WO2022048545A1 - Forme cristalline de composé de pyridopyrimidine - Google Patents

Forme cristalline de composé de pyridopyrimidine Download PDF

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WO2022048545A1
WO2022048545A1 PCT/CN2021/115784 CN2021115784W WO2022048545A1 WO 2022048545 A1 WO2022048545 A1 WO 2022048545A1 CN 2021115784 W CN2021115784 W CN 2021115784W WO 2022048545 A1 WO2022048545 A1 WO 2022048545A1
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crystal form
compound
ray powder
cancer
formula
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PCT/CN2021/115784
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English (en)
Chinese (zh)
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徐招兵
蔡进峰
胡利红
丁照中
陈曙辉
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勤浩医药（苏州）有限公司
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Priority to CN202180044143.0A priority Critical patent/CN116018343A/zh
Publication of WO2022048545A1 publication Critical patent/WO2022048545A1/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
    • A61K31/495—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to a crystal form of a pyridopyrimidine compound and a preparation method thereof, and also includes the application of the crystal form in the preparation of a drug for treating cancer.
  • RAS protein is the product expressed by the RAS gene, which refers to a class of closely related monomeric globulins composed of 189 amino acids with a molecular weight of 21KDa. It can bind to guanine trinucleotide phosphate (GTP) or guanine dinucleotide phosphate (GDP).
  • GTP guanine trinucleotide phosphate
  • GDP guanine dinucleotide phosphate
  • the active state of RAS protein has effects on cell growth, differentiation, cytoskeleton, protein transport and secretion, and its activity is regulated by binding to GTP or GDP.
  • the RAS protein When the RAS protein binds to GDP, it is in a dormant state, that is, in an "inactive" state; when stimulated by upstream specific cell growth factors, the RAS protein is induced to exchange GDP and bind to GTP, which is called “activation”. condition.
  • the RAS protein bound to GTP can activate downstream proteins for signal transmission.
  • the RAS protein itself has weak hydrolysis GTP hydrolysis activity and can hydrolyze GTP to GDP. In this way, the transition from the activated state to the deactivated state can be achieved. In this hydrolysis process, GAP (GTPase activating proteins, GTP hydrolase activating proteins) is also required. It can interact with RAS protein, greatly promoting its ability to hydrolyze GTP to GDP.
  • RAS protein Mutation of the RAS protein will affect its interaction with GAP, which also affects its ability to hydrolyze GTP to GDP, making it always active. Activated RAS proteins continue to give downstream proteins growth signals, which eventually lead to the continuous growth and differentiation of cells, and ultimately produce tumors.
  • GAP Kirsten rat sarcoma virus oncogene homolog
  • HRAS Harvey rat sarcoma virus oncogene homolog
  • NRAS neuronal Blastoma rat sarcoma virus oncogene homolog
  • the G12C mutation is one of the more common mutations in the KRAS gene, which refers to the mutation of glycine No. 12 to cysteine.
  • KRAS G12C mutation is the most common in lung cancer. According to the data reported in the literature (Nat Rev Drug Discov 2014; 13:828-851), KRAS G12C mutation accounts for about 10% of all lung cancer patients.
  • a covalently bound inhibitor ARS-1620 targeting KRAS G12C mutation the compound It has good metabolic stability, exhibits nM-level cell anti-proliferation activity at the cellular level, and can effectively inhibit tumor growth in the pancreatic cancer MIA-Paca2 cell subcutaneous xenograft tumor model.
  • Amgen's KRAS G12C inhibitor AMG 510 started Phase I clinical recruitment (NCT03600883), which is the first organic small molecule KRAS G12C inhibitor to enter clinical research.
  • the present invention provides a crystal form of compound A of formula (I), the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2 ⁇ angles: 9.96 ⁇ 0.20°, 19.83 ⁇ 0.20°, 22.23 ⁇ 0.20°.
  • the above-mentioned crystal form A its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.96 ⁇ 0.20°, 18.09 ⁇ 0.20°, 19.83 ⁇ 0.20°, 22.23 ⁇ 0.20°, 22.65 ⁇ 0.20°, 24.80 ⁇ 0.20°, 25.78 ⁇ 0.20°, 27.42 ⁇ 0.20°.
  • the above-mentioned A crystal form, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.921°, 9.960°, 11.718°, 15.071°, 15.584°, 17.401°, 18.089°, 18.954°, 19.826°, 22.231°, 22.646°, 23.377°, 24.796°, 25.783°, 27.417°, 29.860°, 30.334°, 30.649°, 32.095°, 33.691°, 35.187°, 38.757°, 39.073°.
  • the present invention provides a crystal form of compound A of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.96 ⁇ 0.20°, 19.83 ⁇ 0.20°, and also 22.23 ⁇ 0.20°, and/or 5.92 ⁇ 0.20°, and/or 11.72 ⁇ 0.20°, and/or 15.07 ⁇ 0.20°, and/or 15.58 ⁇ 0.20°, and/or 17.40 ⁇ 0.20°, and/or 18.09 ⁇ 0.20°, and/or 18.95 ⁇ 0.20° , and/or 22.65 ⁇ 0.20°, and/or 23.38 ⁇ 0.20°, and/or 24.80 ⁇ 0.20°, and/or 25.78 ⁇ 0.20°, and/or 27.42 ⁇ 0.20°, and/or 29.86 ⁇ 0.20°, and /or 30.33 ⁇ 0.20°, and/or 30.65 ⁇ 0.20°, and/or 32.10 ⁇ 0.20°, and/or 33.69 ⁇ 0.20°, and/or 35.
  • the XRPD pattern of the above-mentioned crystal form A is shown in FIG. 1 .
  • the above-mentioned crystal form A the differential scanning calorimetry curve of which has an onset of an endothermic peak at 249.10 ⁇ 5°C.
  • the above-mentioned crystal form A the differential scanning calorimetry curve of which has an onset of an endothermic peak at 249.10 ⁇ 3°C.
  • the DSC spectrum of the above-mentioned crystal form A is shown in FIG. 2 .
  • the above-mentioned crystal form A has a weight loss of 0.05409% in the thermogravimetric analysis curve at 120.17 ⁇ 3°C.
  • the above-mentioned crystal form A its TGA spectrum is shown in FIG. 3 .
  • the present invention also provides compounds of formula (II)
  • the present invention also provides compound B crystal form of formula (II), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 10.16 ⁇ 0.20°, 17.75 ⁇ 0.20°, 24.32 ⁇ 0.20°.
  • the above-mentioned crystal form B its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 10.16 ⁇ 0.20°, 17.75 ⁇ 0.20°, 19.25 ⁇ 0.20°, 19.98 ⁇ 0.20°, 22.59 ⁇ 0.20°, 23.06 ⁇ 0.20°, 24.32 ⁇ 0.20°, 30.71 ⁇ 0.20°.
  • the above-mentioned crystal form B its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 4.105°, 8.800°, 10.164°, 11.633°, 13.060°, 14.973°, 15.324°, 16.274°, 16.613°, 17.102°, 17.752°, 18.107°, 19.034°, 19.254°, 19.983°, 20.912°, 22.586°, 23.060°, 24.322°, 24.698°, 25.681°, 26.157°, 27.216° , 28.262°, 28.627°, 29.353°, 30.277°, 30.711°, 32.386°, 33.335°, 34.139°, 35.010°, 35.448°, 35.859°, 36.608°, 37.976°.
  • the present invention provides compound B crystal form of formula (I), the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2 ⁇ angles: 10.16 ⁇ 0.20°, 17.75 ⁇ 0.20°, and also 24.32 ⁇ 0.20°, and/or 4.11 ⁇ 0.20°, and/or 8.80 ⁇ 0.20°, and/or 11.63 ⁇ 0.20°, and/or 13.06 ⁇ 0.20°, and/or 14.97 ⁇ 0.20°, and/or 15.32 ⁇ 0.20°, and/or 16.27 ⁇ 0.20° , and/or 16.61 ⁇ 0.20°, and/or 17.10 ⁇ 0.20°, and/or 18.11 ⁇ 0.20°, and/or 19.03 ⁇ 0.20°, and/or 19.25 ⁇ 0.20°, and/or 19.98 ⁇ 0.20°, and /or 20.91 ⁇ 0.20°, and/or 22.59 ⁇ 0.20°, and/or 23.06 ⁇ 0.20°, and/or 24.70 ⁇ 0.20°, and/or 25.68 ⁇ 0.20°, and/
  • the XRPD pattern of the above-mentioned crystal form B is shown in FIG. 4 .
  • the above-mentioned crystal form B its differential scanning calorimetry curve has an onset of an endothermic peak at 253.00 ⁇ 5°C.
  • the above-mentioned crystal form B its differential scanning calorimetry curve has an onset of an endothermic peak at 253.00 ⁇ 3°C.
  • the DSC spectrum of the above-mentioned crystal form B is shown in FIG. 5 .
  • the above-mentioned crystal form B its thermogravimetric analysis curve has a weight loss of 0.4116% at 150.14 ⁇ 3°C.
  • the above-mentioned crystal form B its TGA spectrum is shown in FIG. 6 .
  • the present invention provides the compound of formula (I) p-toluenesulfonate salt form C, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 19.57 ⁇ 0.20°, 21.56 ⁇ 0.20°, 24.01 ⁇ 0.20°.
  • the above crystal form C its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 12.17 ⁇ 0.20°, 15.78 ⁇ 0.20°, 16.69 ⁇ 0.20°, 19.57 ⁇ 0.20°, 21.56 ⁇ 0.20°, 24.01 ⁇ 0.20°, 25.02 ⁇ 0.20°, 34.80 ⁇ 0.20°.
  • the above-mentioned crystal form C its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.030°, 12.169°, 13.194°, 14.399°, 15.332°, 15.779°, 16.055°, 16.496°, 16.687°, 18.996°, 19.289°, 19.567°, 20.556°, 20.987°, 21.562°, 21.897°, 22.864°, 24.006°, 24.281°, 25.018°, 26.433°, 28.397°, 28.82° , 31.066°, 31.773°, 31.935°, 34.795°.
  • the present invention provides compound C of formula (I), the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2 ⁇ angles: 19.57 ⁇ 0.20°, 21.56 ⁇ 0.20°, and also 24.01 ⁇ 0.20°, and/or 8.03 ⁇ 0.20° 0.20°, and/or 12.17 ⁇ 0.20°, and/or 13.19 ⁇ 0.20°, and/or 14.40 ⁇ 0.20°, and/or 15.33 ⁇ 0.20°, and/or 15.78 ⁇ 0.20°, and/or 16.06 ⁇ 0.20° , and/or 16.50 ⁇ 0.20°, and/or 16.69 ⁇ 0.20°, and/or 19.00 ⁇ 0.20°, and/or 19.29 ⁇ 0.20°, and/or 20.56 ⁇ 0.20°, and/or 20.99 ⁇ 0.20°, and /or 21.90 ⁇ 0.20°, and/or 22.86 ⁇ 0.20°, and/or 24.28 ⁇ 0.20°, and/or 25.02 ⁇ 0.20°, and/or 26.43 ⁇ 0.20°
  • the X-ray powder diffraction pattern of the above crystal form C is shown in FIG. 7 .
  • the above-mentioned crystal form C the differential scanning calorimetry curve of which has an onset of an endothermic peak at 262.38 ⁇ 5°C.
  • the above-mentioned crystal form C the differential scanning calorimetry curve of which has an onset of an endothermic peak at 262.38 ⁇ 3°C.
  • the DSC spectrum of the above-mentioned crystal form C is shown in FIG. 8 .
  • the above-mentioned crystal form C its thermogravimetric analysis curve has a weight loss of 1.542% at 146.27 ⁇ 3°C.
  • the above-mentioned crystal form C its TGA spectrum is shown in FIG. 9 .
  • the present invention provides the compound of formula (I) hydrochloride salt form D, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 17.50 ⁇ 0.20°, 24.50 ⁇ 0.20°, 25.21 ⁇ 0.20°.
  • the above-mentioned crystal form D its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 16.39 ⁇ 0.20°, 17.50 ⁇ 0.20°, 19.49 ⁇ 0.20°, 19.96 ⁇ 0.20°, 22.09 ⁇ 0.20°, 24.50 ⁇ 0.20°, 25.21 ⁇ 0.20°, 27.85 ⁇ 0.20°.
  • the above-mentioned crystal form D its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.742°, 10.435°, 11.853°, 16.392°, 16.927°, 17.499°, 18.248°, 19.487°, 19.958°, 20.317°, 22.091°, 23.558°, 24.498°, 25.207°, 26.215°, 27.851°, 28.506°, 29.667°, 34.121°, 37.360°.
  • the present invention provides a crystalline form of compound D of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 17.50 ⁇ 0.20°, 24.50 ⁇ 0.20°, and also 25.21 ⁇ 0.20°, and/or 6.74 ⁇ 0.20°, and/or 10.44 ⁇ 0.20°, and/or 11.85 ⁇ 0.20°, and/or 16.39 ⁇ 0.20°, and/or 16.93 ⁇ 0.20°, and/or 18.25 ⁇ 0.20°, and/or 19.49 ⁇ 0.20° , and/or 19.96 ⁇ 0.20°, and/or 20.32 ⁇ 0.20°, and/or 22.09 ⁇ 0.20°, and/or 23.56 ⁇ 0.20°, and/or 26.22 ⁇ 0.20°, and/or 27.85 ⁇ 0.20°, and Characteristic diffraction peaks at 28.51 ⁇ 0.20°, and/or 29.67 ⁇ 0.20°, and/or 34.12 ⁇ 0.20°, and/or 37.36 ⁇ 0.20
  • the X-ray powder diffraction pattern of the above-mentioned D crystal form is shown in FIG. 10 .
  • the above-mentioned crystal form D the differential scanning calorimetry curve of which has an onset of an endothermic peak at 171.38 ⁇ 5°C.
  • the above-mentioned crystal form D its differential scanning calorimetry curve has an onset of an endothermic peak at 171.38 ⁇ 3°C.
  • the DSC spectrum of the above-mentioned D crystal form is shown in FIG. 11 .
  • the above-mentioned crystal form D its thermogravimetric analysis curve has a weight loss of 0.7461% at 99.76 ⁇ 3°C, and a weight loss of 5.3141% at 169.75 ⁇ 3°C.
  • the TGA pattern of the above-mentioned D crystal form is shown in FIG. 12 .
  • the present invention also provides the above-mentioned formula (I) compound A crystal form, formula (II) compound B crystal form, formula (I) compound p-toluenesulfonate salt crystal form C and formula (I) compound hydrochloride salt crystal form D in preparation Application in the treatment of cancer drugs.
  • the aforementioned cancers include lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer , cholangiocarcinoma, breast cancer, colon cancer, leukemia and melanoma.
  • the compound of the present invention has good PK property and oral absorption rate, its crystal form is relatively stable, its solubility is good, its hygroscopicity is appropriate, and it is less affected by light and heat, and has good druggability.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • rt stands for room temperature
  • THF tetrahydrofuran
  • CDI carbonyldiimidazole
  • DCM dichloromethane
  • DMF N,N-dimethylformamide
  • MeOH stands for methanol
  • MsOH methanesulfonic acid
  • acetone stands for acetone
  • NIS stands for N-iodosuccinimide
  • HPLC high performance liquid chromatography
  • TLC stands for thin layer chromatography.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • SXRD single crystal X-ray diffractometry
  • the cultivated single crystal is collected by Bruker D8venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning method is as follows: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • Tube voltage 40kV
  • tube current 40mA
  • Test conditions Take a sample (0.5-1 mg) and place it in a DSC aluminum pot for testing.
  • Test conditions take a sample (2-5 mg) and place it in a TGA platinum pot for testing.
  • Fig. 1 is the XRPD spectrum of compound A of formula (I).
  • Figure 2 is the DSC spectrum of the crystal form of compound A of formula (I).
  • Figure 3 is a TGA spectrum of the crystal form of compound A of formula (I).
  • Fig. 4 is the XRPD spectrum of the crystal form of compound B of formula (II).
  • Figure 5 is the DSC spectrum of the crystalline form of compound B of formula (II).
  • Figure 6 is a TGA spectrum of the crystalline form of compound B of formula (II).
  • Figure 7 is the XRPD spectrum of the compound of formula (I) p-toluenesulfonate salt form C.
  • Figure 8 is the DSC spectrum of the compound of formula (I) p-toluenesulfonate salt form C.
  • Figure 9 is the TGA spectrum of the compound of formula (I) p-toluenesulfonate salt form C.
  • Figure 10 is the XRPD spectrum of the compound of formula (I) hydrochloride salt form D.
  • Fig. 11 is the DSC spectrum of the crystalline form D of the compound of formula (I) hydrochloride.
  • Figure 12 is the TGA spectrum of the compound of formula (I) hydrochloride salt form D.
  • Figure 13 is an ellipsoid diagram of the three-dimensional structure of the compound of formula (I).
  • the reaction mixture was filtered, the filter cake was washed with ethyl acetate (2 L), the filtrate was concentrated under reduced pressure, the obtained residue was diluted with ethyl acetate (2 L), followed by water (8 L) and saturated brine (6 L) ), the organic phase was dried over anhydrous sodium sulfate and filtered, the filter cake was washed with ethyl acetate (2 L), and the filtrate was concentrated under reduced pressure.
  • the resulting crude product was dispersed in methyl tert-butyl ether (10 L) and stirred at 25°C for 16 hours.
  • the reaction mixture was filtered, and the filter cake was dried in a vacuum drying oven (50°C, -0.1 MPa) for 16 hours to obtain compound 5.
  • the reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate (20 liters) and water (10 liters), the pH of the aqueous phase was adjusted to 2 with 2 mol/liter aqueous hydrochloric acid, and the separated organic phase was used Washed with saturated brine (5L*2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to obtain a crude product dispersed in a mixed solution of ethanol (2L) and methyl tert-butyl ether (2L) , and stirred at 20°C for 1 hour.
  • Zinc powder (20.36 g, 311.38 mmol), DPPF (69.04 g, 124.56 mmol), Pd 2 (dba) 3 (57.02 g, 62.28 mmol) were added to the reaction system, and the above mixture was heated to 110 °C with stirring 15 hours.
  • To the reaction system was added zinc powder (6 g, 91.76 mmol), DPPF (10 g, 19.84 mmol), zinc cyanide (50 g, 425.80 mmol), Pd 2 (dba) 3 (10 g, 10.92 mmol), the above mixture was further stirred at 110°C for 4 hours. The reaction mixture was cooled to 40°C and filtered.
  • the XRPD spectrum of the crystal form of compound A of formula (I) is shown in FIG. 1
  • the DSC spectrum is shown in FIG. 2
  • the TGA spectrum is shown in FIG. 3 .
  • the XRPD spectrum of the crystal form of compound B of formula (II) is shown in Fig. 4
  • the DSC spectrum is shown in Fig. 5
  • the TGA spectrum is shown in Fig. 6 .
  • Test conditions Take a sample (10-15 mg) and place it in the DVS sample tray for testing.
  • the hygroscopicity evaluation classification is shown in Table 5.
  • Hygroscopic classification Moisture gain weight* deliquescence Absorbs enough water to form a liquid Very hygroscopic ⁇ W% ⁇ 15% hygroscopic 15%> ⁇ W% ⁇ 2% slightly hygroscopic 2%> ⁇ W% ⁇ 0.2% No or almost no hygroscopicity ⁇ W% ⁇ 0.2%
  • the hygroscopic weight gain of compound B of formula (II) is 1.53%, and the hygroscopic weight gain of compound of formula (I) hydrochloride crystalline form D is 3.54%; the compound of formula (I) The hygroscopic weight gain of p-toluenesulfonate salt form C was 2.48%.
  • the crystal form of compound B of formula (II) is slightly hygroscopic.
  • Test item X includes: content and related substances; X* refers to the test items of the 0-day sample (including content and related substances), and X* will be used as a reference for sampling and testing at different time points in the later period; N/A means no sampling.
  • N/A means not detected.
  • Example 8 Solubility experiment of crystalline form simulating gastrointestinal fluid
  • FaSSIF simulates the intestinal fluid in the small intestine in the state of human pre-prandial starvation
  • FeSSIF simulates the intestinal fluid in the small intestine of humans in a state of satiety after a meal
  • SGF Simulates the gastric juice of empty stomach in human starvation state
  • the crystal form of compound B of formula (II) has better solubility, which is about 9 times higher than that of crystal form of compound A of formula (I) in water.
  • crystals of the compound of formula (I) are obtained by culturing at room temperature for 10 days under the condition of ethanol using a solvent evaporation method.
  • Multi-labeled microplate detector Envision, cell culture flask, 384 cell culture microplate, Vi-cell XR cell viability analyzer, CO2 incubator, 300 ⁇ L 12-channel electric pipette, Echo ultrasonic nano-upgrade liquid workstation
  • rows A, P, 1, 24 Add 40 ⁇ L of phosphate buffer to each well of the column, then place the cell plate back into the carbon dioxide incubator for 5 days. Add 20 ⁇ l of Promega CellTiter-Glo reagent per well to the cell plate, shake at room temperature in the dark for 10 minutes to stabilize the luminescence signal. Readings were performed on a PerkinElmer Envision multi-label analyzer.
  • the data of the antiproliferative activity IC50 of the compounds of the present invention on NCI-H358 (G12C mutant) cells, A375 (wild type) cells and MIA PaCa2 (G12C mutant) cells are shown in Table 11-1.
  • the compound of the present invention shows high cell anti-proliferation activity on KRAS G12C mutant cells NCI-H358 and MIA PaCa2, and at the same time has weak anti-proliferative activity on wild-type A375 cells, showing high selectivity.
  • mice Male SD rats were used as the test animals, and LC/MS/MS method was used to determine the drug concentrations in the plasma of rats at different times after intravenous and intragastric administration of the test compounds. To study the pharmacokinetic behavior of test compounds in rats, and to evaluate their pharmacokinetic characteristics.
  • Experimental scheme Experimental animals: 10 healthy adult male SD rats were divided into 4 groups according to the principle of similar body weight, with 2 rats in each group of IV group (two groups) and 3 rats in each group of PO group (two groups). Animals were purchased from Beijing Weitong Lihua Laboratory Animal Co., Ltd.
  • Group IV Weigh an appropriate amount of sample, add appropriate amount of DMSO, PEG400 and water in turn according to the volume ratio of 10:60:30, and then stir and ultrasonicate to reach a clear state of 1.5 mg/mL.
  • PO group Weigh an appropriate amount of sample, add an appropriate amount of DMSO, PEG400 and water in turn according to the volume ratio of 10:60:30, and after stirring and ultrasonicating, it reaches a clear state of 1.0 mg/mL.
  • the IV group was administered intravenously with a volume of 2 mL/kg and a dose of 3 mg/kg; the PO group was administered by intragastric administration with a volume of 10 mL/kg and a dose of 10 mg/kg.
  • test compounds Male SD rats in the intravenous injection group were given the test compounds, and 200 ⁇ L of blood was collected at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, and placed in a commercial pre-filled EDTA-K 2 in the anticoagulant tube. After the test compound was administered to the gavage group, 200 ⁇ L of blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, respectively, and placed in a commercial anticoagulation tube pre-filled with EDTA-K 2 middle. The tubes were centrifuged for 15 minutes to separate plasma and stored at -60°C. Animals were allowed to eat 2 hours after dosing. The content of the test compounds in the plasma of rats after intravenous and intragastric administration was determined by LC/MS/MS. The linear range of the method was 2.00-6000 nM; plasma samples were analyzed after acetonitrile precipitation of proteins.
  • the compound of the present invention showed higher exposure and better oral availability than the reference compound ARS-1620.
  • test compounds The in vivo efficacy of the test compounds on the human non-small cell lung cancer NCI-H358 subcutaneous xenograft tumor model was evaluated.
  • mice Female, 6-8 weeks old, weighing 18-21 grams. A total of 100 are required. Provided by Shanghai Lingchang Laboratory Animal Co., Ltd.
  • TGI (%) The tumor-inhibitory efficacy of the compounds was evaluated by TGI (%).
  • TGI (%) reflecting tumor growth inhibition rate.
  • Calculation of TGI (%): 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 in the solvent control group) - Average tumor volume at the start of treatment in the solvent control group)] ⁇ 100%.
  • the compounds of the present invention show good in vivo efficacy in the human non-small cell lung cancer NCI-H358 subcutaneous xenograft tumor model. Twenty days after the start of administration, the compounds of the present invention had stronger antitumor effects than the reference compound ARS-1620.
  • test compounds The in vivo efficacy of test compounds was evaluated in a human pancreatic cancer x-MIA-PaCa2 cell subcutaneous xenograft tumor model.
  • NU/NU mice female, 6-8 weeks old, weighing 17-20 grams. A total of 100 animals are required (30% more animals vaccinated).
  • TGI (%) The tumor-inhibitory efficacy of the compounds was evaluated by TGI (%).
  • TGI (%) reflecting tumor growth inhibition rate.
  • Calculation of TGI (%): 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 in the solvent control group) - Average tumor volume at the start of treatment in the solvent control group)] ⁇ 100%.
  • the compounds of the present invention show good in vivo efficacy in human pancreatic cancer x-MIA-PaCa2 cell subcutaneous xenograft tumor model. 14 days after the start of administration, the compound of the present invention has stronger antitumor effect than the reference compound ARS-1620.
  • TGI (%) The tumor-inhibitory efficacy of the compounds was evaluated by TGI (%).
  • TGI (%) reflecting tumor growth inhibition rate.
  • Calculation of TGI (%): 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 in the solvent control group) - Average tumor volume at the start of treatment in the solvent control group)] ⁇ 100%.
  • the compounds of the present invention can dose-dependently inhibit the growth of subcutaneously transplanted tumors of human lung cancer NCI-H358 cells in tumor-bearing mice, show significant antitumor activity, and are well tolerated by animals. Compared with the control compound ARS-1620 at the same dose, the compound of the present invention has better antitumor activity.
  • the compounds of the present invention (5, 15, 45 mg/kg, PO, QD ⁇ 4W) can dose-dependently inhibit the growth of human lung cancer LU-01-0030 xenograft mouse model tumor, show significant anti-tumor activity, and Animals tolerated well.
  • the compound of the present invention has a significant inhibitory effect on the tumor growth of MIA PaCa-2 human pancreatic cancer tumor model in a dose-dependent manner; and at the same dose, the compound of the present invention can significantly inhibit the growth of MIA PaCa-2 human pancreatic cancer. Better than ARS-1620.

Abstract

L'invention concerne une forme cristalline d'un composé de pyridopyrimidine et son procédé de préparation, ainsi que l'utilisation de la forme cristalline dans la préparation d'un médicament pour le traitement du cancer.
PCT/CN2021/115784 2020-09-01 2021-08-31 Forme cristalline de composé de pyridopyrimidine WO2022048545A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018064510A1 (fr) * 2016-09-29 2018-04-05 Araxes Pharma Llc Inhibiteurs de protéines mutantes kras g12c
WO2019141250A1 (fr) * 2018-01-19 2019-07-25 南京明德新药研发股份有限公司 Dérivé de pyridone-pyrimidine agissant en tant qu'inhibiteur de mutéine krasg12c

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018064510A1 (fr) * 2016-09-29 2018-04-05 Araxes Pharma Llc Inhibiteurs de protéines mutantes kras g12c
WO2019141250A1 (fr) * 2018-01-19 2019-07-25 南京明德新药研发股份有限公司 Dérivé de pyridone-pyrimidine agissant en tant qu'inhibiteur de mutéine krasg12c

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