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WO2025176139A1 - Forme cristalline d'un dérivé de quinazolinone, son procédé de préparation et son utilisation - Google Patents

Forme cristalline d'un dérivé de quinazolinone, son procédé de préparation et son utilisation

Info

Publication number
WO2025176139A1
WO2025176139A1 PCT/CN2025/077968 CN2025077968W WO2025176139A1 WO 2025176139 A1 WO2025176139 A1 WO 2025176139A1 CN 2025077968 W CN2025077968 W CN 2025077968W WO 2025176139 A1 WO2025176139 A1 WO 2025176139A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystalline form
formula
present
compound
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/077968
Other languages
English (en)
Chinese (zh)
Inventor
宫正
蒋西
赵誉良
范江
窦赢
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Haisco Pharmaceutical Group Co Ltd
Original Assignee
Haisco Pharmaceutical Group Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Haisco Pharmaceutical Group Co Ltd filed Critical Haisco Pharmaceutical Group Co Ltd
Publication of WO2025176139A1 publication Critical patent/WO2025176139A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • 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 a crystal form of a BRAF kinase inhibitor, a preparation method and application thereof, and particularly to a crystal form A of a quinazolinone derivative, a preparation method and application thereof, belonging to the technical field of pharmaceutical chemistry.
  • MAP kinases are a family of serine/threonine kinases that respond to a variety of extracellular growth signals. For example, growth hormone, epidermal growth factor, platelet-derived growth factor, and insulin are all thought to participate in mitogenic stimulation of the MAPK pathway. Activation of this pathway at the receptor level initiates a signaling cascade whereby the Ras GTPase exchanges GDP for GTP. Next, Ras activates Raf kinase (also known as MAPKKK), which in turn activates MEK (MAPKK).
  • MAPKKK Raf kinase
  • the BRAF protein is a member of the RAF family of serine/threonine kinases that participates in the Ras Raf MEK extracellular signal-regulated kinase (ERK) pathway or the mitogen-activated protein kinase (MAPK)/ERK signaling pathway cascade that affects cell division and differentiation. Mutations in the BRAF gene can lead to uncontrolled growth and subsequent tumor formation. BRAF is mutated and/or overactivated in common human cancers such as melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, and ovarian cancer, their metastatic forms, and primary brain tumors. Although some BRAF inhibitors produce excellent extracranial responses, cancers may still develop brain metastases during or following BRAF inhibitor therapy.
  • Brain metastases remain a substantial contributor to overall cancer mortality in subjects with advanced cancer, and despite multimodality treatment and advances in systemic therapy, which includes combinations of surgery, radiotherapy, chemotherapy, immunotherapy, and/or targeted therapies, the prognosis remains poor.
  • BRAF has been identified as a potential target for the treatment of primary brain tumors.
  • the prevalence of the BRAF V600E mutation in primary brain tumors has been reported by Schindler et al. in their analysis of 1,320 central nervous system (CNS) tumors and by Behling et al. in their analysis of 969 CNS tumors in pediatric and adult populations.
  • CNS central nervous system
  • Behling et al. in their analysis of 969 CNS tumors in pediatric and adult populations.
  • the blood-brain barrier is a highly selective physical transport and metabolic barrier that separates the central nervous system (CNS) from the blood.
  • the BBB prevents certain drugs from entering brain tissue and is a limiting factor in the delivery of many peripherally administered agents to the CNS.
  • Many drugs commonly used to treat cancer cannot cross the blood-brain barrier. This means these drugs cannot penetrate the brain and, therefore, cannot effectively kill cancer cells there.
  • Current treatments for subjects with brain tumors include surgical resection, radiation therapy, and/or chemotherapy with agents such as temozolomide and/or bevacizumab.
  • surgical treatment of brain cancer is not always possible; for example, the tumor may be inaccessible or the subject may be unable to withstand the trauma of neurosurgery.
  • kinase inhibitors are used to treat many peripheral cancers.
  • BRAF inhibitors e.g., vemurafenib and dabrafenib
  • active transporters such as P-glycoprotein (P gp) or breast cancer resistance protein (BCRP).
  • the MDR1 efflux ratio of dabrafenib was reported to be 11.4, the BCRP efflux ratio was 21.0, and the total brain to plasma ratio was 0.023; whereas the MDR1 efflux ratio of vemurafenib was reported to be 83, the BCRP efflux ratio was 495, and the total brain to plasma ratio was 0.004.
  • the compound represented by Formula (I) is a selective BRAF kinase inhibitor.
  • the crystal structure of the active pharmaceutical ingredient often affects the chemical stability of the drug. Different crystallization and storage conditions can lead to changes in the compound's crystal structure, sometimes accompanied by the formation of other morphologies.
  • amorphous drug products lack a regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficulty in filtration, easy agglomeration, and poor flowability. Therefore, in-depth research on the crystal form of the compound represented by Formula (I) and related preparation methods is necessary to improve various properties of the compound represented by Formula (I).
  • the present invention provides a crystalline form A of a compound represented by formula (I) and a preparation method thereof, as well as pharmaceutical compositions and medical uses thereof.
  • the present invention provides a crystalline form A of a compound of formula (I):
  • the crystal A of the compound represented by formula (I) of the present invention has the advantages of being easy to process and crystallize, having good stability, good fluidity, being convenient for formulation process, and having good solubility and bioavailability.
  • the present invention provides a crystalline form A of the compound represented by formula (I), which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation and has characteristic diffraction peaks at the following 2 ⁇ positions: 14.54° ⁇ 0.2°, 15.98° ⁇ 0.2°, 16.17° ⁇ 0.2°, 17.65° ⁇ 0.2°, and 20.62° ⁇ 0.2°.
  • the crystalline form A of the compound represented by formula (I) of the present invention using Cu-K ⁇ radiation, has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 ⁇ positions: 7.43° ⁇ 0.2°, 8.79° ⁇ 0.2°, 19.87° ⁇ 0.2°, 20.22° ⁇ 0.2°, 23.18° ⁇ 0.2°, 24.95° ⁇ 0.2°, 26.63° ⁇ 0.2°, and 30.27 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form A of the compound represented by formula (I) of the present invention using Cu-K ⁇ radiation is substantially as shown in FIG3 .
  • the differential scanning calorimetry (DSC) curve of the crystalline form A of the compound represented by formula (I) of the present invention shows a melting endothermic signal at around 191° C., as shown in FIG1 .
  • thermogravimetric analysis (TGA) curve of Form A of the compound represented by formula (I) of the present invention shows no obvious weight loss during heating to 150° C., and decomposes above 230° C., as shown in FIG. 2 .
  • the dynamic moisture adsorption curve analysis chart of the crystal form A of the compound represented by formula (I) of the present invention is shown in FIG4 .
  • FIG6 shows the X-ray powder diffraction patterns of Form A of the compound represented by formula (I) of the present invention before and after testing with artificial simulated gastric fluid, artificial simulated fasting intestinal fluid, and artificial simulated full intestinal fluid.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of Form A of the compound represented by formula (I) above, and a pharmaceutically acceptable carrier and/or excipient, preferably 1-1500 mg.
  • the pharmaceutical composition may be in the form of a unit dosage form (also referred to as a "dosage strength").
  • an "effective amount” or “therapeutically effective amount” refers to administering a sufficient amount of a crystalline form disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system.
  • an "effective amount” for therapeutic use is the amount of a composition comprising a crystalline form disclosed herein required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1 500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-
  • the pharmaceutical composition or formulation of the present invention contains the above-mentioned therapeutically effective amount of the crystalline form of the present invention
  • the present invention relates to a pharmaceutical composition or pharmaceutical preparation, comprising a therapeutically effective amount of the crystalline form of the present invention and a carrier and/or excipient.
  • the pharmaceutical composition can be in the form of a unit dosage form (the amount of the main drug in the unit dosage form is also referred to as a "preparation specification").
  • the present invention also provides use of the above-mentioned crystal form A or composition in drugs for treating/preventing BRAF-mediated diseases.
  • a method for treating a disease in a mammal comprising administering a crystalline form of the present invention and a pharmaceutically acceptable carrier and/or excipient to a subject at a daily dose of 1-1500 mg/day, wherein the daily dose can be a single dose or divided doses.
  • the present invention also relates to a kit, which may include a crystalline form in a single-dose or multi-dose form.
  • the kit contains the crystalline form of the present invention, and the amount of the crystalline form of the present invention is the same as that in the above-mentioned pharmaceutical composition.
  • the crystalline form of the present invention is present in an amount of about 5% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 10% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 15% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 20% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 25% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 30% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 35% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 40% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 45% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 50% to about 100% by weight of the drug substance; in certain embodiments, it is present in
  • the drug substance is present at about 60% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 65% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 70% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 75% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 80% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 85% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 90% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 95% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 98% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 99% to about 100% by weight of the drug substance; in certain embodiments, substantially all of the drug substance is substantially pure crystals.
  • the present invention also provides a method for preparing the crystalline form A of the compound represented by formula (I), which is a dissolution crystallization method, comprising: dissolving the compound of formula I in a good solvent, taking a certain amount of the solution and dropping it into a poor solvent or adding the poor solvent into the solution, stirring to precipitate a solid, separating and drying to obtain the solid.
  • a dissolution crystallization method comprising: dissolving the compound of formula I in a good solvent, taking a certain amount of the solution and dropping it into a poor solvent or adding the poor solvent into the solution, stirring to precipitate a solid, separating and drying to obtain the solid.
  • the present invention also provides another method for preparing the crystalline form A of the compound represented by formula (I), which is a suspension method: comprising adding the compound of formula (I) to a selected single solvent or binary solvent until a suspension is formed, suspending and stirring at room temperature to 50°C for a certain period of time (for example, 1 hour to 10 days, or 2 hours to 24 hours, or 2 hours to 12 hours, or 3 to 5 hours), and then centrifuging the suspension and drying to obtain the crystalline form A.
  • a suspension method comprising adding the compound of formula (I) to a selected single solvent or binary solvent until a suspension is formed, suspending and stirring at room temperature to 50°C for a certain period of time (for example, 1 hour to 10 days, or 2 hours to 24 hours, or 2 hours to 12 hours, or 3 to 5 hours), and then centrifuging the suspension and drying to obtain the crystalline form A.
  • the solvent used in the suspension method is one or a mixed solvent of two or more of ethylene glycol methyl ether, ethylene glycol dimethyl ether, dioxane, DMF, DMSO, ethanol, n-propanol, 4-methyl-2-pentanone, tetrahydrofuran, isopropanol, ethyl acetate, n-heptane, dichloromethane, isopropyl ether, water, methanol, isopropyl acetate, butyl formate, acetonitrile, toluene, chloroform, acetone, ethyl formate, MTBE, and cyclohexane.
  • the present invention also provides another method for preparing the crystalline form A of the compound represented by formula (I), which is a cooling method: comprising dissolving a certain amount of sample in a corresponding solvent at high temperature, transferring the solution to room temperature for cooling, standing or stirring for crystallization, separating, and drying to obtain the crystalline form A.
  • a cooling method comprising dissolving a certain amount of sample in a corresponding solvent at high temperature, transferring the solution to room temperature for cooling, standing or stirring for crystallization, separating, and drying to obtain the crystalline form A.
  • the solvent used in the cooling method is one or a mixed solvent of two or more of methanol, ethyl acetate, isopropyl acetate, butyl formate, acetonitrile, ethylene glycol methyl ether, 4-methyl-2-pentanone, dioxane, ethanol, acetonitrile, DMF, tetrahydrofuran, methanol, ethylene glycol dimethyl ether, and DMSO;
  • the present invention also provides another method for preparing the crystalline form A of the compound represented by formula (I), which is a thermal crystallization method: the method comprises taking a certain amount of sample, placing a glass slide on a hot table, heating to a target temperature at a certain rate (such as 5-20°C/min, or 10-15°C/min), and maintaining the temperature for a period of time (such as 0.5-5min, or 1-3min, or 1-2min), and then naturally cooling to room temperature to obtain a solid.
  • a target temperature such as 5-20°C/min, or 10-15°C/min
  • a period of time such as 0.5-5min, or 1-3min, or 1-2min
  • the present invention also provides another method for preparing Form A of the compound represented by Formula (I), which is a vapor diffusion experiment: the method comprises dropwise adding an appropriate amount of a good solvent to a certain amount of the compound represented by Formula (I) at room temperature to completely dissolve the sample or to prepare a saturated solution of the good solvent; taking a certain amount of each solution, placing the clear solution in a poor solvent atmosphere and standing at room temperature until solid precipitates, and separating to obtain the Form A.
  • the Form A can be obtained by directly placing the solid compound represented by Formula I in a solvent atmosphere and standing at room temperature for 1 to 7 days.
  • the gas phase used in the gas diffusion method is one or a mixed solvent of two or more of cyclohexane, MTBE, ethanol, n-heptane, isopropyl ether, isopropanol, and toluene.
  • the present invention also provides another method for preparing the crystalline form A of the compound represented by formula (I), which is a polymer-induced volatilization method: the method comprises adding a certain amount of the compound of formula (I) to a clear solution of a small amount of polymer and allowing it to stand in the open air at room temperature until the solvent is completely volatilized to obtain a solid.
  • the polymer used in the polymer induced volatilization method is one or a mixed solvent of two or more of polyvinyl alcohol, polyacrylamide, polyisobutyl methacrylate, polyethylene glycol, cellulose acetate, polyvinyl pyrrolidone PVP10, polyvinyl pyrrolidone K88-96, high viscosity hydroxyethyl cellulose HEC-100000, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose.
  • the solvent used in the above preparation method may be a single solvent or a combination of two or more solvents.
  • the crystal of the present invention As used herein, “the crystal of the present invention”, “the crystal form of the present invention”, “the crystal form of the present invention” and the like can be used interchangeably.
  • room temperature generally refers to 4-30°C, preferably 20 ⁇ 5°C.
  • the crystalline structure of the present invention can be analyzed using various analytical techniques known to those skilled in the art, including but not limited to, X-ray powder diffraction (XRD), differential scanning calorimetry (DSC) and/or thermogravimetric analysis (TGA), also known as thermogravimetry (TG).
  • XRD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • TG thermogravimetry
  • 2 ⁇ or 2 ⁇ angle refers to the peak position expressed in degrees (°) based on the setup of an X-ray diffraction experiment, and is typically the unit of the abscissa in a diffraction pattern. If the incident beam forms an angle ⁇ with a certain lattice plane and the reflection is diffracted, the experimental setup requires recording the reflected beam in 2 ⁇ angles. It should be understood that the specific 2 ⁇ value of a specific crystal form mentioned herein is intended to represent the 2 ⁇ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein, and the error range of the 2 ⁇ may be ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • crystal form of the present invention is not limited to the characteristic spectra that are exactly the same as the characteristic spectra described in the drawings disclosed in the present invention, such as XRD, DSC, TGA, and DVS. Any crystal form having characteristic spectra that are substantially the same or essentially the same as those described in the drawings falls within the scope of the present invention.
  • the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compound of the present invention has a DSC pattern with characteristic peak positions, has substantially the same properties as the DSC pattern provided in the accompanying drawings of the present invention, and has a measurement error tolerance of within ⁇ 5°C, generally required to be within ⁇ 3°C.
  • excipient is a substance that is not itself a therapeutic agent but serves as a diluent, adjuvant, binder, and/or vehicle that is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration.
  • pharmaceutical excipients can serve a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners.
  • FIG1 is a differential scanning calorimetry analysis curve of Form A of the compound represented by formula (I).
  • FIG2 is a thermogravimetric analysis spectrum of Form A of the compound represented by formula (I).
  • FIG3 is an X-ray powder diffraction pattern of Form A of the compound represented by formula (I).
  • FIG4 is a dynamic moisture adsorption curve analysis graph of Form A of the compound represented by formula (I).
  • Figure 5 is the X-ray powder diffraction pattern of Form A of the compound represented by formula (I) before and after DVS testing.
  • FIG6 is an X-ray powder diffraction pattern of Form A of the compound represented by formula (I) before and after testing in artificial simulated gastric fluid, artificial simulated fasting intestinal fluid, and artificial simulated full intestinal fluid.
  • FIG7 is a microscope picture of the amorphous form of the compound of formula (I).
  • HPLC determination was performed using a LC-20AT (Shimadzu) high pressure liquid chromatograph (Shim-pack GIST C18, 4.6 ⁇ 250 mm (HSS), 5 ⁇ m).
  • XRD analysis was performed using a Bruker D8 Advance Diffractometer.
  • the 2 ⁇ scan angle ranged from 3° to 45°, with a scan step size of 0.013° and an exposure time of 0.08 seconds.
  • the tube voltage and current were 45 kV and 40 mA, respectively, and the sample pan was a zero-background sample pan.
  • TGA test conditions Thermogravimetric analyzer (TGA) was used on a TA Instruments Q500TGA. A 2-5 mg sample was placed in a pre-equilibrated sample pan and automatically weighed in the TGA oven. The sample was heated to the final temperature at a rate of 10°C/min. A nitrogen purge rate of 60 mL/min was applied to the sample and 40 mL/min was applied to the balance.
  • DSC test conditions A TA Instruments Q200DSC differential scanning calorimeter was used. A 1-2 mg sample was accurately weighed and placed in a standard pan or a perforated DSC Tzero pan. The sample was heated to the final temperature at a rate of 10°C/min. A nitrogen purge rate of 50 mL/min was used.
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.
  • the solution refers to an aqueous solution.
  • amorphous form of the compound of formula (I) was prepared by liquid phase purification with reference to Example 10 of WO2024017294A1. This amorphous form exhibits high static charge and poor fluidity, making it unsuitable for industrial production of the API and formulation preparation. As shown in Table 4, Form A of the compound of formula (I) exhibits superior bulk density and crystal morphology, significantly improving its fluidity compared to the amorphous form.
  • Microscope images of the amorphous form of the compound of formula (I) and the crystalline form A of the compound of formula (I) are shown in Figures 7 and 8, respectively.

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  • Health & Medical Sciences (AREA)
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  • Organic Chemistry (AREA)
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  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Diabetes (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une forme cristalline d'un inhibiteur de BRAF kinase, son procédé de préparation et son utilisation, et concerne spécifiquement la forme cristalline A d'un composé tel que représenté dans la formule (I), un procédé de préparation de la forme cristalline A et une utilisation de la forme cristalline A dans la préparation de médicaments pour le traitement/la prévention de maladies médiées par BRAF.
PCT/CN2025/077968 2024-02-20 2025-02-19 Forme cristalline d'un dérivé de quinazolinone, son procédé de préparation et son utilisation Pending WO2025176139A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202410188688.4 2024-02-20
CN202410188688 2024-02-20

Publications (1)

Publication Number Publication Date
WO2025176139A1 true WO2025176139A1 (fr) 2025-08-28

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105860031A (zh) * 2016-05-17 2016-08-17 合肥工业大学 钯催化剂及其合成方法和应用
CN114026073A (zh) * 2019-06-28 2022-02-08 Array生物制药公司 用于治疗braf相关的疾病和障碍的喹唑啉-4-酮衍生物
CN116096710A (zh) * 2020-06-09 2023-05-09 阿雷生物药品公司 用于治疗braf相关疾病和障碍的4-氧代-3,4-二氢喹唑啉酮化合物
CN116601147A (zh) * 2020-12-18 2023-08-15 豪夫迈·罗氏有限公司 新喹唑啉酮衍生物
WO2024017294A1 (fr) * 2022-07-19 2024-01-25 西藏海思科制药有限公司 Préparation et utilisation d'un dérivé de quinazolinone en tant qu'inhibiteur de kinase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105860031A (zh) * 2016-05-17 2016-08-17 合肥工业大学 钯催化剂及其合成方法和应用
CN114026073A (zh) * 2019-06-28 2022-02-08 Array生物制药公司 用于治疗braf相关的疾病和障碍的喹唑啉-4-酮衍生物
CN116096710A (zh) * 2020-06-09 2023-05-09 阿雷生物药品公司 用于治疗braf相关疾病和障碍的4-氧代-3,4-二氢喹唑啉酮化合物
CN116601147A (zh) * 2020-12-18 2023-08-15 豪夫迈·罗氏有限公司 新喹唑啉酮衍生物
WO2024017294A1 (fr) * 2022-07-19 2024-01-25 西藏海思科制药有限公司 Préparation et utilisation d'un dérivé de quinazolinone en tant qu'inhibiteur de kinase

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