.77
11.3411.34 7.807.80 17.8317.83
12.3312.33 7.187.18 73.7073.70
13.1713.17 6.726.72 2.982.98
13.6213.62 6.506.50 51.8451.84
15.5315.53 5.715.71 92.1992.19
16.5716.57 5.355.35 2.932.93
16.8916.89 5.255.25 15.0015.00
17.2417.24 5.145.14 14.8314.83
17.9917.99 4.934.93 64.7864.78
18.7618.76 4.734.73 20.2920.29
19.5519.55 4.544.54 14.7314.73
21.7421.74 4.094.09 8.938.93
22.5822.58 3.943.94 56.2456.24
22.9022.90 3.883.88 41.9141.91
24.2624.26 3.673.67 33.6233.62
24.9424.94 3.573.57 65.0765.07
25.1725.17 3.543.54 100.00100.00
25.9625.96 3.433.43 12.6012.60
26.5926.59 3.353.35 30.8930.89
27.8627.86 3.203.20 8.968.96
28.5228.52 3.133.13 17.0217.02
29.1829.18 3.063.06 14.9614.96
29.4329.43 3.033.03 8.968.96
30.0830.08 2.972.97 4.414.41
31.3431.34 2.852.85 2.142.14
31.9531.95 2.802.80 3.043.04
32.3632.36 2.772.77 2.572.57
33.2033.20 2.702.70 5.465.46
34.1434.14 2.632.63 4.194.19
36.3336.33 2.472.47 5.935.93
37.5537.55 2.402.40 1.271.27
38.6138.61 2.332.33 2.142.14
39.0639.06 2.312.31 2.642.64
实施例7：晶型H的溶解度Example 7: Solubility of Form H
模拟胃肠道液体例如SGF(模拟胃液)、FaSSIF(模拟禁食状态肠液)、FeSSIF(模拟喂食状态肠液)属于生物相关介质，此类介质能更好地反映胃肠道生理环境对药物释放产生的影响， 在此类介质中测试的溶解度与人体环境中的溶解度更加接近。Simulated gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release. The effect of the solubility tested in such media is closer to that in the human environment.
取本发明的晶型H及WO2007018818A1晶型1各30mg分别溶于2mL的SGF、2mL的FaSSIF、2mL的FeSSIF及2mL的水配制成饱和溶液，平衡0.25小时后用高效液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表7所示。The crystal form H of the present invention and 30 mg of WO2007018818A1 crystal form 1 were respectively dissolved in 2 mL of SGF, 2 mL of FaSSIF, 2 mL of FeSSIF and 2 mL of water to prepare a saturated solution, and after 0.25 hours of equilibration, the saturated solution was tested by high performance liquid chromatography. The content of the sample (mg/mL), the results are shown in Table 7.
表7Table 7
Figure PCTCN2018103414-appb-000006
Figure PCTCN2018103414-appb-000006
结果表明，平衡0.25小时后，晶型H在SGF、FaSSIF、FeSSIF及水中均比现有技术晶型1具有更高的溶解度，特别是在H 2O中，晶型H的溶解度约是现有技术晶型1的35倍。 The results show that after 0.25 hours of equilibrium, Form H has higher solubility in SGF, FaSSIF, FeSSIF and water than in the prior art Form 1, especially in H 2 O, the solubility of Form H is about 35 times the technical crystal form 1.
实施例8：晶型N的制备Example 8: Preparation of Form N
称取6mg的晶型H在DSC仪器上进行加热实验，闭盖以10℃/min加热至142℃，停留2min，得到固体。经检测，所得固体为晶型N，其X射线粉末衍射数据如表8所示，其XRPD图如图17所示。6 mg of Form H was weighed and subjected to a heating test on a DSC instrument, and the lid was heated to 142 ° C at 10 ° C / min for 2 min to obtain a solid. Upon examination, the obtained solid was a crystalline form N, and its X-ray powder diffraction data is shown in Table 8, and its XRPD pattern is shown in FIG.
当进行差示扫描量热分析时，加热至145℃开始出现第一个吸热峰，加热至247℃开始出现第二个吸热峰，其DSC如图18所示。当进行热重分析时，加热至180℃时，具有13.2％的质量损失，其TGA如图19所示。When performing differential scanning calorimetry, the first endothermic peak begins to appear when heated to 145 ° C, and a second endothermic peak begins to appear when heated to 247 ° C. The DSC is shown in FIG. When subjected to thermogravimetric analysis, when heated to 180 ° C, it had a mass loss of 13.2%, and its TGA is shown in FIG.
液态氢谱核磁如图20，核磁数据如下： 1H NMR(400MHz,DMSO)δ8.87(d,J＝4.4Hz,1H),8.25(s,1H),8.12(d,J＝8.8Hz,1H),8.04(d,J＝8.8Hz,2H),7.63–7.55(m,2H),7.41(d,J＝4.5Hz,1H),7.35(s,1H),6.97–6.90(m,1H),4.31(t,J＝7.1Hz,2H),2.83(s,2H),2.64(dt,J＝14.3,7.2Hz,2H),1.90(s,3H),1.74(s,3H)。根据核磁数据可知，晶型N为乙酸溶剂合物，其中Galunisertib化合物与乙酸的摩尔比为1:1。 The liquid hydrogen spectrum nucleus is shown in Fig. 20. The nuclear magnetic data is as follows: 1 H NMR (400 MHz, DMSO) δ 8.87 (d, J = 4.4 Hz, 1H), 8.25 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.63 - 7.55 (m, 2H), 7.41 (d, J = 4.5 Hz, 1H), 7.35 (s, 1H), 6.97 - 6.90 (m, 1H) ), 4.31 (t, J = 7.1 Hz, 2H), 2.83 (s, 2H), 2.64 (dt, J = 14.3, 7.2 Hz, 2H), 1.90 (s, 3H), 1.74 (s, 3H). According to the nuclear magnetic data, the crystal form N is an acetic acid solvate in which the molar ratio of the Galunisertib compound to acetic acid is 1:1.
表8Table 8
2theta2theta d间隔d interval 强度％strength%
7.447.44 11.8811.88 63.0063.00
9.319.31 9.509.50 7.057.05
12.1012.10 7.327.32 64.1064.10
12.4112.41 7.137.13 18.1918.19
14.9314.93 5.935.93 20.5120.51
15.2215.22 5.825.82 5.405.40
16.1316.13 5.495.49 100.00100.00
17.2117.21 5.155.15 11.6411.64
18.4118.41 4.824.82 20.5420.54
18.9618.96 4.684.68 5.655.65
19.6519.65 4.524.52 7.877.87
20.9420.94 4.244.24 4.074.07
21.2121.21 4.194.19 6.946.94
21.9321.93 4.054.05 12.6712.67
22.6522.65 3.933.93 7.097.09
23.3023.30 3.823.82 37.4737.47
24.5124.51 3.633.63 7.707.70
26.2226.22 3.403.40 30.5430.54
26.4126.41 3.373.37 52.2152.21
27.0727.07 3.293.29 22.1622.16
28.2428.24 3.163.16 16.1516.15
30.0830.08 2.972.97 2.332.33
37.0037.00 2.432.43 0.960.96
38.0438.04 2.372.37 3.743.74
实施例9：晶型N的稳定性Example 9: Stability of Form N
称取本发明制备得到的晶型N各5mg，分别放置在25℃/60％RH条件下放置，采用HPLC和XRPD法测定晶型与纯度的变化。结果如表9所示，XRPD对比图如图22所示。5 mg of each of the crystal forms N prepared in the present invention was weighed and placed under the conditions of 25 ° C / 60% RH, and the change in crystal form and purity was determined by HPLC and XRPD. The results are shown in Table 9, and the XRPD comparison chart is shown in Fig. 22.
表9Table 9
Figure PCTCN2018103414-appb-000007
Figure PCTCN2018103414-appb-000007
结果表明，晶型N在25℃/60％RH条件下至少可稳定5周，晶型与化学纯度基本保持不变，晶型N具有较好的物理化学稳定性。The results show that the crystal form N can be stabilized for at least 5 weeks at 25 ° C / 60% RH, the crystal form and chemical purity remain basically unchanged, and the form N has good physical and chemical stability.
实施例10：晶型N的溶解度Example 10: Solubility of Form N
模拟胃肠道液体例如SGF(模拟胃液)、FaSSIF(模拟禁食状态肠液)、FeSSIF(模拟喂食状态肠液)属于生物相关介质，此类介质能更好地反映胃肠道生理环境对药物释放产生的影响，在此类介质中测试的溶解度与人体环境中的溶解度更加接近。Simulated gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release. The effect of the solubility tested in such media is closer to that in the human environment.
取本发明的晶型N及WO2007018818A1晶型1各30mg分别溶于2mL的SGF、2mL的FaSSIF、2mL的FeSSIF及2mL的水配制成饱和溶液，平衡0.25小时后用高效液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表10所示。The crystal form N of the present invention and 30 mg of WO2007018818A1 crystal form 1 were respectively dissolved in 2 mL of SGF, 2 mL of FaSSIF, 2 mL of FeSSIF and 2 mL of water to prepare a saturated solution, and after 0.25 hours of equilibration, the saturated solution was tested by high performance liquid chromatography. The content of the sample (mg/mL), the results are shown in Table 10.
表10Table 10
Figure PCTCN2018103414-appb-000008
Figure PCTCN2018103414-appb-000008
结果表明晶型N在SGF、FaSSIF、FeSSIF和水中均比现有技术晶型1具有更高的溶解度，特别是在水中，晶型N的溶解度约是现有技术晶型1的24倍。The results show that Form N has higher solubility in SGF, FaSSIF, FeSSIF and water than in the prior art Form 1, especially in water, the solubility of Form N is about 24 times that of the prior art Form 1.
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。The above embodiments are merely illustrative of the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (17)

  1. 一种Galunisertib的晶型L，其特征在于，其X射线粉末衍射图在2θ值为12.7°±0.2°、22.6°±0.2°、8.6°±0.2°处具有特征峰。A crystal form L of Galunisertib characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 12.7°±0.2°, 22.6°±0.2°, and 8.6°±0.2°.
  2. 根据权利要求1所述的晶型L，其特征在于，其X射线粉末衍射图在2θ值为24.1°±0.2°、16.7°±0.2°、18.3°±0.2°中的一处或两处或三处具有特征峰。The crystal form L according to claim 1, wherein the X-ray powder diffraction pattern is at one or two of 2θ values of 24.1 ° ± 0.2 °, 16.7 ° ± 0.2 °, and 18.3 ° ± 0.2 ° or There are characteristic peaks in three places.
  3. 根据权利要求1所述的晶型L，其特征在于，其X射线粉末衍射图在2θ值为15.7°±0.2°、19.1°±0.2°、28.9°±0.2°中的一处或两处或三处具有特征峰。The crystal form L according to claim 1, wherein the X-ray powder diffraction pattern is at one or two of 2θ values of 15.7°±0.2°, 19.1°±0.2°, 28.9°±0.2° or There are characteristic peaks in three places.
  4. 一种权利要求1中所述晶型L的制备方法，其特征在于，所述制备方法包含：将乙酰丙酮溶剂合物以2-20℃/min速率加热至130℃～155℃，停留2～10min得到晶型L。A method for preparing a crystalline form L according to claim 1, wherein the preparation method comprises: heating the acetylacetone solvate to a temperature of from 130 ° C to 155 ° C at a rate of from 2 to 20 ° C/min, and staying for 2 to Form L was obtained in 10 min.
  5. 一种Galunisertib的晶型H，其特征在于，其X射线粉末衍射图在2θ值为25.2°±0.2°、15.5°±0.2°、6.5°±0.2°处具有特征峰。A crystal form H of Galunisertib characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 25.2°±0.2°, 15.5°±0.2°, and 6.5°±0.2°.
  6. 根据权利要求5所述的晶型H，其特征在于，其X射线粉末衍射图在2θ值为12.3°±0.2°、18.0°±0.2°、22.6°±0.2°中的一处或两处或三处具有特征峰。The crystal form H according to claim 5, wherein the X-ray powder diffraction pattern is at one or two of 2θ values of 12.3°±0.2°, 18.0°±0.2°, 22.6°±0.2° or There are characteristic peaks in three places.
  7. 根据权利要求5所述的晶型H，其特征在于，其X射线粉末衍射图在2θ值为13.6°±0.2°、24.2°±0.2°、26.6°±0.2°中的一处或两处或三处具有特征峰。The crystal form H according to claim 5, wherein the X-ray powder diffraction pattern is at one or two of 2θ values of 13.6 ° ± 0.2 °, 24.2 ° ± 0.2 °, 26.6 ° ± 0.2 ° or There are characteristic peaks in three places.
  8. 一种权利要求5中所述晶型H的制备方法，其特征在于，所述制备方法包含：A method for preparing a crystalline form H according to claim 5, wherein the preparation method comprises:
    将Galunisertib游离碱在乙酸或者乙酸和烷烃类溶剂的混合溶剂中搅拌，在40℃-80℃温度下搅拌，将析出物离心、干燥得到晶型H。The Galunisertib free base is stirred in acetic acid or a mixed solvent of acetic acid and an alkane solvent, and stirred at a temperature of 40 ° C to 80 ° C, and the precipitate is centrifuged and dried to obtain a crystal form H.
  9. 根据权利要求8所述的制备方法，其特征在于：所述搅拌温度为50℃，所述烷烃类溶剂为正庚烷。The production method according to claim 8, wherein the stirring temperature is 50 ° C, and the alkane solvent is n-heptane.
  10. 一种Galunisertib的晶型N，其特征在于，其X射线粉末衍射图在2θ值为16.1°±0.2°、12.1°±0.2°、7.4°±0.2°处具有特征峰。A crystal form N of Galunisertib characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 16.1 ° ± 0.2 °, 12.1 ° ± 0.2 °, and 7.4 ° ± 0.2 °.
  11. 根据权利要求10所述的晶型N，其特征在于，其X射线粉末衍射图在2θ值为26.4°±0.2°、23.3°±0.2°、27.0°±0.2°中的一处或两处或三处具有特征峰。The crystal form N according to claim 10, wherein the X-ray powder diffraction pattern is at one or two of 2θ values of 26.4°±0.2°, 23.3°±0.2°, 27.0°±0.2° or There are characteristic peaks in three places.
  12. 根据权利要求10所述的晶型N，其特征在于，其X射线粉末衍射图在2θ值为18.4°±0.2°、14.9°±0.2°、28.2°±0.2°中的一处或两处或三处具有特征峰。The crystal form N according to claim 10, wherein the X-ray powder diffraction pattern is at one or two of 28.4 values of 18.4 ° ± 0.2 °, 14.9 ° ± 0.2 °, 28.2 ° ± 0.2 ° or There are characteristic peaks in three places.
  13. 一种权利要求10中所述晶型N的制备方法，其特征在于，所述制备方法包含：将晶型H在密闭环境下以5～20℃/min速率加热至140℃～145℃，停留1～5min得到晶型N。A method for preparing a crystalline form N according to claim 10, wherein the preparation method comprises: heating the crystalline form H to a temperature of from 5 to 20 ° C/min to a temperature of from 140 ° C to 145 ° C in a closed environment, and staying Form N is obtained in 1 to 5 minutes.
  14. 根据权利要求10所述的制备方法，其特征在于：所述加热速率为10℃/min，加热温度142℃，停留时间2min。The preparation method according to claim 10, wherein the heating rate is 10 ° C / min, the heating temperature is 142 ° C, and the residence time is 2 min.
  15. 一种药用组合物，所述药用组合物包含有效治疗量的权利要求1中所述的晶型L、权利要求5中所述的晶型H、权利要求10中所述的晶型N或它们的任意混合，及药学上可 接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form L of claim 1, the crystalline form H of claim 5, and the crystalline form N of claim 10. Or any combination thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  16. 权利要求1中所述的晶型L、权利要求5中所述的晶型H、权利要求10中所述的晶型N或它们的任意混合，在制备TGF-β受体激酶抑制剂药物中的用途。The crystalline form L described in claim 1, the crystalline form H described in claim 5, the crystalline form N described in claim 10, or any mixture thereof, in the preparation of a TGF-β receptor kinase inhibitor drug the use of.
  17. 权利要求1中所述的晶型L、权利要求5中所述的晶型H、权利要求10中所述的晶型N或它们的任意混合，在制备治疗骨髓增生异常综合症药物中的用途。Use of the crystal form L described in claim 1, the crystal form H described in claim 5, the form N described in claim 10, or any mixture thereof, for the preparation of a medicament for treating myelodysplastic syndrome .
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CN1714090A (en) * 2002-11-22 2005-12-28 伊莱利利公司 Quinolinyl-pyrrolopyrazoles
WO2007018818A1 (en) * 2005-07-22 2007-02-15 Eli Lilly And Company A pyridin quinolin substituted pyrrolo [1,2-b] pyrazole monohydrate as tgf-beta inhibitor
WO2018006870A1 (en) * 2016-07-07 2018-01-11 苏州科睿思制药有限公司 Galunisertib crystal form and preparation method therefor and use thereof

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Publication number Priority date Publication date Assignee Title
CN1714090A (en) * 2002-11-22 2005-12-28 伊莱利利公司 Quinolinyl-pyrrolopyrazoles
WO2007018818A1 (en) * 2005-07-22 2007-02-15 Eli Lilly And Company A pyridin quinolin substituted pyrrolo [1,2-b] pyrazole monohydrate as tgf-beta inhibitor
WO2018006870A1 (en) * 2016-07-07 2018-01-11 苏州科睿思制药有限公司 Galunisertib crystal form and preparation method therefor and use thereof

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