WO2022223027A1 - Tolebrutinib晶型、无定型及其制备方法和用途 - Google Patents

Tolebrutinib晶型、无定型及其制备方法和用途 Download PDF

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WO2022223027A1
WO2022223027A1 PCT/CN2022/088495 CN2022088495W WO2022223027A1 WO 2022223027 A1 WO2022223027 A1 WO 2022223027A1 CN 2022088495 W CN2022088495 W CN 2022088495W WO 2022223027 A1 WO2022223027 A1 WO 2022223027A1
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tolebrutinib
solvent
amorphous
water
preparation
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PCT/CN2022/088495
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English (en)
French (fr)
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盛晓红
盛晓霞
代宇
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杭州领业医药科技有限公司
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Priority to EP22791132.8A priority Critical patent/EP4328226A1/en
Priority to CN202280032117.0A priority patent/CN117295735A/zh
Publication of WO2022223027A1 publication Critical patent/WO2022223027A1/zh
Priority to US18/475,489 priority patent/US12103925B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This application relates to the field of medicinal chemistry. Specifically, the present application relates to the crystalline form and amorphous form of tolebrutinib, and the preparation method and use thereof.
  • Polymorphism or polymorphism is a unique property of certain molecules and molecular compositions, the same molecule may form different crystals due to different arrangements, and these crystals have different crystal structures and physical properties, such as solubility, stability , thermal properties, mechanical properties, purification ability, X-ray diffraction patterns, infrared absorption patterns, Raman spectroscopy and solid-state nuclear magnetic resonance.
  • new crystalline forms including anhydrates, hydrates, solvates, etc.
  • active pharmaceutical ingredients may yield more processing advantages or provide substances with better physicochemical properties, such as better bioavailability, storage stability, and ease of use. Processing, easy purification or as an intermediate crystal form to facilitate conversion to other crystal forms. Certain crystal forms of certain compounds used as pharmaceutical active ingredients can also help improve the properties of the drug. It expands the available raw material types in formulations, such as improved dissolution, improved shelf life, easier processing, etc.
  • Tolebrutinib (R&D code SAR442168), developed by Principia, was later acquired by Sanofi and included in its product line.
  • Tolebrutinib is a BTK inhibitor for the treatment of cancer, autoimmune diseases such as Multiple sclerosis and myasthenia gravis, inflammatory diseases and thromboembolic diseases, etc., the structural formula is as follows:
  • the crystalline form of tolebrutinib provided by this application has at least one of the following advantages: good stability, low hygroscopicity, uniform particle size distribution, solubility that meets medicinal requirements, stable storage, and avoids drug transcrystallization during development and storage.
  • the method is reliable and has great development value.
  • the inventor of the present application also surprisingly found an amorphous form of tolebrutinib.
  • solid powders have two types of physical states, amorphous and crystalline.
  • amorphous solids have lower stability and higher hygroscopicity, which limits their medicinal value.
  • the amorphous form of tolebrutinib discovered by the applicant has better solubility than crystalline tolebrutinib, and still has good storage stability and acceptable hygroscopicity, and has high medicinal value.
  • the purpose of this application is to provide the crystalline form and amorphous form of tolebrutinib as well as the preparation method and use thereof.
  • An object of the present application is to provide a tolebrutinib Form 1 (hereinafter referred to as Form1), the 2 ⁇ value of its XRPD pattern is at least 10.4° ⁇ 0.2°, 11.4° ⁇ 0.2°, 20.6° ⁇ 0.2°, 16.7° ⁇ 0.2° and There are four characteristic peaks in 22.7° ⁇ 0.2°.
  • the XRPD pattern of the tolebrutinib Form 1 also has one or two 2 ⁇ values of 4.2° ⁇ 0.2°, 15.8° ⁇ 0.2°, 17.9° ⁇ 0.2°, 20.8 ⁇ 0.2° and 24.8° ⁇ 0.2° and above, or/and its XRPD pattern also has one or both of the 2 ⁇ values of 10.9° ⁇ 0.2°, 21.3° ⁇ 0.2°, 23.5 ⁇ 0.2°, 25.3 ⁇ 0.2° and 25.7 ⁇ 0.2° There are characteristic peaks at and above.
  • the XRPD pattern of the tolebrutinib Form 1 has a diffraction peak at the position of the 2 ⁇ value as shown in the table below:
  • the XRPD spectrum of the tolebrutinib Form 1 is basically as shown in Figure 7.
  • the TGA spectrum of the tolebrutinib Form 1 is basically as shown in Figure 8.
  • the DSC spectrum of the tolebrutinib Form 1 begins to appear an endothermic peak at about 126°C.
  • the DSC spectrum of the tolebrutinib Form 1 is basically as shown in Figure 9.
  • the FT-IR (Fourier infrared) spectrum of the tolebrutinib Form 1 has bands at 840.7 ⁇ 2cm -1 , 978.3 ⁇ 2cm -1 , 1472.3 ⁇ 2cm -1 and 1492.5 ⁇ 2cm -1 .
  • the FT-IR spectrum of the tolebrutinib Form 1 is also 748.5 ⁇ 2cm -1 , 1230.6 ⁇ 2cm -1 , 1396.8 ⁇ 2cm -1 , 1447.4 ⁇ 2cm -1 , 1508.9 ⁇ 2cm -1 , 1588.1 ⁇ 2cm -1 , 1638.1 ⁇ 2cm -1 and 1698.4 ⁇ 2cm -1 one or two or more bands.
  • the FT-IR spectrum of the tolebrutinib Form 1 is basically as shown in Figure 13.
  • the tolebrutinib Form 1 is anhydrous.
  • One of the objects of this application is also to provide a preparation method of tolebrutinib Form 1, which method is selected from any one of the following methods:
  • the solvent 1 is acetone.
  • the dissolving step is performed at room temperature.
  • the volatilization is carried out at room temperature.
  • the good solvent is selected from a single or mixed solvent of ethanol, acetone and tetrahydrofuran;
  • the anti-solvent is selected from a single solvent or a mixed solvent of water, n-heptane and n-hexane, preferably a water-containing mixed solvent.
  • the stirring (1) is an optional step.
  • the stirring (2) is an optional step, and is especially suitable for the embodiment in which the solid is not precipitated immediately after the anti-solvent is added; for the case where the solid is precipitated immediately after the anti-solvent is added, this step can be omitted.
  • the volume ratio of the antisolvent:good solvent is ⁇ 0.1:1, more preferably 1:1-8:1.
  • the dissolving step is performed at room temperature.
  • the stirring is performed at a certain temperature, and the certain temperature is less than or equal to 30°C; the stirring time is greater than or equal to 30 minutes.
  • the solvent 2 is selected from one or a mixed solvent of ethanol or ethyl acetate.
  • the solvent is ethanol.
  • the mass-volume ratio (mg/mL) of the tolebrutinib and solvent 2 is 20:1-100:1.
  • the mass-to-volume ratio (mg/mL) of the tolebrutinib and solvent 2 is 25:1-50:1.
  • the tolebrutinib Form 1 of the present application has the following beneficial effects:
  • Tolebrutinib Form 1 The stability of Tolebrutinib Form 1 is good, which is beneficial to the storage of samples and the stability of preparations.
  • the crystal form of Tolebrutinib Form 1 remained unchanged under long-term and accelerated conditions for 10 months, and the chemical purity of tolebrutinib Form 1 remained basically unchanged before and after storage.
  • the crystal form remains unchanged at 25°C/60% RH for at least 14 days, indicating that the tolebrutinib Form 1 API and the preparation prepared by the application Form 1 are in strict condition. Under harsh conditions, it has good stability.
  • Tolebrutinib Form 1 has low hygroscopicity and has no special requirements for production and placement of environmental humidity. It is suitable for industrial production and is conducive to the storage of compounds and their preparations.
  • Tolebrutinib Form 1 has good solubility, and has a solubility of about 20 mg/mL in a solvent similar to the physiological pH value in the human stomach, which is conducive to achieving ideal drug bioavailability and efficacy and meeting medicinal requirements.
  • Tolebrutinib Form 1 has good compressibility, which is beneficial to the preparation process, improves the appearance of the product, and improves the quality of the product.
  • Tolebrutinib Form 1 has a good appearance and shape, and is solid powder with fine particles, which is beneficial to improve the fluidity.
  • the preparation method of Tolebrutinib Form 1 has mild conditions, high repeatability, and has industrialization prospects.
  • Tolebrutinib Form 1 has very high chemical purity.
  • the Form 1 sample of this application without any special purification operation has a purity of 99.8%, indicating that high purity is a beneficial property of the Form 1 crystal form itself. Even after stable storage, as shown in Table 2, it still has a purity of 99.5% after being left open for 10 months at 40°C/75%RH, indicating that Form 1 has high chemical stability while maintaining high chemical purity. .
  • tolebrutinib Form 1 has good physicochemical properties, is easy to prepare into preparation products, can better ensure the quality of compounds and preparation products, and is conducive to the exertion of the curative effect of tolebrutinib.
  • Another object of the present application is to provide a tolebrutinib Form 2 (hereinafter referred to as Form 2), the 2 ⁇ value of its XRPD pattern is at least 7.8° ⁇ 0.2°, 12.0° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.8° ⁇ 0.2 There are four characteristic peaks in °, 22.9° ⁇ 0.2°.
  • the XRPD pattern of the tolebrutinib Form 2 also has one or two 2 ⁇ values of 11.1° ⁇ 0.2°, 13.7° ⁇ 0.2°, 16.2 ⁇ 0.2°, 23.9° ⁇ 0.2° and 24.9° ⁇ 0.2°
  • the XRPD pattern of the tolebrutinib Form 2 has diffraction peaks at the positions of the 2 ⁇ values as shown in the table below:
  • the XRPD spectrum of the tolebrutinib Form 2 is basically as shown in Figure 14.
  • the TGA spectrum of the tolebrutinib Form 2 is basically as shown in Figure 15.
  • the DSC spectrum of the tolebrutinib Form 2 begins to appear an endothermic peak at 160-164°C.
  • the DSC spectrum of the tolebrutinib Form 2 is basically as shown in Figure 16.
  • the FT-IR spectrum of the tolebrutinib Form 2 has bands at 1699 ⁇ 2cm -1 , 1229 ⁇ 2cm -1 , 1486cm -1 and 1507 ⁇ 2cm -1 .
  • the FT-IR spectrum of the tolebrutinib Form 2 also has bands at one or two or more of 693 ⁇ 2cm -1 , 1395 ⁇ 2cm -1 , 1507 ⁇ 2cm -1 and 1626 ⁇ 2cm -1 .
  • the FT-IR spectrum of the tolebrutinib Form 2 is basically as shown in Figure 19.
  • the tolebrutinib Form 2 is an anhydrous.
  • One of the objects of the present application is also to provide a preparation method of tolebrutinib Form 2, the method is selected from any one of the following methods:
  • the constant temperature stirring time is ⁇ 12 hours, preferably 1-5 days; the constant temperature stirring temperature is ⁇ 30°C, preferably 30-80°C, more preferably 40-70°C.
  • the solvent 3 is selected from methyl tert-butyl ether, n-heptane, methyl ethyl ketone, water, n-butyl acetate, isopropyl ether, sec-butanol, methyl tert-butyl ether, dichloromethane, 1,4- A single or mixed solvent for dioxane.
  • the solvent 3 is selected from a mixed solvent of butanone and water, and the mixed volume ratio is 1:1-1:10; or, it is selected from a mixed solvent of n-butyl acetate and dichloromethane, and the mixed volume ratio is 1 :1-1:10.
  • the solvent 4 is selected from one of toluene and methylcyclohexane or a mixture thereof.
  • the solvent 4 is a mixed solvent of toluene and methylcyclohexane, and the solvent mixing ratio is 5:1-1:2.
  • the solvent 5 is acetonitrile.
  • the tolebrutinib Form 2 of the present application has the following beneficial effects:
  • Tolebrutinib Form 2 has a high melting point, which is very beneficial to high temperature processes such as hot melt extrusion.
  • Tolebrutinib Form 2 The physical and chemical stability of Tolebrutinib Form 2 is good, which is beneficial to the storage of the sample and the stability of the preparation.
  • Tolebrutinib Form 2 was placed under long-term and accelerated conditions for 10 months, and the crystal form remained unchanged, and the chemical purity of tolebrutinib Form 2 remained basically unchanged before and after placement.
  • after tolebrutinib Form 2 was mixed with excipients to make a pharmaceutical preparation, at 25 Under the condition of °C/60%RH, the crystal form remains unchanged for at least 14 days, indicating that the API of tolebrutinib Form 2 and the preparation prepared by using tolebrutinib Form 2 of this application have good stability under severe conditions and are suitable for preparations production and storage.
  • Tolebrutinib Form 2 is a thermodynamically stable crystal form at a temperature of 30°C and above.
  • Tolebrutinib Form 2 has good compressibility, which is beneficial to the preparation process, improves the appearance of the product and improves the quality of the product.
  • Tolebrutinib Form 2 has a good appearance and shape, and is solid powder with fine particles, uniform distribution and good fluidity.
  • Another object of the present application is to provide an amorphous solid form of tolebrutinib, the 2 ⁇ value of the amorphous XRPD pattern has no diffraction peaks in the range of 3-40°.
  • the amorphous XRPD pattern has a diffuse packet in the 2[Theta] value in the range of 10-40[deg.].
  • the amorphous XRPD spectrum is basically as shown in FIG. 1 .
  • the amorphous TGA spectrum is basically as shown in FIG. 2 .
  • the amorphous mDSC spectrum is basically as shown in FIG. 3 .
  • the amorphous FT-IR spectrum has bands at 1703 ⁇ 2cm -1 , 1440 ⁇ 2cm -1 , 788cm -1 and 753 ⁇ 2cm -1 .
  • the amorphous FT-IR spectrum is also at 693 ⁇ 2cm -1 , 950 ⁇ 2cm -1 , 1227 ⁇ 2cm -1 , 1391 ⁇ 2cm -1 , 1487 ⁇ 2cm -1 , 1487 ⁇ 1 Bands are present at one or two or more of 2cm ⁇ 1 , 1588 ⁇ 2cm ⁇ 1 and 1625 ⁇ 2cm ⁇ 1 .
  • the amorphous FT-IR spectrum is basically as shown in FIG. 6 .
  • One of the objects of the present application is also to provide an amorphous preparation method of tolebrutinib, the method is selected from any one of the following methods:
  • the good solvent is one of dimethyl sulfoxide and toluene or a mixture thereof;
  • the anti-solvent is selected from one of water and ether or a mixture thereof.
  • the good solvent is dimethyl sulfoxide; the anti-solvent is water.
  • the volume ratio of the good solvent and the anti-solvent is 10:1-1:10, more preferably 1:1.
  • the solvent 6 is selected from one or more of the following mixed solvents: trifluoroethanol/water, isopropyl acetate/water, tetrahydrofuran/water, 1,4-dioxane/water, acetonitrile/water and chloroform/water.
  • the solvent 6 is a mixed solvent of trifluoroethanol/water.
  • the high temperature is 40-80°C.
  • the low temperature is less than or equal to 10°C.
  • the tolebrutinib amorphous solid form of the present application has the following unexpected combined beneficial effects:
  • the amorphous form of Tolebrutinib of the present application has good stability, which is beneficial to the storage of the sample and the stability of the preparation.
  • Tolebrutinib amorphous remains unchanged after 10 months under long-term and accelerated conditions, and the chemical purity of the amorphous remains basically unchanged before and after storage; the amorphous sample is placed under the conditions of light and oxidation for at least 14 days without conversion. and the chemical purity is basically unchanged before and after placement; and, after the amorphous form is mixed with excipients to make a pharmaceutical preparation, the amorphous form remains unchanged after being placed at 25°C/60% RH for at least 14 days;
  • the medicine and the preparation prepared by using the amorphous form of the present application have better stability under severe conditions.
  • Tolebrutinib of the present application has high amorphous chemical purity, ⁇ 98.9%. And the purity remains unchanged after 10 months of long-term exposure, and 98.0% of the purity is still exposed for 10 months under accelerated conditions.
  • Amorphous Tolebrutinib has low hygroscopicity, and the weight gain is only about 1.9% between 20% RH and 80% RH, which is suitable for industrial production.
  • the amorphous form of Tolebrutinib has good compressibility, which is beneficial to the preparation process, improves the appearance of the product, and improves the quality of the product.
  • Another object of the present application is to provide a pharmaceutical composition of tolebrutinib, the composition comprising one or more of tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib amorphous solid form, or any combination thereof, and at least one pharmaceutically acceptable carrier.
  • One of the objectives of the present application is also to provide a preparation prepared from the above-mentioned tolebrutinib pharmaceutical composition, and the preparation forms include but are not limited to oral solid preparations, external preparations, and injections.
  • the formulations are in the form of tablets, capsules, pills, suppositories, granules, fine granules, powder/powder, sustained-release preparations, immediate-release preparations, solutions, suspensions, elixirs, Aerosols, etc.
  • the formulation is in the form of a tablet.
  • the pharmaceutically acceptable carrier is an adjuvant commonly used in formulations in the art, including but not limited to adhesives, surfactants, diluents, anti-adherents, hydrophilic or hydrophobic polymers, and stabilizers Or stabilizer, disintegrant, antioxidant, defoamer, filler, glidant/lubricant, adsorbent, preservative, plasticizer, sweetener, and any one of its two or more mixture.
  • the filler or diluent is selected from lactose, microcrystalline cellulose, starch, pregelatinized starch, calcium sulfate, calcium hydrogen phosphate, calcium carbonate any one or a combination thereof;
  • the disintegrant is selected from any one of sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone or its combination;
  • the lubricant/glidant is selected from one or a combination of magnesium stearate, talc, and micropowder silica gel.
  • the pharmaceutical composition may also comprise one or more pH adjusting or buffering agents, for example: acids such as acetic acid, boric acid, citric acid, fumaric acid, maleic acid, tartaric acid, malic acid, lactic acid , any one or a combination of phosphoric acid and hydrochloric acid; or a base, such as any one of sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tris or a combination thereof; Or buffers such as citrate/dextrose, sodium bicarbonate, ammonium chloride and the like.
  • Such buffers used as bases may have counterions other than sodium, such as potassium, magnesium, calcium, ammonium, and other counterions; and other amounts necessary to maintain the pH of the components within acceptable ranges, including Solutions or solids of acids, bases and buffers.
  • One of the purposes of this application is to provide one or more of tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib amorphous solid form, or any combination thereof, or the pharmaceutical composition thereof in the preparation of treatment for BTK-mediated related Use in medicine for disorders.
  • One of the purposes of the present application is to provide one or more tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib amorphous solid form, or any combination thereof, or the pharmaceutical composition thereof in preparation for the treatment of cancer, autoimmunity Use in the medicament of sexual, inflammatory and thromboembolic diseases.
  • It is also an object of the present application to provide a method of treating a BTK-mediated disorder comprising administering to a patient an effective amount of one or more of tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib amorphous solid form, or Any combination thereof, or the pharmaceutical composition thereof.
  • Another object of the present application is to provide a method for tolebrutinib and its pharmaceutical composition for the treatment of cancer, autoimmune disease, inflammatory disease and thromboembolic disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of the present application One or more of tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib amorphous solid form, or any combination thereof, or the pharmaceutical composition thereof.
  • the effective amount of one or more tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib amorphous solid form, or any combination thereof of the present application is 0.001-10 mg/kg, preferably 0.005-5 mg /kg.
  • the method may be administered once a day, twice a day, three times a day or more.
  • the single dose can be 0.1 mg to 500 mg/kg/day, and the specific dose will be determined according to the actual situation of the patient.
  • the method is administration once daily, and the single dose is oral 10, 30, 60, 90, 120, 150, 180, 210, 300, 450 or 500 mg of one or more of tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib amorphous solid form, or any combination thereof; more preferably 60 or 120 mg.
  • the diseases include but are not limited to acute hemorrhagic necrotizing leukoencephalitis, acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, alopecia areata, Alopecia universalis, amyloidosis, ankylosing spondylitis, anti-GBM/anti-TBM nephritis, antiphospholipid syndrome (APS), antiphospholipid antibody syndrome, aplastic anemia, arthritis, autoimmune angioedema, autoimmune Immune familial autonomic dysfunction, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retina disease, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, autoimmune hemolytic anemia, axonal and neuronal neuropathy, Balo disease,
  • the multiple sclerosis includes but is not limited to relapsing multiple sclerosis (RMS), primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis ( SPMS).
  • RMS relapsing multiple sclerosis
  • PPMS primary progressive multiple sclerosis
  • SPMS secondary progressive multiple sclerosis
  • One of the objectives of the present application is to provide one or more of tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib amorphous solid form, or any combination thereof, or the combined application of its pharmaceutical composition and other drugs.
  • the other drugs include, but are not limited to, any one or more of anticancer drugs, corticosteroids, non-corticosteroids, immunosuppressants, anti-inflammatory drugs, and combinations thereof.
  • the other drug is selected from ibrutinib, acalatinib, zanubrutinib, Velexbru and orelabrutinib.
  • the experimental operating temperature generally refers to room temperature, and "room temperature” refers to a temperature between 10°C and 30°C.
  • stirring conventional methods in the art can be used, for example, stirring methods include magnetic stirring and mechanical stirring, and the stirring speed is 50-1800 rpm, preferably 300-900 rpm.
  • Isolation can be performed by conventional methods in the art, such as centrifugation or filtration. Filtering under reduced pressure is preferred, and suction filtration is generally performed at a pressure less than atmospheric pressure, preferably less than 0.09 MPa.
  • Drying can be accomplished by using conventional techniques in the art, such as drying at room temperature, air drying or drying under reduced pressure; it can be under reduced pressure or normal pressure, preferably the pressure is less than 0.09 MPa.
  • the drying apparatus and method are not limited, and can be a fume hood, a forced air oven, a spray dryer, a fluidized bed drying or a vacuum oven; it can be carried out under reduced or no reduced pressure, preferably the pressure is less than 0.09Mpa.
  • the ratios involved in this application are mass-volume ratios, and between liquids and liquids, are volume ratios.
  • Fig. 4 DVS figure 1 of the sample of Example 1-1;
  • Figure 10 DVS figure 1 of the sample of Example 2-1;
  • Figure 20 The XRPD overlay of the sample (amorphous) of Example 1-1 placed under long-term (25°C/60%RH/open) and accelerated (40°C/75%RH/open) conditions for 10 months;
  • Figure 21 The XRPD overlay of the sample (Form 1) of Example 2-1 placed under long-term (25°C/60%RH/open) and accelerated (40°C/75%RH/open) conditions for 10 months;
  • Figure 22 The XRPD overlay of the sample (Form 2) of Example 3-1 placed under long-term (25°C/60%RH/open) and accelerated (40°C/75%RH/open) conditions for 10 months;
  • Figure 28 is the XRPD overlay of tablet stability of Example 3-1 sample (Form 2);
  • Figure 30 is the XRPD pattern (tolebrutinib Form 1) of the sample of Example 2-4;
  • Figure 31 is the XRPD pattern (tolebrutinib Form 2) of the sample of Example 3-2;
  • Figure 32 is a DSC chart of the samples of Examples 3-6.
  • X-ray powder diffraction (XRPD) data were taken from BrukerD8 Advance diffractometer; parameters are as follows: Cu target; wavelength is Current and voltage: 40KV, 40mA; Angle range: 3 ⁇ 40°2 ⁇ .
  • thermogravimetric analysis (TGA) data were obtained from TA Instruments Q500 TGA; parameters were as follows: mode: high resolution mode; heating rate: 10°C/min; protective gas: N 2 ; sample pan: platinum crucible.
  • DSC Differential Thermal Analysis
  • mDSC data were collected from TA Instruments Q200 DSC; the parameters were as follows: amplitude: ⁇ 0.048°C, cycle 60s, heating rate: 2°C/min, protective gas: N2; sample pan: covered aluminum crucible.
  • FT-IR Fourier transform infrared spectroscopy
  • the polarized light microscope (PLM) spectrum was taken from the XPV ⁇ 990E polarized light microscope; a small amount of powder sample was placed on a glass slide, a small amount of mineral oil was added dropwise to disperse the sample, a cover glass was placed on the slide, and the sample was placed on the slide. Observing and taking pictures on the stage.
  • PLM polarized light microscope
  • the above crude products can also be obtained through other synthetic routes or procurement.
  • Example 1-1 Preparation of tolebrutinib amorphous
  • the DVS characterization data of sample 1-1 was measured at 25°C, with a weight gain of about 1.9% between 20% RH and 80% RH, as shown in Figure 4-5;
  • the FT-IR spectrum of sample 1-1 is shown in FIG. 6 .
  • Example 1-2 Preparation of tolebrutinib amorphous
  • tolebrutinib crude product was dissolved in 1.5 mL of toluene. After adding 4.0 mL of ether, a solid was precipitated. After stirring for two hours, centrifugation, and vacuum drying at room temperature for 24 hours to obtain amorphous sample 1-2.
  • Example 1-3 Preparation of tolebrutinib amorphous
  • tolebrutinib crude product was taken, dissolved in trifluoroethanol/water (0.3/0.4 ml) at 60°C, filtered, stirred at 4°C for 2 days, separated and dried to obtain amorphous.
  • Example 1-4 Preparation of tolebrutinib amorphous
  • Example 1-3 According to the method of Example 1-3, respectively in isopropyl acetate/water (0.1/0.3ml), tetrahydrofuran/water (0.1/0.4ml), 1,4-dioxane/water (0.05/0.2ml) , acetonitrile/water (0.05/0.2ml) and chloroform/water (0.4/0.2ml), and other conditions remain unchanged, all of which are amorphous.
  • tolebrutinib Form 1 sample 2-1 About 20 mg of crude tolebrutinib was dissolved in 0.5 mL of ethyl acetate at room temperature. After stirring at room temperature for 1 day, the clear solution was cooled to 5 °C and stirred for 4 days. After adding 0.6 mL of purified water dropwise to the clear solution, there was a solid Precipitation, centrifugation, and vacuum drying at room temperature to obtain tolebrutinib Form 1 sample 2-1.
  • the XRPD pattern of sample 2-1 is shown in FIG. 7 .
  • the TGA characterization data of sample 2-1 was determined, and it was anhydrous (1.4% weight loss before 100° C.), and the decomposition temperature was 346° C., as shown in FIG. 8 .
  • the DVS characterization data of sample 2-1 was determined, and it was slightly hygroscopic, and the weight gain between 0%RH and 80%RH was about 0.46%, as shown in Figures 10-11.
  • the PLM characterization data of sample 2-1 was measured, and the particles were fine and uniformly distributed, with a particle size of ⁇ 10 microns, as shown in FIG. 12 .
  • the FT-IR spectrum of sample 2-1 is shown in FIG. 13 .
  • tolebrutinib amorphous solution Take about 20 mg of tolebrutinib amorphous solution at room temperature in 0.5 mL of acetone, filter, and evaporate at room temperature for 1 day to obtain tolebrutinib Form 1 sample.
  • tolebrutinib amorphous solution in 0.5 mL of tetrahydrofuran, filter, add 1.2 mL of water to produce oily droplets, stir at room temperature for one day and then transfer to 4 °C for stirring. After 7 days, the suspension is centrifuged and vacuum dried at room temperature overnight After that, a tolebrutinib Form 1 sample was obtained.
  • tolebrutinib amorphous solution at room temperature in 1.5 mL of acetone, filter, add 4.0 mL of n-heptane to obtain a clear solution, stir at room temperature for one day, then cool down to 4 °C and stir, after 7 days, centrifuge the suspension and vacuum dry at room temperature , to obtain tolebrutinib Form 1 samples.
  • tolebrutinib amorphous solution Take about 20 mg of tolebrutinib amorphous solution at room temperature in 0.5 mL of acetone, add 4.0 mL of n-heptane to obtain a clear solution, stir at room temperature for one day, then cool down to 4 °C and stir, after 7 days, centrifuge the suspension and vacuum dry at room temperature to obtain tolebrutinib Form 1 sample.
  • tolebrutinib Form 1 sample About 50 mg of amorphous tolebrutinib was taken, added with 1 mL of ethanol, stirred at room temperature for 1 day, separated, and dried under vacuum at room temperature to obtain tolebrutinib Form 1 sample.
  • tolebrutinib amorphous Take about 50 mg of tolebrutinib amorphous, add 1 mL of ethyl acetate, stir for 2 days, separate, and vacuum dry at room temperature to obtain tolebrutinib Form 1 sample.
  • tolebrutinib amorphous was formed into a suspension in methyl tert-butyl ether (0.5 mL), the slurry was kept at a constant temperature of 40 °C for 4 days, centrifuged, and dried at room temperature overnight to obtain Form 2 sample 3-1.
  • the XRPD pattern of sample 3-1 is shown in FIG. 14 .
  • the TGA characterization data of sample 3-1 was measured, it was anhydrous, before 100°C, the weight loss was 0.6%, and the decomposition temperature was 342°C, as shown in FIG. 15 .
  • the DSC characterization data of sample 3-1 was measured, the melting point (indicated by Onset value) was 160°C, and the peak value was 167°C, as shown in Figure 16, that is, an endothermic peak appeared when heated to 160°C.
  • the DVS characterization data of sample 3-1 was determined, and the weight gain between 0%RH and 80%RH was about 0.34%, as shown in FIG. 17 .
  • the PLM characterization data of sample 3-1 was measured, and the particles were fine and uniformly distributed, with a particle size of ⁇ 10 microns, as shown in FIG. 18 .
  • the FT-IR spectrum of the measurement sample 3-1 is shown in FIG. 19 .
  • tolebrutinib crude product was taken, placed in an atmosphere of acetonitrile for 4 days, and then vacuum-dried at room temperature overnight to obtain a Form 2 sample.
  • tolebrutinib crude product was added to a toluene/methylcyclohexane system (0.55/0.2 mL), dissolved at 60 °C, stirred at 5 °C for one day, and the clear solution was transferred to 40 °C after 2 days of open volatilization to obtain Form 2 Samples 3-6.
  • the DSC characterization data of samples 3-6 were measured, the melting point (indicated by Onset value) was 164°C, and the peak value was 170°C, as shown in Figure 32, that is, an endothermic peak appeared when heated to 164°C.
  • Example 3-1 about 20 mg of tolebrutinib amorphous was taken and prepared in isopropyl ether (0.5 mL), methanol/isopropyl ether (0.1/0.6 mL), sec-butanol/n-heptane (0.6/0.6 mL), 1,4-dioxane/isopropyl ether (0.2/0.6mL), methyl tert-butyl ether/n-butyl acetate (0.1/1.8mL) to form a suspension, other conditions remain unchanged, Form 2 samples were obtained.
  • isopropyl ether 0.5 mL
  • methanol/isopropyl ether 0.1/0.6 mL
  • sec-butanol/n-heptane 0.6/0.6 mL
  • 1,4-dioxane/isopropyl ether 0.2/0.6mL
  • methyl tert-butyl ether/n-butyl acetate 0.1/1.8mL
  • Example 4 Stability study of tolebrutinib amorphous, tolebrutinib Form 1 and tolebrutinib Form 2
  • Example 1-1 of this application Take an appropriate amount of the tolebrutinib amorphous sample prepared in Example 1-1 of this application, and place it under long-term (25°C/60%RH/open) and accelerated (40°C/75%RH/open) conditions, and periodically detect HPLC and XRPD, the results are shown in Table 1 and Figure 20.
  • tolebrutinib amorphous can be stable for at least 10 months under long-term (25°C/60%RH/exposure) and accelerated (40°C/75%RH/exposure) conditions, and the amorphous form is stable before and after placement.
  • the chemical purity remains basically unchanged; in addition, the amorphous samples can also be placed under the conditions of light (25°C/4500lx/closed) and oxidation (in an atmosphere of carbamide peroxide), which can be stable for at least 14 days, and the amorphous chemical purity before and after placing Basically unchanged.
  • tolebrutinib Form 1 can be stable for at least 10 months under long-term (25°C/60%RH/exposure) and accelerated (40°C/75%RH/exposure) conditions, and Form 1 before and after placement can be stable for at least 10 months.
  • the chemical purity remains basically unchanged; in addition, the Form 1 sample can also be placed under the conditions of light (25°C/4500lx/closed) and oxidation (in an atmosphere of carbamide peroxide), and it can be stable for at least 14 days, and the chemical purity of Form 1 before and after being placed. Basically unchanged.
  • tolebrutinib Form 2 can be stable for at least 10 months under long-term (25°C/60%RH/exposure) and accelerated (40°C/75%RH/exposure) conditions, and Form 2 before and after placement can be stable for at least 10 months.
  • the chemical purity remains basically unchanged; in addition, the Form 2 samples can also be placed under the conditions of light (25°C/4500lx/closed) and oxidation (in an atmosphere of carbamide peroxide) to be stable for at least 14 days, and the chemical purity of Form 2 before and after being placed Basically unchanged.
  • Example 5 Solubility study of tolebrutinib amorphous, tolebrutinib Form 1 and tolebrutinib Form 2
  • the tolebrutinib amorphous, tolebrutinib Form 1 and tolebrutinib Form 2 samples in this application were prepared with pH 1.2 buffer solution (preparation: 375.90 mg potassium chloride solid and 1709.47 mg concentrated hydrochloric acid (37%) were weighed in a 100 mL volumetric flask, Add about 80 mL of pure water, adjust the pH to 1.2 with hydrochloric acid or potassium hydroxide, and adjust the volume to the mark with pure water) and pH 1.2 SGF (preparation: take 765 ⁇ L of concentrated hydrochloric acid (37%), add about 80 mL of water with 1 g of pepsin, chlorinated Sodium 200mg, after shaking, diluted with water to 100mL) to prepare a supersaturated solution, and the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) at a fixed time point.
  • HPLC high performance liquid chromatography
  • the solubility of tolebrutinib amorphous, tolebrutinib Form 1 and tolebrutinib Form 2 of the present application in pH 1.2 buffer solution and pH 1.2 SGF meets the pharmaceutical requirements.
  • Amorphous, Form 1 and Form 2 of the present application have ideal solubility, and all have an order of magnitude of about 20 mg/mL, which is beneficial to achieve ideal drug bioavailability and efficacy, and meet medicinal requirements.
  • Example 6 Compressibility study of tolebrutinib Amorphous, tolebrutinib Form 1 and tolebrutinib Form 2
  • Intertek rotary tablet press was used for tablet compression. When tableting, a circular die of ⁇ 7.5mm was selected, with a filling depth of 17.9mm, and the average main pressure of 1.8KN was used to press into circular tablets.
  • Tolebrutinib amorphous, tolebrutinib Form 1 and tolebrutinib Form 2 remained unchanged before and after the formulation process.
  • the XRPD comparison charts are shown in Figure 23, Figure 24 and Figure 25, respectively.
  • Example 9 Stability of tolebrutinib Amorphous, tolebrutinib Form 1 and tolebrutinib Form 2 in Tablets
  • the prepared amorphous tablets, Form 1 tablets and Form 2 tablets were placed at 25°C/60% RH for 14 days, and XRPD detection was performed before and after placement.
  • the XRPD comparison charts before and after placement are shown in Figure 26, Figure 27 and shown in Figure 28.

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Abstract

提供一种tolebrutinib的晶型、无定型及其制备方法和用途，所述tolebrutinib的晶型至少具有以下一个优点：稳定性良好，引湿性较低，粒度分布均匀，溶解度满足药用要求，能稳定储存，避免药物在开发过程和储存中发生转晶，制备方法可靠，具有很大的开发价值。所述tolebrutinib无定型在拥有比结晶态的tolebrutinib更好的溶解度的同时，依然具有良好的放置稳定性和可以接受的吸湿性，具有很高的药用价值。

Description

Tolebrutinib晶型、无定型及其制备方法和用途
相关申请的引用
本申请要求于2021年4月23日向中华人民共和国国家知识产权局提交的申请号为202110440752.X的发明专利申请以及于2021年4月30日向中华人民共和国国家知识产权局提交的申请号为202110479686.7的发明专利申请的全部权益，并通过引用的方式将其全部内容并入本申请。
技术领域
本申请涉及药物化学领域。具体而言，本申请涉及tolebrutinib的晶型、无定型及其制备方法和用途。
背景技术
多晶型或者多晶现象是某些分子和分子组合物的特有性质，相同的分子可能因不同的排列形式而形成不同晶体，而这些晶体具有不同的晶体结构和物理性质，如溶解度、稳定性、热性质、机械性质、纯化能力、X射线衍射图谱、红外吸收图谱、拉曼光谱和固态核磁等。
发现药物活性成分新的晶型(包括无水物、水合物、溶剂化物等)可能会产生更具加工优势或提供具有更好理化特性的物质，比如更好的生物利用度、储存稳定、易加工处理、易提纯或作为促进转化为其他晶型的中间体晶型。某些作为药学活性成分用的化合物的某特定晶型也可以帮助改善药物的性能。它扩大了制剂学上可选用的原料型态，例如改善溶出度、改善储藏期限、更容易加工等。
Tolebrutinib(研发代码SAR442168)，由普林斯匹(Principia)公司研发，后被赛诺菲(Sanofi)收购而归入其产品线，Tolebrutinib为BTK抑制剂，用于治疗癌症、自身免疫性疾病如多发性硬化和重症肌无力、炎性疾病和血栓栓塞性疾病等，结构式如下：
Figure PCTCN2022088495-appb-000001
而目前现有技术中尚未公开关于该化合物的晶型的相关报道。因此，有必要对tolebrutinib进行全面系统的多晶型筛选，选择具有有益性质的晶型用于tolebrutinib的产品开发。
本申请的发明人在研究过程中惊奇的发现了tolebrutinib的2种晶型。本申请提供的tolebrutinib的晶型至少具有以下一个优点：稳定性良好，引湿性较低，粒度分布均匀，溶解度满足药用要求，能稳定储存，避免药物在开发过程和储存中发生转晶，制备方法可靠，具有很大的开发价值。
同时，本申请的发明人还惊喜地发现一种tolebrutinib的无定型。众所周知，固体粉末有无定型和晶型两种类型的物理状态。通常无定型固体具有较低的稳定性，较高的吸湿性而使其药用价值受限。然而，本申请人发现的tolebrutinib无定型却在拥有比结晶态的tolebrutinib更好的溶解度的同时，依然具有良好的放置稳定性和可以接受的吸湿性，具有很高的药用价值。
发明内容
针对现有技术的不足，本申请的目的是提供tolebrutinib的晶型、无定型及其制备方法和用途。
本申请的一个目的是提供一种tolebrutinib Form 1(以下简称Form1)，其XRPD图谱的2θ值至少在10.4°±0.2°、11.4°±0.2°、20.6°±0.2°、16.7°±0.2°和22.7°±0.2°中的四处有特征峰。
进一步，所述tolebrutinib Form 1的XRPD图谱还在2θ值为4.2°±0.2°、15.8°±0.2°、17.9°±0.2°、20.8±0.2°和24.8°±0.2°中的一处或两处及其以上有特征峰，或/和其XRPD图谱还在2θ值为10.9°±0.2°、21.3°±0.2°、23.5±0.2°、25.3±0.2°和25.7±0.2°中的一处或两处及其以上有特征峰。
更进一步，所述tolebrutinib Form 1的XRPD图谱在2θ值如下表的位置具有衍射峰：
2θ±0.2°
4.2
10.4
2θ±0.2°
10.9
11.4
15.8
16.7
17.9
20.3
20.6
20.8
21.0
21.3
22.7
23.5
23.7
24.8
25.3
25.7
26.9
27.2
27.4
31.1
35.5
本申请优选技术方案中，所述tolebrutinib Form 1的XRPD图谱基本如图7所示。
本申请优选技术方案中，所述tolebrutinib Form 1的TGA图谱基本如图8所示。
本申请优选技术方案中，所述tolebrutinib Form 1的DSC图谱在126℃左右开始出现吸热峰。
本申请优选技术方案中，所述tolebrutinib Form 1的DSC图谱基本如图9所示。
本申请优选技术方案中，所述tolebrutinib Form 1的FT-IR(傅里 叶红外)图谱在840.7±2cm -1、978.3±2cm -1、1472.3±2cm -1、1492.5±2cm -1处有谱带。
优选地，所述tolebrutinib Form 1的FT-IR图谱还在748.5±2cm -1、1230.6±2cm -1、1396.8±2cm -1、1447.4±2cm -1、1508.9±2cm -1、1588.1±2cm -1、1638.1±2cm -1和1698.4±2cm -1中的一处或两处及其以上有谱带。
本申请优选技术方案中，所述tolebrutinib Form 1的FT-IR图谱基本如图13所示。
本申请优选技术方案中，所述tolebrutinib Form 1为无水物。
本申请的目的之一还在于提供tolebrutinib Form 1的制备方法，所述方法选自以下方法中的任一种：
1)将tolebrutinib在溶剂1中溶清形成溶液，挥发，析晶，分离，干燥，即得Form 1。
其中，所述溶剂1为丙酮。
优选地，所述溶清步骤在室温下进行。
优选地，所述挥发在室温下进行。
2)将tolebrutinib在良溶剂中溶清形成溶液，搅拌(1)，加入抗溶剂，搅拌(2)，析晶，分离，干燥，即得Form 1。
其中，所述良溶剂选自乙醇、丙酮和四氢呋喃的单一或混合溶剂；所述抗溶剂选自水、正庚烷、正己烷的单一溶剂或混合溶剂，优选为含水的混合溶剂。
所述搅拌(1)为可选步骤。
所述搅拌(2)为可选步骤，尤其适用于加入抗溶剂后没有马上析出固体的实施例；对于加入抗溶剂后马上析出固体的，可省略该步骤。
优选地，所述抗溶剂:良溶剂的体积比为≥0.1:1，更优选为1:1-8:1。
优选地，所述溶清步骤在室温下进行。
优选地，所述搅拌在一定温度下进行，所述一定温度≤30℃；所述搅拌时间≥30min。
3)将tolebrutinib在溶剂2中形成混悬液，室温搅拌，分离，干 燥，即得Form 1。
其中，所述溶剂2选自乙醇或乙酸乙酯中的一种或混合溶剂。优选地，所述溶剂为乙醇。所述tolebrutinib和溶剂2的质量体积比(mg/mL)为20:1-100:1。
优选地，所述tolebrutinib和溶剂2的质量体积比(mg/mL)为25：1-50:1。
本申请的tolebrutinib Form 1具有以下有益效果：
1)Tolebrutinib Form 1的稳定性较好，有利于样品的储存和制剂的稳定。Tolebrutinib Form 1分别在长期、加速条件下放置10个月晶型保持不变，且放置前后tolebrutinib Form 1的化学纯度基本保持不变。并且，tolebrutinib Form 1与辅料混合做成药物制剂后，在25℃/60％RH条件下放置至少14天晶型保持不变，说明tolebrutinib Form 1原料药和采用本申请Form 1制备的制剂在严苛的条件下，具有较好的稳定性。
2)Tolebrutinib Form 1的引湿性低，对生产和放置环境湿度无特殊要求，适合工业化生产且有利于化合物和其制剂产品的储存。
3)Tolebrutinib Form 1的溶解度良好，在类似人体胃内生理pH值的溶媒中具有约20mg/mL的溶解度，有利于达到理想的药物生物利用度和药效，满足药用要求。
4)Tolebrutinib Form 1具有良好的可压性，有利于制剂工艺，改善产品外观，提升产品质量。
5)Tolebrutinib Form 1具有良好的外观形状，为固体粉末状，颗粒细小，有利于提高流动性。
6)Tolebrutinib Form 1制备方法条件温和，重复性高，具有可产业化前景。
7)Tolebrutinib Form 1具有非常高的化学纯度，本申请未经任何特别纯化操作的Form 1样品已经有99.8％的纯度，说明高纯度是Form 1晶型本身所具备的一个有益性质。即使经过稳定性放置，如表2所示，在40℃/75％RH条件下敞口放置10个月仍有99.5％的纯度，说明Form 1在具备保持高化学纯度的同时具有高化学稳定性。
综上，tolebrutinib Form 1具有良好的理化性质，易于制备成 制剂产品，更能保障化合物和制剂产品质量，有利于tolebrutinib疗效的发挥。
本申请的另一个目的在于提供一种tolebrutinib Form 2(以下简称Form 2)，其XRPD图谱的2θ值至少在7.8°±0.2°、12.0°±0.2°、18.5°±0.2°、18.8°±0.2°、22.9°±0.2°中的四处有特征峰。
进一步，所述tolebrutinib Form 2的XRPD图谱还在2θ值为11.1°±0.2°、13.7°±0.2°、16.2±0.2°、23.9°±0.2°和24.9°±0.2°中的一处或两处及其以上有特征峰，或/和其XRPD图谱还在2θ值为13.3°±0.2°、14.1°±0.2°、20.3±0.2°和21.7±0.2°中的一处或两处及其以上有特征峰。
更进一步，所述tolebrutinib Form 2的XRPD图谱在2θ值如下表的位置具有衍射峰：
2θ±0.2°
7.8
11.1
12.0
13.3
13.7
16.2
18.5
18.8
19.3
20.3
20.9
21.5
21.7
22.9
23.9
24.9
26.4
27.9
2θ±0.2°
29.0
30.4
本申请优选技术方案中，所述tolebrutinib Form 2的XRPD图谱基本如图14所示。
本申请优选技术方案中，所述tolebrutinib Form 2的TGA图谱基本如图15所示。
本申请优选技术方案中，所述tolebrutinib Form 2的DSC图谱在160-164℃开始出现吸热峰。
本申请优选技术方案中，所述tolebrutinib Form 2的DSC图谱基本如图16所示。
本申请优选技术方案中，所述tolebrutinib Form 2的FT-IR图谱在1699±2cm -1、1229±2cm -1、1486cm -1、1507±2cm -1处有谱带。
优选地，所述tolebrutinib Form 2的FT-IR图谱还在693±2cm -1、1395±2cm -1、1507±2cm -1和1626±2cm -1中的一处或两处及其以上有谱带。
本申请优选技术方案中，所述tolebrutinib Form 2的FT-IR图谱基本如图19所示。
本申请优选技术方案中，所述tolebrutinib Form 2为无水物。
本申请的目的之一还在于提供tolebrutinib Form 2的制备方法，所述方法选自下述方法中的任一种：
1)将tolebrutinib在溶剂3中分散为混悬液，恒温搅拌，分离固体，干燥，即得Form 2；
其中，所述恒温搅拌时间≥12小时，优选为1-5天；所述恒温搅拌温度≥30℃，优选为30-80℃，更优选为40-70℃。
所述溶剂3选自甲基叔丁基醚、正庚烷、丁酮、水、乙酸正丁酯、异丙醚、仲丁醇、甲基叔丁基醚、二氯甲烷、1,4-二氧六环的单一或混合溶剂。
优选地，所述溶剂3选自丁酮和水的混合溶剂，混合体积比为1:1-1:10；或者，选自乙酸正丁酯和二氯甲烷的混合溶剂，混合体积 比为1:1-1:10。
2)将tolebrutinib在溶剂4中溶解形成溶液，敞口挥发，干燥。
其中，所述溶剂4选自甲苯和甲基环己烷的一种或其混合。
优选地，所述溶剂4为甲苯和甲基环己烷的混合溶剂，溶剂混合比例为5:1-1:2。
3)将tolebrutinib置于密闭的溶剂5容器中≥1天，干燥，即得Form 2。
其中，所述溶剂5为乙腈。
本申请的tolebrutinib Form 2具有以下有益效果：
1)Tolebrutinib Form 2具有较高的熔点，非常有利于热熔挤出等高温工艺。
2)Tolebrutinib Form 2的引湿性非常低，在0-80％RH只有0.3％的吸湿，更适合工业化生产和储存。
3)Tolebrutinib Form 2的物理和化学稳定性较好，有利于样品的储存和制剂的稳定。Tolebrutinib Form 2分别在长期、加速条件下放置10个月晶型保持不变，且放置前后tolebrutinib Form 2的化学纯度基本保持不变，并且，tolebrutinib Form 2与辅料混合做成药物制剂后，在25℃/60％RH条件下放置至少14天晶型保持不变，说明tolebrutinib Form 2的原料药和采用本申请tolebrutinib Form 2制备的制剂在严苛的条件下，具有较好的稳定性，适合制剂生产和储存。
4)通过竞争性晶浆试验得知，Tolebrutinib Form 2是30℃及以上温度的热力学稳定晶型。
5)Tolebrutinib Form 2的溶解度良好，有利于达到理想的药物生物利用度和药效，满足药用要求。
6)Tolebrutinib Form 2具有好的可压性，有利于制剂工艺，改善产品外观，提升产品质量。
7)Tolebrutinib Form 2具有良好的外观形状，为固体粉末状，颗粒细小，分布均匀，流动性好。
8)Tolebrutinib Form 2的制备方法条件温和，重复性高具有可产业化前景。
本申请的目的之一还在于提供一种tolebrutinib的无定型固体形式，所述无定型的XRPD图谱的2θ值在3-40°范围内不具有衍射峰。
优选地，所述无定型的XRPD图谱的2θ值在10-40°范围内具有一个漫散包。
本申请优选技术方案中，所述无定型的XRPD图谱基本如图1所示。
本申请优选技术方案中，所述无定型的TGA图谱基本如图2所示。
本申请优选技术方案中，所述无定型的mDSC图谱基本如图3所示。
本申请优选技术方案中，所述无定型的FT-IR图谱在1703±2cm -1、1440±2cm -1、788cm -1和753±2cm -1处有谱带。
本申请优选技术方案中，所述无定型的FT-IR图谱还在693±2cm -1、950±2cm -1、1227±2cm -1、1391±2cm -1、1487±2cm -1、1487±2cm -1、1588±2cm -1和1625±2cm -1中的一处或两处及其以上有谱带。
本申请优选技术方案中，所述无定型的FT-IR图谱基本如图6所示。
本申请的目的之一还在于提供tolebrutinib无定型的制备方法，所述方法选自以下方法中的任一种：
1)将tolebrutinib在良溶剂中溶清，再加入抗溶剂，搅拌，析出固体，分离，干燥。
其中，所述良溶剂为二甲亚砜和甲苯中的一种或其混合；所述抗溶剂选自水和乙醚的一种或其混合。
优选地，所述良溶剂为二甲亚砜；所述抗溶剂为水。
优选地，所述良溶剂和抗溶剂的体积比为10:1-1:10，更优选为1:1。
2)将tolebrutinib在溶剂6中高温溶清，过滤，低温搅拌，分离，干燥。
其中，所述溶剂6选自以下混合溶剂中的一种或多种：三氟乙醇/水、乙酸异丙酯/水、四氢呋喃/水、1,4-二氧六环/水、乙腈/水和氯 仿/水。
优选地，所述溶剂6为三氟乙醇/水的混合溶剂。
优选地，所述高温为40-80℃。
优选地，所述低温≤10℃。
令人惊奇的是，本申请tolebrutinib无定型固体形式具有以下意料不到的综合有益效果：
1)本申请的Tolebrutinib无定型的稳定性好，有利于样品的储存和制剂的稳定。Tolebrutinib无定型分别在长期、加速条件下放置10个月无定型保持不变，且放置前后无定型的化学纯度基本保持不变；无定型样品在光照和氧化的条件下放置至少14天未发生转晶，且放置前后化学纯度基本不变；并且，无定型与辅料混合做成药物制剂后，在25℃/60％RH条件下放置至少14天无定型保持不变；说明本申请tolebrutinib无定型原料药和采用本申请无定型制备的制剂在严苛的条件下，具有较好的稳定性。
2)本申请的Tolebrutinib无定型化学纯度高，≥98.9％。且经10个月长期条件敞口放置后纯度不变，在加速条件下敞口十个月放置仍有98.0％的纯度。
3)Tolebrutinib无定型的溶解度良好，高于Tolebrutinib Form1和Form 2，有利于达到理想的药物生物利用度和药效，满足药用要求。
4)Tolebrutinib无定型的引湿性低，在20％RH-80％RH间增重仅约1.9％，适合工业化生产。
5)Tolebrutinib无定型具有好的可压性，有利于制剂工艺，改善产品外观，提升产品质量。
本申请的目的之一还在于提供一种tolebrutinib的药物组合物，所述组合物包括一种或多种的tolebrutinib Form 1、或tolebrutinib Form 2、或tolebrutinib无定型固体形式，或其任意组合，以及至少一种药学上可接受的载体。
本申请的目的之一还在于提供一种上述tolebrutinib药物组合物制备成的制剂，所述制剂形式包括但不限于口服固体制剂、外用制剂、注射剂。
本申请优选技术方案中，所述制剂形式为片剂、胶囊、丸剂、栓剂、颗粒剂、细粒剂、粉末/散剂、缓释制剂、速释制剂、溶液剂、混悬剂、酏剂、气雾剂等。
本申请优选技术方案中，所述制剂形式为片剂。
所述药学上可接受的载体为本领域制剂中常用的辅料，包括但不限于粘合剂、表面活性剂、稀释剂、抗粘附剂、亲水性或疏水性高分子聚合物、安定剂或稳定剂、崩解剂、抗氧化剂、消泡剂、填充剂、助流剂/润滑剂、吸附剂、防腐剂、增塑剂、甜味剂中的任一种及其两种及以上的混合物。
本申请优选技术方案中，当所述制剂为口服固体制剂时，所述填充剂或稀释剂选自乳糖、微晶纤维素、淀粉、预胶化淀粉、硫酸钙、磷酸氢钙、碳酸钙中的任一种或其组合；所述崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮中的任一种或其组合；所述润滑剂/助流剂选自硬脂酸镁、滑石粉、微粉硅胶中的一种或其组合。
进一步，所述药物组合物还可以包含一种或多种pH调整剂或缓冲剂，举例来说：酸，例如乙酸、硼酸、柠檬酸、富马酸、马来酸、酒石酸、苹果酸、乳酸、磷酸、盐酸的任一种或其组合；或者碱，例如氢氧化钠、磷酸钠、硼酸钠、柠檬酸钠、乙酸钠、乳酸钠、三羟甲基氨基甲烷的任一种或其组合物；或者缓冲剂，例如柠檬酸盐/葡萄糖、碳酸氢钠、氯化铵和类似物。用作碱的此类缓冲剂可具有除钠以外的平衡离子，例如钾、镁、钙、铵和其它平衡离子；以及其他将组分的pH维持在可接受范围内所需的量，包含此类酸、碱和缓冲剂的溶液或固体。
本申请的目的之一还在于提供一种或多种的tolebrutinib Form1、或tolebrutinib Form 2、或tolebrutinib无定型固体形式、或其任意组合，或其所述的药物组合物在制备治疗BTK介导相关病症的药物中的用途。
本申请的目的之一还在于提供一种或多种的tolebrutinib Form1、或tolebrutinib Form 2、或tolebrutinib无定型固体形式、或其任意组合，或其所述的药物组合物在制备治疗癌症、自身免疫性疾病、 炎性疾病和血栓栓塞性疾病的药物中的用途。
本申请的目的之一还在于提供一种治疗BTK介导的病症的方法，其包括向患者施加有效量一种或多种的tolebrutinib Form 1、或tolebrutinib Form 2、或tolebrutinib无定型固体形式、或其任意组合，或其所述的药物组合物。
本申请的目的之一还在于提供tolebrutinib及其药物组合物用于治疗癌症、自身免疫性疾病、炎性疾病和血栓栓塞性疾病的方法，所述方法包括给予需要的患者治疗有效量的本申请的一种或多种的tolebrutinib Form 1、或tolebrutinib Form 2、或tolebrutinib无定型固体形式、或其任意组合，或其所述的药物组合物。
优选地，所述有效量的本申请的一种或多种的tolebrutinib Form 1、或tolebrutinib Form 2、或tolebrutinib无定型固体形式、或其任意组合，为0.001-10mg/kg，优选为0.005-5mg/kg。
优选地，所述方法可以是一天一次，一天两次，一天三次或以上给药。单次剂量可以是0.1mg～500mg/kg/天，具体的剂量将根据病人的实际情况决定。
优选地，所述方法为每日一次给药，单次剂量为口服10、30、60、90、120、150、180、210、300、450或500mg的一种或多种的tolebrutinib Form 1、或tolebrutinib Form 2、或tolebrutinib无定型固体形式、或其任意组合；更优选为60或120mg。
本申请优选技术方案中，所述疾病包括但不限于急性出血性坏死性脑白质炎、急性播散性脑脊髓炎、阿狄森氏病(Addison's disease)、无丙种球蛋白血症、斑秃、普秃、淀粉样变性病、强直性脊椎炎、抗GBM/抗TBM肾炎、抗磷脂综合征(APS)、抗磷脂抗体综合征、再生障碍性贫血、关节炎、自身免疫性血管性水肿、自身免疫性家族性自主神经机能异常、自身免疫性肝炎、自身免疫性高血脂、自身免疫性内耳疾病(AIED)、自身免疫性心肌炎、自身免疫性卵巢炎、自身免疫性胰腺炎、自身免疫性视网膜病、自身免疫性血小板减少性紫癜(ATP)、自身免疫性甲状腺疾病、自身免疫性荨麻疹、自身免疫性溶血性贫血、轴突及神经元神经病变、巴洛病(Balo disease)、白塞氏 病(Behcet's disease)、大疱性类天疱疮、心肌症、卡斯特雷曼氏症(Castleman disease)、乳糜泻、查加斯病(Chagas disease)、慢性疲劳综合征、慢性炎性脱髓鞘性多发性神经病(CIDP)、慢性复发性多灶性骨髓炎(CRMO)、过敏性肉芽肿血管炎(Churg-Strauss syndrome)、瘢痕性类天疱疮/良性黏膜类天疱疮、腹腔病、耳蜗前庭综合征(Cogans syndrome)、冷凝集素病、先天性心脏传导阻滞、柯萨奇病毒性心肌炎(coxsackie myocarditis)、CREST病、克罗恩病(Crohn's disease)、脱髓鞘性神经病变、疱疹样皮炎、皮肌炎、德维克氏病(Devic's disease)(视神经脊髓炎)、糖尿病、盘状狼疮、杜丝勒综合征(Dressler's syndrome)、干眼病、家族性自主神经异常、子宫内膜异位、嗜酸细胞性食管炎、嗜酸性筋膜炎、结节性红斑、自发混合性冷球蛋白血症、伊文氏综合征(Evans syndrome)、实验性过敏性脑脊髓炎、纤维肌痛症、纤维化性肺泡炎、巨细胞性动脉炎(颞动脉炎)、巨细胞性心肌炎、肾小球性肾炎、古德帕斯特综合征(Goodpasture's syndrome)、肉芽肿性多血管炎(GPA)(以前被称为韦格纳肉芽肿)、格雷夫斯病(Graves'disease)、格林-巴利综合征(Guillain-Barre syndrome)、桥本氏甲状腺炎(Hashimoto's thyroiditis)、溶血性贫血、亨-舍二氏紫癜(Henoch-Schonlein purpura)、妊娠疱疹、低丙球蛋白血症、特发性肺纤维化、特发性血小板减少性紫癜(ITP)、IgA肾病、IgG4相关的硬化性疾病、免疫调节脂蛋白、包涵体肌炎、炎性肠病、间质性膀胱炎、幼年型关节炎、幼年型糖尿病(1类糖尿病)、幼年型肌炎、川崎综合征(Kawasaki syndrome)、兰伯特-伊顿综合征(Lambert-Eaton syndrome)、白细胞破碎性血管炎、扁平苔癣、硬化性苔藓、木样结膜炎、线性IgA疾病(LAD)、狼疮(SLE)、包含狼疮性肾炎的狼疮、莱姆病(lyme disease)、慢性病、梅尼埃病(Meniere's disease)、显微镜下多血管炎、混合性结蒂组织病(MCTD)、蚕蚀性角膜溃疡、Mucha-Habermann氏病、黏膜类天疱疮、多发性硬化、重症肌无力、肌炎、发作性嗜睡病、神经性肌强直、嗜中性白血球减少症、眼部瘢痕性类天疱疮、眼阵挛-肌阵挛综合征、视神经炎、Ord氏甲状腺炎、骨关节炎、复发性风湿病、PANDAS(链球菌相关的儿童自身 免疫性神经精神障碍)、副肿瘤性小脑变性、阵发性睡眠性血红蛋白尿症(PNH)、Parry Romberg综合征、睫状体扁平部炎(周边葡萄膜炎)、Parsonnage-Turner综合征、周围神经病变、静脉周性脑脊髓炎、恶性贫血、天疱疮(例如寻常天疱疮、落叶型天疱疮)、POEMS综合征、结节性多动脉炎、风湿性多肌痛症、多肌炎、心肌梗死后综合征、心包切开术后综合征、原发性胆汁性肝硬化、原发性硬化性胆管炎、原发性胆汁性肝硬化、孕酮性皮炎、银屑病、银屑病性关节炎、银屑病性关节炎、纯红细胞再生障碍、坏疽性脓皮病、雷诺氏现象(raynauds phenomenon)、反应性关节炎、反射交感性营养不良、赖特综合征(Reiter's syndrome)、复发性多软骨炎、不宁腿综合征、腹膜后纤维化、风湿热、类风湿性关节炎、类肉状瘤病、施密特综合征(Schmidt syndrome)、巩膜炎、硬皮病、休格兰氏综合征(Sjogren's syndrome)、精子及睾丸自身免疫、僵人综合征、斯提耳氏病(Still's disease)、亚急性细菌性心内膜炎(SBE)、Susac氏综合征、交感性眼炎、高安氏大动脉炎(Takayasu's arteritis)、颞动脉炎/巨细胞性动脉炎、血小板减少性紫癜(TTP)、托-享二氏综合征(Tolosa-Hunt syndrome)、横贯性脊髓炎、I、II和III类自身免疫多腺性综合征、溃疡性结肠炎、未分化结缔组织病(UCTD)、葡萄膜炎、血管炎、水疱大疱性皮肤病、白癜风、外阴痛或狼疮、多发性硬化症(MS)。
本申请优选技术方案中，所述多发性硬化症包括但不限于复发性多发性硬化症(RMS)、原发性进行性多发性硬化症(PPMS)、继发性进行性多发性硬化症(SPMS)。
本申请的目的之一还在于提供一种或多种的tolebrutinib Form1、或tolebrutinib Form 2、或tolebrutinib无定型固体形式、或其任意组合、或其药物组合物与其他药物的联合应用。
所述其他药物包括但不限于抗癌药、皮质类固醇、非皮质激素、免疫抑制剂、抗炎药的任一种或两种以上及其组合。
优选地，所述其他药物选自伊布替尼、阿卡替尼、泽布替尼、Velexbru和奥布替尼。
除非特殊注明：
实验操作温度一般指室温，“室温”是指10℃～30℃的温度。
“搅拌”，可以采用本领域的常规方法，例如搅拌方式包括磁力搅拌、机械搅拌，搅拌速度为50～1800转/分，优选为300～900转/分。
“分离”可以采用本领域的常规方法，例如离心或过滤。优选减压过滤，一般是以小于大气压的压力进行抽滤，优选压力小于0.09MPa。
“干燥”，可以采用本领域的常规技术完成，例如常温干燥、鼓风干燥或减压干燥；可以减压或常压，优选压力小于0.09MPa。干燥仪器和方法不受限制，可以是通风橱、鼓风烘箱、喷雾干燥器、流化床干燥或真空烘箱；可以在减压或不减压下进行，优选为压力小于0.09Mpa。
如无特殊说明，本申请涉及的比例，液体与固体之间，为质量体积比，液体与液体之间，为体积比。
附图说明
图1实施例1-1样品的XRPD图谱(tolebrutinib无定型)；
图2实施例1-1样品的TGA图；
图3实施例1-1样品的mDSC图；
图4实施例1-1样品的DVS图一；
图5实施例1-1样品的DVS图二；
图6实施例1-1样品的FT-IR图；
图7实施例2-1样品的XRPD图谱(tolebrutinib Form 1)；
图8实施例2-1样品的TGA图；
图9实施例2-1样品的DSC图；
图10实施例2-1样品的DVS图一；
图11实施例2-1样品的DVS图二；
图12实施例2-1样品的PLM图；
图13实施例2-1样品的FT-IR图；
图14实施例3-1样品的XRPD图谱(tolebrutinib Form 2)；
图15实施例3-1样品的TGA图；
图16实施例3-1样品的DSC图；
图17实施例3-1样品的DVS图；
图18实施例3-1样品的PLM图；
图19实施例3-1样品的FT-IR图；
图20实施例1-1样品(无定型)在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下放置10个月的XRPD叠图；
图21实施例2-1样品(Form 1)在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下放置10个月的XRPD叠图；
图22实施例3-1样品(Form 2)在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下放置10个月的XRPD叠图；
图23实施例1-1样品(无定型)制剂前后的XRPD叠图；
图24实施例2-1样品(Form 1)制剂前后的XRPD叠图；
图25实施例3-1样品(Form 2)制剂前后的XRPD叠图；
图26实施例1-1样品(无定型)片剂稳定性的XRPD叠图；
图27实施例2-1样品(Form 1)片剂稳定性的XRPD叠图；
图28实施例3-1样品(Form 2)片剂稳定性的XRPD叠图；
图29实施例1-2样品的XRPD图谱(tolebrutinib无定型)；
图30是实施例2-4样品的XRPD图谱(tolebrutinib Form 1)；
图31是实施例3-2样品的XRPD图谱(tolebrutinib Form 2)；
图32是实施例3-6样品的DSC图。
具体实施方式
下面结合附图和实施例对本申请的技术方案进行详细描述，但并不因此将本申请限制在所述的实施例范围之中。
在本申请中，X-射线粉末衍射(XRPD)数据采自于BrukerD8 Advance diffractometer；参数如下：Cu靶；波长为
Figure PCTCN2022088495-appb-000002
电流电压：40KV，40mA；角度范围：3～40°2θ。
在本申请中，热重分析(TGA)数据采自于TA Instruments Q500 TGA；参数如下：模式：高分辨模式；升温速率：10℃/min；保护气体：N 2；样品盘：铂金坩埚。
在本申请中，差热分析(DSC)数据采自于TA Instruments Q200 DSC；参数如下：升温速率：10℃/min；保护气体：N 2；样品盘： 加盖的铝坩埚。
在本申请中，mDSC数据采自于TA Instruments Q200 DSC；参数如下：振幅：±0.048℃，周期60s，升温速率：2℃/min，保护气体：N2；样品盘：加盖的铝坩埚。
在本申请中，动态水份吸附分析(DVS)数据和等温吸附分析数据采自于TA Instruments Q5000 TGA；参数如下：温度：25℃；相对湿度范围：0％RH-80％RH；dm/dt＝0.001％/min；平衡时间：90min；保护气体：N2；样品盘：铂金坩埚。
在本申请中，傅里叶红外光谱(FT-IR)数据采自于Bruker Tensor 27；参数如下：ATR法，采集范围600cm -1-4000cm -1，分辨率4cm -1。
在本申请中，偏振光显微镜(PLM)图谱采自于XPV～990E偏振光显微镜；取少量粉末样品置于载玻片上，滴加少量矿物油分散样品，盖上盖玻片，放置在载物台上进行观测并拍照。
本申请中，化学稳定性和溶解度的检测参数如下：
Figure PCTCN2022088495-appb-000003
下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。本申请所用试剂和原料除了特殊说明外，均市售可得。
制备例
参考WO2016196840A1的实施例3中合成路线，获得tolebrutinib粗制产物。
上述粗制产物也可以通过其他合成路线或采购获得。
实施例1-1：tolebrutinib无定型的制备
取约20毫克tolebrutinib粗制产物溶清在1.0mL二甲亚砜中，加入1.0mL水后，有固体析出，搅拌两小时后，离心，室温真空干燥24小时，得到样品1-1。
样品1-1的XRPD图谱如附图1所示；
测定样品1-1的TGA表征数据，在100℃之前，失重1.5％，分解温度为359℃，如附图2所示；
测定样品1-1的mDSC表征数据Tg温度为80.5℃，如附图3所示；
测定样品1-1的DVS表征数据在25℃下，20％RH-80％RH间增重约1.9％，如附图4-5所示；
样品1-1的FT-IR图谱如附图6所示。
实施例1-2：tolebrutinib无定型的制备
取约20毫克tolebrutinib粗制产物溶清在1.5mL甲苯中，加入4.0mL乙醚后，有固体析出，搅拌两小时后，离心，室温真空干燥24小时，得到无定型样品1-2。
实施例1-3：tolebrutinib无定型的制备
取约30毫克tolebrutinib粗制产物，60℃在三氟乙醇/水(0.3/0.4ml)中溶清，过滤，4℃搅拌2天，分离，干燥，即得无定型。
实施例1-4：tolebrutinib无定型的制备
按照实施例1-3的方法，分别在乙酸异丙酯/水(0.1/0.3ml)、四氢呋喃/水(0.1/0.4ml)、1,4-二氧六环/水(0.05/0.2ml)、乙 腈/水(0.05/0.2ml)和氯仿/水(0.4/0.2ml)中溶清，其他条件不变，均得到无定型。
实施例2-1：tolebrutinib Form 1的制备
取约20毫克tolebrutinib粗制产物室温溶清在0.5mL乙酸乙酯中，室温搅拌1天后，将澄清溶液降温至5℃搅拌4天后，向澄清溶液中逐滴加入0.6mL纯化水后，有固体析出，离心，室温真空干燥，得到tolebrutinib Form 1样品2-1。
样品2-1的XRPD数据如下表所示：
2θ I％
4.2 13.2
10.4 51.2
10.9 15.9
11.4 33.5
15.8 21.7
16.7 14.9
17.9 35.5
20.3 6.8
20.6 54.6
20.8 46.6
21.0 20.7
21.3 11.6
22.7 100.0
23.5 11.3
23.7 8.3
24.8 18.5
25.3 23.3
25.7 18.0
26.9 6.8
27.2 5.3
27.4 6.3
31.1 7.6
2θ I％
35.5 8.2
样品2-1的XRPD图谱如附图7所示。
测定样品2-1的TGA表征数据，为无水物(在100℃之前，失重1.4％)，分解温度为346℃，如附图8所示。
测定样品2-1的DSC表征数据，熔点(以Onset值示)为126℃，peak值为133℃，如附图9所示，即加热至126℃，开始出现一个吸热峰。
测定样品2-1的DVS表征数据，略有引湿性，0％RH-80％RH间增重约0.46％，如附图10-11所示。
测定样品2-1的PLM表征数据，颗粒细小，分布均匀，粒径≤10微米，如附图12所示。
样品2-1的FT-IR图谱如附图13所示。
实施例2-2：tolebrutinib Form 1的制备
取约20毫克tolebrutinib无定型室温溶清在0.5mL丙酮中，过滤，室温挥发1天后，得到tolebrutinib Form 1样品。
实施例2-3：tolebrutinib Form 1的制备
取约20毫克tolebrutinib无定型溶清在0.5mL四氢呋喃中，过滤，加入1.2mL水后产生油状液滴，室温搅拌一天后转移至4℃搅拌，7天后，将悬浊液离心，室温真空干燥过夜后，得到tolebrutinib Form 1样品。
实施例2-4：tolebrutinib Form 1的制备
取约20毫克tolebrutinib无定型室温溶清在1.5mL丙酮中，过滤，加入4.0mL正庚烷得到澄清溶液，室温搅拌一天后降温至4℃搅拌，7天后，将悬浊液离心，室温真空干燥，得到tolebrutinib Form 1样品。
其XRPD数据如下表所示：
2θ I％
4.2 13.6
10.4 50.8
10.9 16.1
11.4 33.8
15.9 22.0
16.7 14.8
17.9 35.1
20.4 8.0
20.6 54.6
20.8 47.5
21.0 19.8
21.3 13.2
22.8 100.0
23.5 12.2
23.8 9.2
24.8 19.6
25.3 23.4
25.7 18.3
26.9 6.9
27.4 6.4
31.1 8.0
35.5 8.5
其XRPD图谱如附图30所示。
实施例2-5：tolebrutinib Form 1的制备
取约20毫克tolebrutinib无定型室温溶清在0.5mL丙酮中，加入4.0mL正庚烷得到澄清溶液，室温搅拌一天后降温至4℃搅拌，7天后，将悬浊液离心，室温真空干燥，得到tolebrutinib Form 1样品。
实施例2-6：tolebrutinib Form 1的制备
取约50毫克tolebrutinib无定型，加入1mL乙醇，室温搅拌1天，分离，室温真空干燥，得到tolebrutinib Form 1样品。
实施例2-7：tolebrutinib Form 1的制备
取约50毫克tolebrutinib无定型，加入1mL乙酸乙酯，搅拌2天，分离，室温真空干燥，得到tolebrutinib Form 1样品。
实施例2-8：tolebrutinib Form 1的制备
取约20毫克tolebrutinib粗制产物室温溶清在0.5mL乙醇中，室温搅拌1天后，将澄清溶液降温至5℃搅拌4天后，向澄清溶液中逐滴加入4.0mL正庚烷后，有固体析出，离心，室温真空干燥，得到tolebrutinib Form 1样品。
实施例3-1：tolebrutinib Form 2的制备
取约20毫克tolebrutinib无定型在甲基叔丁基醚(0.5mL)形成混悬液，恒温40℃晶浆4天后，离心，室温干燥过夜后，得到Form 2样品3-1。
样品3-1的XRPD数据如下表所示：
2θ° I％
7.8 44.1
11.1 20.5
12.0 20.1
13.3 14.2
13.7 16.3
16.2 25.3
18.5 71.8
18.8 58.6
2θ° I％
19.3 6.0
20.3 10.8
20.9 5.7
21.5 6.5
21.7 8.9
22.9 100.0
23.9 18.3
24.9 38.1
26.4 5.3
27.9 4.3
29.0 9.1
30.4 10.2
样品3-1的XRPD图谱显示如附图14所示。
测定样品3-1的TGA表征数据，为无水物，在100℃之前，失重0.6％，分解温度342℃，如附图15所示。
测定样品3-1的DSC表征数据，熔点(以Onset值示)为160℃，peak值为167℃，如附图16所示，即加热至160℃出现一个吸热峰。
测定样品3-1的DVS表征数据，0％RH-80％RH间增重约0.34％，如附图17所示。
测定样品3-1的PLM表征数据，颗粒细小，分布均匀，粒径≤10微米，如附图18所示。
测定样品3-1的FT-IR图谱如附图19所示。
实施例3-2：tolebrutinib Form 2的制备
取约20毫克tolebrutinib粗制品在丁酮/水(0.1/0.5mL)形成混悬液，恒温70℃搅拌3天后，离心，室温干燥过夜后，得到Form 2样品。
其XRPD数据如下表所示：
2θ I％
7.7 69.9
11.1 36.0
12.1 56.4
13.3 17.3
13.7 34.6
16.2 53.0
18.6 89.6
18.8 57.0
19.3 7.6
20.2 28.0
20.9 11.0
21.5 17.8
21.7 14.3
22.9 100.0
23.8 34.3
24.9 28.9
26.4 11.7
27.9 7.9
29.0 12.4
30.4 16.7
26.4 11.7
27.9 7.9
29.0 12.4
30.4 16.7
其XRPD图谱如附图31所示。
实施例3-3：tolebrutinib Form 2的制备
取约20毫克tolebrutinib无定型在正庚烷(0.5mL)形成混悬液，恒温50℃搅拌5天后，离心，室温干燥过夜后，得到Form 2样品。
实施例3-4：tolebrutinib Form 2的制备
取约20毫克tolebrutinib无定型在乙酸正丁酯/二氯甲烷(0.2/1.2mL)形成混悬液，恒温40℃搅拌5天后，离心，室温干燥过夜后，得到Form 2样品。
实施例3-5：tolebrutinib Form 2的制备
取约20毫克tolebrutinib粗制品，置于乙腈的气氛4天后，室温真空干燥过夜，得到Form 2样品。
实施例3-6：tolebrutinib Form 2的制备
取约30毫克tolebrutinib粗制品加入甲苯/甲基环己烷体系(0.55/0.2mL)中，60℃溶解，5℃搅拌一天后，将澄清溶液转移至40℃敞口挥发2天后，得到Form 2样品3-6。
测定样品3-6的DSC表征数据，熔点(以Onset值示)为164℃，peak值为170℃，如附图32所示，即加热至164℃出现一个吸热峰。
实施例3-7：tolebrutinib Form 2的制备
按照实施例3-1的方法，取约20毫克tolebrutinib无定型，分别在异丙醚(0.5mL)、甲醇/异丙醚(0.1/0.6mL)、仲丁醇/正庚烷(0.6/0.6mL)、1,4-二氧六环/异丙醚(0.2/0.6mL)、甲基叔丁基醚/乙酸正丁酯(0.1/1.8mL)中形成混悬液，其它条件不变，均得到Form 2样品。
实施例4：tolebrutinib无定型、tolebrutinib Form 1和tolebrutinib Form 2的稳定性研究
取本申请实施例1-1制备的tolebrutinib无定型样品适量，分别在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下放置，定期检测HPLC和XRPD，结果如表1和图20所示。
表1 tolebrutinib无定型的稳定性
起始样品 起始纯度 放置条件 放置时间 放置后样品 放置后纯度
无定型 98.88％ 25℃/60％RH/敞口 10个月 无定型 98.87％
无定型 98.88％ 40℃/75％RH/敞口 10个月 无定型 98.00％
实验结果表明：tolebrutinib无定型分别在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下放置至少可以稳定10个月，且放置前后无定型的化学纯度基本保持不变；此外无定型样品还可以分别在光照(25℃/4500lx/闭口)和氧化(过氧化脲气氛中)条件下放置至少可以稳定14天，且放置前后无定型的化学纯度基本保持不变。
取本申请实施例2-1制备的tolebrutinib Form 1样品适量，分别在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下放置，定期检测HPLC和XRPD，结果如表2和图21所示。
表2 tolebrutinib Form 1的稳定性
起始样品 起始纯度 放置条件 放置时间 放置后样品 放置后纯度
Form 1 99.84％ 25℃/60％RH/敞口 10个月 Form 1 99.77％
Form 1 99.84％ 40℃/75％RH/敞口 10个月 Form 1 99.54％
实验结果表明：tolebrutinib Form 1分别在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下放置至少可以稳定10个月，且放置前后Form 1的化学纯度基本保持不变；此外Form 1样品还可以分别在光照(25℃/4500lx/闭口)和氧化(过氧化脲气氛中)条件下放置至少可以稳定14天，且放置前后Form 1的化学纯度基本保持不变。
称取本申请实施例3-1制备的tolebrutinib Form 2样品，分别在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下 放置，定期检测XRPD和HPLC，结果如表3和图22所示。
表3 tolebrutinib Form 2的稳定性
起始样品 起始纯度 放置条件 放置时间 放置后样品 放置后纯度
Form 2 99.02％ 25℃/60％RH/敞口 10个月 Form 2 98.87％
Form 2 99.02％ 40℃/75％RH/敞口 10个月 Form 2 98.24％
实验结果表明：tolebrutinib Form 2分别在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下放置至少可以稳定10个月，且放置前后Form 2的化学纯度基本保持不变；此外Form 2样品还可以分别在光照(25℃/4500lx/闭口)和氧化(过氧化脲气氛中)条件下放置至少可以稳定14天，且放置前后Form 2的化学纯度基本保持不变。
实施例5：tolebrutinib无定型、tolebrutinib Form 1和tolebrutinib Form 2的溶解度研究
将本申请中的tolebrutinib无定型、tolebrutinib Form 1和tolebrutinib Form 2样品分别用pH1.2缓冲液(配制：称取375.90mg氯化钾固体和1709.47mg浓盐酸(37％)于100mL容量瓶中，加入纯水约80mL，用盐酸或氢氧化钾调节pH至1.2，纯水定容至刻度)和pH 1.2SGF(配制：取浓盐酸(37％)765μL，加水约80mL与胃蛋白酶1g、氯化钠200mg，摇匀后，加水稀释成100mL)配制成过饱和溶液，在固定的时间点采用高效液相色谱(HPLC)测定饱和溶液中样品的含量。结果如表4：
表4 无定型、Form 1和Form 2在pH 1.2缓冲液和pH 1.2 SGF中的溶解度
Figure PCTCN2022088495-appb-000004
从表4数据可知，本申请的tolebrutinib无定型、tolebrutinib Form 1和tolebrutinib Form 2在pH 1.2缓冲液和pH 1.2 SGF中 的溶解度满足药用要求。本申请的无定型、Form 1和Form 2具有理想的溶解度，均具有约20mg/mL的量级，有利于达到理想的药物生物利用度和药效，满足药用要求。
实施例6：tolebrutinib无定型、tolebrutinibForm 1和tolebrutinib Form 2的可压性研究
采用天祥旋转压片机进行压片，压片时，选用Φ7.5mm的圆形冲模，充填深度17.9mm，采用1.8KN的主压均值压制成圆形片剂，采用片剂硬度仪测试其径向破碎力(硬度，H)；采用游标卡尺测量片剂的直径(D)和厚度(L)，利用公式T＝2H/πDL*9.8计算粉体的抗张强度，结果见表5：
表5 无定型、Form 1和Form 2的可压型
  无定型 Form 1 Form 2
直径(mm) 7.49 7.51 7.51
厚度(mm) 4.15 4.18 4.18
硬度(kg) 7.18 6.40 8.31
抗张强度(MPa) 1.4 1.3 1.7
结果表明：tolebrutinib无定型、tolebrutinib Form 1和tolebrutinib Form 2均具有优越的可压性，满足药用需求。
实施例7：片剂的制备
按照表6的处方，将API、乳糖水合物、聚乙烯吡咯烷酮、羟丙基纤维素、微晶纤维素和硬脂酸镁混合并压缩，得到片芯，然后将片芯用薄膜包衣的水溶液/悬浮液涂膜，即制备得到片剂。
表6 片剂处方
Figure PCTCN2022088495-appb-000005
Figure PCTCN2022088495-appb-000006
Tolebrutinib无定型、tolebrutinib Form 1和tolebrutinib Form 2在制剂处方工艺前后晶型保持不变，XRPD对比图分别如图23、图24和图25所示。
实施例8：胶囊剂的制备
按照表7处方，将各处方组分过筛并混合，装入硬明胶胶囊中，即制备得到胶囊。
表7 胶囊处方
Figure PCTCN2022088495-appb-000007
实施例9：tolebrutinib无定型、tolebrutinib Form 1和tolebrutinib Form 2在片剂中的稳定性
分别将制备的无定型片剂、Form 1片剂和Form 2片剂在25℃/60％RH放置14天，并在放置前后进行XRPD检测，放置前后XRPD对比图分别如图26、图27和图28所示。
结果表明，无定型片剂、Form 1片剂和Form 2片剂至少可以在25℃/60％RH条件下保持14天稳定。
上述实施例为本申请较佳的实施方式，但本申请的实施方式并不受上述实施例的限制，其他的任何未背离本申请的精神实质与原理下 所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本申请的保护范围之内。

Claims (27)

  1. 结构式如下式所示的tolebrutinib Form 2，
    Figure PCTCN2022088495-appb-100001
    其特征在于，其XRPD图谱的2θ值至少在7.8°±0.2°、12.0°±0.2°、18.5°±0.2°、18.8°±0.2°、22.9°±0.2°中的四处有特征峰。
  2. 根据权利要求1所述的tolebrutinib Form 2，其特征在于，所述Form 2的XRPD图谱还在2θ值为11.1°±0.2°、13.7°±0.2°、16.2±0.2°、23.9°±0.2°和24.9°±0.2°中的一处或两处及其以上有特征峰。
  3. 根据权利要求1或2所述的tolebrutinib Form 2，其特征在于，所述Form 2的XRPD图谱还在2θ值为13.3°±0.2°、14.1°±0.2°、20.3±0.2°和21.7±0.2°中的一处或两处及其以上有特征峰。
  4. 根据权利要求1-3任一项所述的tolebrutinib Form 2，其特征在于，所述Form 2的XRPD图谱还在2θ值如下表的位置具有衍射峰：
    2θ±0.2° 7.8 11.1 12.0 13.3 13.7 16.2 18.5 18.8 19.3 20.3 20.9 21.5
    2θ±0.2° 21.7 22.9 23.9 24.9 26.4 27.9 29.0 30.4
    。
  5. 根据权利要求1-4中任一项所述的tolebrutinib Form 2，其特征在于，所述Form 2的XRPD图谱基本如图14所示。
  6. 根据权利要求1-5任一项所述的tolebrutinib Form 2，其特征在于，所述Form 2的DSC图谱在160-164℃开始出现吸热峰。
  7. 根据权利要求1-6任一项所述的tolebrutinib Form 2，其特征在于，所述Form 2的FT-IR图谱在1699±2cm -1、1229±2cm -1、1486cm -1、1507±2cm -1处有谱带。
  8. 根据权利要求1-7任一项所述的tolebrutinib Form 2的制备方法，其特征在于，所述制备方法选自下述方法中的任一种：
    1)将tolebrutinib在溶剂3中分散为混悬液，恒温搅拌，分离固体，干燥，即得Form 2；
    其中，所述恒温搅拌时间≥12小时，优选为1-5天；所述恒温搅拌温度≥30℃，优选为30-80℃，更优选为40-70℃；
    所述溶剂3选自甲基叔丁基醚、正庚烷、丁酮、水、乙酸正丁酯、异丙醚、仲丁醇、甲基叔丁基醚、二氯甲烷、1,4-二氧六环的单一或混合溶剂；
    优选地，所述溶剂3选自丁酮和水的混合溶剂，混合体积比为1:1-1:10；或者，选自乙酸正丁酯和二氯甲烷的混合溶剂，混合体积比为1:1-1:10；
    2)将tolebrutinib在溶剂4中溶解形成溶液，敞口挥发，干燥；
    其中，所述溶剂4选自甲苯和甲基环己烷的一种或其混合。
    优选地，所述溶剂4为甲苯和甲基环己烷的混合溶剂，溶剂混合比例为5:1-1:2。
    3)将tolebrutinib置于密闭的溶剂5容器中≥1天，干燥；
    其中，所述溶剂5为乙腈。
  9. 结构式如下式所示的tolebrutinib Form 1，
    Figure PCTCN2022088495-appb-100002
    其特征在于，其XRPD图谱的2θ值至少在10.4°±0.2°、11.4°±0.2°、20.6°±0.2°、16.7°±0.2°和22.7°±0.2°中的四处有特征峰。
  10. 根据权利要求9所述的tolebrutinib Form 1，其特征在于，所述Form 1的XRPD图谱还在2θ值为4.2°±0.2°、15.8°±0.2°、17.9°±0.2°、20.8±0.2°和24.8°±0.2°中的一处或两处及其以上有特征峰。
  11. 根据权利要求9或10所述的tolebrutinib Form 1，其特征在于，所述Form 1的XRPD图谱还在2θ值为10.9°±0.2°、21.3°±0.2°、23.5±0.2°、25.3±0.2°和25.7±0.2°中的一处或两处及其以上有特征峰。
  12. 根据权利要求9-11任一项所述的tolebrutinib Form 1，其特征在于，所述Form 1的XRPD图谱在2θ值如下表的位置有衍射峰：
    2θ±0.2° 4.2 10.4 10.9 11.4 15.8 16.7
    2θ±0.2° 17.9 20.3 20.6 20.8 21.0 21.3 22.7 23.5 23.7 24.8 25.3 25.7 26.9 27.2 27.4 31.1 35.5
    。
  13. 根据权利要求9-12任一项所述的tolebrutinib Form 1，其特征在于，所述Form 1的XRPD图谱基本如图7所示。
  14. 根据权利要求9-13任一项所述的tolebrutinib Form 1，其特征在于，所述Form 1的DSC图谱在126℃左右开始出现吸热峰。
  15. 根据权利要求9-14任一项所述的tolebrutinib Form 1，所述Form 1的FT-IR图谱在840.7±2cm -1、978.3±2cm -1、1472.3±2cm -1、1492.5±2cm -1处有谱带。
  16. 根据权利要求9-15任一项所述tolebrutinib Form 1的制备方法，其特征在于，所述方法选自以下方法中的任一种：
    1)将tolebrutinib在溶剂1中溶清形成溶液，挥发，析晶，分离，干燥，即得Form 1；
    其中，所述溶剂1为丙酮；
    优选地，所述溶清步骤在室温下进行；
    优选地，所述挥发在室温下进行；
    2)将tolebrutinib在良溶剂中溶清形成溶液，搅拌(1)，加入抗溶剂，搅拌(2)，析晶，分离，干燥，即得Form 1；
    其中，所述良溶剂选自乙醇、丙酮和四氢呋喃的单一或混合溶剂；所述抗溶剂选自水、正庚烷、正己烷的单一溶剂或混合溶剂，优选为含水的混合溶剂；
    所述搅拌(1)和搅拌(2)为可选步骤；
    优选地，所述抗溶剂:良溶剂的体积比为≥0.1:1，更优选为1:1-8:1；
    优选地，所述溶清步骤在室温下进行；
    优选地，所述搅拌在一定温度下进行，所述一定温度≤30℃；所述搅拌时间≥30min；
    3)将tolebrutinib在溶剂2中形成混悬液，室温搅拌，分离，干燥，即得Form 1；
    其中，所述溶剂2选自乙醇或乙酸乙酯中的一种或混合溶剂。优选地，所述溶剂为乙醇；
    所述tolebrutinib和溶剂2的质量体积比(mg/mL)为20:1-100:1；
    优选地，所述tolebrutinib和溶剂2的质量体积比(mg/mL)为25-50:1。
  17. 结构式如下式所示的tolebrutinib无定型固体形式，
    Figure PCTCN2022088495-appb-100003
    其特征在于，所述无定型的XRPD图谱的2θ值在3-40°范围内不具有衍射峰。
  18. 根据权利要求17所述的tolebrutinib无定型固体形式，其特 征在于，所述无定型的XRPD图谱的2θ值在10-40°范围内具有一个漫散包。
  19. 根据权利要求17或18所述的tolebrutinib无定型固体形式，其特征在于，所述无定型的XRPD图谱基本如图1所示。
  20. 根据权利要求17-19任一项所述的tolebrutinib无定型固体形式，其特征在于，所述无定型的FT-IR图谱在1703±2cm -1、1440±2cm -1、788cm -1和753±2cm -1处有谱带。
  21. 根据权利要求17-20任一项所述的tolebrutinib无定型固体形式的制备方法，其特征在于，所述制备方法选自以下方法中的任一种：
    1)将tolebrutinib在良溶剂中溶清，再加入抗溶剂，搅拌，析出固体，分离，干燥；
    其中，所述良溶剂为二甲亚砜和甲苯中的一种或其混合；所述抗溶剂选自水和乙醚的一种或其混合。
    优选地，所述良溶剂为二甲亚砜；所述抗溶剂为水；
    优选地，所述良溶剂和抗溶剂的体积比为10:1-1:10，更优选为1:1；
    2)将tolebrutinib在溶剂6中高温溶清，过滤，低温搅拌，分离，干燥；
    其中，所述溶剂6选自以下混合溶剂中的一种或多种：三氟乙醇/水、乙酸异丙酯/水、四氢呋喃/水、1,4-二氧六环/水、乙腈/水和氯仿/水；
    优选地，所述溶剂6为三氟乙醇/水的混合溶剂；
    优选地，所述高温为40-80℃；
    优选地，所述低温≤10℃。
  22. 一种药物组合物，所述组合物包含一种或多种权利要求1-7任一项所述的tolebrutinib Form 2、或权利要求9-15任一项所述的tolebrutinib Form 1、或权利要求17-20任一项所述的tolebrutinib无定型固体形式、或其任意组合，以及至少一种药学上可接受的载体。
  23. 一种或多种权利要求1-7任一项所述的tolebrutinib Form  2、或权利要求9-15任一项所述的tolebrutinib Form 1、或权利要求17-20任一项所述的tolebrutinib无定型固体形式、或其任意组合、或其所述的药物组合物在制备治疗BTK介导相关病症的药物中的用途。
  24. 一种或多种权利要求1-7任一项所述的tolebrutinib Form 2、或权利要求9-15任一项所述的tolebrutinib Form 1、或权利要求17-20任一项所述的tolebrutinib无定型固体形式、或其任意组合、或其药物组合物在制备治疗癌症、自身免疫性疾病、炎性疾病和血栓栓塞性疾病的药物中的用途。
  25. 一种治疗BTK介导的病症的方法，其包括向患者施加有效量的种或多种权利要求1-7任一项所述的tolebrutinib Form 2、或权利要求9-15任一项所述的tolebrutinib Form 1、或权利要求17-20任一项所述的tolebrutinib无定型固体形式、或其任意组合、或其药物组合物。
  26. 一种治疗癌症、自身免疫性疾病、炎性疾病和血栓栓塞性疾病的方法，所述方法包括给予需要的患者治疗有效量的种或多种权利要求1-7任一项所述的tolebrutinib Form 2、或权利要求9-15任一项所述的tolebrutinib Form 1、或权利要求17-20任一项所述的tolebrutinib无定型固体形式、或其任意组合、或其药物组合物。
  27. 一种或多种权利要求1-7任一项所述的tolebrutinib Form 2、或权利要求9-15任一项所述的tolebrutinib Form 1、或权利要求17-20任一项所述的tolebrutinib无定型固体形式、或其任意组合、或其药物组合物其他药物的联合应用。
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220389011A1 (en) * 2020-12-10 2022-12-08 Crystal Pharmaceutical (Suzhou) Co., Ltd. Crystalline form of tolebrutinib and preparation method thereof
WO2023122072A1 (en) * 2021-12-21 2023-06-29 Genzyme Corporation Crystalline forms of (r)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1h-imidazo[4,5-c]pyridin-2(3h)-one and salts thereof
WO2023172663A1 (en) 2022-03-09 2023-09-14 Teva Pharmaceuticals International Gmbh Solid state forms of tolebrutinib and of tolebrutinib salts
US11969418B2 (en) 2020-01-20 2024-04-30 Genzyme Corporation Therapeutic tyrosine kinase inhibitors for relapsing multiple sclerosis (RMS)
WO2024137604A1 (en) * 2022-12-20 2024-06-27 Genzyme Corporation Drug formulations of (r)-l-(l-acryloylpiperidin-3-yl)-4-amino-3-(4- phenoxyphenyl)-1h-imidazo[4,5-c]pyridin-2(3h)-one

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016196840A1 (en) 2015-06-03 2016-12-08 Principia Biopharma Inc. Tyrosine kinase inhibitors
WO2017041536A1 (zh) * 2015-09-11 2017-03-16 东莞市真兴贝特医药技术有限公司 氧代二氢咪唑并吡啶类化合物及其应用
WO2021150476A1 (en) * 2020-01-20 2021-07-29 Genzyme Corporation Therapeutic tyrosine kinase inhibitors for relapsing multiple sclerosis (rms)
WO2022121670A1 (zh) * 2020-12-10 2022-06-16 苏州科睿思制药有限公司 Tolebrutinib的晶型及其制备方法和用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016196840A1 (en) 2015-06-03 2016-12-08 Principia Biopharma Inc. Tyrosine kinase inhibitors
CN106459049A (zh) * 2015-06-03 2017-02-22 普林斯匹亚生物制药公司 酪氨酸激酶抑制剂
WO2017041536A1 (zh) * 2015-09-11 2017-03-16 东莞市真兴贝特医药技术有限公司 氧代二氢咪唑并吡啶类化合物及其应用
WO2021150476A1 (en) * 2020-01-20 2021-07-29 Genzyme Corporation Therapeutic tyrosine kinase inhibitors for relapsing multiple sclerosis (rms)
WO2022121670A1 (zh) * 2020-12-10 2022-06-16 苏州科睿思制药有限公司 Tolebrutinib的晶型及其制备方法和用途

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11969418B2 (en) 2020-01-20 2024-04-30 Genzyme Corporation Therapeutic tyrosine kinase inhibitors for relapsing multiple sclerosis (RMS)
US20220389011A1 (en) * 2020-12-10 2022-12-08 Crystal Pharmaceutical (Suzhou) Co., Ltd. Crystalline form of tolebrutinib and preparation method thereof
US12049463B2 (en) * 2020-12-10 2024-07-30 Genzyme Corporation Crystalline form of Tolebrutinib
WO2023122072A1 (en) * 2021-12-21 2023-06-29 Genzyme Corporation Crystalline forms of (r)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1h-imidazo[4,5-c]pyridin-2(3h)-one and salts thereof
WO2023172663A1 (en) 2022-03-09 2023-09-14 Teva Pharmaceuticals International Gmbh Solid state forms of tolebrutinib and of tolebrutinib salts
WO2024137604A1 (en) * 2022-12-20 2024-06-27 Genzyme Corporation Drug formulations of (r)-l-(l-acryloylpiperidin-3-yl)-4-amino-3-(4- phenoxyphenyl)-1h-imidazo[4,5-c]pyridin-2(3h)-one

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