WO2024027825A1 - Inhibiteur de cdk et polymorphe de phosphate de celui-ci - Google Patents

Inhibiteur de cdk et polymorphe de phosphate de celui-ci Download PDF

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WO2024027825A1
WO2024027825A1 PCT/CN2023/111237 CN2023111237W WO2024027825A1 WO 2024027825 A1 WO2024027825 A1 WO 2024027825A1 CN 2023111237 W CN2023111237 W CN 2023111237W WO 2024027825 A1 WO2024027825 A1 WO 2024027825A1
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crystal form
ray powder
powder diffraction
diffraction pattern
compound
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PCT/CN2023/111237
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Chinese (zh)
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姜辰
付强
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齐鲁制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • This application discloses a CDK inhibitor, multiple crystal forms of its phosphate, preparation methods thereof, and their application in treating cancer diseases.
  • Cyclin-dependent kinases are an important class of cellular enzymes that cooperate with cyclins and play an important role in the regulation of the cell cycle. Cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6 and possibly other heterodimers are important regulators of different stages of the cell cycle Factor (Harper, J.W., Adams, P.D., Cyclin-Dependent Kinases, Chem. Rev. 2001, 101, 2511-2526).
  • CDK2 forms a kinase complex with cyclin E or A and plays a decisive role in driving the cell cycle from the G1 phase to the S phase and maintaining the S phase.
  • the main mechanism is that Cyclin E and CDK2 work together to phosphorylate the retinoblastoma susceptibility gene (Rb) protein.
  • Rb retinoblastoma susceptibility gene
  • the phosphorylation of the Rb protein leads to the release of E2F (transcription factor).
  • E2F transcription factor
  • the released E2F binds to the upstream of some genes ( Usually located in the promoter or enhancer region), it initiates the transcriptional expression of those genes related to the cell cycle, causing cells to enter the S phase from the end of G1 phase.
  • CDK2 abnormal expression of CDK2 is closely related to the occurrence of cancer, such as CCNE1 amplified ovarian cancer, KRAS mutant lung cancer, hormone-dependent breast cancer and prostate cancer (Tadesse S, Anshabo AT, Portman N, Lim E, Tilley W, Caldon CE, Wang S, Targeting CDK2 in cancer: challenges and opportunities for therapy, Drug Discovery Today, 2020, 25, 406-413).
  • CDK inhibitors have become a current research focus on anti-tumor drugs.
  • CDK4/6 target mainly for breast cancer, such as Pfizer's Palbociclib, Novartis' Ribociclib and Eli Lilly's abemaciclib.
  • Molecules including CDK2 multi-target inhibitors such as fadraciclib, Roscovitine and PF-06873600 are in different clinical stages.
  • no CDK2 inhibitors have been approved for marketing. Therefore, new CDK inhibitors continue to be developed, especially those that are effective against CDK2 targets. inhibitors, which are of great research significance.
  • Patent PCT/CN2022/074491 discloses a small molecule inhibitor targeting CDK2/4/6, especially the CDK2 target. Its structure is shown in formula (A), and its chemical name is N-(1-((4 -((3S,5S)-3,5-dimethylpiperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)-4-((S)-tetrahydrofuran-3-yl)oxy methyl)-5-(trifluoromethyl)pyrimidin-2-amine.
  • This small molecule inhibitor can selectively inhibit CDK 2/4/6 kinases compared to CDK 1/7/9 kinases. It is especially excellent in the inhibitory activity of CDK 2 kinases.
  • this small molecule inhibitor has good cell proliferation inhibitory activity, and has shown good tumor inhibitory activity and good tolerance in in vivo efficacy experiments, and is expected to be developed into clinical drugs.
  • the present application discloses a polymorphic form of a CDK inhibitor, a CDK inhibitor phosphate, a polymorphic form, a preparation method of the crystal form, and their application in the treatment of cancer diseases.
  • the first aspect of the application provides a compound of formula (A) (i.e., N-(1-((4-((3S,5S)-3,5-dimethylpiperazin-1-yl)phenyl)sulfonate) Crystalline Form I of acyl)piperidin-4-yl)-4-((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine), wherein,
  • the X-ray powder diffraction pattern of Form I has characteristic peaks at 2 ⁇ values of 10.49°, 12.10°, 17.74°, 19.88°, and 21.66°, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystalline form I has a 2 ⁇ value of 10.03°, 10.49°, 12.10°, There are characteristic peaks at 14.28°, 14.81°, 17.74°, 18.28°, 19.88°, 20.57°, 21.66°, 23.11°, 23.76°, and 26.29°, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystalline form I has a 2 ⁇ value of 10.03°, 10.49°, 11.48°, 12.10°, 13.50°, 14.28°, 14.81°, 16.16°, 16.87°
  • 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form I is substantially as shown in Figure 1.
  • the DSC spectrum of the above-mentioned crystalline form I has an endothermic characteristic peak at about 200°C.
  • the TGA-DSC spectrum of the above crystalline Form I is substantially as shown in Figure 2.
  • the XRPD pattern diffraction peak analysis data of the crystal form I of the compound of formula (A) is basically as shown in Table 1.
  • the second aspect of the application also provides a compound of formula (A) (i.e. N-(1-((4-((3S,5S)-3,5-dimethylpiperazin-1-yl)phenyl)) Form II of sulfonyl)piperidin-4-yl)-4-((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine), the crystal
  • the X-ray powder diffraction pattern of Type II has characteristic peaks at 2 ⁇ values of 8.09°, 13.31°, 16.59°, 19.55°, 21.59°, and 25.01°, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystalline form II has a 2 ⁇ value of 6.13°, 8.09°, 11.60°, 13.31°, 14.44°, 16.59°, 17.13°, 18.27°, 19.55°
  • the X-ray powder diffraction pattern of the above-mentioned crystalline form II has a 2 ⁇ value of 6.13°, 8.09°, 9.94°, 11.60°, 13.31°, 14.44°, 16.59°, 17.13°, 17.71°
  • the X-ray powder diffraction pattern of the above-mentioned Form II is substantially as shown in Figure 3.
  • the TGA-DSC spectrum of the above-mentioned crystal form II is substantially as shown in Figure 4.
  • the XRPD pattern diffraction peak analysis data of the crystal form II of the compound of formula (A) is basically as shown in Table 2.
  • the third aspect of the application also provides a compound of formula (A) (i.e. N-(1-((4-((3S,5S)-3,5-dimethylpiperazin-1-yl)phenyl)) Sulfonyl)piperidin-4-yl)-4-((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine) phosphate, wherein formula (A ) compound and phosphoric acid molar ratio is 1:1,
  • the inventor of the present application has tried to form salts of the compound of formula (A) with various inorganic acids or organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, succinic acid and p-toluenesulfonic acid. etc., but only the phosphate of formula (A) was found to have better crystallinity, hygroscopicity, solubility and stability.
  • Some other acids cannot form salts with the compound of formula (A), some have poor crystallinity, or are mostly amorphous, and some can obtain crystal forms, but the crystal forms are prone to moisture or have poor stability.
  • the fourth aspect of the present application also provides a crystal form III of the phosphate salt of the compound of formula (A).
  • the X-ray powder diffraction pattern of the crystal form III has a 2 ⁇ value of 5.85°, 8.94°, 14.86°, and 16.00°. There is a characteristic peak at 2 ⁇ , and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form III has a 2 ⁇ value of 5.85°, 8.94°, 10.29°, 13.21°, 14.86°, 16.00°, 17.01°, 17.65°, 19.25° There is a characteristic peak at 2 ⁇ , and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form III has a 2 ⁇ value of 3.43°, 5.85°, 8.94°, 10.29°, 11.69°, 12.30°, 13.21°, 14.86°, 16.00°
  • the X-ray powder diffraction pattern of Form III described above is substantially as shown in Figure 8.
  • the TGA-DSC spectrum of the above-mentioned Form III is substantially as shown in Figure 9.
  • the XRPD pattern diffraction peak analysis data of the above-mentioned crystal form III is basically as shown in Table 3.
  • the fifth aspect of the present application also provides a crystalline form IV of the phosphate of the compound of formula (A).
  • the X-ray powder diffraction pattern of the crystalline form IV has a 2 ⁇ value of 13.07°, 15.66°, 16.11°, and 16.84°. , there is a characteristic peak at 21.89°, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystalline form IV has a 2 ⁇ value of 7.81°, 13.07°, 15.20°, 15.66°, 16.11°, 16.84°, 19.61°, 21.89°, 22.16° , there is a characteristic peak at 23.57°, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystalline form IV has a 2 ⁇ value of 7.81°, 10.97°, 13.07°, 14.20°, 15.20°, 15.66°, 16.11°, 16.84°, 19.61°
  • the X-ray powder diffraction pattern of the above-described Form IV is substantially as shown in Figure 10.
  • the DSC spectrum of the above crystalline form IV has an endothermic characteristic peak at about 229°C.
  • the TGA-DSC spectrum of the above-mentioned Form IV is substantially as shown in Figure 11.
  • the XRPD pattern diffraction peak analysis data of the above-mentioned crystal form IV is basically as shown in Table 4.
  • the sixth aspect of the application also provides a pharmaceutical composition, which includes the crystal form I described in the first aspect of the application, the crystal form II described in the second aspect of the application, and the phosphate salt described in the third aspect of the application. , the crystal form III described in the fourth aspect of this application or the crystal form IV described in the fifth aspect of this application, and a pharmaceutically acceptable carrier.
  • the seventh aspect of the application also provides the crystal form I described in the first aspect of the application, the crystal form II described in the second aspect of the application, the phosphate described in the third aspect of the application, and the crystal form II described in the fourth aspect of the application.
  • the eighth aspect of the application also provides the crystal form I described in the first aspect of the application, the crystal form II described in the second aspect of the application, the phosphate described in the third aspect of the application, and the crystal form II described in the fourth aspect of the application.
  • the ninth aspect of the present application also provides the crystalline form I described in the first aspect of the present application, the crystalline form II described in the second aspect of the present application, and the third aspect of the present application for use as medicine or for treating CDK-mediated cancer.
  • the cancer includes ovarian cancer, breast cancer, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL).
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • the cancer is breast cancer.
  • the tenth aspect of this application also provides a preparation method for the crystal form I described in the first aspect of this application, including the following steps:
  • step (b) Add a second solvent to the solution in step (a) and stir for a certain period of time;
  • the first solvent in the above preparation method is selected from at least one of acetone, methanol, tetrahydrofuran, ethyl acetate, acetonitrile and dichloromethane.
  • the second solvent in the above preparation method is selected from at least one of water, n-heptane, and n-hexane.
  • the certain stirring time is 1-3 hours, preferably 2 hours.
  • the crystal form in this application has good chemical stability, physical stability and low hygroscopicity, is less affected by temperature, humidity and light, and is convenient for storage and formulation development.
  • Figure 1 is an XRPD (X-ray powder diffraction) spectrum of crystal form I of the compound of formula (A).
  • Figure 2 is a TGA-DSC (differential scanning calorimetry-thermogravimetric analysis) spectrum of crystal form I of the compound of formula (A).
  • Figure 3 is the XRPD spectrum of crystal form II of the compound of formula (A).
  • Figure 4 is a TGA-DSC spectrum of crystal form II of the compound of formula (A).
  • Figure 5 is a DVS (dynamic vapor phase adsorption) spectrum of crystal form I of the compound of formula (A).
  • Figure 6 is a comparative XRPD spectrum of crystal form I of the compound of formula (A) before and after the DVS experiment.
  • Figure 7 is a comparative XRPD spectrum before and after the stability experiment of the crystal form I of the compound of formula (A).
  • Figure 8 is an XRPD spectrum of Form III of the phosphate salt of the compound of formula (A).
  • Figure 9 is a TGA-DSC spectrum of Form III of the phosphate salt of the compound of formula (A).
  • Figure 10 is an XRPD spectrum of Form IV of the phosphate salt of the compound of formula (A).
  • Figure 11 is a TGA-DSC spectrum of Form IV of the phosphate salt of the compound of formula (A).
  • Figure 12 is a DVS spectrum of Form IV of the phosphate salt of the compound of formula (A).
  • Figure 13 is a comparative XRPD spectrum before and after the stability experiment of the phosphate form IV of the compound of formula (A).
  • pharmaceutically acceptable carrier refers to a medium generally accepted in the art for delivering biologically active agents to animals, especially mammals, including, for example, adjuvants, excipients, or Excipients such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, aromatics, antibacterial agents, antifungal agents, Lubricants and dispersants.
  • the formulation of pharmaceutically acceptable carriers depends on a number of factors within the purview of one of ordinary skill in the art.
  • compositions containing the agent include both aqueous and non-aqueous media and a variety of solid and semi-solid dosage forms.
  • Such carriers include many different ingredients and additives in addition to the active agent, and such additional ingredients are well known to those of ordinary skill in the art to be included in the formulation for a variety of reasons (e.g., to stabilize the active agent, binders, etc.) .
  • X-ray powder diffraction patterns have one or more measurement errors depending on slight changes in measurement conditions.
  • the structure of the crystals, crystals or crystal forms disclosed or claimed in this application may vary depending on test conditions, purity, equipment It exhibits similar but not identical analytical properties within a reasonable error range as other constant variables known to those skilled in the art.
  • the diffraction angle (2 ⁇ ) in powder X-ray powder diffraction usually produces an error within the range of ⁇ 0.20°. Therefore, this application not only includes crystals with completely consistent diffraction angles in powder X-ray powder diffraction, but also includes Crystals with consistent diffraction angles within an error range of ⁇ 0.20°.
  • the crystalline form of Compound A of the present application is not limited to crystals having the same X-ray powder diffraction pattern as shown in the accompanying drawings, and has substantially the same X-ray powder diffraction pattern as shown in the accompanying drawings. Any crystal with a diffraction pattern falls within the scope of this application.
  • DSC data can reflect changes in the form of a substance. Strong endothermic peaks can indicate that the substance has dehydrated or desolvated, or has undergone crystallization, or has melted. When reflecting the melting state, the corresponding temperature is usually understood as the substance. melting point. This value will be affected by compound purity, sample weight, heating rate, particle size, and calibration and maintenance of the test equipment. Those skilled in the art can understand that the temperature when a substance transforms from a solid state to a liquid state is usually a temperature range rather than a fixed point value.
  • the temperature corresponding to the endothermic peak can be characterized by the onset value or peak value or other reasonable values. or the melting point of a substance.
  • the maximum endothermic transition temperature of the crystal form may be within the range of the above-disclosed specific value ⁇ 5.0°C, preferably within the range of ⁇ 2.0°C.
  • thermogravimetric analysis TGA
  • evaporation loss of weight
  • the temperature at which the crystal form decomposes, sublimates, or evaporates can be within the range of ⁇ 3.0°C of the specific numerical value disclosed above, for example, within the range of ⁇ 2.0°C.
  • “Stability” of a crystalline form includes “chemical stability” and/or “physical stability”. “Chemical stability” refers to the degree of degradation reaction of the crystal form under certain temperature, humidity, and light conditions. “Chemical stability” reflects the stability of the crystal form under storage conditions. “Physical stability” refers to the degree to which the crystal form is converted into a solid form under certain specific conditions, such as high temperature, high humidity, grinding, tableting, desolvation, and adsorption of solvents, into another crystal form. Therefore, “physical stability” can reflect to a certain extent the stability of the crystal form during the use of preparations and other processes.
  • the crystalline structures of the present application can be prepared by a variety of methods, including crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state conversion from another phase, crystallization from a supercritical fluid, and jet spray.
  • Techniques for crystallizing or recrystallizing a crystalline structure from a solvent mixture including solvent evaporation, lowering the temperature of the solvent mixture, seeding of a supersaturated solvent mixture of the molecule and/or salt, lyophilizing the solvent mixture, adding an antisolvent to the solvent mixture wait.
  • drying refers to the process of removing solvent from the obtained solid, including but not limited to natural drying at room temperature, high temperature drying, vacuum drying and other methods.
  • the intermediate compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art. Well-known equivalents and preferred embodiments include but are not limited to the embodiments of the present application.
  • the naming of the title compound was converted from the compound structure with the help of Chemdraw. If there is any inconsistency between the compound name and the compound structure, it can be determined by comprehensively integrating relevant information and reaction routes; if it cannot be confirmed through other methods, the given compound structural formula shall prevail.
  • the preparation methods of some compounds in this application refer to the preparation methods of similar compounds mentioned above. Persons in the art should know that when using or referring to the preparation methods cited therein, the feed ratio of the reactants, the reaction solvent, the reaction temperature, etc. can be appropriately adjusted according to the different reactants.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred implementations include but are not limited to the embodiments of this application.
  • the solid sample is analyzed with an X-ray powder diffractometer (X'Pert PRO). Take an appropriate amount of fine powder of the test sample, place it in the groove of the sample holder, and press it into a flat and dense plane with a glass piece.
  • the XRPD measurement parameters are shown in Table 5. .
  • Thermogravimetric analysis of solids was performed using TA Instrument's thermogravimetric analyzer. Approximately 1-5 mg of sample was placed in a peeled aluminum sample pan, the sample was heated according to the parameters listed in Table 6, and the data was analyzed using TRIOS.
  • Thermogravimetry-differential scanning calorimetry analysis of solids was performed using a simultaneous thermal analyzer from Mettler Toledo. Use a small spoon to take an appropriate amount of the test sample and place it in the crucible, spread it evenly, weigh it, heat the sample according to the parameters listed in Table 7, and use STARe to analyze the data.
  • the hygroscopicity of the samples was measured using the DVS Intrinsic dynamic moisture adsorption instrument. Place the sample into the tared sample basket, the instrument automatically weighs, and analyzes the sample according to the parameters in Table 8.
  • Chromatographic column Use an anion exchange chromatographic column [analytical column Ionpac TM AS11-HC (4mm ⁇ 250mm), guard column Ionpac TM AG11-HC (4mm ⁇ 50mm)];
  • AERS 500 4mm or equivalent suppressor AERS 500 4mm or equivalent suppressor
  • Running time approximately 20 minutes.
  • Step 1 Compound 1B-3 (508 mg, 1.81 mmol) was dissolved in dichloromethane (30 mL) at room temperature. Subsequently, N,N-diisopropylethylamine (702 mg, 5.43 mmol) and 4-bromo-benzenesulfonyl chloride (508 mg, 2.00 mmol) were added thereto under an ice-water bath. After the reaction solution was stirred at room temperature for 2 hours, water (60 ml) was added to quench the mixture. The mixture was extracted with dichloromethane (20 ml ⁇ 3 times), and the organic phases were combined.
  • Step 2 In a sealed jar, dissolve (S)-3-hydroxytetrahydrofuran (42 mg, 0.48 mmol) in tetrahydrofuran (2 mL). Subsequently, sodium hydride (21 mg, 0.88 mmol) was added thereto under an ice-water bath. After reacting for 15 minutes, compound 99-1 (200 mg, 0.40 mmol) was added, and the reaction solution was heated to 100°C. After reaction for 4 hours, water (60 ml) was added to the reaction solution to quench the reaction solution. The mixture was extracted with dichloromethane (20 ml ⁇ 3 times), and the organic phases were combined.
  • Step 1 Under nitrogen protection conditions, compound 99 (25g, 45.3 mmol), (2S, 6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (11.6 g, 45.3 mmol) ), tris(dibenzylideneacetone)dipalladium (4.1 g, 4.53 mmol), 2-dicyclohexylphosphon-2,4,6-triisopropylbiphenyl (1.3 g, 9.02 mmol) and carbonic acid Cesium (29.4 g, 90.6 mmol) was dissolved in 1,4-dioxane (1.25 L). The reaction solution was heated to 100°C and stirred overnight.
  • Step 2 Compound 168-1 (18.1 g, 26.4 mmol) was dissolved in 1,4dioxane (100 mL). Subsequently, dioxane hydrochloride solution (100 ml) was added thereto. The reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The obtained residue was washed with sodium bicarbonate aqueous solution (300 ml), the mixture was extracted with ethyl acetate (200 ml ⁇ 3 times), and the organic phases were combined. The organic phase Wash with saturated brine (100 ml), dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure.
  • This experiment uses the capillary migration ability change assay (MSA) method to test the inhibitory effect of the compound on CDK1/CDK2/CDK4/CDK6/CDK7/CDK9 kinase activity, and concludes that the compound’s inhibitory effect on CDK1/CDK2/CDK4/CDK6/CDK7/CDK9 kinase The half inhibitory concentration IC 50 of activity.
  • MSA capillary migration ability change assay
  • CDK1/CDK2/CDK4/CDK6/CDK7/CDK9 were purchased from Carna Company, Carliper substrate CTD3/substrate 18/substrate 8 were purchased from Gill Biochemical Company, Dinaciclib/Palbociclib were purchased from Selleckchem Company, DMSO (dimethyl sulfoxide) It was purchased from Sigma Company, and the 384-well plate was purchased from Corning Company.
  • test compound test concentration is 1 ⁇ M, 10 ⁇ M or 30 ⁇ M is the starting concentration, dilute 3 times to 10 concentrations, and detect in duplicate. Dilute to a 100x final concentration of 100% DMSO solution in a 384-well source plate. Use the Dispenser Echo 550 to transfer 250 nL of compound at 100x the final concentration to the destination 384-well plate. Add 250nL DMSO to the positive and negative control wells.
  • % inhibition rate (inhibition) (conversion%_max-conversion%_sample)/(conversion%_max-conversion%_min) ⁇ 100%
  • Conversion%_sample is the conversion rate reading of the sample
  • Conversion%_min the mean value of the negative control wells, representing the conversion rate reading of the wells without enzyme activity
  • Conversion%_max the mean value of the positive control wells, representing the conversion rate reading of the wells without compound inhibition.
  • the inhibitory IC 50 data of the compounds of the present application on CDK kinase activity are shown in Table 9. Among them: compounds with IC 50 ⁇ 0.5nM are represented by AA, compounds with 0.5nM ⁇ IC 50 ⁇ 2.5nM are represented by AB, compounds with 2.5nM ⁇ IC 50 ⁇ 10nM are represented by AC, and compounds with 10nM ⁇ IC 50 ⁇ 50nM are represented by B. To identify, compounds with 50nM ⁇ IC 50 ⁇ 100nM are identified with C, compounds with 100nM ⁇ IC 50 ⁇ 1000nM are identified with D, and compounds with IC 50 >1000nM are identified with E.
  • Compound A of this application has good CDK 2/4/6 kinase inhibitory activity, especially excellent in the inhibitory activity of CDK 2 kinase; Compound A of this application can be selected compared to CDK 1/7/9 kinase It specifically inhibits CDK 2/4/6 kinases, especially in the inhibitory activity of CDK 2 kinase. Its kinase selectivity can reach nearly 10 times, even dozens or hundreds of times.
  • This experiment uses the CellTiter-Glo method to test the inhibitory effect of compounds on HCC1806/NIH:OVCAR-3 cell proliferation, and Find the concentration IC 50 (nM) at which the compound inhibits cell growth by half.
  • HCC1806 was purchased from Tongpai (Shanghai) Biotechnology Co., Ltd.; NIH:OVCAR-3 was purchased from the ATCC Cell Bank of the United States.
  • FBS fetal bovine serum
  • Penicillin-Streptomycin Penicillin-Streptomycin
  • GlutaMAX-I Supplement purchased from GIBCO.
  • PF-06873600 was purchased from Selleck.
  • CellTiter-Glo reagent was purchased from Promega Company.
  • Envision microplate reader detects chemiluminescence signal.
  • the IC 50 of Compound A of the present application on the cell proliferation of the HCC1806/NIH:OVCAR-3 cell line can be less than 100nM, which has a better inhibitory effect than the reference compound PF-06873600.
  • HCC1806 was purchased from Tongpai (Shanghai) Biotechnology Co., Ltd.; NIH:OVCAR-3 was purchased from the ATCC Cell Bank of the United States.
  • fetal bovine serum (FBS), and Penicillin-Streptomycin were purchased from GIBCO.
  • PF-06873600 was purchased from MCE Company.
  • OVCAR-3 was purchased from ATCC cell bank in the United States. 1640 medium, fetal bovine serum (FBS), and Penicillin-Streptomycin were purchased from GIBCO. PF-06873600 was purchased from MCE Company.
  • the obtained solid was subjected to XRPD and TGA-DSC testing and characterization.
  • the solid was crystalline form I.
  • the TGA-DSC spectrum is shown in Figure 2, which has an obvious endothermic peak around 200°C.
  • the obtained solid was subjected to XRPD and TGA-DSC testing and characterization, and the solid was crystalline form II.
  • the TGA-DSC spectrum is shown in Figure 4.
  • Figure 5 is the DVS curve of Form I
  • Figure 6 is the XRPD spectrum of Form I before and after the DVS test.
  • the DVS results show that the crystalline form I absorbs moisture and gains weight by 0.14% at 80% RH and 0.16% at 90%RH, indicating that the crystalline form has almost no hygroscopicity.
  • the XRPD of the remaining solid after the DVS experiment was tested, and the results showed that The crystal form has not changed.
  • the PO 4 3- content measured by ion chromatography is 14.9%, which is close to the theoretical content of monophosphate PO 4 3- (13.9%). Combined with the above nuclear magnetic results, it is confirmed that it is in the form of monophosphate, that is, the compound of formula (A) and phosphoric acid The molar ratio is 1:1.
  • the obtained solid was subjected to XRPD and TGA-DSC testing and characterization, and the solid was crystalline form III.
  • the TGA-DSC spectrum is shown in Figure 9.
  • the obtained solid was characterized by XRPD and TGA-DSC tests and found that the solid was crystal form IV.
  • the TGA-DSC spectrum is shown in Figure 11. In the DSC spectrum, there is a characteristic endothermic peak at 229°C.
  • Figure 12 is the DVS curve of the crystal form IV.
  • the DVS results show that the hygroscopic weight gain of the crystal form IV is 0.398% at 80% RH and 0.491% at 90% RH, indicating that the crystal form is slightly hygroscopic.

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Abstract

La présente invention concerne un polymorphe d'un composé de formule (A), c'est-à-dire la N-(1-((4-((3S,5S)-3,5-diméthylpipérazine-1-yl)phényl)sulfonyl)pipéridin-4-yl)-4-((S)-tétrahydrofuran-3-yl)oxy)-5(trifluorométhyl)pyrimidine-2-amine, et un polymorphe d'un phosphate du composé de formule (A). Une forme cristalline selon la présente invention présente une bonne stabilité chimique et une bonne stabilité physique, et une faible hygroscopicité, est moins affectée par la température, l'humidité et l'éclairage, et facilite le stockage et le développement de préparation.
PCT/CN2023/111237 2022-08-05 2023-08-04 Inhibiteur de cdk et polymorphe de phosphate de celui-ci WO2024027825A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101490041A (zh) * 2006-05-26 2009-07-22 阿斯利康(瑞典)有限公司 作为细胞增殖抑制剂的2-杂环氨基-4-咪唑基嘧啶
WO2020180959A1 (fr) * 2019-03-05 2020-09-10 Incyte Corporation Composés de pyrazolyl pyrimidinylamine en tant qu'inhibiteurs de cdk2
US20210047294A1 (en) * 2019-08-14 2021-02-18 Incyte Corporation Imidazolyl pyrimidinylamine compounds as cdk2 inhibitors
WO2021170076A1 (fr) * 2020-02-28 2021-09-02 Fochon Pharmaceuticals, Ltd. Composés en tant qu'inhibiteurs de cdk2/4/6
WO2022166793A1 (fr) * 2021-02-05 2022-08-11 上海齐鲁制药研究中心有限公司 Inhibiteur de cdk

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101490041A (zh) * 2006-05-26 2009-07-22 阿斯利康(瑞典)有限公司 作为细胞增殖抑制剂的2-杂环氨基-4-咪唑基嘧啶
WO2020180959A1 (fr) * 2019-03-05 2020-09-10 Incyte Corporation Composés de pyrazolyl pyrimidinylamine en tant qu'inhibiteurs de cdk2
US20210047294A1 (en) * 2019-08-14 2021-02-18 Incyte Corporation Imidazolyl pyrimidinylamine compounds as cdk2 inhibitors
WO2021170076A1 (fr) * 2020-02-28 2021-09-02 Fochon Pharmaceuticals, Ltd. Composés en tant qu'inhibiteurs de cdk2/4/6
WO2022166793A1 (fr) * 2021-02-05 2022-08-11 上海齐鲁制药研究中心有限公司 Inhibiteur de cdk

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