WO2022170864A1 - Forme cristalline du mésylate de beumosul, son procédé de préparation et son utilisation - Google Patents

Forme cristalline du mésylate de beumosul, son procédé de préparation et son utilisation Download PDF

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WO2022170864A1
WO2022170864A1 PCT/CN2021/140731 CN2021140731W WO2022170864A1 WO 2022170864 A1 WO2022170864 A1 WO 2022170864A1 CN 2021140731 W CN2021140731 W CN 2021140731W WO 2022170864 A1 WO2022170864 A1 WO 2022170864A1
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compound
crystal form
mesylate
ray powder
powder diffraction
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PCT/CN2021/140731
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English (en)
Chinese (zh)
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陈敏华
施文睿
张婧
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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
    • A61K31/495—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
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of crystal chemistry. Specifically, it relates to the crystalline form of Belumosudil mesylate and its preparation method and use.
  • cGVHD Chronic graft-versus-host disease
  • QOL quality of life
  • alloHCT allogeneic hematopoietic cell transplantation
  • REZUROCK TM (Belumosudil) is approved in the United States for the treatment of adult and pediatric patients 12 years of age and older with cGVHD after failure of at least two prior systemic therapy regimens.
  • Belumosudil is the only approved therapy targeting Rho-related coiled-coil kinase 2 (ROCK2).
  • ROCK2 Rho-related coiled-coil kinase 2
  • a crystal is a solid in which the molecules of a compound are arranged in a three-dimensional order in a microstructure to form a crystal lattice.
  • Polymorphism is the phenomenon in which a compound exists in more than one crystal form. Compounds may exist in one or more crystalline forms, but their existence and identity cannot be specifically expected. APIs with different crystal forms have different physicochemical properties, which may lead to different dissolution and absorption of the drug in the body, thereby affecting the clinical efficacy of the drug to a certain extent. Especially for some insoluble oral solid or semi-solid preparations, the crystal form is very important to the product performance. In addition to this, the physicochemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is an important part of drug research and drug quality control.
  • the prior art does not disclose the solid form of compound I mesylate, only the preparation method of compound I and the brown solid of compound I are disclosed.
  • the preparation method of compound I disclosed in the prior art WO2006105081A2 is as follows: using preparative HPLC to purify the crude product of compound I, and then obtaining compound I, the form of compound I is not disclosed.
  • CN106916145B discloses compound I as a brown solid.
  • the inventors of the present application repeated the preparation methods disclosed in WO2006105081A2 and CN106916145B to obtain solids of compound I, which were named as prior art P1 and prior art P2 respectively.
  • the technology has problems such as high solvent content, low solubility, high hygroscopicity, and poor stability, and is not suitable for medicinal development.
  • the inventors of the present application have carried out in-depth research on the solid form of compound I and its salts, and have unexpectedly found the crystallization of compound I mesylate provided by the invention, which is in solubility, hygroscopicity, Purification, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, bioavailability and other aspects have advantages in at least one aspect, especially no solvent residue, high solubility, good stability, low hygroscopicity, The problems existing in the prior art are solved, and it is of great significance to the development of medicines containing compound I.
  • the main purpose of the present invention is to provide a solid of compound I mesylate, a preparation method thereof, and a pharmaceutical composition comprising the solid.
  • the present invention provides the crystalline form of compound I mesylate.
  • the present invention provides the anhydrate of compound I mesylate.
  • the present invention provides the hydrate of compound I mesylate.
  • the present invention provides the crystalline form CSI of Compound I mesylate (hereinafter referred to as "crystalline form CSI").
  • the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at the diffraction angle 2 ⁇ value of 7.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSI has a diffraction angle 2 ⁇ value of 8.4° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.2° ⁇ 0.2° at 1 or 2
  • a diffraction angle 2 ⁇ value of 8.4° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.2° ⁇ 0.2° at 1 or 2
  • characteristic peaks at or at 3 preferably, the X-ray powder diffraction pattern of the crystalline form CSI is at 3 of the diffraction angle 2 ⁇ values of 8.4° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.2° ⁇ 0.2°
  • characteristic peaks are characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CSI has a diffraction angle 2 ⁇ value of 16.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 23.5° ⁇ 0.2°, or 2 There are characteristic peaks at or at 3 places; preferably, the X-ray powder diffraction pattern of the crystalline form CSI is at 3 places in the diffraction angle 2 ⁇ value of 16.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 23.5° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CSI has diffraction angle 2 ⁇ values of 7.1° ⁇ 0.2°, 8.4° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.2° ⁇ 0.2° , 16.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 23.5° ⁇ 0.2°, 17.2° ⁇ 0.2°, 25.5° ⁇ 0.2° any 1, or 2, or 3, or 4, or 5 There are characteristic peaks at, or 6, or 7, or 8, or 9.
  • the X-ray powder diffraction pattern of the crystalline form CSI is substantially as shown in FIG. 3 .
  • thermogravimetric analysis diagram is basically shown in FIG. 4 .
  • the differential scanning calorimetry analysis of the crystalline form CSI is basically as shown in Figure 6, which has an endothermic peak around 267 ° C (the initial temperature is about 264 ° C), and the endothermic peak is the crystalline form.
  • the melting endotherm of CSI is basically as shown in Figure 6, which has an endothermic peak around 267 ° C (the initial temperature is about 264 ° C), and the endothermic peak is the crystalline form.
  • the melting endotherm of CSI is basically as shown in Figure 6, which has an endothermic peak around 267 ° C (the initial temperature is about 264 ° C), and the endothermic peak is the crystalline form.
  • the melting endotherm of CSI is basically as shown in Figure 6, which has an endothermic peak around 267 ° C (the initial temperature is about 264 ° C), and the endothermic peak is the crystalline form.
  • the melting endotherm of CSI is basically as shown in Figure 6, which has an endothermic peak around 267 ° C (the initial
  • the crystalline form CSI is anhydrous.
  • the present invention also provides a preparation method of the crystal form CSI, the preparation method comprising:
  • the alcohol solvent is preferably ethanol; the ketone solvent is preferably acetone; the molar ratio of the solid compound I to methanesulfonic acid is preferably 1:1.
  • the present invention provides the mesylate salt crystal form CSII of Compound I (hereinafter referred to as "crystal form CSII").
  • the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angle 2 ⁇ values of 6.3° ⁇ 0.2°, 12.7° ⁇ 0.2°, 15.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSII has a diffraction angle 2 ⁇ value of 7.9° ⁇ 0.2°, 19.2° ⁇ 0.2°, 19.9° ⁇ 0.2°, or 2
  • a diffraction angle 2 ⁇ value of 7.9° ⁇ 0.2°, 19.2° ⁇ 0.2°, 19.9° ⁇ 0.2°, or 2
  • characteristic peaks at or at 3 places preferably, the X-ray powder diffraction pattern of the crystalline form CSII is at 3 places in the diffraction angle 2 ⁇ value of 7.9° ⁇ 0.2°, 19.2° ⁇ 0.2°, 19.9° ⁇ 0.2°
  • the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at 1 or 2 places in the diffraction angle 2 ⁇ value of 14.5° ⁇ 0.2°, 20.4° ⁇ 0.2°; preferably In particular, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at two positions among the diffraction angle 2 ⁇ values of 14.5° ⁇ 0.2° and 20.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSII has diffraction angle 2 ⁇ values of 6.3° ⁇ 0.2°, 12.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, 7.9° ⁇ 0.2° , 19.2° ⁇ 0.2°, 19.9° ⁇ 0.2°, 14.5° ⁇ 0.2°, 20.4° ⁇ 0.2°, 9.9° ⁇ 0.2°, 25.2° ⁇ 0.2°, 26.5° ⁇ 0.2°, or 2 There are characteristic peaks at, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11.
  • the X-ray powder diffraction pattern of Form CSII is substantially as shown in FIG. 13 .
  • thermogravimetric analysis diagram is basically as shown in FIG. 14 .
  • Non-limitingly, crystalline form CSII has an endothermic peak around 100°C, an exothermic peak around 206°C, and an endothermic peak around 255°C (starting temperature is about 253°C), differential scanning
  • the calorimetric analysis diagram is shown in Figure 15.
  • the crystalline form CSII is a hydrate.
  • the crystalline form CSII contains no more than 10% water by mass.
  • the crystalline form CSII contains no more than 8% water by mass.
  • the crystalline form CSII contains no more than 6% water by mass.
  • the present invention also provides a preparation method of the crystal form CSII, the preparation method comprising:
  • the solid compound I, methanesulfonic acid, a mixed solvent of alcohols and water or a mixed solvent of ethers and water are mixed and stirred to obtain crystal form CSII.
  • the molar ratio of the solid compound I to methanesulfonic acid is preferably 0.9:1-1.1:1, more preferably 1:1;
  • the alcohol solvent is preferably isopropanol;
  • the ether solvent is preferably tetrahydrofuran;
  • the volume ratio of alcohols and water or ethers and water in the mixed solvent is preferably 9:1.
  • the present invention provides the use of crystal form CSI, crystal form CSII or any mixture of the two crystal forms for preparing other crystal forms of compound I methanesulfonic acid.
  • the present invention provides a pharmaceutical composition comprising an effective therapeutic amount of the crystal form of Compound I mesylate and pharmaceutically acceptable excipients.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective therapeutic amount of crystal form CSI, crystal form CSII or any mixture of the two crystal forms and pharmaceutically acceptable excipients.
  • the present invention provides the use of the crystalline form of compound I mesylate in the preparation of ROCK2 inhibitor medicine.
  • the present invention provides the use of crystal form CSI, crystal form CSII or any mixture of the two crystal forms in the preparation of ROCK2 inhibitor drugs.
  • the present invention provides the use of the crystalline form of Compound I mesylate in the preparation of a medicament for the treatment of chronic graft-versus-host disease, systemic sclerosis and idiopathic pulmonary fibrosis.
  • the present invention provides the use of crystal form CSI, crystal form CSII or any mixture of the two crystal forms in the preparation of a drug for the treatment of chronic graft-versus-host disease, systemic sclerosis and idiopathic pulmonary fibrosis.
  • the crystalline form CSI provided by the present invention has higher solubility.
  • the solubility of crystalline form CSI is more than 2 times that of the prior art P1 and 1.5 times that of the prior art P2.
  • Compound I is a poorly water-soluble drug belonging to BCS class IV.
  • the crystal form CSI provided by the present invention has higher solubility, which is beneficial to improve the absorption of the drug in the human body and improve the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the curative effect of the drug, thereby reducing the amount of the drug side effects and improve the safety of medicines.
  • the crystalline form CSI provided by the present invention has lower hygroscopicity.
  • the test results show that the crystal form of the present invention remains unchanged before and after the CSI moisture absorption test, and the moisture absorption weight gain (0-80% RH) is significantly lower than that of the prior art P1.
  • the hygroscopicity of the crystalline form CSI is better than that of the prior art.
  • high hygroscopicity can easily cause chemical degradation and solid state transformation of the API, which directly affects the physicochemical stability of the API.
  • high hygroscopicity will reduce the fluidity of the API, thereby affecting the processing technology of the API.
  • drugs with high hygroscopicity need to maintain low humidity during production and storage, which puts forward higher requirements for production and requires high costs. More importantly, the high hygroscopicity can easily cause changes in the content of active ingredients in the drug, affecting the quality of the drug.
  • the crystal form CSI provided by the invention has low hygroscopicity, is not harsh on the environment, reduces the cost of material production, storage and quality control, and has strong economic value.
  • the crystal form CSI API provided by the present invention has good stability.
  • the crystal form of CSI API is placed under the condition of 25°C/60%RH, the crystal form does not change for at least 6 months, and the chemical purity is above 99.5%, and the purity basically remains unchanged during the storage process. It shows that the crystalline CSI API has good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystalline form of the CSI API has not changed when placed at 40°C/75%RH for at least 6 months, and the crystal form has not changed at 60°C/75%RH for at least 1 month, and the chemical purity is More than 99.5%, the purity remains basically unchanged during storage. It shows that the crystalline CSI API has good stability under accelerated conditions and more severe conditions. High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of APIs. Therefore, the stability of the drug substance under accelerated and more severe conditions is critical for the drug.
  • the crystalline form of CSI API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during drug storage.
  • Crystalline CSI has good physical and chemical stability, ensuring consistent and controllable quality of APIs and preparations, and reducing drug quality changes, bioavailability changes, and toxic and side effects caused by changes in crystal form or impurities.
  • the crystalline form CSI has better grinding stability.
  • the prior art P1 is basically transformed into amorphous after grinding, while the crystal form of the CSI bulk drug of the present invention remains unchanged after grinding, and has good physical stability.
  • it is often necessary to grind and pulverize the API, and good physical stability can reduce the risk of lowering the crystallinity of the API and the risk of crystal transformation during the preparation process.
  • the crystalline form CSI provided by the present invention has almost no solvent residue, while the prior art P2 has about 0.34 molar equivalent of ethyl acetate (about 62000 ppm).
  • ethyl acetate is a class 3 solvent with an upper limit of 5000ppm. It can be seen from this that the solvent content of the prior art P2 is far beyond the upper limit and is not suitable for medicinal use.
  • the crystalline form CSII provided by the present invention has higher solubility.
  • the solubility is more than 2 times that of the prior art P1 and 1.3 times that of the prior art P2.
  • Compound I is a poorly water-soluble drug belonging to BCS class IV.
  • the crystal form CSII provided by the present invention has higher solubility, which is beneficial to improve the absorption of the drug in the human body and improve the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the curative effect of the drug, thereby reducing the amount of the drug side effects and improve the safety of medicines.
  • the crystalline form CSII provided by the present invention has lower hygroscopicity.
  • the test results show that the crystal form of the present invention remains unchanged before and after the moisture absorption test of CSII, and the moisture gain (40-80% RH) is about 1/5 of that of the prior art P1.
  • the hygroscopicity of the crystalline form CSII is obviously better than that of the prior art.
  • high hygroscopicity can easily cause chemical degradation and solid state transformation of the API, which directly affects the physicochemical stability of the API.
  • high hygroscopicity will reduce the fluidity of the API, thereby affecting the processing technology of the API.
  • drugs with high hygroscopicity need to maintain low humidity during production and storage, which puts forward higher requirements for production and requires high costs. More importantly, the high hygroscopicity can easily cause changes in the content of active ingredients in the drug, affecting the quality of the drug.
  • the crystal form CSII provided by the invention has low hygroscopicity, is not harsh on the environment, reduces the cost of material production, storage and quality control, and has strong economic value.
  • the crystal form CSII bulk drug provided by the present invention has good stability.
  • the crystal form CSII API is placed under the condition of 25°C/60%RH, the crystal form has not changed for at least 6 months, and the chemical purity is above 99.5%, and the purity basically remains unchanged during the storage process. It shows that the crystalline form CSII API has good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystal form of CSII API has not changed after being placed at 40°C/75%RH for at least 6 months, and the chemical purity is above 99.5%, and the purity remains basically unchanged during storage. It shows that the crystalline form CSII API has good stability under accelerated conditions.
  • Crystal form CSII has good physical and chemical stability, ensuring consistent and controllable quality of raw materials and preparations, and reducing drug quality changes, bioavailability changes, and toxic and side effects caused by crystal form changes or impurities.
  • the crystalline form CSII has better grinding stability.
  • the prior art P1 is basically transformed into amorphous after grinding, while the crystal form of the CSI bulk drug of the present invention remains unchanged after grinding, and has good physical stability.
  • it is often necessary to grind and pulverize the API, and good physical stability can reduce the risk of lowering the crystallinity of the API and the risk of crystal transformation during the preparation process.
  • the crystalline form CSII provided by the present invention has almost no solvent residue, while the prior art P2 has about 0.34 molar equivalent of ethyl acetate (about 62000 ppm).
  • ethyl acetate is a class 3 solvent with an upper limit of 5000ppm. It can be seen from this that the solvent content of the prior art P2 is far beyond the upper limit and is not suitable for medicinal use.
  • Fig. 1 is the XRPD diagram of the prior art P1
  • FIG. 2 is the XRPD diagram of the prior art P2
  • Figure 3 is the XRPD pattern of the crystalline form CSI
  • Figure 4 is the TGA diagram of the crystal form CSI
  • Figure 5 is the XRPD pattern of the crystalline form CSI
  • Figure 6 is the DSC chart of crystal form CSI
  • FIG. 7 is a XRPD comparison diagram before and after grinding of the prior art P1 (top: after grinding; bottom: before grinding)
  • Fig. 8 is the XRPD comparison diagram of crystal form CSI before and after grinding (top: after grinding; bottom: before grinding)
  • FIG. 9 is a DVS diagram of the prior art P1
  • Figure 10 is the DVS diagram of the crystal form CSI
  • Figure 11 is a comparison chart of XRPD before and after DVS test of crystal form CSI (top: before test; bottom: after test)
  • Figure 12 is the XRPD comparison chart of crystalline form CSI before and after storage under different conditions (from bottom to top: before storage, 25°C/60%RH open packaging for 6 months, 25°C/60%RH sealed packaging for 6 months 6 months at 40°C/75%RH open packaging, 6 months at 40°C/75%RH sealed packaging, 1 month at 60°C/75%RH open packaging, 60°C/75%RH Store in airtight packaging for 1 month)
  • Figure 13 is the XRPD pattern of the crystalline form CSII
  • Figure 14 is a TGA diagram of crystal form CSII
  • Figure 15 is the DSC chart of crystal form CSII
  • Figure 16 is the XRPD comparison diagram of crystal form CSII before and after grinding (top: after grinding; bottom: before grinding)
  • Figure 17 is the XRPD comparison chart before and after the DVS test of the crystal form CSII (top: before test; bottom: after test)
  • Figure 18 is the XRPD comparison chart of crystal form CSII before and after storage under different conditions (from bottom to top: before storage, 25°C/60%RH open packaging for 6 months, 25°C/60%RH sealed packaging for 6 months months, 6 months at 40°C/75%RH open packaging, 6 months at 40°C/75%RH sealed packaging)
  • the X-ray powder diffraction patterns described in the examples of the present invention were collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the method parameters of the described X-ray powder diffraction are as follows:
  • thermogravimetric analysis (TGA) plots described in the present invention were collected on a TA Q500.
  • the method parameters of thermogravimetric analysis (TGA) of the present invention are as follows:
  • DSC Differential Scanning Calorimetry
  • the dynamic moisture adsorption (DVS) map of the present invention is collected on the Intrinsic dynamic moisture adsorption instrument produced by SMS company (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software.
  • the method parameters of the described dynamic moisture adsorption instrument are as follows:
  • Relative humidity range 0%RH-95%RH
  • the hydrogen nuclear magnetic resonance spectrum data ( 1 H NMR) of the present invention was collected from a Bruker Avance II DMX 400 MHz nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL.
  • the dynamic solubility test method of the present invention is shown in Table 1.
  • the related substance detection method of the present invention is shown in Table 2.
  • the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rpm, wherein the magnetic stirring speed is preferably 300-900 rpm, and the mechanical stirring speed is 300-900 rpm. Preferably 100-300 rpm.
  • the “separation” is accomplished by conventional methods in the art, such as centrifugation or filtration.
  • the operation of "centrifugation” is as follows: put the sample to be separated in a centrifuge tube and centrifuge at a speed of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube, and separate the solids.
  • the "drying” is accomplished by conventional methods in the art, such as vacuum drying, blast drying or natural air drying.
  • the drying temperature may be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. Drying time can be 2-48 hours, or overnight. Drying takes place in a fume hood, blast oven or vacuum oven.
  • room temperature is not a specific temperature value, but refers to a temperature range of 10-30°C.
  • the “characteristic peak” refers to a representative diffraction peak used to identify crystals.
  • the peak position can usually have an error of ⁇ 0.2°.
  • crystal or “crystal form” can be characterized by X-ray powder diffraction.
  • X-ray powder diffraction pattern will vary depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of experimental conditions, so the diffraction peak intensity cannot be used as the sole or decisive factor for determining the crystal form.
  • the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystals, and the diffraction peak intensities shown in the present invention are illustrative and not for absolute comparison. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to here, and any X-ray powder diffraction pattern with the characteristic peaks in these patterns Crystal forms with the same or similar X-ray powder diffraction patterns all fall within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of images reflect the same or different crystal forms.
  • the crystalline form CSI and crystalline form CSII described herein are pure and substantially not mixed with any other crystalline forms.
  • substantially free when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less More than 5% (weight) of other crystal forms, more than 1% (weight) of other crystal forms.
  • the compound I and/or its salts as raw materials include, but are not limited to, solid form (crystalline or amorphous), oily, liquid form and solution.
  • the compound I and/or its salts as starting materials are in solid form.
  • Compound I used in the following examples can be prepared according to the prior art, for example, according to the method described in the document WO2006105081A2.
  • prior art P1 is obtained, and the XRPD pattern of prior art P1 is shown in FIG. 1 .
  • the resulting solid P2 was calculated to contain about 0.34 molar equivalents of ethyl acetate (about 62,000 ppm).
  • ethyl acetate belongs to class 3 solvents, and the upper limit of its allowable content is 5000ppm.
  • the content of ethyl acetate in the prior art solid P2 is much higher than the upper limit of the ICH guidelines, which is not suitable for medicinal use.
  • Embodiment 2 The preparation method of crystal form CSI
  • samples 1-2 are all crystal forms of CSI according to the present invention.
  • the XRPD pattern of sample 1 obtained in this example is shown in FIG. 3 , and the XRPD data is shown in Table 4.
  • the TGA of sample 1 obtained in this example is shown in FIG. 4 , and when heated to 100° C., there is a mass loss of about 0.2%.
  • Embodiment 3 The preparation method of crystal form CSI
  • the obtained crystalline solid is the crystal form CSI described in the present invention, and its X-ray powder diffraction data is shown in Figure 5, and the XRPD data is shown in Table 5.
  • FeSSIF Simulated Fed State Intestinal Fluid
  • the crystalline form CSI of the present invention and the prior art solid were placed in a mortar and manually ground for 5 minutes, and the XRPD of the samples before and after grinding was tested. The results are shown in Table 7. The results show that the crystalline form CSI has better grinding stability compared with the prior art.
  • Example 7 The hygroscopicity of crystal form CSI and prior art
  • the XRPD of the crystal form CSI before and after the DVS test was tested, and the results are shown in Figure 11.
  • the experimental results show that the crystal form of CSI remains unchanged after undergoing 0%RH-95%RH-0%RH cycles. It shows that the crystalline form CSI has good stability under high humidity.
  • Airtight packaging put the sample in a glass vial, tighten the bottle cap with a cap, and seal it in an aluminum foil bag.
  • Open packaging place the sample in a glass vial, cover the bottle with a layer of aluminum foil and perforate the foil.
  • the experimental results show that the crystalline form CSI can be stable for at least 6 months under the conditions of 25°C/60%RH and 40°C/75%RH. It can be seen that the crystalline form CSI can maintain good stability under long-term and accelerated conditions. Crystalline CSI is stable for at least 1 month under the conditions of 60°C/75%RH, and it can be seen that the stability of crystallized CSI is also very good under more severe conditions.
  • Embodiment 10 The preparation method of crystal form CSII
  • the obtained crystalline solid is the crystal form CSII of the present invention, its X-ray powder diffraction pattern is shown in Figure 13, and the X-ray powder diffraction data is shown in Table 10.
  • the TGA of the crystalline form CSII is shown in Figure 14, and when heated to 100°C, it has a mass loss of about 5.9%.
  • Embodiment 11 The preparation method of crystal form CSII
  • the crystalline form CSII and the prior art solid were placed in a mortar and manually ground for 5 minutes, and the XRPD of the samples before and after grinding was tested. The results are shown in Table 13. The results show that, compared with the prior art, the crystalline form CSII has better grinding stability.
  • the crystal form CSII is a hydrate, and the DVS test takes the ambient humidity (40%RH) as the initial humidity test.
  • the XRPD of the crystal form CSII before and after the DVS test was tested, and the results are shown in Figure 17.
  • the experimental results show that the crystal form of CSII remains unchanged after undergoing a 40-95-0-95% RH cycle. It shows that the crystalline form CSII has good stability under high humidity.
  • Sealed packaging put the sample in a glass vial, tighten the bottle cap with a cap, and seal it in an aluminum foil bag.
  • Open packaging place the sample in a glass vial, cover the bottle with a layer of aluminum foil and perforate the foil.
  • the experimental results show that the crystalline form CSII can be stable for at least 6 months under the conditions of 25°C/60%RH and 40°C/75%RH. It can be seen that the crystalline form CSII has good stability under both long-term and accelerated conditions.

Abstract

La présente invention concerne une forme cristalline de mésylate de belumosudil (ci-après appelé composé I) et un procédé de préparation de la forme cristalline, une composition pharmaceutique comprenant la forme cristalline, et une utilisation de la forme cristalline dans la préparation de médicaments inhibiteurs de ROCK2 et de médicaments pour le traitement d'une maladie chronique du greffon contre l'hôte, la sclérose systémique et la fibrose pulmonaire idiopathique. Par comparaison avec l'état de la technique, la forme cristalline du mésylate de belumosudil fournie par la présente invention a une ou plusieurs propriétés améliorées, et a une valeur importante pour l'optimisation et le développement des médicaments à l'avenir.
PCT/CN2021/140731 2021-02-09 2021-12-23 Forme cristalline du mésylate de beumosul, son procédé de préparation et son utilisation WO2022170864A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023285706A1 (fr) * 2021-07-16 2023-01-19 Sandoz Ag Formes à l'état solide de sel d'acide 2-(3-(4-(1h-indazol-5-ylamino)quinazolin-2-yl )phénoxy)-n-isopropylacétamide méthane sulfonique
US11773083B2 (en) 2020-07-22 2023-10-03 Teva Pharmaceuticals International Gmbh Solid state forms of Belumosudil and Belumosudil salts

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101208094A (zh) * 2005-03-25 2008-06-25 表面线段公司 药代动力学改善的化合物
CN105120869A (zh) * 2012-10-05 2015-12-02 卡德门企业有限公司 眼部病症的治疗
EP3875078A1 (fr) * 2020-03-06 2021-09-08 Dompe' Farmaceutici S.P.A. Des composes pour pour le traitement de covid-19
WO2022020850A1 (fr) * 2020-07-22 2022-01-27 Teva Pharmaceuticals International Gmbh Formes solides de belumosudil et de sels de belumosudil

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101208094A (zh) * 2005-03-25 2008-06-25 表面线段公司 药代动力学改善的化合物
CN105120869A (zh) * 2012-10-05 2015-12-02 卡德门企业有限公司 眼部病症的治疗
EP3875078A1 (fr) * 2020-03-06 2021-09-08 Dompe' Farmaceutici S.P.A. Des composes pour pour le traitement de covid-19
WO2022020850A1 (fr) * 2020-07-22 2022-01-27 Teva Pharmaceuticals International Gmbh Formes solides de belumosudil et de sels de belumosudil

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11773083B2 (en) 2020-07-22 2023-10-03 Teva Pharmaceuticals International Gmbh Solid state forms of Belumosudil and Belumosudil salts
US11932627B2 (en) 2020-07-22 2024-03-19 Teva Pharmaceuticals International Gmbh Solid state forms of Belumosudil and Belumosudil salts
WO2023285706A1 (fr) * 2021-07-16 2023-01-19 Sandoz Ag Formes à l'état solide de sel d'acide 2-(3-(4-(1h-indazol-5-ylamino)quinazolin-2-yl )phénoxy)-n-isopropylacétamide méthane sulfonique

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