WO2022048551A1 - Polymorphe d'un inhibiteur de tyrosine kinase de bruton, son procédé de préparation et son utilisation - Google Patents

Polymorphe d'un inhibiteur de tyrosine kinase de bruton, son procédé de préparation et son utilisation Download PDF

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WO2022048551A1
WO2022048551A1 PCT/CN2021/115856 CN2021115856W WO2022048551A1 WO 2022048551 A1 WO2022048551 A1 WO 2022048551A1 CN 2021115856 W CN2021115856 W CN 2021115856W WO 2022048551 A1 WO2022048551 A1 WO 2022048551A1
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crystal form
compound
preparation
formula
ray powder
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PCT/CN2021/115856
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Chinese (zh)
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李金晶
江涛涛
曾振亚
杨菡
陈曦
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Priority to CN202180053967.4A priority Critical patent/CN116096369A/zh
Publication of WO2022048551A1 publication Critical patent/WO2022048551A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the invention belongs to the technical field of medicine, in particular, the invention relates to a polymorphic form of a BTK inhibitor, a preparation method and application thereof, and the inhibitor is (R)-6-((1-acryloylpiperidine- 3-yl)amino)-7-fluoro-4-((2-fluoro-4-morpholinophenyl)amino)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridine- 3-keto.
  • Bruton's tyrosine kinase (BTK) kinase is a non-receptor tyrosine kinase in the TEC kinase family. It is a key regulator of the BCR signaling pathway and plays an important role in the maturation, proliferation and survival of B cells.
  • BTK is overexpressed in a variety of B-cell lymphomas and is currently the only clinically validated target for drug development in the TEC kinase family. Inhibition of BTK inhibits the proliferation of a range of B-cell lymphomas.
  • BCR B-cell antigen receptor
  • BTK inhibitors act on chronic lymphocytic leukemia (CLL) cells to induce cytotoxicity and inhibit the proliferation of CLL cells. It inhibits the proliferation of primary B cells activated by BCR, and inhibits the secretion of TNF ⁇ , IL-1 ⁇ and IL-6 in primary monocytes. In a collagen-induced arthritis model, BTK inhibitors significantly reduce clinical arthritis symptoms such as foot swelling and joint inflammation by inhibiting B cell activity.
  • CLL chronic lymphocytic leukemia
  • Patent WO2019062329A1 discloses the structure of a class of compounds with better BTK inhibitory activity, and specifically discloses the compound 6-((1-acryloylpiperidin-3-yl)amino)-7-fluoro-4-((2-fluoro -4-morpholinophenyl)amino)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one, the compound has high inhibitory activity on enzymes and cells.
  • the R configuration of the compound had poor solubility when it existed in an amorphous state, and such a result may have an impact on the later drug development.
  • the present invention further researches the R-configuration compound, and completes the present application based on the research.
  • the present invention provides two kinds of (R)-6-((1-acryloylpiperidin-3-yl)amino)-7-fluoro-4-((2-fluoro-4)
  • the new crystal form provided by the present invention has improved solubility and more favorable in vivo pharmacokinetic characteristics, which is helpful for further drug development.
  • the Form IV is an anhydrous form or a hydrate form.
  • the Form IV is an anhydrous form.
  • the X-ray powder diffraction pattern of the crystal form IV detected using Cu-K ⁇ radiation has diffraction peaks at the diffraction angle 2 ⁇ (°) values of the following group IV-1: 5.90 ⁇ 0.2, 14.91 ⁇ 0.2, 17.51 ⁇ 0.2, 24.90 ⁇ 0.2 and 26.37 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form IV further comprises diffraction peaks at 1, 2, or more or all of the diffraction angle 2 ⁇ (°) values selected from the following Group IV-2: 10.41 ⁇ 10.41 ⁇ 0.2, 12.19 ⁇ 0.2, 18.80 ⁇ 0.2, 21.49 ⁇ 0.2 and 25.44 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form IV further includes diffraction peaks at 8.91 ⁇ 0.2, 12.49 ⁇ 0.2, and 12.76 ⁇ 0.2 diffraction angle 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of Form IV further comprises diffraction angle 2 ⁇ (°) values at 15.48 ⁇ 0.2, 16.05 ⁇ 0.2, 18.29 ⁇ 0.2, 19.76 ⁇ 0.2, 22.45 ⁇ 0.2 and 23.57 ⁇ 0.2 diffraction peaks at.
  • the X-ray powder diffraction pattern of Form IV further comprises diffraction peaks at 1, 2, 3, or more or all of the diffraction angle 2 ⁇ (°) values selected from the following Group IV-3: 8.91 ⁇ 0.2, 12.49 ⁇ 0.2, 12.76 ⁇ 0.2, 13.94 ⁇ 0.2, 15.48 ⁇ 0.2, 16.05 ⁇ 0.2, 18.29 ⁇ 0.2, 19.76 ⁇ 0.2, 22.45 ⁇ 0.2, 23.57 ⁇ 0.2, 27.73 ⁇ 0.2, 28.67 ⁇ 0.2 and 35.37 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the crystal form IV is selected from 6 or more or all of the group IV-1, IV-2 and IV-3 (eg 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) with peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the crystal form IV has diffraction peaks at the 2 ⁇ (°) values shown in Table 1, and the relative intensities of each peak are shown in Table 1:
  • the X-ray powder diffraction pattern of the Form IV is substantially as characterized in FIG. 1 .
  • the differential scanning calorimetry curve of the crystal form IV has an endothermic peak at 167.89°C ⁇ 3°C, and the heat of fusion is about 55.84 J/g.
  • the differential scanning calorimetry curve of Form IV has an endothermic peak at 167.89°C ⁇ 1°C.
  • the Form IV has a differential scanning calorimetry profile substantially as shown in FIG. 2 .
  • the crystalline form IV has a weight loss of about 0.29% as detected by thermogravimetric analysis at 30°C to 150°C.
  • the Form IV has a thermogravimetric analysis pattern substantially as shown in FIG. 3 .
  • the dynamic moisture adsorption of the crystal form IV has a weight gain of about 0.7% in a relative humidity range of 0% to 80%, and the percentage is a percentage by weight.
  • the Form IV has a DVS pattern substantially as shown in FIG. 4 .
  • the preparation method is simple, the obtained crystal form has high purity, and is suitable for industrial production.
  • the preparation method of the crystal form IV comprises the following steps:
  • the mixture in step (S102) is cooled to room temperature.
  • the mixture in step (S102) is cooled to 20°C to 25°C.
  • the solvent in step (S101) is selected from one or more of water, ethanol, n-propanol and isopropanol.
  • the solvent in step (S101) is isopropanol.
  • the heating time is 0.5-12 hours; preferably, the heating time is 1-2 hours.
  • the mixture in the step (S102), after the mixture is cooled to room temperature, the mixture is kept for 0-12 hours, preferably 1-2 hours.
  • the Form V is an anhydrous form or a hydrate form.
  • the Form V is an anhydrous form.
  • the X-ray powder diffraction pattern of Form V detected using Cu-K ⁇ radiation has diffraction peaks at the following values of diffraction angle 2 ⁇ (°) of set V-1: 7.33 ⁇ 0.2, 9.91 ⁇ 0.2 and 17.53 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form V further includes diffraction peaks at 13.67 ⁇ 0.2 diffraction angle 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of Form V further includes diffraction peaks at diffraction angle 2 ⁇ (°) values of 15.69 ⁇ 0.2 and 16.20 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the Form V further includes diffraction peaks at diffraction angle 2 ⁇ (°) values of 12.49 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form V further includes diffraction peaks at diffraction angle 2 ⁇ (°) values of 18.95 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form V further includes diffraction peaks at diffraction angle 2 ⁇ (°) values of 20.19 ⁇ 0.2 and 21.76 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form V further includes diffraction peaks at the following values of diffraction angle 2 ⁇ (°) of Group V-2: 12.49 ⁇ 0.2, 15.69 ⁇ 0.2, 20.19 ⁇ 0.2, and 23.02 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form V further includes diffraction peaks at diffraction angle 2 ⁇ (°) values of 13.67 ⁇ 0.2 and 16.20 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the Form V further includes diffraction peaks at diffraction angle 2 ⁇ (°) values of 13.67 ⁇ 0.2 and 18.95 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form V further includes diffraction peaks at diffraction angle 2 ⁇ (°) values of 16.20 ⁇ 0.2 and 18.95 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form V further includes diffraction peaks at diffraction angle 2 ⁇ (°) values of 13.67 ⁇ 0.2, 16.20 ⁇ 0.2, and 18.95 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form V further includes diffraction peaks at diffraction angle 2 ⁇ (°) values of 21.76 ⁇ 0.2 and 30.21 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form V further includes diffraction peaks at diffraction angle 2 ⁇ (°) values of 24.80 ⁇ 0.2 and 25.53 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form V further comprises diffraction peaks at 2 or more or all of the diffraction angle 2 ⁇ (°) values selected from the following Group V-3: 13.67 ⁇ 13.67 ⁇ 0.2, 16.20 ⁇ 0.2, 18.95 ⁇ 0.2, 21.76 ⁇ 0.2, 24.80 ⁇ 0.2, 25.53 ⁇ 0.2 and 30.21 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the Form V is at 6 or more or all selected from Groups V-1, V-2, and V-3 (eg, 6, 7, 8, 9, 10, 11, 12, 13, 14, etc.) have diffraction peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the crystal form V has diffraction peaks at the 2 ⁇ (°) values shown in Table 2, and the relative intensities of the diffraction peaks are shown in Table 2:
  • the X-ray powder diffraction pattern of the Form V is substantially as characterized in FIG. 5 .
  • the differential scanning calorimetry curve of the crystal form V has an endothermic peak at 197.31°C ⁇ 3°C, and the heat of fusion is about 71.30 J/g.
  • the differential scanning calorimetry curve of the Form V has an endothermic peak at 197.31°C ⁇ 1°C.
  • the Form V has a differential scanning calorimetry profile substantially as shown in FIG. 6 .
  • the crystal form V has a weight loss of about 0.50% as detected by thermogravimetric analysis at 25°C to 150°C; and a weight loss of about 0.29% detected by thermogravimetric analysis between 150°C and 225°C.
  • the Form V has a thermogravimetric analysis pattern substantially as shown in FIG. 7 .
  • the dynamic moisture adsorption of the crystal form V has a weight gain of less than 0.2% in a relative humidity range of 0% to 80%, and the percentage is a percentage by weight.
  • the Form V has a DVS pattern substantially as shown in FIG. 8 .
  • a preparation method of the crystal form V of the compound of formula X has good reproducibility, easy process control, stable process method, high purity of the obtained crystal form, and is suitable for industrial production.
  • the preparation method of the crystal form V comprises the following steps:
  • step (S202) the mixture is cooled to room temperature.
  • step (S202) the mixture is cooled to 20°C to 25°C.
  • the solvent is selected from water, C 2-4 alkyl alcohol, acetonitrile, toluene, xylene, 1,4-dioxane, 1,2-dichloroethane One or more of alkane and ethyl acetate.
  • the C 2-4 alkyl alcohol is one or more of ethanol, n-propanol, isopropanol, and ethylene glycol, and the preferred solvent is isopropanol.
  • the ratio (m/v) of the mass (m) of the compound of formula X to the solvent volume (v) is 50g/L ⁇ 400g/L (preferably 100g/L ⁇ 200g/L) ).
  • step (S201) the mixture of the compound of formula X and the solvent is heated to 70-150°C, preferably 70-120°C, more preferably 70-90°C, more preferably 70-80°C.
  • the heating time is 0.5-48 hours, preferably 0.5-12 hours, more preferably 1-5 hours, and more preferably 1-2 hours.
  • a step (S2021) is further included: after cooling the mixture to 40-65°C (preferably 55-65°C), keeping the mixture for a period of time.
  • the holding time is 1-12 hours, and further, preferably, the holding time is 8-10 hours.
  • step (S2021) the mixture is cooled to 40-65°C (preferably 55-65°C) at a cooling rate of 4°C/hour-6°C/hour (preferably 5°C/hour), and kept for 8 ⁇ 10 hours.
  • step (S2021) the mixture is naturally cooled to 40-65°C (preferably 55-65°C), and kept for 8-9 hours.
  • step (S202) after the mixture is cooled to room temperature, the mixture is kept for 1-2 hours.
  • the preparation method of the crystal form V comprises the following steps:
  • step (S301) the compound of formula X and isopropanol are mixed and heated to reflux or 70-80° C., and kept for 0.5 to 48 hours; further, for 0.5 to 12 hours; further, for 0.5 to 12 hours 1 to 5 hours; further, keep the temperature for 1 to 2 hours.
  • step (S302) after cooling the mixture to 40-65° C., the mixture is kept for 1-12 hours; further, the mixture is kept for 8-10 hours.
  • step (S303) after cooling the mixture to room temperature, the temperature is maintained for 1-12 hours; further, preferably, the mixture is maintained for 1-2 hours.
  • the sixth aspect of the present invention provides a crystal form V of the compound of formula X prepared by the preparation method of the fifth aspect.
  • the seventh aspect of the present invention provides the crystal form IV of the first aspect, the crystal form IV of the third aspect, the crystal form V of the fourth aspect, or the crystal form V of the sixth aspect. Use in the preparation of BTK inhibitors.
  • the eighth aspect of the present invention provides the crystal form IV of the first aspect, the crystal form IV of the third aspect, the crystal form V of the fourth aspect, or the crystal form V of the sixth aspect. Use in the preparation of a medicament for the treatment and/or prevention of diseases mediated by B cells.
  • a ninth aspect of the present invention provides a method for treating a disease mediated by B cells, comprising administering to a patient in need a therapeutically effective amount of the crystal form IV described in the first aspect, the crystal form IV described in the third aspect, The crystal form V of the fourth aspect or the crystal form V of the sixth aspect.
  • the disease mediated by B cells is selected from the group consisting of: neoplastic disease, proliferative disease, allergic disease, autoimmune disease and inflammatory disease.
  • the disease mediated by B cells is selected from the group consisting of: solid tumors, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, rheumatoid arthritis, psoriasis Arthritis, osteoarthritis, systemic lupus erythematosus, psoriasis, rheumatoid spondylitis and gouty arthritis.
  • the disease mediated by B cells is a solid tumor.
  • the solid tumor is at least one selected from the group consisting of lymphoma, soft tissue sarcoma, lymphocytic lymphoma, mantle cell lymphoma, melanoma and multiple myeloma.
  • Fig. 2 Differential scanning calorimetry (DSC) spectrum of crystal form IV (the abscissa is temperature (°C), and the ordinate is heat flow rate (mW));
  • Fig. 6 Differential scanning calorimetry (DSC) spectrum of crystal form V (the abscissa is temperature (°C), and the ordinate is heat flow rate (mW));
  • Fig. 7 Thermogravimetric analysis (TGA) pattern of crystal form V (the abscissa is temperature (°C), and the ordinate is weight percentage (%));
  • Fig. 9 Comparison of XRPD patterns of Form IV placed at 60°C for 1 month, 40°C/75%RH for 1 month and the initial sample (the abscissa is the angle 2 ⁇ (°), the ordinate is the intensity) ;
  • Fig. 10 Comparison of XRPD patterns of crystal form V placed at 60°C for 1 month, 40°C/75%RH for 1 month and the initial sample (the abscissa is 2 ⁇ (°); the ordinate is the intensity);
  • Figure 11 The amorphous X-ray powder diffraction (XRPD) pattern of the free base of the compound of formula X (using Cu-K ⁇ radiation, the abscissa is 2 ⁇ (°); the ordinate is the intensity);
  • the compound of formula X is (R)-6-((1-acryloylpiperidin-3-yl)amino)-7-fluoro-4-((2-fluoro-4-morpholinophenyl) ) amino)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one, its crystal forms IV and V have improved solubility and more favorable in vivo pharmacokinetics It is not easy to absorb moisture and has good chemical and physical stability. In addition, it was found that the compound of formula X has better inhibitory activity on BTK WT kinase than its racemate compound.
  • the crystal form IV and crystal form V of the compound of formula X provided by the present invention can be used for preparing BTK inhibitors or preparing medicines for treating BTK-related diseases.
  • the BTK-related disease is cancer, abnormal cell proliferative disease, infection, inflammatory disorder, autoimmune disease, cardiovascular disease, neurodegenerative disease, hematopoietic toxicity disease caused by radiation, or a combination thereof.
  • the cancer is breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, Neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, Thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, choriocarcinoma, or pediatric tumor, or any combination thereof.
  • the breast cancer is HR-positive, HER2-negative advanced breast cancer.
  • a “therapeutically effective amount” refers to an amount that produces function or activity in humans and/or animals and is acceptable to humans and/or animals.
  • patient refers to an animal, preferably a mammal, more preferably a human.
  • mammal refers to warm-blooded vertebrate mammals including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.
  • treating refers to alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or disorder (eg, cancer). Treatment also includes curing, preventing the development or alleviating to some extent one or more symptoms of a disease or disorder.
  • "using Cu-K ⁇ radiation” means that the corresponding spectrum is obtained by detecting the K ⁇ radiation of the Cu target.
  • the diffraction peaks may have deviations within the acceptable range in the art, which should not be interpreted as Limitations of the present invention.
  • Solids exist in either amorphous or crystalline form. In the case of crystalline forms, the molecules are localized within three-dimensional lattice sites. When a compound crystallizes out of a solution or slurry, it can crystallize in different spatial lattice arrangements (a property known as "polymorphism"), forming crystals with different crystalline forms that are referred to as “polymorphs” or “crystal forms”. Different polymorphs of a given substance may differ from one another in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystal form, packing pattern, flowability and/or solid state stability.
  • Production scale crystallization can be accomplished by manipulating the solution such that the solubility limit of the compound of interest is exceeded. This can be accomplished by a variety of methods, for example, dissolving the compound at a relatively high temperature and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying or by some other method to reduce the liquid volume.
  • the solubility of the compound of interest can be reduced by adding an antisolvent or a solvent in which the compound has low solubility, or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility.
  • crystallisation see Crystallization, Third Edition, JW Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
  • room temperature generally refers to 4-30°C, preferably 20 ⁇ 5°C.
  • XRPD can detect the change of crystal form, crystallinity, crystal structure and other information, and is a common method to identify crystal form.
  • the peak position of the XRPD pattern mainly depends on the structure of the crystal form, and the measurement of the 2 ⁇ of the XRPD pattern may be slightly different between different instruments, so the value of the 2 ⁇ cannot be regarded as absolute. According to the condition of the instrument used in the experiment of the present invention, there is an error of ⁇ 0.2° in the diffraction peak.
  • the crystal form of the compound of formula X of the present invention has a specific crystal form and has a specific characteristic peak in the XRPD pattern.
  • DSC scanning analysis is a technique for measuring the relationship between the energy difference between the measured substance and the reference substance and the temperature during the heating process.
  • the peak position, shape and number of peaks on the DSC spectrum are related to the properties of the substance, so they can be qualitatively used to identify the substance. This method is commonly used in the art to detect various parameters such as phase transition temperature, glass transition temperature, and reaction heat of substances.
  • the peak positions of the DSC spectra may vary slightly between different instruments, so the numerical values of the peak positions of the DSC endothermic peaks cannot be regarded as absolute.
  • the value of experimental error or difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C.
  • TGA is a technique for measuring the change of the mass of a substance with temperature under program control. It is suitable for checking the loss of solvent in the crystal or the process of sublimation and decomposition of the sample. It can be speculated that the crystal contains water of crystallization or crystallization solvent.
  • the mass change shown by the TGA curve depends on many factors such as sample preparation and instrument; the mass change detected by TGA varies slightly between different instruments. Depending on the condition of the instrument used for the experiments of the present invention, there is an error of ⁇ 0.1% in mass variation.
  • the crystal form IV and crystal form V of the compound of the formula X of the present invention have good crystallinity, high stability, not easy to absorb moisture, and have better solubility and more favorable pharmacokinetic characteristics compared with the amorphous form. , including relatively high plasma exposure and long half-life, contribute to the enhanced bioavailability of the amorphous compound of formula X.
  • the preparation method of the crystal form IV is simple, the obtained crystal form has high purity, and is suitable for industrial production.
  • the preparation method of crystal form V has good reproducibility, easy process control and stable process method, and is suitable for industrial production. Therefore, Form IV and Form V have the possibility of being further developed into medicines.
  • LC-MS liquid mass spectrometry
  • 1 H NMR nuclear magnetic resonance
  • LC-MS liquid mass spectrometry
  • 1 H NMR Bruker AVANCE-400 nuclear magnetic instrument, the internal standard is tetramethylsilane (TMS).
  • LC-MS Agilent 1200HPLC System, 6140MS LC/MS mass spectrometer (purchased from Agilent), column WatersX-Bridge, 150 ⁇ 4.6 mm, 3.5 ⁇ m.
  • Preparative high performance liquid chromatography Pre-HPLC: Waters PHW007, column XBridge C18, 4.6*150mm, 3.5um.
  • DCM dichloromethane
  • DMF dimethylformamide
  • DMSO dimethyl sulfoxide
  • THF tetrahydrofuran
  • EA ethyl acetate
  • DIPA diisopropylamine
  • DIPEA N,N-diisopropylamine Propylethylamine
  • n-BuLi n-butyllithium
  • NaBH(OAc) 3 sodium triacetoxyborohydride
  • Xantphos means 4,5-bis(diphenylphosphine)-9,9-dimethyloxy Xanthene
  • TFA for trifluoroacetic acid
  • Pd 2 (dba) 3 for tris(dibenzylideneacetone)dipalladium
  • Xphos for 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl
  • NMP represents N-methylpyrrolidone
  • Et 3 SiH represents triethyls
  • the powder X-ray diffraction pattern of the crystal form is obtained by a known method in the art, using an Equinox 3000S/N X-ray powder diffraction analyzer.
  • the test conditions of the instrument are shown in Table 3 below:
  • the position of each peak is determined by 2 ⁇ (°). It will be appreciated that different instruments and/or conditions may result in slightly different data, with variations in peak position and relative intensities.
  • the intensity division of the peaks only reflects the approximate size of the peaks at each position.
  • the diffraction peak with the highest peak height of the crystal form is used as the base peak, and its relative intensity is defined as 100 % .
  • the peak with the 2 ⁇ (°) value of V 7.33 is the base peak), and the ratio of the peak height to the base peak height of other peaks is taken as the relative intensity I/I 0 .
  • the definition of the relative intensity of each peak is shown in the following table. :
  • High performance liquid chromatography In the present invention, high performance liquid chromatography (HPLC) was collected on Agilent 1260 HPLC.
  • the TGA spectrum was measured by a TA Q500/5000 thermogravimetric analyzer. Measurement conditions: protective gas: nitrogen (40 mL/min); temperature range: room temperature -350 °C; scanning rate: 10.0 °C/min.
  • the DSC spectrum was measured by a METTLER DSC3 differential scanning calorimeter. Measurement conditions: protective gas: nitrogen (50 mL/min); temperature range: -30-300 °C; scanning rate: 10.0 °C/min.
  • the dynamic moisture adsorption (DVS) curve was measured with a TA Q5000SA dynamic moisture adsorption instrument. Measurement conditions: temperature: 25°C; relative humidity range: 0%-80%.
  • Step 1 A solution of compound 1a-1 (6.0 g, 30.0 mmol) in THF (80 mL) was added at -78 °C with n-BuLi (27 mL, 66 mmol) and DIPA (6.6 g, 66 mmol), the mixture was stirred for 1 h and then DMF ( 10 mL) and warmed to room temperature to continue stirring for 2 h.
  • LC-MS was followed to complete the reaction.
  • HCl (2N) was added to the system to adjust pH to 5-6, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 6.8 g of compound 1a-2.
  • Step 2 Compound 1a-2 (6.8 g, 30.0 mmol) in 1,4-dioxane (80 mL) was added to compound 1a.1 (15 g, 90.0 mmol), acetic acid (2 mL) and NaBH(OAc) 3 (18.9 g, 90.0 mmol) and the mixture was stirred at 50 °C overnight. LC-MS was followed to complete the reaction. The reaction solution was evaporated to dryness under reduced pressure, washed with saturated brine, extracted with DCM, the organic layer was dried, concentrated, and purified by column chromatography to obtain 4.8 g of compound 1a. MS m/z (ESI): 371 [M+H] + .
  • Step 1 Compound 1b-1 (1.5 g, 5.17 mmol), morpholine (470 mg, 5.39 mmol), Pd 2 (dba) 3 (210 mg, 0.23 mmol), Xphos (240 mg, 0.503 mmol) were added to a 100 mL three-necked flask ), a solution of cesium carbonate (3.38 g, 10.37 mmol) in 1,4-dioxane (20 mL) was reacted at 110 °C for 3 h. LC-MS was followed to complete the reaction.
  • Step 2 Compound 1b-2 (1.38 g, 4.657 mmol), methanol (20 mL) and HCl/1,4-dioxane (4M, 10 mL) were added to a 100 mL flask, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to remove the solvent, the residue was washed with saturated sodium bicarbonate, extracted with dichloromethane, and the organic layer was dried and concentrated to obtain 900 mg of compound 1b as a yellow solid. MS m/z (ESI): 197.2 [M+H] + .
  • Step 1 Compound 1a (740 mg, 2 mmol) in NMP (10 mL) was added with (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester, namely compound 2.1 (600 mg, 3 mmol) and DIPEA (780 mg, 6 mmol), The mixture was microwaved at 180°C for 30 min under argon atmosphere, followed by LC-MS until the reaction was complete. The reaction solution was cooled to room temperature, diluted with DCM, washed with water and saturated brine respectively, the organic layer was dried, concentrated, and purified by column chromatography to obtain 300 mg of compound X-1. MS m/z (ESI): 535 [M+H] + .
  • Step 2 Compound X-1 (250 mg, 0.5 mmol), Compound 1b (118 mg, 0.6 mmol), Pd 2 (dba) 3 (45 mg, 0.05 mmol), Xantphos (54 mg, 0.1 mmol), Cesium Carbonate (326 mg, 1 mmol) ) solution in 1,4-dioxane (15 mL) was microwaved at 160 °C for 50 min under argon atmosphere. LC-MS was followed to complete the reaction. The reaction solution was cooled to room temperature, diluted with EA, washed with water and saturated brine respectively, the organic layer was dried, concentrated, and purified by column chromatography to obtain 185 mg of compound X-2. MS m/z (ESI): 695.3 [M+H] + .
  • Step 3 To a solution of compound X-2 (185 mg, 0.27 mmol) in DCM (12 mL) was added TFA (4.5 mL). The mixture was stirred at room temperature for 1 h. LC-MS was followed to complete the reaction. Most of the TFA was removed under reduced pressure, and saturated sodium bicarbonate solution was added to adjust the pH to 7-8, extracted with DCM, the organic layers were combined, dried and concentrated to obtain compound X-3, which was directly used in the next reaction. MS m/z (ESI): 595.2 [M+H] + .
  • Step 4 A solution of compound X-3 (100 mg) in DCM (10 mL) was added under argon atmosphere acryloyl chloride (15.4 mg, 0.17 mmol) and DIPEA (66 mg, 0.51 mmol), respectively. The mixture was stirred at room temperature for 2 h. LC-MS was followed to complete the reaction. The reaction solution was washed with saturated brine, extracted with DCM, the organic layer was dried and concentrated to obtain a crude product, which was purified by column chromatography to obtain 86 mg of compound X-4. MS m/z (ESI): 649 [M+H] + .
  • the obtained solid compound X was sent to XRPD for detection, and its powder X-ray diffraction pattern showed no characteristic peaks, and the powder X-ray diffraction pattern was shown in FIG. 11 , and it was in an amorphous form.
  • Method 1 Weigh 3.5 g of the compound of formula X (amorphous) into a container, add 35 mL of isopropanol, heat up to reflux, and reflux for 1.5 h. Then, the temperature was lowered at a cooling rate of 5 °C/h. When the temperature was lowered to 63 °C, a large amount of solid was precipitated, and the temperature was kept and stirred for 10 h. Then naturally cooled to room temperature, and then kept stirring for 1.5 h; filtered, and the filter cake was dried under reduced pressure at 45°C to constant weight, and the obtained solid was sent to DSC to detect that it was a single crystal form, as shown in Figure 6.
  • Method 2 Weigh 1.54 kg of the compound of formula X (amorphous) into a container, add to 7.7 L of isopropanol, heat up at 70-80° C., and keep stirring for 1.5 h. Cool down naturally to 55-65°C, keep stirring for 8-9h. Naturally and slowly cool down to 20-25°C, keep stirring for 2h. Filter, rinse with isopropanol, and dry under reduced pressure at 40-50°C to constant weight to obtain 1.223 kg of solid.
  • thermogravimetric analyzer (3) Analysis and identification by TA Q500/5000 thermogravimetric analyzer:
  • the TGA patterns of the solids obtained by the first and second methods are basically as shown in Figure 7, and the crystal form V has a slow weight loss of about 0.50% before 150 °C, There is a slow weight loss of about 0.29% between 150 ° C and 225 ° C, and the stability is good at high temperature.
  • the purity of the initial sample was determined by HPLC prior to the start of the accelerated stability test.
  • the ratio of the purity of the sample in the accelerated stability test to the purity of the initial sample was used as the criterion for evaluating the stability of the sample. If the ratio of the purity was less than 95%, the chemical property of the sample was considered unstable.
  • the specific experimental results are shown in Table 4.
  • pH 4.5 medium Weigh 18 g of sodium acetate, add 9.8 ml of glacial acetic acid, and dilute to 1 L with water.
  • pH 6.8 medium Weigh 6.8 g of potassium dihydrogen phosphate and 0.94 g of sodium hydroxide, add water and dilute to 1L.
  • 0.2% SLS/pH6.8 medium Weigh 7.8g of sodium dihydrogen phosphate dihydrate and 0.9g of sodium hydroxide into 1L of water, adjust the pH to 6.8 with 2N sodium hydroxide, mix well and add 2g of SLS, mix well That is, 0.2% SLS/pH6.8 medium is obtained.
  • solubility of crystal form IV and crystal form V in 0.2% SLS/pH6.8 medium is better than that in water, pH4.5 and pH6.8 medium.
  • the solubility of the crystal form IV and the crystal form V is significantly improved, which improves the solubility of the drug and is beneficial to improve the bioavailability.
  • Administration and blood sample collection Oral administration (PO) by gavage, the dose is 1 capsule/rat (5mg/rat), after administration 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and Blood samples were collected at 9 time points over 24 hours. The animals were manually controlled at the time of collection, and approximately 150 ⁇ L of blood was collected through the fundus venous plexus of the rat into a tube containing K 2 EDTA. Blood samples were placed on wet ice and plasma samples were obtained by centrifugation (8000 rpm, 4 minutes, 4°C) within 15 minutes and stored at -80°C until analysis. Compounds were prepared on the day of the experiment.
  • the plasma samples were analyzed by liquid chromatography-tandem mass spectrometry (model: Triple Quad TM 4000), and the chromatographic column was: Waters XBridge-C18 (2.1 ⁇ 50 mm, 5 ⁇ m).
  • Preparation of standard curve prepare a standard curve with a linear range of 1.00-3000ng/mL for the compounds to be tested in blank Wistar rat plasma matrix, and at the same time prepare quality control samples with concentrations of 3,500, 2400ng/mL at low, medium and high concentrations.
  • Processing of biological samples Place the frozen plasma samples on ice to thaw, and after the samples are thawed, place them on a vortexer and vortex for 5 minutes. Take 20 ⁇ L of plasma samples, standard curve and quality control reference samples and add them to a 96-well plate, and then add 200 ⁇ L of acetonitrile-precipitated protein containing internal standard dexamethasone (brand: NIFDC, batch number: 6TUC-T4C2, preparation concentration 2000ng/mL).
  • both the crystalline form IV and the crystalline form V have significantly improved half-life and plasma exposure levels.
  • the plasma exposure level AUC of the crystal form IV administration group was about 1.5 times that of the amorphous form
  • the half-life T 1/2 of the crystal form IV was about 1.3 times that of the amorphous form
  • the plasma exposure level of the crystal form IV was about 1.3 times.
  • AUC and half-life T 1/2 are better than amorphous.
  • the plasma exposure level AUC of the crystal form V administration group is about 2 times that of amorphous, the half-life T 1/2 of crystal form V is about 3 times that of amorphous, and the plasma exposure level AUC and half-life T 1/2 of crystal form V Significantly better than amorphous.
  • Embodiment 8 Lantha screening kinase reaction experimental method
  • the blank well replaced the kinase with reaction buffer, and the kinase well (Enzyme) did not add any drug.
  • After 60 minutes of reaction in the dark on a shaker at 25°C. Add 10 ⁇ l Detection Solution (mixture of Invitrogen PV3528 and EDTA, dilute with TR-FRET dilution buffer, EDTA working concentration is 5 mM, Lanthascreening Tb PY20 antibody working concentration is 0.2 nM), and shake for 30 minutes at room temperature. Plates were read on a Victor X5 fluorescence microplate reader (PerkinElmer) and absorbance was measured at excitation wavelength 340 nm, emission wavelengths 500 nm and 520 nm.
  • the calculation method of the inhibition rate (refer to the specification of Invitrogen, PV3363) is as follows:
  • Emission rate(ER) Coumarin Emission(520nm)/Fluorescein Emission(500nm)
  • Inhibition rate (ER kinase -ER test compound )/(ER kinase -ER blank ) ⁇ 100%.
  • the median inhibitory concentration IC50 was calculated by fitting with XLFIT 5.0 software (IDBS, UK). The results are shown in Table 8:

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Abstract

L'invention concerne un polymorphe d'un inhibiteur de tyrosine kinase de Bruton, son procédé de préparation et son utilisation, et concerne en particulier deux formes cristallines de (R)-6-((1-acryloylpipéridin-3-yl)amino)-7-fluoro-4-((2-fluoro-4-morpholinophényl)amino)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one, son procédé de préparation et son utilisation. Les deux formes cristallines ont une meilleure stabilité, sont moins hygroscopiques, ont une solubilité et des caractéristiques pharmacocinétiques améliorées, et un procédé de préparation stable, de telle sorte qu'elles peuvent être produites en masse.
PCT/CN2021/115856 2020-09-01 2021-09-01 Polymorphe d'un inhibiteur de tyrosine kinase de bruton, son procédé de préparation et son utilisation WO2022048551A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102753548A (zh) * 2009-12-23 2012-10-24 武田药品工业株式会社 作为syk抑制剂的稠合的杂芳族吡咯烷酮
WO2017128917A1 (fr) * 2016-01-29 2017-08-03 北京诺诚健华医药科技有限公司 Dérivés de cycles condensés de parazole et procédé de préparation de ces derniers, et application de ces derniers dans le traitement de cancers, d'inflammation et de maladies immunitaires
WO2019062329A1 (fr) * 2017-09-28 2019-04-04 上海海雁医药科技有限公司 Dérivé 4,6,7-trisubstitué de 1,2-dihydropyrrol[3,4-c]pyridin/pyrimidin-3-one et son utilisation
WO2020187267A1 (fr) * 2019-03-18 2020-09-24 上海海雁医药科技有限公司 Inhibiteur de btk, sel pharmaceutiquement acceptable, polymorphe et application de celui-ci

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102753548A (zh) * 2009-12-23 2012-10-24 武田药品工业株式会社 作为syk抑制剂的稠合的杂芳族吡咯烷酮
WO2017128917A1 (fr) * 2016-01-29 2017-08-03 北京诺诚健华医药科技有限公司 Dérivés de cycles condensés de parazole et procédé de préparation de ces derniers, et application de ces derniers dans le traitement de cancers, d'inflammation et de maladies immunitaires
WO2019062329A1 (fr) * 2017-09-28 2019-04-04 上海海雁医药科技有限公司 Dérivé 4,6,7-trisubstitué de 1,2-dihydropyrrol[3,4-c]pyridin/pyrimidin-3-one et son utilisation
WO2020187267A1 (fr) * 2019-03-18 2020-09-24 上海海雁医药科技有限公司 Inhibiteur de btk, sel pharmaceutiquement acceptable, polymorphe et application de celui-ci

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