WO2023155841A1 - 嘧啶并环类化合物的盐型、晶型 - Google Patents

嘧啶并环类化合物的盐型、晶型 Download PDF

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WO2023155841A1
WO2023155841A1 PCT/CN2023/076503 CN2023076503W WO2023155841A1 WO 2023155841 A1 WO2023155841 A1 WO 2023155841A1 CN 2023076503 W CN2023076503 W CN 2023076503W WO 2023155841 A1 WO2023155841 A1 WO 2023155841A1
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compound
formula
crystal form
ray powder
present
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PCT/CN2023/076503
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English (en)
French (fr)
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段淑文
胡文龙
刘迎春
胡利红
丁照中
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南京明德新药研发有限公司
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Publication of WO2023155841A1 publication Critical patent/WO2023155841A1/zh

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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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a salt form and crystal form of a class of pyrimidocyclic compounds and a preparation method thereof, in particular to the application of the salt form and crystal form of the compound of formula (II) in the preparation of therapeutically related medicines.
  • CDKs Cell cycle-dependent kinases
  • CDKs According to the different functions of CDKs, they can be divided into two categories: 1) one type of CDK participates in cell cycle regulation, mainly including CDK1, CDK2, CDK4, CDK6, etc.; 2) another type of CDK participates in transcriptional regulation, mainly including CDK7, CDK8, CDK9, CDK10, CDK11, etc.
  • CDK4/6 is a key regulator of the cell cycle, and the CDK4/6 and cyclin D complex formed by combining with cyclin D (cyclin D) can make a series of substrates including retinoblastoma protein (Rb) After phosphorylation, it releases and activates the pre-bound transcription factor E2F, making the cells transition from G1 phase to S phase, causing cell growth and proliferation, and finally leading to the formation of tumors.
  • CDK4/6 is abnormally activated in a variety of tumors, so inhibiting CDK4/6 activity can inhibit tumor growth.
  • CDK4/6 inhibitors are rapidly changing the treatment pattern of hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative advanced and metastatic breast cancer , to strive for more survival time for advanced patients.
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • the effect of these inhibitors may be limited by the development of primary and secondary resistance over time.
  • the amplification or high expression of Cyclin E is an important reason for the drug resistance of CDK4/6 inhibitors (J.Clin.Oncol.2019,37,1148 1150), and the amplification or overexpression of Cyclin E is associated with It is closely related to the poor prognosis (N. Engl. J. Med, 2002, 347, 15661575).
  • Cyclin E In HER2+ breast cancer, it has also been reported that the amplification of Cyclin E is related to the drug resistance of trastuzumab (Proc. Natl. Acad. Sci., 2011, 108, 3671 3676). The overexpression of Cyclin E also plays an important role in the progression of triple-negative breast cancer (Breast Care, 2011, 6, 273 278) or inflammatory breast cancer Oncotarget, 2017, 8, 14897 14911). Therefore, the development of CDK2/4/6 inhibitors may benefit patients with primary and secondary resistance to CDK4/6 inhibitors.
  • the present invention provides the crystal form A of the compound of formula (I)
  • the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) has diffraction peaks at the following 2 ⁇ angles: 7.78 ⁇ 0.20°, 9.36 ⁇ 0.20°, 10.12 ⁇ 0.20°, 12.12 ⁇ 0.20°, 12.72 ⁇ 0.20°, 14.32 ⁇ 0.20°, 15.44 ⁇ 0.20°, 18.04 ⁇ 0.20°, 18.50 ⁇ 0.20°, 19.74 ⁇ 0.20°, 20.24 ⁇ 0.20°, 20.68 ⁇ 0.20°, 21.58 ⁇ 0.20°, 22.96 ⁇ 0.20°, 23.42 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) has diffraction peaks at the following 2 ⁇ angles: 12.72 ⁇ 0.20°, 14.32 ⁇ 0.20°, 18.04 ⁇ 0.20°, 18.50 ⁇ 0.20°, 19.74 ⁇ 0.20°, 20.24 ⁇ 0.20°, 21.58 ⁇ 0.20°, 22.96 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) has diffraction peaks at the following 2 ⁇ angles: 3.279°, 3.522°, 7.779°, 9.357°, 10.119°, 12.122 °, 12.719°, 13.746°, 14.318°, 15.439°, 18.041°, 18.499°, 19.740°, 20.239°, 20.680°, 21.581°, 22.960°, 23.418°, 24.281°, 24.618°, 25.022° , 25.560°, 26.340°, 27.883°, 30.184°, 30.878°, 32.480°, 33.241°, 33.620°, 34.437°, 35.837°.
  • the crystal form A of the compound of formula (I) above has diffraction peaks at the following 2 ⁇ angles in its X-ray powder diffraction pattern: 18.50 ⁇ 0.20°, 20.24 ⁇ 0.20°, also at the following 2 ⁇ angles Have diffraction peaks: 21.58 ⁇ 0.20°, and/or 3.28 ⁇ 0.20°, and/or 3.52 ⁇ 0.20°, and/or 7.78 ⁇ 0.20°, and/or 9.36 ⁇ 0.20°, and/or 10.12 ⁇ 0.20°, and /or 12.12 ⁇ 0.20°, and/or 12.72 ⁇ 0.20°, and/or 13.75 ⁇ 0.20°, and/or 14.32 ⁇ 0.20°, and/or 15.44 ⁇ 0.20°, and/or 18.04 ⁇ 0.20°, and/or 19.74 ⁇ 0.20°, and/or 20.68 ⁇ 0.20°, and/or 22.96 ⁇ 0.20°, and/or 23.42 ⁇ 0.20°, and/or 24.28 ⁇ 0.20°, and/or 24.
  • the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) is basically as shown in FIG. 1 .
  • the differential scanning calorimetry curve of the crystal form A of the compound of formula (I) has an endothermic peak at 173.33 ⁇ 3°C and an exothermic peak at 295.00 ⁇ 3°C.
  • the differential scanning calorimetry curve of the crystal form A of the compound of formula (I) is basically as shown in FIG. 2 .
  • the crystal form A of the compound of formula (I) above has a thermogravimetric analysis curve with a weight loss of 7.780% at 220.000 ⁇ 3°C.
  • thermogravimetric analysis curve of the crystal form A of the compound of formula (I) is basically as shown in FIG. 3 .
  • the present invention provides a compound of formula (II)
  • the present invention provides the crystal form B of the compound of formula (II)
  • the X-ray powder diffraction pattern of the crystal form B of the compound of formula (II) has diffraction peaks at the following 2 ⁇ angles: 6.53 ⁇ 0.20°, 8.63 ⁇ 0.20°, 10.32 ⁇ 0.20°, 10.82 ⁇ 0.20°, 16.20 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form B of the compound of formula (II) has diffraction peaks at the following 2 ⁇ angles: 10.32 ⁇ 0.20°, 10.82 ⁇ 0.20°, 15.73 ⁇ 0.20°, 16.20 ⁇ 0.20°, 23.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form B of the compound of formula (II) has diffraction peaks at the following 2 ⁇ angles: 6.53 ⁇ 0.20°, 8.63 ⁇ 0.20°, 10.32 ⁇ 0.20°, 10.82 ⁇ 0.20°, 15.73 ⁇ 0.20°, 16.20 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form B of the compound of formula (II) has diffraction peaks at the following 2 ⁇ angles: 6.53 ⁇ 0.20°, 8.63 ⁇ 0.20°, 10.32 ⁇ 0.20°, 10.82 ⁇ 0.20°, 15.73 ⁇ 0.20°, 16.20 ⁇ 0.20°, 23.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form B of the compound of formula (II) has diffraction peaks at the following 2 ⁇ angles: 10.32 ⁇ 0.20°, 10.82 ⁇ 0.20°, 15.73 ⁇ 0.20°, 16.20 ⁇ 0.20°, 18.70 ⁇ 0.20°, 20.49 ⁇ 0.20°, 22.89 ⁇ 0.20°, 23.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form B of the compound of formula (II) has diffraction peaks at the following 2 ⁇ angles: 5.39 ⁇ 0.20°, 6.53 ⁇ 0.20°, 8.63 ⁇ 0.20°, 10.32 ⁇ 0.20°, 10.82 ⁇ 0.20°, 14.55 ⁇ 0.20°, 15.73 ⁇ 0.20°, 16.20 ⁇ 0.20°, 18.70 ⁇ 0.20°, 20.49 ⁇ 0.20°, 22.89 ⁇ 0.20°, 23.62 ⁇ 0.20°, 24.46 ⁇ 0.20°, 26.49 ⁇ 0.20°, 29.60 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form B of the compound of formula (II) has diffraction peaks at the following 2 ⁇ angles: 3.541°, 5.390°, 5.950°, 6.532°, 8.633°, 10.317 °, 10.817°, 11.338°, 11.708°, 12.222°, 13.021°, 13.450°, 14.205°, 14.548°, 15.733°, 16.200°, 16.457°, 17.092°, 17.703°, 18.267°, 18.702° , 19.042°, 19.215°, 19.604°, 19.882°, 20.263°, 20.491°, 20.696°, 21.018°, 21.232°, 21.672°, 22.056°, 22.894°, 23.104°, 23.615°, 24.459°, 24.631°, 2 4.969°, 25.155° , 25.963°, 26.485°, 26.9
  • the X-ray powder diffraction pattern of the crystal form B of the compound of formula (II) has diffraction peaks at the following 2 ⁇ angles: 10.32 ⁇ 0.20°, 10.82 ⁇ 0.20°, and at the following 2 ⁇ angles Have diffraction peaks: 16.20 ⁇ 0.20°, and/or 3.54 ⁇ 0.20°, and/or 5.39 ⁇ 0.20°, and/or 5.95 ⁇ 0.20°, and/or 6.53 ⁇ 0.20°, and/or 8.63 ⁇ 0.20°, and /or 11.34 ⁇ 0.20°, and/or 11.71 ⁇ 0.20°, and/or 12.22 ⁇ 0.20°, and/or 13.02 ⁇ 0.20°, and/or 13.45 ⁇ 0.20°, and/or 14.21 ⁇ 0.20°, and/or 14.55 ⁇ 0.20°, and/or 15.73 ⁇ 0.20°, and/or 16.46 ⁇ 0.20°, and/or 17.09 ⁇ 0.20°, and/or 17.70 ⁇ 0.20°, and/or 18.27 ⁇ 0.20°, and
  • the X-ray powder diffraction pattern of the crystal form B of the compound of formula (II) is basically as shown in FIG. 4 .
  • the crystal form B of the above-mentioned compound of formula (II) has an endothermic peak at 94.09 ⁇ 3°C in its differential scanning calorimetry curve, an endothermic peak at 186.92 ⁇ 3°C, and an endothermic peak at 216.35°C There is an exothermic peak at ⁇ 3°C.
  • the differential scanning calorimetry curve of the crystal form B of the compound of formula (II) has an endothermic peak at 186.92 ⁇ 3°C and an exothermic peak at 216.35 ⁇ 3°C.
  • the differential scanning calorimetry curve of the crystal form B of the compound of formula (II) is basically as shown in FIG. 5 .
  • the crystal form B of the compound of the formula (II) has a thermogravimetric analysis curve with a weight loss of 1.094% at 196 ⁇ 3°C.
  • thermogravimetric analysis curve of the crystal form B of the compound of formula (II) is basically as shown in FIG. 6 .
  • the present invention provides a compound of formula (III)
  • the present invention also provides the crystal form C of the compound of formula (III)
  • the crystal form C of the compound of formula (III) above has diffraction peaks at the following 2 ⁇ angles in its X-ray powder diffraction pattern: 6.04 ⁇ 0.20°, 7.10 ⁇ 0.20°, 12.60 ⁇ 0.20°, 16.22 ⁇ 0.20°, 18.08 ⁇ 0.20°, 19.58 ⁇ 0.20°, 21.54 ⁇ 0.20°, 24.00 ⁇ 0.20°.
  • the crystal form C of the compound of formula (III) above has diffraction peaks at the following 2 ⁇ angles in its X-ray powder diffraction pattern: 6.040°, 7.101°, 12.020°, 12.600°, 14.944°, 15.540 °, 16.219°, 17.400°, 18.080°, 18.840°, 19.579°, 20.760°, 21.539°, 22.320°, 23.999°, 27.500°, 31.798°, 34.177°.
  • the X-ray powder diffraction pattern of the crystal form C of the compound of formula (III) is basically as shown in FIG. 8 .
  • the above-mentioned crystal form C of the compound of formula (III) has a differential scanning calorimetry curve with an endothermic peak at 126.90 ⁇ 3°C, an exothermic peak at 213.47 ⁇ 3°C, and an exothermic peak at 350.02 There is an exothermic peak at ⁇ 3°C.
  • the differential scanning calorimetry curve of the crystal form C of the compound of formula (III) is basically as shown in FIG. 9 .
  • the crystal form C of the compound of formula (III) has a thermogravimetric analysis curve with a weight loss of 4.287% at 150.000 ⁇ 3°C.
  • thermogravimetric analysis curve of the crystal form C of the compound of formula (III) is basically as shown in FIG. 10 .
  • the crystal form A of the compound of formula (I), and/or the crystal form B of the compound of formula (II), and/or the crystal form C of the compound of formula (III) Application of drugs in the treatment of breast cancer.
  • the invention has better PK property and oral absorption rate for the compound, and the crystal form is stable, the hygroscopicity is good, and the drug effect is good.
  • rt stands for room temperature
  • THF tetrahydrofuran
  • NMP N-methylpyrrolidone
  • MeSO 3 H stands for methanesulfonic acid
  • DME ethylene glycol dimethyl ether
  • DCM stands for dichloromethane
  • Xphos stands for 2-bicyclohexylphosphine-2'4'6'-triisopropylbiphenyl
  • EtOAc stands for ethyl acetate
  • MeOH stands for methanol
  • acetone stands for acetone
  • 2-Me-THF 2-methyltetrahydrofuran
  • IPA stands for isopropyl alcohol.
  • Weight loss represents weight loss; Weight percent loss represents weight loss percentage; Residue represents residue; Residue percent represents residue percentage; Integral represents total exothermic (endothermic) amount; Normalized represents standard exothermic (endothermic) amount; Peak represents peak value; Onset represents the initial melting temperature; Endset represents the final melting temperature; Left limit represents the left limit temperature; Right limit represents the right limit temperature.
  • Test method About 10-20 mg of sample is used for XRPD detection.
  • Phototube voltage 40kV
  • phototube current 40mA
  • the present invention 's differential thermal analysis (Differential Scanning Calorimeter, DSC) method
  • Test method Take a sample ( ⁇ 1mg) and place it in a DSC aluminum pot for testing. Under the condition of 50mL/min N 2 , heat the sample from 30°C (room temperature) to 300°C (or 350°C) at a heating rate of 10°C/min. °C).
  • Thermogravimetric Analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
  • Test method Take a sample (2 ⁇ 5mg) and place it in a TGA platinum pot for testing. Under the condition of 25mL/min N 2 , at a heating rate of 10°C/min, heat the sample from room temperature to 350°C or lose 20% of its weight.
  • Figure 1 is the XRPD spectrum of (I) compound crystal form A.
  • Fig. 2 is the DSC spectrogram of (I) compound crystal form A.
  • Fig. 3 is the TGA spectrogram of (I) compound crystal form A.
  • Figure 4 is the XRPD spectrum of Form B of compound (II).
  • Figure 5 is the DSC spectrum of Form B of compound (II).
  • Figure 6 is the TGA spectrum of Form B of compound (II).
  • Figure 7 is the DVS spectrum of Form B of compound (II).
  • Figure 8 is the XRPD spectrum of Form C of compound (III).
  • Figure 9 is the DSC spectrum of Form C of compound (III).
  • Figure 10 is the TGA spectrum of Form C of compound (III).
  • Embodiment 1 the preparation of formula (I) compound
  • Step A compound A1 (10 g, 38.01 mmol, 1 eq), compound A2 (15.01 g, 45.61 mmol, 1.2 eq), Pd(t-Bu3P) (971.17 mg, 1.90 mmol, 0.05 eq) DMF (100 mL) was heated to 130°C and stirred for 2 hours. The reaction mixture was cooled to 20°C and potassium fluoride (7 g) was added, and the resulting mixture was stirred at 20°C for 15 minutes. The reaction mixture was filtered, water (100 mL) was added to the filtrate, and extracted with ethyl acetate (100 mL*2).
  • Step B Mix compound A3 (5 g, 22.50 mmol, 1 eq), mercuric sulfate (6.67 g, 22.50 mmol, 1 eq) and sulfuric acid (12 mol/L, 3.75 ml, 2 eq) in acetone (120 ml ) and water (30 ml) was heated to 80°C and stirred for 14 hours. The reaction mixture was concentrated, and water (100 mL) was added to the obtained residue, which was filtered. The filtrate was extracted with dichloromethane (100 mL*5). The combined organic phases were washed with saturated brine (200 mL*2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated.
  • Step C At -30°C, ammonia gas (5.96 g, 350.00 mmol, 31.68 equiv) was bubbled into ethanol (50 mL) to obtain an ammonia gas/ethanol solution (7 mol/L, 50 mL).
  • Compound A4 (2.5 g, 11.05 mmol, 1 eq) was added to the above ammonia/ethanol solution, and the mixture was placed in a 30 ml tank, heated to 130°C (oil bath temperature), and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain compound A5.
  • Step D A solution of compound A5 (1 g, 4.83 mmol, 1 eq) in POCl3 (10 mL) was stirred at 50 °C for 0.5 h. The reaction mixture was diluted with ethyl acetate (50 mL), and the resulting mixture was slowly added dropwise to a stirred mixture of saturated sodium bicarbonate (100 mL) and ethyl acetate (50 mL). The organic phase was washed with saturated brine (100 ml*1), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated.
  • Step E under the protection of nitrogen, compound A6 (875.83 mg, 3.88 mmol, 1 eq), NBS (2.07 g, 11.64 mmol, 3 eq) and AIBN (63.72 mg, 388.05 micromol, 0.1 eq)
  • NBS 2.07 g, 11.64 mmol, 3 eq
  • AIBN 63.72 mg, 388.05 micromol, 0.1 eq
  • the carbon chloride (10 mL) solution was heated to 75°C and stirred for 15 hours.
  • Step G DAST (73.98 mg, 458.94 micromol, 60.64 liter, 2.2 equiv), and the resulting mixture was stirred at 25°C for 1 hour.
  • LCMS (ESI) m/z: 208.1 (M+1); 1 H NMR (400MHz, CDCl 3 ) ⁇ 9.22 (s, 1H), 7.89 (s, 1H), 6.84-6.49 (m, 1H), 2.69 (s,3H).
  • Step H Add compound A10 (152.91 mg, 138 micromol, 3 equiv ) and diisopropylethylamine (177.80 mg, 138 micromoles, 239.62 microliters, 3 equivalents), and the reaction solution was stirred at 100 degrees Celsius for 12 hours under nitrogen protection.
  • the reaction solution was quenched with water (15 mL), extracted twice with ethyl acetate (20 mL), the organic phase was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Dry and concentrate to give a residue.
  • Step I Add sodium tungstate dihydrate (742.23 mg, 2.25 mmol, 0.02 equivalent) to a solution of ethanol (760 ml) containing compound A11 (38 g, 112.51 mmol, 1 equivalent) and heat the system to 80 degrees Celsius , added hydrogen peroxide (38.27 g, 337.53 mmol, 32.43 ml, 30% purity, 3 eq) dropwise at 80° C. and stirred for 2 hours.
  • ethanol 760 ml
  • hydrogen peroxide 38.27 g, 337.53 mmol, 32.43 ml, 30% purity, 3 eq
  • Step J Compound A13 (31.85 g, 148.33 mmol, 1.5 eq) and diisopropylethylamine (19.17 g, 148.33 mmol, 25.84 mL, 1.5 eq) in DMSO (300 mL) were mixed After stirring for 30 minutes, a solution of compound A12 (37 g, 98.88 mmol, 1 eq) in dimethyl sulfoxide (300 ml) was added dropwise into the reaction system, and the temperature was raised to 80° C. and stirred for 3 hours.
  • reaction solution was cooled to 50 degrees Celsius, it was slowly diluted with water (900 ml) and stirred for 30 minutes, filtered, the filter cake was washed with water (100 ml*2 times), dispersed in ethanol (150 ml), stirred at room temperature for 2 hours, and then filtered .
  • the filter cake was washed with tert-butyl methyl ether (50 ml*2 times) to obtain the compound of formula (I), which was detected as crystal form A by XRPD.
  • the XRPD, DSC and TGA spectra of Form A are shown in Figure 1, Figure 2 and Figure 3, respectively.
  • Embodiment 2 Preparation of the crystal form B of the compound of formula (II)
  • Embodiment 3 Preparation of formula (III) compound crystal form C
  • mice male fasting SD rats were used as the experimental animals, and the drug concentration in plasma at different times after the rats were intravenously and intragastrically administered the test compound was determined by LC/MS/MS method. Study the pharmacokinetic behavior of the test compound in rats and evaluate its pharmacokinetic characteristics.
  • Experimental program :
  • mice 4 healthy male SD rats were divided into 2 groups according to the principle of similar body weight, 2 in each group of IV group, and 2 in each group of PO group. Animals were purchased from Beijing Weitong Lihua Experimental Animal Co., Ltd.
  • Group IV Weigh an appropriate amount of samples respectively, prepare a concentration of 0.4 mg/mL, stir and ultrasonically reach a clear state, and the solvent is 10% DMSO, 10% solutol, 80% water.
  • PO group Take an appropriate amount of sample, dilute to 0.5 mg/mL with an appropriate amount of 0.5% hydroxypropyl methylcellulose (HPMC), stir and sonicate to obtain a homogeneous suspension.
  • HPMC hydroxypropyl methylcellulose
  • IV group was administered intravenously, and the dosage of each test compound was 2 mg/kg; PO group was administered intragastrically, respectively, and the dosage of each test compound was 5 mg/kg.
  • the plasma was collected, transferred to a pre-cooled centrifuge tube, snap-frozen in dry ice, and stored in an ultra-low temperature freezer at -60°C or lower until LC-MS/MS analysis was performed. Animals were allowed to eat 4 hours after dosing.
  • the compound of the present invention has a high exposure in rats and exhibits good pharmacokinetic properties.
  • Test animals 4 healthy female Beagle dogs, divided into two groups, two in each group.
  • Group PO-1 Weigh an appropriate amount of sample, dilute it to 0.4 mg/mL with an appropriate amount of 0.5% hydroxypropyl methylcellulose (HPMC, 2600-5600 cps), stir and sonicate to obtain a homogeneous suspension.
  • HPMC hydroxypropyl methylcellulose
  • Group PO-2 Weigh an appropriate amount of sample, dilute it to 2.0 mg/mL with an appropriate amount of 0.5% hydroxypropyl methylcellulose (HPMC, 2600-5600 cps), stir and sonicate to obtain a homogeneous suspension.
  • HPMC hydroxypropyl methylcellulose
  • LC-MS/MS analysis Animals were allowed to eat 4 hours after dosing. LC/MS/MS method was used to determine the content of the test compound in the blood plasma of Beagle dogs after intragastric administration.
  • the compound of the present invention has a high exposure in the dog body and exhibits good pharmacokinetic properties.
  • Cell culture In vitro monolayer culture of human ovarian cancer OVCAR-3 cells, the culture conditions are RPMI 1640 medium plus 10% fetal bovine serum, 100U/mL penicillin and 100 ⁇ g/mL streptomycin, 37 ° C 5% CO 2 incubator nourish. Routine digestion with trypsin-EDTA was performed for passage. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and inoculated.
  • Tumor inoculation 0.2 mL (1 ⁇ 107 cells) of OVCAR-3 cells (plus Matrigel, volume ratio 1:1) were subcutaneously inoculated on the right back of each mouse, and grouping began when the average tumor volume reached about 149 mm medication.
  • Dosage and frequency of administration from day 0 to day 21, 20 mg/kg is administered twice a day; from day 22 to day 35, 20 mg/kg is administered once a day;
  • TGI (%) reflects tumor growth inhibition rate.
  • TGI (%) [1-(Average tumor volume at the end of administration of a certain treatment group-Average tumor volume at the beginning of administration of this treatment group)/(Average tumor volume at the end of treatment of the solvent control group-Average at the beginning of treatment of the solvent control group Tumor Product)] ⁇ 100%.
  • the compound of the present invention has an excellent tumor-inhibiting effect in the human ovarian cancer OVCAR-3 cell subcutaneous xenograft tumor BALB/c nude mouse model.
  • the purpose of this experiment is to evaluate the compounds of the present invention in MCF-7 breast cancer cell xenograft BALB/c nude mice (provided by the Experimental Animal Management Department of Shanghai Institute of Family Planning Science, the number of tested animals in each experimental group is 6 ) antitumor effect in the model.
  • Dosage and frequency of administration from day 0 to day 28, once a day, 20mg/kg or 40mg/kg;
  • mice were subcutaneously inoculated with 0.36 mg, 60-day slow-release estrogen tablets on the left shoulder three days before inoculation.
  • the cells were collected and counted, and the cell concentration was adjusted to 10 ⁇ 10 7 cells/mL, and an equal volume of Matrigel was added and mixed for inoculation.
  • 0.2 mL of MCF-7 tumor cell suspension (10 ⁇ 10 6 ) was inoculated subcutaneously on the right shoulder of each mouse.
  • the average tumor volume was 153-154 mm 3 , and the drugs were administered in groups, once a day.
  • Tumor volume and body weight were measured twice a week after grouping, and the tumor proliferation rate (T/C) and tumor growth inhibition rate (TGI) were calculated for the last tumor measurement data on the 28th day after grouping. Evaluated by TGI (%) or relative tumor proliferation rate T/C (%). TGI (%) reflects tumor growth inhibition rate.
  • the compound of the present invention has excellent antitumor effect in the subcutaneous xenograft tumor BALB/c nude mouse model of human breast cancer MCF7 cells.
  • Cell culture In vitro monolayer culture of human breast cancer HCC1806 cells, the culture condition is RPMI 1640 medium plus 10% fetal bovine blood Clear, 100U/ml penicillin and 100 ⁇ g/ml streptomycin, cultured in a 5% CO 2 incubator at 37°C. Routine digestion with trypsin-EDTA was performed for passage. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and inoculated.
  • mice BALB/c nude mice, female, 6 weeks old, weighing 14-16 grams. Provided by the Experimental Animal Management Department of Shanghai Institute of Family Planning Sciences.
  • Tumor inoculation subcutaneously inoculate 0.2ml (1 ⁇ 106 cells) of HCC1806 cell suspension (plus Matrigel, volume ratio: 1:1) on the right back of each mouse, and start when the average tumor volume reaches about 121mm Dosing in groups.
  • Dosage and frequency of administration from the 0th day to the 21st day, 20mg/kg, administered twice a day; or according to 40mg/kg, administered once a day;
  • TGI (%) reflects tumor growth inhibition rate.
  • TGI (%) [1-(Average tumor volume at the end of administration of a certain treatment group-Average tumor volume at the beginning of administration of this treatment group)/(Average tumor volume at the end of treatment of the solvent control group-Average at the beginning of treatment of the solvent control group Tumor volume)] ⁇ 100%.
  • the compound of the present invention has an excellent tumor-inhibiting effect in the subcutaneous xenograft tumor BALB/c nude mouse model of human breast cancer HCC1806 cells.

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Abstract

一类嘧啶并环类化合物的盐型、晶型及其制备方法，具体公开了式(II)化合物的盐型和晶型在制备治疗相关药物中的应用。

Description

嘧啶并环类化合物的盐型、晶型
本申请主张如下优先权：
CN 202210141771.7，申请日2022年02月16日。
技术领域
本发明涉及一类嘧啶并环类化合物的盐型、晶型及其制备方法，具体涉及式(II)化合物的盐型和晶型在制备治疗相关药物中的应用。
背景技术
细胞周期依赖激酶(CDKs)是在调节真核细胞的分裂和增殖过程中发挥重要作用的一类细胞酶它们参与细胞的增殖，转录等生理过程。临床研究表明多种癌症的发生与细胞周期调控密切相关，例如原癌基因的激活或抑癌基因的失活，往往会使细胞周期的调控发生异常，从而导致细胞的无限增殖和肿瘤的形成，因此诱导细胞周期阻滞可有效抑制肿瘤的生长。根据CDK功能的不同，可以将其分为两大类：1)一类CDK参与细胞周期调控，主要包括CDK1、CDK2、CDK4、CDK6等；2)另一类CDK参与转录调节，主要包括CDK7、CDK8、CDK9、CDK10、CDK11等。这其中，CDK4/6是细胞周期的关键调节因子，其与周期素D cyclin D)结合形成的CDK4/6和cyclin D复合物，可使视网膜母细胞瘤蛋白(Rb)在内的一系列底物磷酸化后释放并激活预先结合的转录因子E2F，使细胞由G1期向S期转变，引起细胞生长增殖，最终导致肿瘤的形成。CDK4/6在多种肿瘤中存在异常活化，因此抑制CDK4/6活性可以抑制肿瘤生长。
作为近些年冉冉升起的抗癌神药，CDK4/6抑制剂正在迅速改变激素受体(HR)阳性、人表皮生长因子受体2(HER2)阴性的晚期和转移性乳腺癌的治疗格局，为晚期患者争取更多的生存时间。然而，但与其他激酶一样，随着时间的推移，这些抑制剂的作用可能会受到原发性和继发性耐药发展的限制。其中，Cyclin E的扩增或高表达是CDK4/6抑制剂产生耐药的一个重要原因(J.Clin.Oncol.2019,37,1148 1150)，且Cyclin E的扩增或过表达与乳腺癌的不良预后密切相关(N.Engl.J.Med,2002,347,15661575)。在HER2+乳腺癌中，同样有报道指出Cyclin E的扩增与曲妥珠单抗的耐药相关(Proc.Natl.Acad.Sci.,2011,108,3671 3676)。Cyclin E的过表达在三阴性乳腺癌(Breast Care,2011,6,273 278)或发炎性乳腺癌Oncotarget,2017,8,14897 14911)进展中也起到重要作用。因此，开发CDK2/4/6抑制剂，可能使得对CDK4/6抑制剂原发性和继发性耐药病人获益。
发明内容
本发明提供式(I)化合物的晶型A
其X射线粉末衍射图谱在下列2θ角处具有衍射峰：18.50±0.20°、20.24±0.20°、21.58±0.20°。
在本发明的一些方案中，上述式(I)化合物的晶型A，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：7.78±0.20°、9.36±0.20°、10.12±0.20°、12.12±0.20°、12.72±0.20°、14.32±0.20°、15.44±0.20°、18.04±0.20°、18.50±0.20°、19.74±0.20°、20.24±0.20°、20.68±0.20°、21.58±0.20°、22.96±0.20°、23.42±0.20°。
在本发明的一些方案中，上述式(I)化合物的晶型A，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：12.72±0.20°、14.32±0.20°、18.04±0.20°、18.50±0.20°、19.74±0.20°、20.24±0.20°、21.58±0.20°、22.96±0.20°。
在本发明的一些方案中，上述式(I)化合物的晶型A，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：3.279°、3.522°、7.779°、9.357°、10.119°、12.122°、12.719°、13.746°、14.318°、15.439°、18.041°、18.499°、19.740°、20.239°、20.680°、21.581°、22.960°、23.418°、24.281°、24.618°、25.022°、25.560°、26.340°、27.883°、30.184°、30.878°、32.480°、33.241°、33.620°、34.437°、35.837°。
在本发明的一些方案中，上述式(I)化合物的晶型A，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：18.50±0.20°、20.24±0.20°，还在下列2θ角处具有衍射峰：21.58±0.20°、和/或3.28±0.20°、和/或3.52±0.20°、和/或7.78±0.20°、和/或9.36±0.20°、和/或10.12±0.20°、和/或12.12±0.20°、和/或12.72±0.20°、和/或13.75±0.20°、和/或14.32±0.20°、和/或15.44±0.20°、和/或18.04±0.20°、和/或19.74±0.20°、和/或20.68±0.20°、和/或22.96±0.20°、和/或23.42±0.20°、和/或24.28±0.20°、和/或24.62±0.20°、和/或25.02±0.20°、和/或25.56±0.20°、和/或26.34±0.20°、和/或27.88±0.20°、和/或30.18±0.20°、和/或30.88±0.20°、和/或32.48±0.20°、和/或33.24±0.20°、和/或33.62±0.20°、和/或34.44±0.20°、和/或35.84±0.20°。
在本发明的一些方案中，上述式(I)化合物的晶型A，其X射线粉末衍射图谱基本上如图1所示。
在本发明的一些方案中，上述式(I)化合物的晶型A，其X射线粉末衍射图谱的解析数据如表1所示：
表1式(I)化合物的晶型A的XRPD图谱解析数据

在本发明的一些方案中，上述式(I)化合物的晶型A，其差示扫描量热曲线在173.33±3℃处具有吸热峰，在295.00±3℃处具有放热峰。
在本发明的一些方案中，上述式(I)化合物的晶型A，其差示扫描量热曲线基本上如图2所示。
在本发明的一些方案中，上述式(I)化合物的晶型A，其热重分析曲线在220.000±3℃处失重达7.780％。
在本发明的一些方案中，上述式(I)化合物的晶型A，其热重分析曲线基本上如图3所示。
本发明提供式(II)化合物
本发明提供式(II)化合物的晶型B
其X射线粉末衍射图谱在下列2θ角处具有衍射峰：10.32±0.20°、10.82±0.20°、16.20±0.20°。
在本发明的一些方案中，上述式(II)化合物的晶型B，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.53±0.20°、8.63±0.20°、10.32±0.20°、10.82±0.20°、16.20±0.20°。
在本发明的一些方案中，上述式(II)化合物的晶型B，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：10.32±0.20°、10.82±0.20°、15.73±0.20°、16.20±0.20°、23.62±0.20°。
在本发明的一些方案中，上述式(II)化合物的晶型B，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.53±0.20°、8.63±0.20°、10.32±0.20°、10.82±0.20°、15.73±0.20°、16.20±0.20°。
在本发明的一些方案中，上述式(II)化合物的晶型B，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.53±0.20°、8.63±0.20°、10.32±0.20°、10.82±0.20°、15.73±0.20°、16.20±0.20°、23.62±0.20°。
在本发明的一些方案中，上述式(II)化合物的晶型B，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：10.32±0.20°、10.82±0.20°、15.73±0.20°、16.20±0.20°、18.70±0.20°、20.49±0.20°、22.89±0.20°、23.62±0.20°。
在本发明的一些方案中，上述式(II)化合物的晶型B，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.39±0.20°、6.53±0.20°、8.63±0.20°、10.32±0.20°、10.82±0.20°、14.55±0.20°、15.73±0.20°、16.20±0.20°、18.70±0.20°、20.49±0.20°、22.89±0.20°、23.62±0.20°、24.46±0.20°、26.49±0.20°、29.60±0.20°。
在本发明的一些方案中，上述式(II)化合物的晶型B，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：3.541°、5.390°、5.950°、6.532°、8.633°、10.317°、10.817°、11.338°、11.708°、12.222°、13.021°、13.450°、14.205°、14.548°、15.733°、16.200°、16.457°、17.092°、17.703°、18.267°、18.702°、19.042°、19.215°、19.604°、19.882°、20.263°、20.491°、20.696°、21.018°、21.232°、21.672°、22.056°、22.894°、23.104°、23.615°、24.459°、24.631°、24.969°、25.155°、25.963°、26.485°、26.939°、27.238°、27.568°、28.175°、29.297°、29.604°、31.133°、32.190°、32.440°、32.797°、33.058°、33.402°、33.955°、35.386°、35.953°、37.088°、38.228°、38.628°、39.344°。
在本发明的一些方案中，上述式(II)化合物的晶型B，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：10.32±0.20°、10.82±0.20°，还在下列2θ角处具有衍射峰：16.20±0.20°、和/或3.54±0.20°、和/或5.39±0.20°、和/或5.95±0.20°、和/或6.53±0.20°、和/或8.63±0.20°、和/或11.34±0.20°、和/或11.71±0.20°、和/或12.22±0.20°、和/或13.02±0.20°、和/或13.45±0.20°、和/或14.21±0.20°、和/或14.55±0.20°、和/或15.73±0.20°、和/或16.46±0.20°、和/或17.09±0.20°、和/或17.70±0.20°、和/或18.27±0.20°、和/或18.70±0.20°、 和/或19.04±0.20°、和/或19.22±0.20°、和/或19.60±0.20°、和/或19.88±0.20°、和/或20.26±0.20°、和/或20.49±0.20°、和/或20.70±0.20°、和/或21.02±0.20°、和/或21.23±0.20°、和/或21.67±0.20°、和/或22.06±0.20°、和/或22.89±0.20°、和/或23.10±0.20°、和/或23.62±0.20°、和/或24.46±0.20°、和/或24.63±0.20°、和/或24.97±0.20°、和/或25.16±0.20°、和/或25.96±0.20°、和/或26.49±0.20°、和/或26.94±0.20°、和/或27.24±0.20°、和/或27.57±0.20°、和/或28.18±0.20°、和/或29.30±0.20°、和/或29.60±0.20°、和/或31.13±0.20°、和/或32.19±0.20°、和/或32.44±0.20°、和/或32.80±0.20°、和/或33.06±0.20°、和/或33.40±0.20°、和/或33.96±0.20°、和/或35.39±0.20°、和/或35.95±0.20°、和/或37.09±0.20°、和/或38.23±0.20°、和/或38.63±0.20°、和/或39.34±0.20°、和/或
在本发明的一些方案中，上述式(II)化合物的晶型B，其X射线粉末衍射图谱基本上如图4所示。
在本发明的一些方案中，上述式(II)化合物的晶型B，其X射线粉末衍射图谱的解析数据如表2所示。
表2式(II)化合物的晶型B的XRPD图谱解析数据

在本发明的一些方案中，上述式(II)化合物的晶型B，其差示扫描量热曲线在94.09±3℃处具有吸热峰，在186.92±3℃处具有吸热峰，在216.35±3℃处具有放热峰。
在本发明的一些方案中，上述式(II)化合物的晶型B，其差示扫描量热曲线在186.92±3℃处具有吸热峰，在216.35±3℃处具有放热峰。
在本发明的一些方案中，上述式(II)化合物的晶型B，其差示扫描量热曲线基本上如图5所示。
在本发明的一些方案中，上述式(II)化合物的晶型B，其热重分析曲线在196±3℃处失重达1.094％。
在本发明的一些方案中，上述式(II)化合物的晶型B，其热重分析曲线基本上如图6所示。
本发明提供式(III)化合物
本发明还提供式(III)化合物的晶型C
其X射线粉末衍射图谱在下列2θ角处具有衍射峰：7.10±0.20°、12.60±0.20°、24.00±0.20°。
在本发明的一些方案中，上述式(III)化合物的晶型C，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.04±0.20°、7.10±0.20°、12.60±0.20°、16.22±0.20°、18.08±0.20°、19.58±0.20°、21.54±0.20°、24.00±0.20°.
在本发明的一些方案中，上述式(III)化合物的晶型C，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.040°、7.101°、12.020°、12.600°、14.944°、15.540°、16.219°、17.400°、18.080°、18.840°、19.579°、20.760°、21.539°、22.320°、23.999°、27.500°、31.798°、34.177°。
在本发明的一些方案中，上述式(III)化合物的晶型C，其X射线粉末衍射图谱基本上如图8所示。
在本发明的一些方案中，上述式(III)化合物的晶型C，其X射线粉末衍射图谱的解析数据如表3所示。
表3式(III)化合物晶型C的XRPD图谱解析数据

在本发明的一些方案中，上述式(III)化合物的晶型C，其差示扫描量热曲线在126.90±3℃处具有吸热峰，在213.47±3℃处具有放热峰，在350.02±3℃处具有放热峰。
在本发明的一些方案中，上述式(III)化合物的晶型C，其差示扫描量热曲线基本上如图9所示。
在本发明的一些方案中，上述式(III)化合物的晶型C，其热重分析曲线在150.000±3℃处失重达4.287％。
在本发明的一些方案中，上述式(III)化合物的晶型C，其热重分析曲线基本上如图10所示。
在本发明的一些方案中，上述式(I)化合物的晶型A、和/或式(II)化合物的晶型B、和/或式(III)化合物的晶型C在制备治疗物在制备治疗乳腺癌药物中的应用。
技术效果
本发明对化合物具有较好的PK性质及口服吸收率，其晶型稳定、引湿性良好、药效良好。
定义和说明
本发明采用下述缩略词：r.t.代表室温；THF代表四氢呋喃；NMP代表N-甲基吡咯烷酮；MeSO3H代表甲烷磺酸；DME代表乙二醇二甲醚；DCM代表二氯甲烷；Xphos代表2-双环己基膦-2’4’6’-三异丙基联苯；EtOAc代表乙酸乙酯；MeOH代表甲醇；acetone代表丙酮；2-Me-THF代表2-甲基四氢呋喃；IPA代表异丙醇。
Weight loss代表失重；Weight percent loss代表失重百分比；Residue代表残余物；Residue percent代表残余物百分比；Integral代表总放热(吸热)量；Normalized代表标准放热(吸热)量；Peak代表峰值；Onset代表初熔温度；Endset代表终熔温度；Left limit代表左极限温度；Right limit代表右极限温度。
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法
仪器型号：布鲁克D8 advance X-射线衍射仪
测试方法：大约10～20mg样品用于XRPD检测。
详细的XRPD参数如下：
光管：Cu,kα,
光管电压：40kV，光管电流：40mA
发散狭缝：0.60mm
探测器狭缝：10.50mm
防散射狭缝：7.10mm
扫描范围：4-40deg
步径：0.02deg
步长：0.12秒
样品盘转速：15rpm
本发明差热分析(Differential Scanning Calorimeter,DSC)方法
仪器型号：TAQ2000差示扫描量热仪
测试方法：取样品(～1mg)置于DSC铝锅内进行测试，在50mL/min N2条件下，以10℃/min的升温速率，加热样品从30℃(室温)到300℃(或350℃)。
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法
仪器型号：TAQ5000IR热重分析仪
测试方法：取样品(2～5mg)置于TGA铂金锅内进行测试，在25mL/min N2条件下，以10℃/min的升温速率，加热样品从室温到350℃或失重20％。
附图说明
图1为(I)化合物晶型A的XRPD谱图。
图2为(I)化合物晶型A的DSC谱图。
图3为(I)化合物晶型A的TGA谱图。
图4为(II)化合物晶型B的XRPD谱图。
图5为(II)化合物晶型B的DSC谱图。
图6为(II)化合物晶型B的TGA谱图。
图7为(II)化合物晶型B的DVS谱图。
图8为(III)化合物晶型C的XRPD谱图。
图9为(III)化合物晶型C的DSC谱图。
图10为(III)化合物晶型C的TGA谱图。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1：式(I)化合物的制备
中间体化合物A9的制备：
步骤A:将化合物A1(10克，38.01毫摩尔，1当量)，化合物A2(15.01克，45.61毫摩尔，1.2当量)，Pd(t-Bu3P)2(971.17毫克，1.90毫摩尔，0.05当量)的DMF(100毫升)加热至130℃搅拌2小时。将反应混合物冷却至20℃并加入氟化钾(7克)，得到的混合物在20℃下搅拌15分钟。将反应混合物过滤，向滤液中加水(100毫升)，用乙酸乙酯(100毫升*2)萃取。将合并的有机相用饱和食盐水(100毫升*2)洗涤，经无水硫酸钠干燥后过滤，滤液浓缩。得到的残余物通过硅胶柱层析(石油醚/乙酸乙酯＝15/1至5/1)纯化，得到化合物A3。1H NMR(400MHz,CDCl3)δ8.66(s,1H),4.04-3.97(m,3H),2.65-2.55(m,3H),2.13(s,3H).LCMS(ESI)m/z:223.4(M+1).
步骤B:将化合物A3(5克，22.50毫摩尔，1当量)，硫酸汞(6.67克，22.50毫摩尔，1当量)和硫酸(12摩尔/升，3.75毫升，2当量)的丙酮(120毫升)和水(30毫升)的混合溶液加热至80℃，搅拌14小时。将反应混合物浓缩，向得到的残余物中加水(100毫升)，过滤。滤液用二氯甲烷(100毫升*5)萃取。将合并的有机相用饱和食盐水(200毫升*2)洗涤，经无水硫酸钠干燥后过滤，滤液浓缩。得到的残余物通过制备高效液相色谱(色谱柱：Phenomenex luna C18 250*50mm*10μm；流动相A：水(含0.05％的盐酸)；流动相B：乙腈；梯度洗脱：0％-30％，18分钟)纯化，得到化合物A4。LCMS(ESI)m/z:227.0(M+1)；1H NMR(400MHz,CDCl3)δ8.54(s,1H),4.29-4.13(m,2H),2.64(s,3H),2.39(s,3H)。
步骤C：在-30℃下，向乙醇(50毫升)中鼓入氨气(5.96克，350.00毫摩尔，31.68当量)得到氨气/乙醇溶液(7摩尔/升，50毫升)。将化合物A4(2.5克，11.05毫摩尔，1当量)加入到上述氨气/乙醇溶液中，将该混合物置于30毫升闷罐中，加热至130℃(油浴温度)，搅拌16小时。将反应混合物减压浓缩，得到化合物A5。LCMS(ESI)m/z:208.1(M+1)。
步骤D：将化合物A5(1克，4.83毫摩尔，1当量)的POCl3(10毫升)溶液在50℃下搅拌0.5小时。 将反应混合物用乙酸乙酯(50毫升)稀释，得到的混合物缓慢滴加至搅拌是饱和碳酸氢钠(100毫升)和乙酸乙酯(50毫升)的混合物中。将有机相用饱和食盐水(100毫升*1)洗涤，经无水硫酸钠干燥后过滤，滤液浓缩。得到的残余物通过制备薄层色谱硅胶板(石油醚/乙酸乙酯＝2/1)纯化，得到化合物A6。LCMS(ESI)m/z:226.8(M+1).
步骤E：在氮气保护下，将化合物A6(875.83毫克，3.88毫摩尔，1当量)，NBS(2.07克，11.64毫摩尔，3当量)和AIBN(63.72毫克，388.05微摩尔，0.1当量)的四氯化碳(10毫升)溶液加热至75℃，搅拌15小时。将反应液浓缩，得到的残余物通过硅胶柱层析(石油醚/乙酸乙酯＝30/1)纯化，得到化合物A7。LCMS(ESI)m/z:306.0(M+1)；1H NMR(400MHz,CDCl3)δ9.22(s,1H),7.75(s,1H),4.68(s,2H),2.78-2.76(m,3H)。
步骤F：向化合物A7(280毫克，919.26微摩尔，1当量)的乙腈(10毫升)溶液中加入NMO(215.37毫克，1.84毫摩尔，194.03微升，2当量)，得到的反应液在25℃下搅拌2小时。向上述反应液中加入亚硫酸钠(0.5克)，并在25℃下搅拌30分钟。将反应液过滤，滤液减压浓缩，得到的残余物通过制备薄层色谱硅胶板(石油醚/乙酸乙酯＝4/1)纯化，得到化合物A8。1H NMR(400MHz,CDCl3)δ10.06(s,1H),9.28(s,1H),8.23(s,1H),2.71(s,3H).LCMS(ESI)m/z:240.1(M+1)。
步骤G：在0℃且在氮气保护下，向化合物A8(50毫克，208.61微摩尔，1当量)的二氯甲烷(1毫升)溶液中缓慢滴加DAST(73.98毫克，458.94微摩尔，60.64微升，2.2当量)，得到的混合物在25℃下搅拌1小时。将反应液直接通过制备薄层色谱硅胶板(石油醚/乙酸乙酯＝5/1)纯化，得到化合物A9。LCMS(ESI)m/z:208.1(M+1)；1H NMR(400MHz,CDCl3)δ9.22(s,1H),7.89(s,1H),6.84-6.49(m,1H),2.69(s,3H)。
式(I)化合物的制备：
步骤H：在20-30摄氏度下，向化合物A9(120毫克，458.58微摩尔，1当量)的二甲基亚砜(4毫升)溶液中依次加入化合物A10(152.91毫克，138微摩尔，3当量)和二异丙基乙基胺(177.80毫克，138微摩尔，239.62微升，3当量)，反应液在氮气保护下于100摄氏度下搅拌12小时。反应液用水(15毫升)淬灭，用乙酸乙酯(20毫升)萃取两次，有机相用饱和食盐水(20毫升)洗涤，无水硫酸钠干 燥，浓缩得到残余物。残余物经柱层析纯化(展开剂：石油醚：乙酸乙酯＝1:0到1:1)得到化合物A11。
步骤I：向含有化合物A11(38克，112.51毫摩尔，1当量)的乙醇(760毫升)溶液中加入二水合钨酸钠(742.23毫克，2.25毫摩尔，0.02当量)后将体系加热到80摄氏度，在80摄氏度下滴加双氧水(38.27克，337.53毫摩尔，32.43毫升，30％纯度，3当量)并搅拌反应2小时。缓慢降温到0摄氏度并搅拌1小时，得到的混悬液过滤，滤饼用冷的乙醇(50毫升*2次)洗涤，滤饼加入300毫升叔丁基甲基醚搅拌1小时后过滤，滤饼用叔丁基甲基醚(100毫升*2次)洗涤得到化合物A12。
步骤J：将含有化合物A13(31.85克，148.33毫摩尔，1.5当量)和二异丙基乙基胺(19.17克，148.33毫摩尔，25.84毫升，1.5当量)的二甲亚砜(300毫升)溶液搅拌30分钟，将化合物A12(37克，98.88毫摩尔，1当量)的二甲亚砜(300毫升)溶液滴加到反应体系中，升温至80摄氏度搅拌3小时。反应液降温至50摄氏度后缓慢用水(900毫升)稀释并搅拌30分钟，过滤，滤饼用水(100毫升*2次)洗涤后分散在乙醇(150毫升)中并在室温下搅拌2小时后过滤。滤饼用叔丁基甲基醚(50毫升*2次)洗涤，得到式(I)化合物，经XRPD检测为晶型A。晶型A的XRPD、DSC和TGA谱图分别如图1、图2和图3所示。LCMS(ESI)m/z:467.1(M+1)+。1H NMR(400MHz,DMSO-d6):δ＝9.14(s,1H),8.80(s,1H),7.96-7.89(m,1H),7.47(s,1H),7.23(s,1H),6.70(t,J＝55.6Hz,1H),4.41-4.28(m,1H),3.75(s,3H),3.59-3.55(m,2H),2.99-2.93(m,2H),2.88(s,3H),2.04-2.00(m,2H),1.84(s,3H),1.64-1.55(m,2H).
实施例2：式(II)化合物的晶型B的制备
取24g的式(I)化合物(50.71毫摩尔，1当量)溶解到240毫升四氢呋喃溶液中并在20摄氏度下搅拌10分钟，过滤除掉不溶物，将含有对甲苯磺酸(9.17克，53.25毫摩尔，1.05当量)的48毫升四氢呋喃溶液滴加到体系中后，在20摄氏度搅拌2小时。然后向体系中加入480毫升叔丁基甲基醚并在20摄氏度下继续搅拌12小时。所得悬浮液过滤，滤饼干燥后得式(II)化合物的晶型B。晶型B的XRPD、DSC、TGA和DVS谱图分别如图4、图5、图6和图7所示。1H NMR(400MHz,DMSO-d6)δ9.15(br s,1H),8.8-9.1(m,2H),7.97(br s,1H),7.4-7.6(m,3H),7.27(br s,1H),7.12(d,2H,J＝7.8Hz),6.5-6.9(m,1H),4.35(br s,1H),3.76(s,3H),3.57(br d,2H,J＝11.8Hz),2.9-3.0(m,2H),2.88(s,3H),2.29(s,3H),2.02(br d,2H,J＝10.8Hz),1.86(s,3H),1.60(q,2H,J＝10.4Hz)
实施例3：式(III)化合物晶型C的制备
称取300毫克式(I)化合物(633.43微摩尔，1当量)溶解于四氢呋喃(9毫升)中，该溶液升温至40摄氏度搅拌10分钟。将含有苯磺酸(105.20毫克，665.10微摩尔，1.05当量)的叔丁基甲基醚(9毫升)溶液滴加至反应体系中，并在15摄氏度搅拌2小时。所得悬浮液过滤，滤饼干燥后得式(III)化合物晶型C。晶型C的XRPD、DSC和TGA谱图分别如图8、图9和图10所示。1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.86(br s,1H),7.94(br s,1H),7.59(dd,2H,J＝2.0,7.5Hz),7.48(s,1H),7.3-7.4(m,3H),7.24(s,1H),6.5-6.9(m,1H),4.34(br s,1H),3.75(s,3H),3.6-3.6(m,2H),2.9-3.0(m,2H),2.89(s,3H),2.02(br d,2H,J＝10.1Hz),1.85 (s,3H),1.5-1.7(m,2H)
生物测试：
实验例1：DMPK性质评价
(1)大鼠体内药代动力学研究
实验目的：以雄性禁食SD大鼠为受试动物，应用LC/MS/MS法测定大鼠静脉和灌胃给与受试化合物后不同时刻血浆中的药物浓度。研究受试化合物在大鼠体内的药代动力学行为，评价其药动学特征。实验方案：
试验动物：健康雄性SD大鼠4只，按照体重相近的原则分成2组，IV组每组2只，PO组每组2只。动物购买自北京维通利华实验动物有限公司。
药物配制：
IV组：分别称取适量样品，配制浓度为0.4mg/mL，搅拌超声后达到澄清状态，溶媒为10％DMSO,10％solutol,80％水。
PO组：取适量样品，用适量0.5％羟丙基甲基纤维素(HPMC)稀释至0.5mg/mL，搅拌超声得到均一混悬液。
给药：禁食一夜后，IV组进行静脉给药，受试化合物的给药剂量各为2mg/kg；PO组分别进行灌胃给药，受试化合物的给药剂量各为5mg/kg。
实验操作：
雄性SD大鼠静脉注射组分别给予受试化合物后，在0.083，0.25，0.5，1，2，4，8，及24小时从颈静脉采血200μL，置于预先加有EDTA-K2的商品化抗凝管中。灌胃给药组分别给予受试化合物后，分别在0.25，0.5，1，2，4，8，12及24小时从颈静脉采血200μL，置于预先加有EDTA-K2的商品化抗凝管中，随后离心处理(3,200g，4℃，10分钟)后取血浆，将血浆转移至预冷的离心管，在干冰中速冻，并储存在-60℃或更低的超低温冰箱中，直到进行LC-MS/MS分析。给药4小时后动物可进食。
表4本发明实施例化合物在大鼠中的药代动力学结果
实验结论：本发明化合物在大鼠体内暴露量高，展现出良好的药代动力学性质。
(2)犬体内药代动力学研究
实验目的：以禁食比格犬为受试动物，应用LC/MS/MS法测定比格犬静脉和灌胃给与受试化合物后不同时刻血浆中的药物浓度。研究受试化合物在比格犬体内的药代动力学行为，评价其药动学特征。实验方案：
试验动物：健康雌性比格犬共4只，分成两组，每组两只。
药物配制：
PO-1组：称取适量样品，用适量0.5％羟丙基甲基纤维素(HPMC，2600-5600cps)稀释至0.4mg/mL，搅拌超声得到均一混悬液。
PO-2组：称取适量样品，用适量0.5％羟丙基甲基纤维素(HPMC，2600-5600cps)稀释至2.0mg/mL，搅拌超声得到均一混悬液。
给药：禁食一夜后，PO-1组分别进行灌胃给药，受试化合物的给药剂量各为2mg/kg。PO-2组分别进行灌胃给药，受试化合物的给药剂量各为10mg/kg。
实验操作：
灌胃给药组分别给予受试化合物后，分别在0.25，0.5，1，2，4，8，及24小时从外周静脉采血200μL，置于预先加有EDTA-K2的商品化抗凝管中，随后离心处理(3,200g，4℃，10分钟)后取血浆，将血浆转移至预冷的离心管，在干冰中速冻，并储存在-60℃或更低的超低温冰箱中，直到进行LC-MS/MS分析。给药4小时后动物可进食。用LC/MS/MS法测定比格犬灌胃给药后，血浆中的受试化合物含量。
表5本发明实施例化合物在比格犬中的药代动力学结果
实验结论：本发明化合物在表格犬体内暴露量高，展现出良好的药代动力学性质。
实验例2：体内药效评价
人卵巢癌OVCAR-3细胞皮下异种移植肿瘤BALB/c裸小鼠模型的体内药效学研究
实验操作：
细胞培养：人卵巢癌OVCAR-3细胞体外单层培养，培养条件为RPMI 1640培养基中加10％胎牛血清，100U/mL青霉素和100μg/mL链霉素，37℃ 5％CO2孵箱培养。用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％，数量到达要求时，收取细胞，计数，接种。
动物：BALB/c裸小鼠，雌性，6-8周龄，体重18-22克。由上海市计划生育科学研究所实验动物经营部(原上海西普尔必凯)提供。
肿瘤接种：将0.2mL(1×107个)OVCAR-3细胞(加基质胶，体积比为1:1)皮下接种于每只小鼠的右后背，肿瘤平均体积达到约149mm3时开始分组给药。
给药剂量和频次:第0天至第21天，20mg/kg，每天两次给药；第22天至第35天，20mg/kg，每天一次给药；
实验指标：实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b2，a和b分别表示肿瘤的长径和短径。
TGI(％)，反映肿瘤生长抑制率。TGI(％)＝[1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体 积)]×100％。
表6式(II)在人卵巢癌OVCAR-3细胞皮下异种移植肿瘤BALB/c裸小鼠模型的药效结果
实验结论：本发明化合物在人卵巢癌OVCAR-3细胞皮下异种移植肿瘤BALB/c裸小鼠模型中有优异的抑瘤效果。
人乳腺癌MCF7细胞皮下异种移植肿瘤BALB/c裸小鼠模型的体内药效学研究
本实验的目的是评价本发明化合物在MCF-7乳腺癌细胞异种移植BALB/c裸小鼠(由上海市计划生育科学研究所实验动物经营部提供，每个实验组的受试动物数为6)模型中的抗肿瘤效果。给药剂量和频次:第0天至第28天，每天一次给药，20mg/kg或者40mg/kg；
小鼠在接种前三天在左侧肩部皮下接种0.36mg，60天缓释雌激素片。当细胞处于对数生长期时，收取细胞并计数，调节细胞浓度至10×107细胞/mL，加入等体积的Matrigel混匀后用于接种。每只小鼠右侧肩部皮下接种0.2mL MCF-7肿瘤细胞混悬液(10×106)。在肿瘤细胞接种后第8天，平均肿瘤体积153-154mm3，进行分组给药，每天给药一次。自分组后每周进行两次肿瘤体积和体重测量，对分组后第28天最后一次量瘤数据进行肿瘤增殖率(T/C)及肿瘤生长抑制率(TGI)的计算，化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％，相对肿瘤增殖率T/C(％)＝TRTV/CRTV×100％(TRTV：治疗组平均RTV；CRTV：阴性对照组平均RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝Vt/V0，其中V0是分组给药时(即D0)测量所得肿瘤体积，Vt为某一次测量时的肿瘤体积，TRTV与CRTV取同一天数据。
表7式(II)在人乳腺癌MCF7细胞皮下异种移植肿瘤BALB/c裸小鼠模型的药效结果
实验结论：本发明化合物在人乳腺癌MCF7细胞皮下异种移植肿瘤BALB/c裸小鼠模型中有优异的抑瘤效果。
人乳腺癌HCC1806细胞皮下异种移植肿瘤BALB/c裸小鼠模型的体内药效学研究
实验操作：
细胞培养：人乳腺癌HCC1806细胞体外单层培养，培养条件为RPMI 1640培养基中加10％胎牛血 清，100U/ml青霉素和100μg/ml链霉素，37℃ 5％CO2孵箱培养。用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％，数量到达要求时，收取细胞，计数，接种。
动物：BALB/c裸小鼠，雌性，6周龄，体重14-16克。由上海市计划生育科学研究所实验动物经营部提供。
肿瘤接种：将0.2ml(1×106个)HCC1806细胞(加基质胶，体积比为1:1)悬液皮下接种于每只小鼠的右后背，肿瘤平均体积达到约121mm3时开始分组给药。
给药剂量和频次:第0天至第21天，20mg/kg，每天两次给药；或按照40mg/kg，每天一次给药；
实验指标：实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b2，a和b分别表示肿瘤的长径和短径。
TGI(％)，反映肿瘤生长抑制率。TGI(％)＝[1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。
表8式(II)在人乳腺癌HCC1806细胞皮下异种移植肿瘤BALB/c裸小鼠模型的药效结果
实验结论：本发明化合物在人乳腺癌HCC1806细胞皮下异种移植肿瘤BALB/c裸小鼠模型中有优异的抑瘤效果。

Claims (10)

  1. 式(II)化合物的晶型B
    其X射线粉末衍射图谱在下列2θ角处具有衍射峰：10.32±0.20°、10.82±0.20°、16.20±0.20°。
  2. 根据权利要求1所述的式(II)化合物的晶型B，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.53±0.20°、8.63±0.20°、10.32±0.20°、10.82±0.20°、16.20±0.20°；或者，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：10.32±0.20°、10.82±0.20°、15.73±0.20°、16.20±0.20°、23.62±0.20°。
  3. 根据权利要求2所述的式(II)化合物的晶型B，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.53±0.20°、8.63±0.20°、10.32±0.20°、10.82±0.20°、15.73±0.20°、16.20±0.20°、23.62±0.20°。
  4. 根据权利要求3所述的式(II)化合物的晶型B，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：3.541°、5.390°、5.950°、6.532°、8.633°、10.317°、10.817°、11.338°、11.708°、12.222°、13.021°、13.450°、14.205°、14.548°、15.733°、16.200°、16.457°、17.092°、17.703°、18.267°、18.702°、19.042°、19.215°、19.604°、19.882°、20.263°、20.491°、20.696°、21.018°、21.232°、21.672°、22.056°、22.894°、23.104°、23.615°、24.459°、24.631°、24.969°、25.155°、25.963°、26.485°、26.939°、27.238°、27.568°、28.175°、29.297°、29.604°、31.133°、32.190°、32.440°、32.797°、33.058°、33.402°、33.955°、35.386°、35.953°、37.088°、38.228°、38.628°、39.344°。
  5. 根据权利要求4所述的式(II)化合物的晶型B，其X射线粉末衍射图谱基本上如图4所示。
  6. 根据权利要求1-5任意一项所述的式(II)化合物的晶型B，其差示扫描量热曲线在186.92±3℃处具有吸热峰，在216.35±3℃处具有放热峰。
  7. 根据权利要求6所述的式(II)化合物的晶型B，其差示扫描量热曲线基本上如图5所示。
  8. 根据权利要求1-5任意一项所述的式(II)化合物的晶型B，其热重分析曲线在196±3℃处失重达1.094％。
  9. 根据权利要求8所述的式(II)化合物的晶型B，其热重分析曲线基本上如图6所示。
  10. 根据权利要求1-9任意一项所述式(II)化合物的晶型B在制备治疗物在制备治疗乳腺癌药物中的应用。
PCT/CN2023/076503 2022-02-16 2023-02-16 嘧啶并环类化合物的盐型、晶型 WO2023155841A1 (zh)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107614499A (zh) * 2015-05-29 2018-01-19 帝人制药株式会社 吡啶并［3，4‑d］嘧啶衍生物及其药学上可允许的盐
CN110036012A (zh) * 2016-11-28 2019-07-19 帝人制药株式会社 吡啶并[3,4-d]嘧啶衍生物及其药学上可接受的盐
WO2022037592A1 (zh) * 2020-08-17 2022-02-24 南京明德新药研发有限公司 嘧啶并环类化合物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107614499A (zh) * 2015-05-29 2018-01-19 帝人制药株式会社 吡啶并［3，4‑d］嘧啶衍生物及其药学上可允许的盐
CN110036012A (zh) * 2016-11-28 2019-07-19 帝人制药株式会社 吡啶并[3,4-d]嘧啶衍生物及其药学上可接受的盐
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