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WO2021197339A1 - Forme cristalline de composé de quinopyrrolidine-2-one servant d'inhibiteur d'atm et son utilisation - Google Patents

Forme cristalline de composé de quinopyrrolidine-2-one servant d'inhibiteur d'atm et son utilisation Download PDF

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WO2021197339A1
WO2021197339A1 PCT/CN2021/084062 CN2021084062W WO2021197339A1 WO 2021197339 A1 WO2021197339 A1 WO 2021197339A1 CN 2021084062 W CN2021084062 W CN 2021084062W WO 2021197339 A1 WO2021197339 A1 WO 2021197339A1
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crystal form
compound
formula
angles
ray powder
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钱文远
杨纯道
代国强
黎健
陈曙辉
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Medshine Discovery Inc
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Medshine Discovery Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • the invention relates to a crystal form of a quinopyrrolidin-2-one compound as an ATM inhibitor and a preparation method thereof, and its application in the preparation of a medicine for treating diseases related to solid tumors.
  • Ataxia telangiectasia mutated gene is an autosomal recessive genetic gene, homozygous shows a progressive neurodegenerative disease, the patient is about 1 year old, showing the cerebellum Sexual ataxia, tumor-like small blood vessels dilated in the eyes, face and neck around 6 years old, and often died of infection.
  • ATM gene is an important gene related to DNA damage repair, so patients generally show that they are particularly sensitive to X-rays and their DNA repair ability is significantly reduced. Approximately 1% of humans are heterozygous for ATM mutant genes. Although they do not show disease, they also increase the risk of cancer.
  • the ATM gene is located on chromosome 11q22-q23, with a total length of 150kb, a coding sequence of 12kb, and a total of 66 exons. It is one of the human genes with the most exons found so far, and one of the most important genes. Kind of nursing gene.
  • ATM protein which is a serine/threonine protein kinase containing 3056 amino acids and a relative molecular weight of 370,000. It is mainly located in the nucleus and microsomes, and is involved in the progress of the cell cycle and the cell cycle checkpoint for DNA damage. reaction.
  • ATM protein kinase belongs to the phosphatidylinositol 3-kinase-related kinase family (PIKK). It is an autophosphorylated protein and usually exists in the form of an inactive dimer. When a double-strand break occurs in DNA, ATM protein kinase is phosphorylated and depolymerized within a few minutes at the earliest, and the phosphorylated ATM protein kinase reaches its maximum in 2 to 3 hours.
  • PIKK phosphatidylinositol 3-kinase-related kinase family
  • the signaling pathways of ATM protein in DNA damage repair mainly include: 1ATM-CHK2-Cdc25A/B/C signaling pathway; 2ATM-CHK2-p53 signaling pathway; 3ATM-Nbs1-Smc1/3 signaling pathway; 4ATM-p38MAPK-MK2 signaling path.
  • M means MRE11 (meiotic recombinant protein) has nuclease activity and the ability to bind DNA; R is Rad50 has ATPase activity; N It means that NBS1 is involved in the localization of the complex in the nucleus and helps its normal assembly at DNA breakpoints.
  • the various proteins in the MRN complex must coordinate with each other to adjust the ATM protein to bind to the broken end of the DNA and help the broken DNA to complete the repair.
  • ATM plays a key role in the repair of DNA double-strand breaks. Since the probability of double-strand breaks in normal cells is relatively small, selective ATM inhibitors have little effect when used alone, but because ATM is the entire DNA damage repair pathway
  • the key link of ATM inhibitors is that there are many possible combinations of ATM inhibitors. At present, it has been combined with radiotherapy, combined with chemotherapy, and other target inhibitors such as PARP inhibitors for DNA damage repair in preclinical and clinical studies. The combination and so on.
  • AstraZeneca’s AZD0156 is the first compound to enter Phase I clinical studies. At present, AZD1390 and Merck’s M-3541 have also entered Phase I clinical studies.
  • ATM kinase inhibitors are used to treat related diseases as solid tumors, where the solid tumors include but are not limited to: lung cancer, breast cancer, head and neck cancer, prostate cancer, lymphoma, ovarian cancer, cell carcinoma, esophageal cancer, leukemia, Bladder cancer, stomach cancer, melanoma, urothelial cancer, brain tumor, colorectal cancer, liver cancer, mesothelioma, intrahepatic cholangiocarcinoma, etc.
  • the present invention provides crystal form A of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 4.96 ⁇ 0.20°, 14.85 ⁇ 0.20°, 20.51 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 4.96 ⁇ 0.20°, 12.74 ⁇ 0.20°, 14.85 ⁇ 0.20°, 18.00 ⁇ 0.20°, 19.86 ⁇ 0.20°, 20.51 ⁇ 0.20°, 21.14 ⁇ 0.20°, 29.19 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 4.96 ⁇ 0.20°, 12.74 ⁇ 0.20°, 14.85 ⁇ 0.20°, 18.00 ⁇ 0.20°, 19.86 ⁇ 0.20°, 20.51 ⁇ 0.20°, 21.14 ⁇ 0.20°, 23.76 ⁇ 0.20°, 24.89 ⁇ 0.20°, 29.19 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction at the following 2 ⁇ angles: 4.96°, 12.74°, 14.53°, 14.85°, 17.63°, 18.00°, 19.86°, 20.51° , 22.14°, 23.76°, 24.50°, 24.89°, 27.96°, 28.22°, 29.19°.
  • the XRPD pattern of the above-mentioned crystal form A is shown in FIG. 1.
  • the XRPD pattern analysis data of the above-mentioned crystal form A is shown in Table 1:
  • the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 178.69 ⁇ 3.0°C.
  • the DSC spectrum of the above-mentioned crystal form A is shown in FIG. 2.
  • thermogravimetric analysis curve of the above-mentioned crystal form A has a weight loss of 0.2038% at 178.29°C ⁇ 3.0°C.
  • the TGA pattern of the above-mentioned crystal form A is shown in FIG. 3.
  • the present invention also provides the B crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 19.19 ⁇ 0.20°, 21.76 ⁇ 0.20°, 22.39 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.94 ⁇ 0.20°, 9.35 ⁇ 0.20°, 15.47 ⁇ 0.20°, 16.35 ⁇ 0.20°, 19.19 ⁇ 0.20°, 21.76 ⁇ 0.20°, 22.39 ⁇ 0.20°, 25.09 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.94 ⁇ 0.20°, 9.35 ⁇ 0.20°, 13.06 ⁇ 0.20°, 14.80 ⁇ 0.20°, 15.47 ⁇ 0.20°, 16.35 ⁇ 0.20°, 19.19 ⁇ 0.20°, 19.81 ⁇ 0.20°, 21.76 ⁇ 0.20°, 22.39 ⁇ 0.20°, 24.21 ⁇ 0.20°, 25.09 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction at the following 2 ⁇ angles: 4.94°, 9.35°, 10.52°, 10.84°, 11.13°, 12.04°, 13.06°, 14.24° , 14.80°, 15.13°, 15.47°, 16.35°, 16.61°, 16.82°, 17.61°, 18.43°, 19.19°, 19.81°, 20.36°, 20.60°, 21.76°, 22.13°, 22.39°, 23.77°, 24.21 °, 24.82°, 25.09°, 26.97°, 28.72°, 28.92°, 32.79°, 33.27°.
  • the XRPD pattern of the above-mentioned crystal form B is shown in FIG. 4.
  • the XRPD pattern analysis data of the above-mentioned crystal form B is shown in Table 2:
  • the differential scanning calorimetry curve of the above-mentioned crystal form B has an endothermic peak at 167.54.0 ⁇ 3.0°C, 177.98 ⁇ 3.0°C, and 246.93 ⁇ 3.0°C, respectively; at 168.36 ⁇ 3.0°C There is a peak of exothermic peak.
  • the DSC spectrum of the above-mentioned crystal form B is shown in FIG. 5.
  • thermogravimetric analysis curve of the above-mentioned crystal form B has a weight loss of 0.3265% at 56.15°C ⁇ 3.0°C, a weight loss of 0.3400% at 99.48°C ⁇ 3.0°C, and a weight loss of 0.3400% at 165.87°C ⁇ 3.0°C. Weightlessness reached 0.1831%.
  • the TGA pattern of the above-mentioned crystal form B is shown in FIG. 6.
  • the present invention also provides crystal form C of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 4.62 ⁇ 0.20°, 9.21 ⁇ 0.20°, 20.46 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 4.62 ⁇ 0.20°, 9.21 ⁇ 0.20°, 12.69 ⁇ 0.20°, 14.46 ⁇ 0.20°, 16.53 ⁇ 0.20°, 17.97 ⁇ 0.20°, 18.48 ⁇ 0.20°, 20.46 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction at the following 2 ⁇ angles: 4.62°, 4.95°, 9.21°, 12.69°, 13.84°, 14.46°, 14.82°, 15.27° , 16.16°, 16.53°, 17.63°, 17.97°, 18.48°, 19.43°, 20.46°, 20.71°, 21.85°, 22.08°, 23.79°, 27.95°, 28.22°, 29.25°.
  • the XRPD pattern of the above-mentioned crystal form C is shown in FIG. 7.
  • the XRPD pattern analysis data of the above-mentioned crystal form C is shown in Table 3:
  • the differential scanning calorimetry curve of the above-mentioned crystal form C has an endothermic peak at 177.38 ⁇ 3.0°C and 253.96 ⁇ 3.0°C, respectively.
  • the DSC spectrum of the above-mentioned crystal form C is shown in FIG. 8.
  • thermogravimetric analysis curve of the above crystal form C has a weight loss of 0.4696% at 120.00°C ⁇ 3.0°C.
  • the TGA pattern of the above-mentioned crystal form C is shown in FIG. 9.
  • the present invention also provides the D crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 4.95 ⁇ 0.20°, 15.49 ⁇ 0.20°, 19.21 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 4.95 ⁇ 0.20°, 9.37 ⁇ 0.20°, 15.49 ⁇ 0.20°, 16.37 ⁇ 0.20°, 19.21 ⁇ 0.20°, 21.78 ⁇ 0.20°, 22.41 ⁇ 0.20°, 25.13 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 4.95 ⁇ 0.20°, 9.37 ⁇ 0.20°, 13.08 ⁇ 0.20°, 14.28 ⁇ 0.20°, 14.59 ⁇ 0.20°, 16.37 ⁇ 0.20°, 17.63 ⁇ 0.20°, 19.21 ⁇ 0.20°, 21.78 ⁇ 0.20°, 22.41 ⁇ 0.20°, 24.23 ⁇ 0.20°, 25.13 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction at the following 2 ⁇ angles: 4.24°, 4.62°, 4.95°, 9.37°, 10.55°, 12.07°, 13.08°, 13.77° , 14.28°, 14.84°, 15.13°, 15.49°, 16.37°, 16.85°, 17.63°, 17.88°, 18.45°, 19.21°, 19.94°, 20.42°, 20.67°, 21.10°, 21.78°, 22.17°, 22.41 °, 23.79°, 24.23°, 25.13°, 25.66°, 27.01°, 27.61, 28.94°, 29.21°, 31.26°, 32.85°, 33.24°.
  • the XRPD pattern of the above-mentioned crystal form D is shown in FIG. 10.
  • the XRPD pattern analysis data of the above-mentioned crystal form D is shown in Table 4:
  • the differential scanning calorimetry curve of the above-mentioned crystal form D has an endothermic peak at 178.09 ⁇ 3.0°C and 251.68 ⁇ 3.0°C, respectively.
  • the DSC spectrum of the above-mentioned crystal form D is shown in FIG. 11.
  • thermogravimetric analysis curve of the above-mentioned crystal form D has a weight loss of 0.5113% at 73.63°C ⁇ 3.0°C, and a weight loss of 0.6314% at 177.27°C ⁇ 3.0°C.
  • the TGA spectrum of the above-mentioned crystal form D is shown in FIG. 12.
  • the present invention also provides the application of the above crystal form A or B crystal form or C crystal form or D crystal form in the preparation of drugs for treating diseases related to ATM inhibitors.
  • the present invention also provides a method for preparing the compound of formula (I),
  • Catalyst F is selected from bis(dibenzylideneacetone)palladium, tetratriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium/2-biscyclohexylphosphine-2,6-dimethoxybiphenyl, bis(dibenzylideneacetone)palladium, (Dibenzylideneacetone)palladium/2-biscyclohexylphosphine-2,6-dimethoxybiphenyl, [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane and Palladium acetate/4,5-bis(diphenylphosphorus)-9,9-dimethylxanthene;
  • the base G is selected from potassium phosphate, sodium carbonate and potassium acetate
  • Solvent H is selected from dimethyl sulfoxide/water, isopropanol/water, ethanol/water and 1,4-dioxane/water;
  • the above preparation method includes the following reaction route:
  • Reagent A is selected from lithium diisopropylamide
  • Solvent B is selected from tetrahydrofuran
  • Reagent C is selected from n-butyl lithium and dual pinacol borate;
  • Reagent D is selected from triisopropyl borate and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;
  • Solvent E is selected from tetrahydrofuran and 1,4-dioxane;
  • Catalyst I is selected from Raney nickel/hydrogen, palladium carbon/hydrogen and zinc powder/ammonium chloride;
  • Solvent J is selected from ethanol, methanol and tetrahydrofuran/water.
  • Reagent K is selected from potassium carbonate
  • Reagent L is selected from dimethyl carbonate
  • the solvent M is selected from dimethyl sulfoxide.
  • the compound of the present invention has stable crystal forms, is less affected by light, heat and humidity, has good drug efficacy in vivo, and has broad prospects for preparation of medicines; the compound of the present invention has a significant ATM kinase inhibitory effect and has good selectivity for DNA-PK kinase.
  • the process for synthesizing the compound of formula (I) and its intermediates provided by the present invention has the beneficial effects of low-cost and easy-to-obtain raw materials, mild and controllable reaction conditions, easy separation and purification, and easy industrialization.
  • the raw materials of the process method are conventional or common reagents, which are easily available in the market and low in price;
  • the reagents used in each step of the reaction are all small molecules, which are easy to purify and do not need to be purified by column chromatography in the whole process.
  • the present invention has high industrial application value and economic value in preparing the compound of formula (I) and its intermediates.
  • 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 combining them with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • 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 single crystal X-ray diffraction method uses the Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultured single crystal.
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • TFA trifluoroacetic acid
  • TsOH stands for p-toluenesulfonic acid
  • mp stands for melting point
  • EtSO 3 H stands for ethanesulfonic acid
  • MeSO 3 H stands for methanesulfonic acid
  • THF stands for tetrahydrofuran
  • EtOAc stands for ethyl acetate
  • DCM stands for dichloromethane
  • DMF stands for N,N-dimethylformamide
  • LDA stands for lithium diisopropylamide
  • NBS stands for N-bromosuccinimide
  • n- BuLi stands for n-butyl lithium
  • DIPA stands for diisopropylamine
  • TBAB stands for tetrabutylammonium bromide
  • Pd 2 (dba) 3 stands for tris(dibenzylideneacetone) dipall
  • Test method Approximately 10-20mg sample is used for XRPD detection.
  • Light tube voltage 40kV
  • light tube current 40mA
  • Test method Take a sample (0.5 ⁇ 1mg) and place it in a DSC aluminum pot for testing. Under the condition of 50mL/min N 2 and at a heating rate of 10°C/min, heat the sample from 30°C (or room temperature) to 300°C.
  • TGA Thermal Gravimetric Analyzer
  • Test method Take a sample (2 ⁇ 5mg) and place it in a TGA platinum pot for testing. Under the condition of 25mL/minN 2 and at a heating rate of 10°C/min, heat the sample from room temperature to 300°C or a weight loss of 20%.
  • Test method Take a sample (10-15mg) and place it in the DVS sample pan for testing.
  • Hygroscopicity classification ⁇ W% deliquescence Absorb 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%
  • ⁇ W% represents the moisture absorption and weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
  • Fig. 1 is an XRPD spectrum of Cu-K ⁇ radiation of the crystal form of compound A of formula (I).
  • Figure 2 is a 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 an XRPD spectrum of Cu-K ⁇ radiation of the crystal form of compound B of formula (I).
  • Figure 5 is a DSC chart of the crystal form of compound B of formula (I).
  • Figure 6 is a TGA spectrum of the crystal form of compound B of formula (I).
  • Fig. 7 is an XRPD spectrum of Cu-K ⁇ radiation of the crystalline form C of compound of formula (I).
  • Fig. 8 is a DSC chart of the crystal form of compound C of formula (I).
  • Figure 9 is a TGA spectrum of the crystal form of compound C of formula (I).
  • Fig. 10 is an XRPD spectrum of Cu-K ⁇ radiation of the crystal form D of compound of formula (I).
  • Figure 11 is a DSC chart of the crystalline form D of compound of formula (I).
  • Figure 12 is a TGA spectrum of the crystal form D of compound of formula (I).
  • Figure 13 is a DVS spectrum of the crystal form of compound A of formula (I).
  • Figure 14 shows the relative weight change
  • Figure 15 shows the tumor growth curve.
  • the mixed solution of compound 1-2 was cooled to 30°C, and ice (80 g) and concentrated hydrochloric acid (15 mL) were added.
  • the above mixed solution was added to a solution of compound 1-3 (34.3 g, 146.57 mmol) in HCl (12M, 90 mL) and H 2 O (200 mL), and stirred at 30°C for 12 hours.
  • N,N-dimethylformamide 35.62mg, 487.30 ⁇ mol, 37.49 ⁇ L
  • 1-5 10g, 34.84mmol
  • thionyl chloride 100mL
  • the solvent was removed by rotary evaporation under reduced pressure, and the residual solid was slurried with ethyl acetate (20 mL)/petroleum ether (50 mL) at 20° C. for 30 minutes to obtain compound 1-6.
  • n-BuLi (2.5M, 3.93mL) was slowly added to DIPA (993.72mg, 9.82mmol, 1.39mL) in THF (10mL) solution, and the reaction system was stirred at -30°C for 30 minutes , And then slowly added methyl tetrahydropyran-4-carboxylate (1.49g, 10.31mmol, 1.38mL) in THF (10mL) solution, the reaction system was stirred at -65°C for 1 hour, and finally compound 1-6 ( 1.5 g, 4.91 mmol) in THF (10 mL), and the reaction system was stirred at -65°C for 2 hours.
  • reaction was quenched by adding water (5mL), then diluted with saturated brine (10mL), extracted with EtOAc (30mL, 10mL*3), and the combined organic phase was washed with saturated brine (30mL, 10mL*3), Dry with anhydrous sodium sulfate, concentrate to obtain a residual solid, and go through column chromatography (0-5% THF/PE) to obtain compound 1-7.
  • compound 1-9 (200mg, 547.65 ⁇ mol), 2-fluoropyridine-5-boronic acid (154.34mg, 1.10mmol), Na 2 CO 3 (116.09mg, 1.10mmol), Pd 2 (dba ) 3 (50.15mg, 54.77 ⁇ mol) and Xphos (50.15mg, 54.77 ⁇ mol) in dioxane (18mL) and water (2mL) solutions were stirred at 100°C for 2 hours. The reaction mixture was concentrated to obtain a residual solid, and the solid was subjected to column chromatography (0-50% EtOAc/PE) to obtain compound 1-10.
  • 2-fluoropyridine-5-boronic acid 154.34mg, 1.10mmol
  • Na 2 CO 3 116.09mg, 1.10mmol
  • Pd 2 (dba ) 3 50.15mg, 54.77 ⁇ mol
  • Xphos 50.15mg, 54.77 ⁇ mol
  • reaction solution was naturally warmed to room temperature about 15°C, reacted for 16h, stirring at 220rpm, and 170mL of 2M HCl solution was added to the reaction solution.
  • the quenching temperature was controlled at 10-15°C; the mixture was rotary evaporated under reduced pressure to remove THF (2300 mL).
  • 1250 mL of 2M HCl solution was added to the remaining mixture to adjust the pH to 5.5-6, which was monitored by a precision pH test paper with a pH monitoring range of 5.5-9.
  • stirring for 0.5 hours at 15°C a light yellow solid precipitated out, and the solid (crude product) was collected by suction filtration under reduced pressure.
  • the 50L reactor was evacuated and filled with nitrogen repeatedly three times, and the reactor was always filled with nitrogen flow.
  • 1.4 kg of compound 1-7, 1.34, compound 2-7, and 97.09 g of bis(dibenzylideneacetone) palladium were sequentially added using an addition funnel. Wash the feeding bottle and the feeding port of the reactor with 3L dimethyl sulfoxide, and add the lotion to the system. Under a nitrogen atmosphere, the reaction system was heated to 60-65°C, and stirring was continued within this temperature range for 14 hours.
  • the reaction solution is diluted with 14L ethyl acetate at about 60 ⁇ 65°C (to prevent the product from separating out and becomes turbid at this time). After stirring evenly (temperature 40 ⁇ 50°C), it is spread with 1000g diatomaceous earth (thickness 2 ⁇ 3cm) while it is hot. ) Filter under reduced pressure, rinse the diatomaceous earth layer with 2L ethyl acetate (30-40°C), combine the filtrate and transfer it to a temporary storage bucket. Control the temperature of the water bath at 45 ⁇ 50°C, and the vacuum degree ⁇ -0.1MPa. Concentrate the solution in the temporary storage tank until no distillate drops to obtain the crude product and DMSO system.
  • the organic phase is concentrated until no distillate drops to obtain 1.50kg of a yellow solid compound.
  • the temperature of the water bath is controlled at 45-50°C, and the degree of vacuum is ⁇ -0.1MPa, and the organic phase is concentrated until no distillate drops to obtain 1.31kg of yellow solid.
  • the solid was slurried with 4L methanol at 40-45°C for 2 hours, filtered under reduced pressure, rinsed with 4L methanol, pumped to a drip-free flow, and 1.2kg of yellow solid was collected. Transfer the solid material to be baked into a dry and clean vacuum drying oven, control the temperature at 45 ⁇ 50°C, the degree of vacuum is ⁇ -0.1MPa, bake the material for 4-6 hours, start weighing from 4 hours until the weight loss is ⁇ 0.2g. A yellow-green powder compound 2-8 (1.17 kg, 62.5% yield) was obtained.
  • the stirring speed is adjusted to 250r/min, then the heating system is heated to 75-80°C, and the temperature is kept for 30-96 hours.
  • the temperature at the end of the reaction dropped to 30-40°C.
  • the Raney nickel is sucked out of the reaction system with a magnetic rod, and quickly transferred to a cup for quenching (the magnetic rod can be stopped if there is no adsorbent on the surface of the magnetic rod).
  • reaction solution was pumped into a 5L three-necked flask, and then 0.5L of dichloromethane was used to flush the residue in the kettle into the three-necked flask, and then 3L of dichloromethane dissolved product was added to the three-necked flask (to prevent product precipitation),
  • filter under reduced pressure through a funnel spread with 200.32g diatomaceous earth (3 ⁇ 4cm thickness) (wet with 0.5L dichloromethane before filtering), rinse the diatomaceous earth layer with 0.5L dichloromethane, and pump to Drop the filtrate drop by drop to stop, combine the filtrate and transfer to the temporary storage bucket.
  • the crude product 826.2g obtained from 11 batches was slurried with 4.13L of methanol at 20 ⁇ 30°C for 12-48 hours.
  • the system was always a suspension, filtered (under reduced pressure), and filtered with methanol (50mL ⁇ 3 times) rinsing, pumping until no droplets drip, and collecting 820.2 g of white solid.
  • the filter cake was dissolved with 385 mL of dichloromethane and separated to obtain the crude compound.
  • the reaction system was filtered under reduced pressure, and the filter cake was rinsed once with 71 mL of ethanol until no liquid dripped. Collect the filter cake, evaporate the solvent until no distillate drops, control the temperature of the water bath at 45-50°C and the vacuum degree ⁇ -0.1Mpa to obtain 298 g of light yellow powder with a yield of 83.5%.
  • the reaction solution was filtered, and the filter cake was rinsed once with 105 mL of methanol until there was no dripping.
  • the filter cake is transferred to a vacuum drying oven, the temperature is controlled at 40 °C, the vacuum degree is ⁇ -0.1 MPa, and the filter cake is baked for 43 hours.
  • An off-white powder was obtained, namely 491.02 g of compound A crystal form of formula (I), yield: 94.7%.
  • the sample placed under the conditions of 60°C high temperature, 92.5%RH high humidity, 40°C/75%RH and 60°C/75%RH is wrapped with aluminum foil paper, and then some small holes are pierced on the aluminum foil paper to ensure that the sample can be Full exposure to ambient air means complete exposure lofting; ICH specified illumination (visible light 1.2 ⁇ 10 6 Lux.hr + ultraviolet light 200W.hr/m 2 ) samples are fully exposed at room temperature (25°C) except for Photo-dark, The photo-dark sample is completely wrapped in tin foil and placed under the light of ICH specified illuminance at room temperature (25°C) for illumination; the 0-day sample is the initial sample, the 0-day sample is sealed with a screw cap and the bottle is wrapped with a sealing film Store it at -20°C after covering it for testing. The sample is placed under high temperature and high humidity conditions for 10 days; placed at 40°C/75% RH for 3 months, and at 60°C/75% RH for 1 month.
  • the test results
  • the sample placed under the conditions of 60°C high temperature, 92.5%RH high humidity, 40°C/75%RH and 60°C/75%RH is wrapped with aluminum foil paper, and then some small holes are pierced on the aluminum foil paper to ensure that the sample can be Full exposure to ambient air means complete exposure lofting; ICH specified illumination (visible light 1.2 ⁇ 10 6 Lux.hr + ultraviolet light 200W.hr/m 2 ) samples are fully exposed at room temperature (25°C) except for Photo-dark, The photo-dark sample is completely wrapped in tin foil and placed under the illumination of ICH specified illuminance at room temperature (25°C) for light; 0 day sample is the initial sample, 0 day sample is sealed with a screw cap and the cap is wrapped with a sealing film Then store it at -20°C for testing. The sample is placed under high temperature and high humidity conditions for 10 days; placed at 40°C/75% RH for 3 months, and at 60°C/75% RH for 1 month.
  • Human-derived ATM kinase was incubated in a buffer solution containing 30 nM GST-cMyc-p53 and Mg/ATP. The concentration of Mg/ATP was determined according to different needs. The reaction was initiated by adding a Mg/ATP complex. After about 30 minutes of incubation at room temperature, add stop solution containing EDTA to terminate the reaction. Finally, for phosphorylated p53, a detection buffer containing d2-labeled anti-GST monoclonal antibody and europium-labeled phosphorylated Ser15 antibody was added.
  • HTRF homogeneous time-resolved fluorescence
  • the human DNA-PK kinase is incubated in a buffer solution containing 50 nM GST-cMyc-p53 and Mg/ATP. The concentration of Mg/ATP is determined according to different needs.
  • the reaction is initiated by adding a Mg/ATP complex. After about 30 minutes of incubation at room temperature, add stop solution containing EDTA to terminate the reaction. Finally, for phosphorylated p53, a detection buffer containing d2-labeled anti-GST monoclonal antibody and europium-labeled phosphorylated Ser15 antibody was added.
  • HTRF homogeneous time-resolved fluorescence
  • the compound of formula (I) has a significant inhibitory effect on ATM kinase and has good selectivity for DNA-PK kinase.
  • test drugs ATM inhibitor and etoposide were administered intraperitoneally or orally in a BALB/c nude mouse model of human lung cancer H446 cell subcutaneous xenograft tumor.
  • IP intraperitoneal injection
  • PO oral
  • QD once a day
  • BIW twice a week
  • QD PG-D0, 3D on, 4D off from PG-D1
  • BIW+QD PG-D0, 3D on, 4D off from PG-D1 ⁇ 4W: give etoposide on Monday, and ATM inhibitors from Tuesday to Thursday, once a day, once a week Circulate, dosing for four weeks.
  • Human lung cancer cells H446 (ATCC, Manassas, VA, HTB-171) were cultured in a monolayer in vitro under RPMI-1640, with 10% fetal bovine serum, 100U/mL penicillin and 100 ⁇ g/mL streptomycin, 37 Cultivation with 5% CO2. Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90%, the cells are collected, counted, and seeded.
  • the experimental index is to investigate whether the tumor growth is inhibited, delayed or cured.
  • the tumor diameter was measured with vernier calipers twice a week.
  • TGI (%) [1- (Average tumor volume at the end of a certain treatment group-the average tumor volume at the beginning of the treatment group) / (Average tumor volume at the end of the solvent control group- The average tumor volume at the start of treatment in the solvent control group)] ⁇ 100%.
  • T/C (%) where T is the average tumor volume obtained from the last measurement (PG-D26) of the treatment group, and C is the average tumor volume obtained from the last measurement (PG-D26) of the control group.
  • the body weight of experimental animals is used as a reference index for indirect determination of drug toxicity. In this model, none of the administration groups showed significant weight loss (Figure 14). Mice No. 42161 was found dead on the 15th day after the etoposide, 15mg/kg and AZD0156, 5mg/kg combination groups were administered. In the treatment group where etoposide was combined with the compound of formula (I) and AZD0156, some animals lost more than 10% but not less than 15% in body weight.
  • the test drugs ATM inhibitor and etoposide affect the body weight of the H446 cell subcutaneous xenograft female BALB/c nude mouse model. Figure 14 shows. The relative weight change is calculated based on the weight of the animal at the beginning of the administration. The data points represent the average weight change percentage within the group, and the error bars represent the standard error (SEM).
  • the tumor volume changes in each group after the treatment of the test drug ATM inhibitor and etoposide in the female BALB/c nude mouse model of subcutaneous xenotransplanted tumor with H446 cells are shown in Table 11.
  • the tumor growth curve is shown in Figure 15.
  • the data points represent the average tumor volume within the group, and the error bars represent the standard error (SEM).
  • Anti-tumor efficacy evaluation index (calculated based on tumor volume on the 26th day after administration)
  • c.p value is calculated based on tumor volume.

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Abstract

L'invention concerne une forme cristalline d'un composé de quinopyrrolidine-2-one (I), qui sert d'inhibiteur d'ATM, son procédé de préparation et son utilisation dans la préparation d'un médicament pour le traitement de maladies liées à une tumeur solide.
PCT/CN2021/084062 2020-03-30 2021-03-30 Forme cristalline de composé de quinopyrrolidine-2-one servant d'inhibiteur d'atm et son utilisation Ceased WO2021197339A1 (fr)

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WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025217307A1 (fr) 2024-04-09 2025-10-16 Revolution Medicines, Inc. Procédés de prédiction de la réponse à un inhibiteur de ras(on) et polythérapies
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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CN108349971A (zh) * 2015-11-03 2018-07-31 阿斯利康(瑞典)有限公司 咪唑并[4,5-c]喹啉-2-酮化合物以及它们在治疗癌症中的用途
CN108348515A (zh) * 2015-11-05 2018-07-31 阿斯利康(瑞典)有限公司 咪唑并[4,5-c]喹啉-2-酮化合物以及它们在治疗癌症中的用途
WO2017194632A1 (fr) * 2016-05-11 2017-11-16 Astrazeneca Ab Composés imidazo[4,5-c]quinolin-2-one et leur utilisation pour traiter le cancer
CN110386932A (zh) * 2018-04-20 2019-10-29 艾科思莱德制药公司 用于抗肿瘤疗法中的双重atm和dna-pk抑制剂
WO2020063855A1 (fr) * 2018-09-30 2020-04-02 南京明德新药研发有限公司 Dérivé de quinolino-pyrrolidin-2-one et application associée

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025217307A1 (fr) 2024-04-09 2025-10-16 Revolution Medicines, Inc. Procédés de prédiction de la réponse à un inhibiteur de ras(on) et polythérapies
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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