WO2023093859A1 - Sel d'inhibiteur de kinase axl, son procédé de préparation et son utilisation - Google Patents

Sel d'inhibiteur de kinase axl, son procédé de préparation et son utilisation Download PDF

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WO2023093859A1
WO2023093859A1 PCT/CN2022/134408 CN2022134408W WO2023093859A1 WO 2023093859 A1 WO2023093859 A1 WO 2023093859A1 CN 2022134408 W CN2022134408 W CN 2022134408W WO 2023093859 A1 WO2023093859 A1 WO 2023093859A1
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compound
formula
salt
pharmaceutically acceptable
crystal form
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Chinese (zh)
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张林林
马昌友
吴有智
裴俊杰
吴舰
徐丹
朱春霞
田舟山
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南京正大天晴制药有限公司
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Priority to CN202280074029.7A priority Critical patent/CN118251400A/zh
Publication of WO2023093859A1 publication Critical patent/WO2023093859A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/42—Separation; Purification; Stabilisation; Use of additives
    • C07C303/44—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • 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

  • the invention belongs to the technical field of medicine, and the compound is an AXL kinase inhibitor, and specifically relates to a salt of the AXL inhibitor, a preparation method and a medical application thereof.
  • RTKs Receptor tyrosine kinases
  • Ligand-receptor binding induces receptor dimerization and activation of its intracellular kinase domain, which in turn leads to the recruitment, phosphorylation and activation of multiple downstream signaling cascades (Robinson, D.R. et al., Oncogene, 19:5548-5557, 2000).
  • RTKs have been identified in the human genome that regulate a variety of cellular processes, including cell survival, growth, differentiation, proliferation, adhesion, and motility (Segaliny, A.I. et al., J. Bone Oncol, 4:1 -12, 2015).
  • AXL (also known as UFO, ARK, and Tyro7) belongs to the TAM family of receptor tyrosine kinases, which also includes Mer and Tyro3. Among them, AXL and Tyro3 have the most similar gene structure, while AXL and Mer have the most similar amino acid sequence of tyrosine kinase domain. Like other receptor tyrosine kinases (RTKs), the structure of the TAM family consists of an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain. The extracellular domain of AXL has a unique structure that juxtaposes immunoglobulin and type III fibronectin repeat units and is reminiscent of a neutrophil adhesion molecule.
  • TAM family members have a common ligand—growth arrest specific protein 6 (Gas6), which can bind to all TAM receptor tyrosine kinases. After AXL binds to Gas6, it will lead to receptor dimerization and AXL autophosphorylation, thereby activating multiple downstream signal transduction pathways and participating in multiple processes of tumorigenesis (Linger, R.M et al., Ther.Targets, 14(10 ), 1073-1090, 2010; Rescigno, J. et al., Oncogene, 6(10), 1909-1913, 1991).
  • Gas6 growth arrest specific protein 6
  • AXL is widely expressed in normal tissues of the human body, such as monocytes, macrophages, platelets, endothelial cells, cerebellum, heart, skeletal muscle, liver, and kidney, among which the expression is highest in cardiac muscle and skeletal muscle, and bone marrow CD34+ cells and stromal cells also have a higher expression High expression, very low expression in normal lymphoid tissue (Wu YM, Robinson DR, Kung HJ, Cancer Res, 64(20), 7311-7320, 2004; hung BI et al., DNA Cell Biol, 22(8), 533-540 , 2003).
  • AXL gene was overexpressed or ectopically expressed in hematopoietic cells, mesenchymal cells and endothelial cells.
  • the overexpression of AXL kinase is particularly prominent.
  • Inhibition of AXL receptor tyrosine kinase can reduce the pro-survival signals of tumor cells, block the invasion ability of tumors, and increase the sensitivity of targeted drug therapy and chemotherapy. Therefore, finding effective AXL inhibitors is an important direction for the development of tumor-targeted drugs.
  • the present invention provides a pharmaceutically acceptable salt of the compound of formula I, wherein the salt is selected from organic acid salts or inorganic acid salts, wherein the organic acid salts are selected from methanesulfonate, benzenesulfonate, oxalate
  • the inorganic acid salt is selected from one of hydrochloride, hydrobromide, sulfate or phosphate, the compound of formula I
  • the structure is as follows:
  • the organic acid salt is mesylate.
  • the mesylate salt is a hydrate of the mesylate salt.
  • the mesylate salt is the dihydrate of the mesylate salt.
  • the molar ratio of the compound of formula I to the organic acid in the organic acid salt is 1:1.
  • the molar ratio of the compound of formula I to the inorganic acid in the inorganic acid salt is 1:1 or 1:2.
  • the salt of an inorganic acid is a hydrochloride.
  • the molar ratio of the compound of formula I to hydrogen chloride in the hydrochloride salt is 1:1 or 1:2.
  • the molar ratio of the compound of formula I to hydrogen chloride in the hydrochloride salt is 1:2.
  • the molar ratio of the compound of formula I to sulfuric acid in the sulfate salt is 1:1.
  • the molar ratio of the compound of formula I to hydrobromic acid in the hydrobromide salt is 1:1.
  • the molar ratio of the compound of formula I to phosphoric acid in the phosphate salt is 1:1.
  • the salt in the present invention is obtained by a salt-forming reaction between the compound of formula I and the corresponding acid.
  • the compound of formula I is converted into a cation and combined with the acid radical of the corresponding acid to form the salt. Therefore, the molar ratio of the compound of formula I to the acid in the present invention can be understood as the molar ratio of the cation of the compound of formula I to the acid group of the corresponding acid in the salt.
  • the present invention provides the mesylate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to methanesulfonic acid is 1:1, or the molar ratio of the cation of the compound of formula I to the acid group of methanesulfonic acid The ratio is 1:1.
  • the present invention provides a crystal form of a pharmaceutically acceptable salt of the compound of formula I, wherein the salt is selected from organic acid salts or inorganic acid salts, wherein the organic acid salts are selected from methanesulfonate, benzenesulfonate , oxalate, fumarate, citrate and hippurate, the inorganic acid salt is selected from hydrochloride, hydrobromide or phosphate.
  • the present invention provides a crystalline form of the mesylate salt of the compound of Formula I.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the mesylate salt crystal is detailed in Table 1 below:
  • the present invention provides a crystalline form of the mesylate salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 1 .
  • the present invention provides a crystalline form of the monohydrochloride salt of a compound of formula I.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the monohydrochloride crystal is detailed in Table 2 below:
  • the present invention provides a crystalline form of the monohydrochloride salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 4 . In some embodiments, the present invention provides a crystalline form of the dihydrochloride salt of the compound of formula I.
  • the dihydrochloride salt is crystalline, and the 2 ⁇ of its X-ray powder diffraction pattern is detailed in Table 3 below:
  • the present invention provides a crystal form of the dihydrochloride salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 5 .
  • the present invention provides a crystalline form of the phosphate salt of a compound of formula I.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the phosphate crystal is detailed in Table 4 below:
  • the present invention provides a crystalline form of the phosphate salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 6 .
  • the present invention provides a crystalline form of a hippurate salt of a compound of Formula I.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the hippurate crystal is detailed in Table 5 below:
  • the present invention provides a crystalline form of hippurate of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 7 .
  • the present invention provides an amorphous form of the sulfate salt of the compound of formula I.
  • the present invention provides a crystalline form of the hydrobromide salt of a compound of formula I.
  • the 2 ⁇ of the hydrobromide crystal is shown in Table 6 below in detail in its X-ray powder diffraction pattern:
  • the present invention provides a crystal form of the hydrobromide salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 9 .
  • the present invention provides a crystalline form of the besylate salt of the compound of formula I.
  • the benzenesulfonate salt is crystalline, and the 2 ⁇ of its X-ray powder diffraction pattern is detailed in Table 7 below:
  • the present invention provides a crystalline form of the besylate salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 10 .
  • the present invention provides a crystalline form of the oxalate salt of the compound of formula I.
  • the oxalate salt crystals, the 2 ⁇ of its X-ray powder diffraction pattern are detailed in Table 8 below:
  • the present invention provides the crystalline form of the oxalate salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 11 .
  • the present invention provides a crystalline form of the fumarate salt of the compound of formula I.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the fumarate crystals is detailed in Table 9 below:
  • the present invention provides a crystalline form of the fumarate salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 12 .
  • the present invention provides a crystalline form of the citrate salt of the compound of formula I.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the citrate crystals is detailed in Table 10 below:
  • the present invention provides a crystalline form of the citrate salt of the compound of formula I, the X-ray powder diffraction pattern of which is shown in FIG. 13 .
  • the present invention provides a crystal form A of the compound of formula I, whose X-ray powder diffraction pattern is 7.6° ⁇ 0.2°, 10.2° ⁇ 0.2°, 17.6° ⁇ 0.2°, 20.3° ⁇ 0.2° at 2 ⁇ There are diffraction peaks at 20.9° ⁇ 0.2°.
  • the crystal form A has an X-ray powder diffraction pattern at 2 ⁇ of 4.1° ⁇ 0.2°, 7.6° ⁇ 0.2°, 10.2° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 17.6° There are diffraction peaks at ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.9° ⁇ 0.2° and 22.2° ⁇ 0.2°.
  • the crystal form A has an X-ray powder diffraction pattern at 2 ⁇ of 4.1° ⁇ 0.2°, 5.6° ⁇ 0.2°, 7.6° ⁇ 0.2°, 10.2° ⁇ 0.2°, 10.9° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.2° ⁇ 0.2°, 17.6° ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.9° ⁇ 0.2°, 22.2° ⁇ 0.2°, 23.2° ⁇ 0.2 °, 24.6° ⁇ 0.2°, 27.0° ⁇ 0.2°, 28.8° ⁇ 0.2°, 37.0° ⁇ 0.2° and 37.7° ⁇ 0.2° have diffraction peaks.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the crystal form A is detailed in the table below:
  • the X-ray powder diffraction of the crystal form A in 2 ⁇ angle has a pattern as shown in FIG. 14 .
  • the present invention provides a method for preparing a pharmaceutically acceptable salt of the compound of formula I or a crystal form of the pharmaceutically acceptable salt thereof, which comprises the step of forming a salt of the compound of formula I with a corresponding acid.
  • the reaction solvent of the preparation method is selected from mixed solvents of alcohol solvents and alkane solvents, mixed solvents of ketone solvents and alkane solvents, mixed solvents of ester solvents and alkane solvents, nitrile solvents - A mixed solvent of an aqueous solvent and an alkane solvent, a mixed solvent of an alkylbenzene solvent and an alkane solvent, or a mixed solvent of a halogenated hydrocarbon solvent and an alkane solvent.
  • the alcohol solvent is selected from methanol, ethanol or isopropanol; the ketone solvent is selected from acetone or butanone; preferably acetone; the ester solvent is selected from ethyl acetate or butyl acetate ; Preferred ethyl acetate;
  • the nitriles-water solvent is selected from the mixed solution of nitriles-water, and the alkane solvent is selected from n-heptane.
  • the crystal form of the pharmaceutically acceptable salt is a mesylate salt crystal form
  • the mesylate salt crystal form is prepared by a method comprising the following steps:
  • step S2 stirring and reacting the compound of formula (I), methanesulfonic acid and ethyl acetate, adding the crystal form obtained in step S1 and continuing to stir;
  • the present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of the compound of formula I.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is a solid pharmaceutical preparation suitable for oral administration, preferably a tablet or a capsule.
  • the present invention also provides a pharmaceutical composition comprising the crystal form of the pharmaceutically acceptable salt of the compound of formula I.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is a solid pharmaceutical preparation suitable for oral administration, preferably a tablet or a capsule.
  • the present invention provides a crystal form composition, wherein the pharmaceutically acceptable salt of the compound of formula I above, and the crystal form of the pharmaceutically acceptable salt of the compound of formula I account for the weight of the crystal form composition above 50.
  • the present invention also provides a pharmaceutical composition comprising the above crystal composition; the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the present invention also provides a pharmaceutically acceptable salt of the compound of formula I or its crystal form composition or its pharmaceutical composition for use as a medicine.
  • the present invention also provides a pharmaceutically acceptable salt crystal form of the compound of formula I or its crystal form composition or pharmaceutical composition thereof for use as a medicine.
  • the present invention also provides a method for preventing and/or treating AXL kinase-mediated diseases or disease states, which comprises administering the salt of the compound of formula I of the present invention, or its crystal form, to individuals in need Composition or its pharmaceutical composition.
  • the present invention also provides a method for preventing and/or treating AXL kinase-mediated diseases or disease states, which comprises administering the crystalline form of the salt of the compound of formula I of the present invention, Its crystal form composition or its pharmaceutical composition.
  • the present invention also provides the salt of the compound of formula I of the present invention, its crystal form composition or its pharmaceutical composition for preventing and/or treating AXL kinase-mediated diseases or disease states.
  • the present invention also provides the crystalline form of the salt of the compound of formula I of the present invention, its crystalline form composition or its pharmaceutical composition for preventing and/or treating AXL kinase-mediated diseases or disease states .
  • the AXL kinase-mediated disease or condition is cancer.
  • the cancer is a disease associated with hematological and solid tumors.
  • the pharmaceutically acceptable salts of the present invention also include their hydrated forms.
  • pharmaceutically acceptable carrier refers to those carriers that have no obvious stimulating effect on the body and will not impair the biological activity and performance of the active compound. Including but not limited to any diluents, disintegrants, binders, glidants, and wetting agents approved by the State Food and Drug Administration for human or animal use.
  • fumaric acid refers to fumaric acid, which has the structure:
  • alcohol solvent refers to a substance derived from one or more hydroxyl groups (OH) replacing one or more hydrogen atoms on a C1-C6 alkane
  • C1-C6 alkane refers to a substance containing 1-6 carbon atoms
  • Specific examples of linear or branched alkanes and alcohol solvents include, but are not limited to: methanol, ethanol, isopropanol or n-propanol.
  • alkane solvent refers to straight chain or branched chain or cyclic alkanes containing 5-7 carbon atoms, specific examples include but not limited to n-hexane, cyclohexane, n-heptane.
  • ester solvent refers to a chain compound containing an ester group -COOR and a carbon number of 3-10, wherein R is a C1-C6 alkyl group, and the C1-C6 alkyl group refers to a chain compound containing 1-6
  • R is a C1-C6 alkyl group
  • C1-C6 alkyl group refers to a chain compound containing 1-6
  • Specific examples of straight-chain or branched-chain alkanes with carbon atoms and ester solvents include but are not limited to methyl acetate, ethyl acetate, and propyl acetate.
  • halogenated hydrocarbon solvent refers to a substance derived from one or more halogen atoms replacing one or more hydrogen atoms on a C1-C6 alkane
  • the C1-C6 alkane refers to a substance containing 1-6 carbon atoms
  • the halogen atoms refer to fluorine, chlorine, bromine, and iodine.
  • Specific examples of halogenated hydrocarbon solvents include but are not limited to dichloromethane or chloroform.
  • ketone solvent refers to a chain or cyclic compound containing carbonyl -CO- and having 3-10 carbon atoms, specific examples include but not limited to acetone, methyl ethyl ketone or cyclohexanone.
  • benzene-based solvent means a solvent containing a phenyl group, and specific examples include toluene, xylene, cumene, or chlorobenzene.
  • equivalent refers to the equivalent amount of other raw materials required in accordance with the equivalent relationship of chemical reactions, taking the basic raw materials used in each step as 1 equivalent.
  • the "X-ray powder diffraction pattern" in the present invention is obtained by using Cu-K ⁇ radiation measurement.
  • the diffraction pattern obtained from a crystalline compound is often characteristic for a particular crystal, where the relative intensity of the bands (especially at low angles) may vary due to The effect of dominant orientation due to differences in crystallization conditions, particle size and other measurement conditions varies. Therefore, the relative intensities of the diffraction peaks are not characteristic of the targeted crystals.
  • XRPD X-ray powder diffraction
  • the position of the peak can move, and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2°. Therefore, this error should be taken into account when determining each crystal structure.
  • the peak positions of their XRPD spectra are similar on the whole, and the relative intensity error may be large.
  • DSC Differential Scanning Calorimetry
  • Thermogravimetric analysis refers to a thermal analysis technique that measures the relationship between the mass of the sample to be tested and the temperature change at a programmed temperature.
  • TGA Thermogravimetric analysis
  • IMDM (Iscove's Modified Dulbecco's Medium): Iscove (person's name) modified Dulbecco (person's name) medium.
  • Fig. 1 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound mesylate in embodiment 5;
  • Fig. 2 shows the differential scanning calorimetry (DSC) figure of formula I compound mesylate in embodiment 5;
  • Fig. 3 shows the thermogravimetric (TGA) figure of formula I compound mesylate in embodiment 5;
  • Fig. 4 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound monohydrochloride in embodiment 3;
  • Fig. 5 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound dihydrochloride in embodiment 3;
  • Fig. 6 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound phosphate in embodiment 3;
  • Fig. 7 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound hippurate in embodiment 3;
  • Fig. 8 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound sulfate in embodiment 3;
  • Fig. 9 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound hydrobromide in embodiment 3;
  • Fig. 10 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound besylate in embodiment 3;
  • Fig. 11 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound oxalate in embodiment 3;
  • Fig. 12 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound fumarate in embodiment 3;
  • Fig. 13 shows the X-ray powder diffraction (XRPD) spectrogram of formula I compound citrate in embodiment 3;
  • Figure 14 shows the X-ray powder diffraction (XRPD) spectrum of the crystal form A of the compound of formula I in Example 6.
  • test conditions of each instrument are as follows:
  • Temperature rise range room temperature - 300°C
  • Method Put the sample in an aluminum pan, then place the aluminum pan in a platinum pan, expose it in a nitrogen atmosphere, and raise the temperature from room temperature to the set temperature at a rate of 10°C/min.
  • Heating range 20-300°C
  • the sample was placed in an aluminum pan, and after capping, the temperature was raised from 20°C to the set temperature at a rate of 10°C/min in a nitrogen atmosphere.
  • the crude product was purified by reverse-phase high-performance liquid chromatography (column is YMC Actus Triart C18, 30*150mm, particle diameter 5 ⁇ m, mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60mL/ min, gradient: 20%B to 50%B, 8min, wavelength: 220nm, retention time: 6.83min, column temperature: 25°C), the title product (20.2mg) was obtained.
  • Example 1 Related compounds prepared in Example 1 carry out related enzyme activities, cells, and related activities in vivo
  • the specific structure of the positive drug 1 (BGB324) used in the activity test is as follows:
  • 1 ⁇ enzyme buffer 200 ⁇ L of Enzymatic buffer kinase 5X, 10 ⁇ L of 500 mM MgCl 2 , 10 ⁇ L of 100 mM DTT, 6.26 ⁇
  • DMSO dilute the compounds and positive drugs prepared in the examples from 10 mM to 100 ⁇ M, and titrate with a compound titrator (Tecan, D300e), and the titrator will automatically spray the required concentration into each well, the first step A concentration of 1 ⁇ M, 1/2 log gradient dilution, a total of 8 concentrations. Centrifuge at 2500rpm for 30s and incubate at room temperature for 15min.
  • ATP (Sigma, A7699) was diluted with 1 ⁇ enzyme buffer, from 10 mM to 75 ⁇ M (5 ⁇ ), and the final concentration was 15 ⁇ M; substrate TK Substrate 3-biotin (Cisbio, 61TK0BLC) was diluted with 1 ⁇ enzyme buffer solution from 500 ⁇ M to 5 ⁇ M (5 ⁇ ), and the final concentration was 1 ⁇ M; ATP was mixed with the substrate in equal volume, and 4 ⁇ L was added to each well using a BioTek automatic liquid dispenser; centrifuged at 2500 rpm for 30 s, at 25 ° C React for 45 minutes.
  • Streptavidin-XL665 (Cisbio, 610SAXLG) was diluted from 16.67 ⁇ M to 250nM (4 ⁇ ) with HTRF KinEASE detection buffer (cisbio), and the final concentration was 62.5nM;
  • TK Antibody-Cryptate (Cisbio) was diluted with HTRF KinEASE detection buffer (cisbio) was diluted from 100 ⁇ to 5 ⁇ , and the final concentration was 1 ⁇ ;
  • XL665 was mixed with Antibody in equal volume, 10 ⁇ L was added to each well using a BioTek automatic dispenser, centrifuged at 2500 rpm for 30 seconds, and reacted at 25°C for 1 hour. After the reaction, the multifunctional plate reader HTRF was used for detection.
  • MV-4-11 human myelomonocytic leukemia cell line, medium: IMDM+10% fetal bovine serum
  • IMDM+10% fetal bovine serum was purchased from Nanjing Kebai Biotechnology Co., Ltd., and placed in an incubator at 37°C and 5% CO 2 nourish.
  • Cells in the logarithmic growth phase were plated in 96-well plates at cell densities of 8000/well, 6000/well, 5000/well, 4000/well and 3000/well, and a blank control group was set at the same time.
  • Signal value of the test substance the mean value of the fluorescent signal of the cell + medium + compound group
  • Signal value of the blank group the average value of the fluorescence signal of the culture medium group (containing 0.5% DMSO);
  • Signal value of negative control group mean value of fluorescence signal of cell+medium group (containing 0.5% DMSO).
  • the IC 50 (MV4-11, nM) of the antiproliferative activity of the compound of Example 1 on MV4-11 cells was 6.97.
  • test compound The inhibitory effect of the test compound and the positive drug on the growth of human acute monocytic leukemia cell MV-4-11 xenografted tumor model in nude mice in vivo.
  • MV-4-11 cells in the logarithmic growth phase were collected, counted and resuspended, and the cell concentration was adjusted to 7.0 ⁇ 10 7 cells/mL; injected subcutaneously into the right axilla of nude mice, each animal was inoculated with 200 L (14 ⁇ 10 6 cells/monkey), the MV-4-11 xenograft tumor model was established. When the tumor volume reaches 100-300 mm 3 , tumor-bearing mice with good health and similar tumor volume are selected.
  • Solvent control group PEG400&citric acid buffer (20:80, v:v).
  • tumor volume (mm 3 ) l ⁇ w 2 /2
  • RTV relative tumor volume
  • TV initial is the tumor volume measured during group administration
  • TV t is the tumor volume at each measurement during administration.
  • TV t (T) represents the tumor volume measured each time in the treatment group
  • TV initial (T) represents the tumor volume of the treatment group when administered in groups
  • TV t (C) represents the tumor volume measured each time in the solvent control group
  • TV initial (C) represents the tumor volume of the solvent control group at the time of group administration.
  • RTV T represents the RTV of the treatment group
  • RTV C represents the RTV of the solvent control group.
  • the experimental data in the table is the relevant data obtained when the experiment ends (the end of the experiment is defined as: after 21 days or when the tumor volume of the solvent control group reaches 2000 mm 3 and the experiment ends (whichever is reached earlier)).
  • Each compound was prepared as a 10 mg/mL stock solution in DMSO.
  • mice Male ICR mice aged 6-10 weeks (source of mice: Weitong Lihua Experimental Animal Technology Co., Ltd.), 6 in each group, were fasted overnight and fed 4 hours after administration. On the day of the experiment, the mice were given 10 mg kg- 1 compound test solution by intragastric administration. At 0, 5min, 15min, 30min, 1h, 2h, 4h, 8h, and 24h after administration, about 100 ⁇ L of blood was collected from the orbit of the mice and placed in an EDTA-K 2 anticoagulant tube. Whole blood samples were centrifuged at 1500-1600 g for 10 min, and the separated plasma was stored in a -40-20°C refrigerator for biological sample analysis. LC-MS/MS method was used to determine the plasma concentration.
  • Fig. 4-13 is respectively formula I compound hydrochloride, dihydrochloride, phosphate, hippurate, sulfate, hydrobromide, benzenesulfonate, oxalate, fumarate, citric acid X-ray powder diffraction (XRPD) pattern of the salt.
  • XRPD X-ray powder diffraction
  • Embodiment 6 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7] wheel Preparation of Form A of En-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide (compound of formula I)

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Abstract

La présente invention concerne un sel d'un composé de formule (I) et une forme cristalline de celui-ci, son procédé de préparation et son utilisation. Le sel est choisi dans le groupe constitué par le mésylate, le benzène sulfonate, l'oxalate, le fumarate, le citrate, l'urate équin, le chlorhydrate, le bromhydrate, le sulfate ou le phosphate.
PCT/CN2022/134408 2021-11-26 2022-11-25 Sel d'inhibiteur de kinase axl, son procédé de préparation et son utilisation WO2023093859A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101796046A (zh) * 2007-07-16 2010-08-04 阿斯利康(瑞典)有限公司 嘧啶衍生物934
CN102356075A (zh) * 2009-01-23 2012-02-15 里格尔药品股份有限公司 抑制jak途径的组合物和方法
WO2015038868A1 (fr) * 2013-09-13 2015-03-19 Cephalon, Inc. Dérivés de 2,4-diaminopyrimidine bicycliques condensés
CN106458914A (zh) * 2014-03-28 2017-02-22 常州捷凯医药科技有限公司 作为axl抑制剂的杂环化合物
WO2018102366A1 (fr) * 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines en tant qu'inhibiteurs de kinase 1 progénitrices hématopoïétiques (hpk1)
WO2020253860A1 (fr) * 2019-06-21 2020-12-24 江苏豪森药业集团有限公司 Inhibiteur de dérivé d'oxyde de phosphore aryle, son procédé de préparation et son utilisation
WO2021125803A1 (fr) * 2019-12-16 2021-06-24 한국화학연구원 Nouveau dérivé de pyrimidine et utilisation correspondante
WO2021239133A1 (fr) * 2020-05-29 2021-12-02 南京正大天晴制药有限公司 Composé de pyrimidine utilisé en tant qu'inhibiteur d'axl

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101796046A (zh) * 2007-07-16 2010-08-04 阿斯利康(瑞典)有限公司 嘧啶衍生物934
CN102356075A (zh) * 2009-01-23 2012-02-15 里格尔药品股份有限公司 抑制jak途径的组合物和方法
WO2015038868A1 (fr) * 2013-09-13 2015-03-19 Cephalon, Inc. Dérivés de 2,4-diaminopyrimidine bicycliques condensés
CN106458914A (zh) * 2014-03-28 2017-02-22 常州捷凯医药科技有限公司 作为axl抑制剂的杂环化合物
WO2018102366A1 (fr) * 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines en tant qu'inhibiteurs de kinase 1 progénitrices hématopoïétiques (hpk1)
WO2020253860A1 (fr) * 2019-06-21 2020-12-24 江苏豪森药业集团有限公司 Inhibiteur de dérivé d'oxyde de phosphore aryle, son procédé de préparation et son utilisation
WO2021125803A1 (fr) * 2019-12-16 2021-06-24 한국화학연구원 Nouveau dérivé de pyrimidine et utilisation correspondante
WO2021239133A1 (fr) * 2020-05-29 2021-12-02 南京正大天晴制药有限公司 Composé de pyrimidine utilisé en tant qu'inhibiteur d'axl

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