WO2022135568A1 - Forme cristalline d'un dérivé pyrimido-hétérocyclique azoté à cinq chaînons et son procédé de préparation - Google Patents

Forme cristalline d'un dérivé pyrimido-hétérocyclique azoté à cinq chaînons et son procédé de préparation Download PDF

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WO2022135568A1
WO2022135568A1 PCT/CN2021/141214 CN2021141214W WO2022135568A1 WO 2022135568 A1 WO2022135568 A1 WO 2022135568A1 CN 2021141214 W CN2021141214 W CN 2021141214W WO 2022135568 A1 WO2022135568 A1 WO 2022135568A1
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formula
crystal form
compound represented
compound
ray powder
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PCT/CN2021/141214
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English (en)
Chinese (zh)
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张志鹏
李志亚
胡逸民
周先强
杜振兴
王捷
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江苏恒瑞医药股份有限公司
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Priority to CN202180086707.7A priority Critical patent/CN116669734A/zh
Publication of WO2022135568A1 publication Critical patent/WO2022135568A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00

Definitions

  • the present disclosure relates to a crystal form of a pyrimido five-membered nitrogen heterocyclic derivative, a preparation method and medical use thereof, and belongs to the field of pharmacy.
  • Src homology domain 2 containing tyrosine phosphatase-2 (SHP2) is an evolutionarily conserved non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene. It consists of two SH2 domains (N-SH2, C-SH2) and a PTP catalytic domain. It is widely expressed in various human tissues and plays an important role in maintaining tissue development and cell homeostasis. SHP2 is involved in signaling through the Ras-mitogen-activated protein kinase, JAK-STAT or phosphoinositide 3-kinase AKT pathways.
  • PTP non-receptor protein tyrosine phosphatase
  • SHP2 represents a target that may be of high interest for the development of new therapeutics for the treatment of various diseases.
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 4.847, 9.801, 13.778, 14.770, 15.444 and 26.077.
  • the crystal form A of the compound represented by the formula (I) provided by the present disclosure is at 4.847, 9.801, 13.138, 13.778, 14.770, 15.444, There are characteristic peaks at 18.363, 19.856, 21.092, 23.371, 26.077, and 28.130.
  • the crystal form A of the compound represented by the formula (I) provided by the present disclosure is at 4.847, 9.801, 13.138, 13.778, 14.770, 15.444, There are characteristic peaks at 18.363, 19.856, 21.092, 22.034, 23.371, 24.460, 26.077, 28.130, 28.970, 31.894, 32.920, 33.916, and 38.924.
  • the X-ray powder diffraction spectrum of the crystal form A of the compound represented by formula (I) provided by the present disclosure is shown in FIG. 2 .
  • the present disclosure provides a preparation method of the A crystal form of the compound represented by formula (I), which is selected from:
  • the solvent II is selected from tetrahydrofuran, ethyl acetate, toluene, acetone, methanol, ethanol, acetonitrile, methyl tert-butyl ether, water, isotope At least one of propyl ether, butanone, n-hexane; or
  • the present disclosure provides a crystal form B of the compound represented by formula (I).
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 4.606, 9.110, 11.423, 13.745, 16.006 and 22.973.
  • the crystal form B of the compound represented by the formula (I) provided by the present disclosure is at 4.606, 9.110, 11.423, 13.745, 16.006, 18.349, There are characteristic peaks at 22.973, 25.285, 27.505, and 29.262.
  • the crystal form B of the compound represented by the formula (I) provided by the present disclosure is at 4.606, 9.110, 11.423, 13.745, 16.006, 18.349, There are characteristic peaks at 19.767, 22.973, 24.700, 25.285, 27.505, 29.262, 31.451, 32.407, 34.072, 35.983, 37.216, 38.388.
  • the present disclosure provides a crystal form C of a compound represented by formula (I).
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 8.905, 12.920, 13.428, 14.074, 18.458 and 22.519.
  • the crystal form C of the compound represented by the formula (I) provided by the present disclosure is at 8.905, 12.920, 13.428, 14.074, 16.104, 17.996, There are characteristic peaks at 18.458, 18.965, 20.580, 22.519, 23.949, 26.395, 28.795 and 31.748.
  • the crystal form C of the compound represented by the formula (I) provided by the present disclosure is at 8.905, 12.920, 13.428, 14.074, 16.104, 17.996, There are characteristic peaks at 18.458, 18.965, 20.580, 22.519, 23.949, 25.011, 26.395, 27.226, 28.379, 28.795, 30.041, 31.748, 32.487, 35.578, 37.978, 41.393.
  • a preparation method of the C crystal form of the compound shown in formula (I), the compound shown in formula (I) and at least one selected from dioxane, N-methylpyrrolidone, N,N-dimethylformamide are prepared.
  • a solvent is mixed to obtain a clear solution, and the clear solution is mixed with at least one solvent selected from methyl tertiary butyl ether and isopropanol to crystallize out.
  • the present disclosure provides a D crystal form of the compound represented by formula (I).
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 4.766, 9.594, 14.089, 14.471, 18.981, 19.609 and 25.987.
  • the D crystal form of the compound represented by the formula (I) provided by the present disclosure is at 4.766, 9.594, 13.461, 14.089, 14.471, 16.602, There are characteristic peaks at 18.981, 19.609, 20.238, 22.616, 24.187, 24.770, 25.264, 25.987, 29.123, 30.380, 32.714, 34.688, 39.042, 39.535, 44.382.
  • the present disclosure provides a crystal form E of the compound represented by formula (I).
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 4.603, 9.209, 13.920, 15.097, 19.700 and 25.454.
  • the crystal form E of the compound represented by the formula (I) provided by the present disclosure is at 4.603, 9.209, 12.888, 13.920, 15.097, 18.641, There are characteristic peaks at 19.194, 19.700, 20.529, 22.876, 25.454, 25.664, 27.775, and 29.504.
  • the crystal form E of the compound represented by the formula (I) provided by the present disclosure is at 4.603, 9.209, 12.888, 13.920, 15.097, 18.641, 19.194 ⁇ 19.700 ⁇ 20.529 ⁇ 21.863 ⁇ 22.876 ⁇ 23.659 ⁇ 24.349 ⁇ 25.054 ⁇ 25.454 ⁇ 25.664 ⁇ 27.203 ⁇ 27.698 ⁇ 27.775 ⁇ 28.906 ⁇ 29.504 ⁇ 29.965 ⁇ 30.747 ⁇ 31.944 ⁇ 34.430 ⁇ 38.756 ⁇ 39.263 ⁇ 42.577 ⁇
  • a kind of preparation method of the E crystal form of compound shown in formula (I), described method is selected from:
  • the compound represented by formula (I) is mixed with solvent V to obtain a clear solution, the clear solution is mixed with solvent VI, and crystallized out, and the solvent V is selected from N,N-dimethylformamide, N,N- At least one of dimethylformamide, methanol, dimethyl sulfoxide and dichloromethane solvent; the solvent VI is selected from isopropyl ether, methyl tert-butyl ether, isopropanol, dioxane, At least one of acetone, n-hexane, toluene and acetonitrile; or
  • the present disclosure provides an X-ray powder diffraction pattern of the compound represented by the formula (I), which has characteristic peaks at 4.656, 14.068, 15.183, 18.858, and 23.235 in the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ .
  • the F crystal form of the compound represented by the formula (I) provided by the present disclosure the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is 4.656, 9.341, 12.670, 13.443, 14.068 at the 2 ⁇ angle , 14.850, 15.183, 18.858, 19.436, 20.518, 23.235, 25.591, 28.386, 29.543 have characteristic peaks.
  • the F crystal form of the compound represented by the formula (I) provided by the present disclosure is at 4.656, 9.341, 12.670, 13.443, 14.068, 14.850, 15.183 ⁇ 16.122 ⁇ 18.032 ⁇ 18.858 ⁇ 19.436 ⁇ 20.518 ⁇ 22.150 ⁇ 22.571 ⁇ 23.235 ⁇ 24.442 ⁇ 24.863 ⁇ 25.591 ⁇ 26.585 ⁇ 27.765 ⁇ 28.386 ⁇ 28.934 ⁇ 29.543 ⁇ 30.245 ⁇ 31.113 ⁇ 32.116 ⁇ 32.491 ⁇ 36.608 ⁇ 38.199 ⁇ 38.620 ⁇ 40.679 ⁇ There is a characteristic peak at 43.206.
  • the present disclosure provides a method for preparing the F crystal form of the compound represented by the formula (I), which comprises mixing the compound represented by the formula (I) with ethanol-water, and then crystallization.
  • the present disclosure provides a crystal form G of the compound represented by formula (I).
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 4.869, 9.735, 13.290, 14.713 and 20.020.
  • the crystal form G of the compound represented by the formula (I) provided by the present disclosure is at 4.869, 9.735, 10.863, 13.290, 14.713, 14.968, There are characteristic peaks at 17.852, 19.399, 20.020, 20.593, 21.796, 22.793, 24.251, 24.681, 25.510, 25.907, 26.327, 27.617, and 30.155.
  • the crystal form G of the compound represented by the formula (I) provided by the present disclosure is at 4.869, 9.735, 10.863, 13.290, 14.713, 14.968, 17.852 ⁇ 19.399 ⁇ 20.020 ⁇ 20.593 ⁇ 21.796 ⁇ 22.793 ⁇ 24.251 ⁇ 24.681 ⁇ 25.510 ⁇ 25.907 ⁇ 26.327 ⁇ 27.617 ⁇ 28.051 ⁇ 29.696 ⁇ 30.155 ⁇ 31.101 ⁇ 32.405 ⁇ 33.402 ⁇ 35.019 ⁇ 39.615 ⁇ 41.021 ⁇ 45.193 ⁇ 46.644 ⁇ 54.898 ⁇ peak.
  • the present disclosure provides an H crystal form of a compound represented by formula (I).
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 8.608, 12.983, 13.476, 17.716, 20.144, and 23.371.
  • the H crystal form of the compound represented by the formula (I) provided by the present disclosure is at 8.608, 11.238, 12.983, 13.476, 17.716, 18.227, There are characteristic peaks at 19.392, 20.144, 21.435, 21.914, 22.935, 23.371, 23.814, 25.416 and 30.620.
  • the H crystal form of the compound represented by the formula (I) provided by the present disclosure is at 8.608, 11.238, 11.718, 12.983, 13.476, 14.485, 17.716 ⁇ 18.227 ⁇ 19.392 ⁇ 20.144 ⁇ 21.435 ⁇ 21.914 ⁇ 22.935 ⁇ 23.371 ⁇ 23.814 ⁇ 25.416 ⁇ 26.499 ⁇ 28.195 ⁇ 28.887 ⁇ 30.620 ⁇ 31.767 ⁇ 32.874 ⁇ 33.970 ⁇ 34.839 ⁇ 35.854 ⁇ 37.045 ⁇ 38.478 ⁇ 39.958 ⁇ 41.311 ⁇ 43.925 ⁇ 44.582 ⁇ There are characteristic peaks.
  • the preparation method of the crystal form described in the present disclosure further comprises the steps of filtration, washing or drying.
  • the present disclosure provides A crystal form, B crystal form, C crystal form, D crystal form, E crystal form, F crystal form, G crystal form and H crystal form of the compound represented by the formula (I) prepared by the above preparation method. crystal form.
  • each deuterium atom (D) has an abundance of at least 20%.
  • each deuterium atom (D) has an abundance of at least 50%.
  • each deuterium atom (D) has an abundance of at least 90%.
  • each deuterium atom (D) has an abundance of at least 98%.
  • the present disclosure also provides a pharmaceutical composition, comprising the crystal form of the compound represented by the aforementioned formula (I), or the crystal form of the compound represented by the formula (I) prepared by the aforementioned method, or a mixture, and optionally from a pharmaceutical acceptable carrier, diluent or excipient.
  • the present disclosure also provides a pharmaceutical composition prepared from the crystal form of the compound represented by the aforementioned formula (I).
  • the present disclosure also provides a preparation method of a pharmaceutical composition, comprising combining the crystal form of the compound represented by the aforementioned formula (I), or the crystal form of the compound represented by the formula (I) prepared by the aforementioned method, or a mixture thereof with The step of admixing a pharmaceutically acceptable carrier, diluent or excipient.
  • the present disclosure also provides the crystal form of the compound represented by the aforementioned formula (I), or the crystal form of the compound represented by the formula (I) prepared by the aforementioned method, or a mixture thereof, or the aforementioned composition, or prepared by the aforementioned method.
  • the present disclosure also provides the crystal form of the compound represented by the aforementioned formula (I), or the crystal form of the compound represented by the formula (I) prepared by the aforementioned method, or a mixture thereof, or the aforementioned composition, or prepared by the aforementioned method.
  • the present disclosure also provides the crystal form of the compound represented by the aforementioned formula (I), or the crystal form of the compound represented by the formula (I) prepared by the aforementioned method, or the aforementioned composition, or the aforementioned composition prepared by the aforementioned method in Use in the preparation of a medicament for preventing or treating Noonan syndrome and Leopard skin syndrome.
  • the present disclosure also provides the crystal form of the compound represented by the aforementioned formula (I), or the crystal form of the compound represented by the formula (I) prepared by the aforementioned method, or the aforementioned composition, or the aforementioned composition prepared by the aforementioned method in Preparation for preventing or treating juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, pancreatic cancer, head and neck squamous cell carcinoma , gastric cancer, liver cancer, anaplastic large cell lymphoma and glioblastoma drug use.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in this disclosure refers to the diffraction angle, and ⁇ is the Bragg angle, in degrees or degrees; the error range of each characteristic peak 2 ⁇ is ⁇ 0.20, which can be -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01 , 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.
  • crystallization precipitation in the present disclosure includes, but is not limited to, stirring crystallization, cooling crystallization, beating crystallization and volatile crystallization.
  • DSC Different Scanning Calorimetry or DSC refers to the measurement of the temperature difference, heat flow difference between a sample and a reference during the heating or constant temperature of the sample to characterize all physical changes related to thermal effects and Chemical changes to obtain phase transition information of the sample.
  • the drying temperature mentioned in the present disclosure is generally 25°C-100°C, preferably 40°C-70°C, and drying under normal pressure or under reduced pressure is possible.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (ie, at least 1000 times greater than the natural abundance of deuterium (which is 0.015%)) % of deuterium incorporated).
  • Exemplary compounds having natural abundance greater than deuterium may be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 4000 times more abundant 5000 times more abundant deuterium, at least 6000 times more abundant deuterium or more abundant deuterium.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS was measured with a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer.
  • HPLC HPLC used Agilent 1260DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Thermo U3000 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm chromatographic column).
  • HPLC uses Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200 LC high pressure liquid chromatograph (Ultimate XB-C18 3.0*150mm chromatographic column or Xtimate C18 2.1*30mm chromatographic column).
  • Chiral HPLC analysis was determined using Chiralpak IC-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3 ⁇ m, Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3 ⁇ m, Chiralpak AS-3 150 ⁇ 4.6mm I.D., 3 ⁇ m, Chiralpak AS-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm I.D., 3 ⁇ m, Chiralcel OD-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm I.D., 5 ⁇ m, Chiralcel OJ-3 150 ⁇ 4.6mm I.D., 3 ⁇ m column;
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • the chiral preparative column used DAICEL CHIRALPAK IC (250mm*30mm, 10 ⁇ m) or Phenomenex-Amylose-1 (250mm*30mm, 5 ⁇ m).
  • the CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).
  • the average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: petroleum ether/ethyl acetate/methanol, the volume ratio of the solvent depends on the polarity of the compound For adjustment, a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • XRPD is X-ray powder diffraction detection: the measurement is carried out with a BRUKERD8 X-ray diffractometer, specific information collected: Cu anode (40kV, 40mA), Cu-K ⁇ 1 rays K ⁇ 2 rays K ⁇ rays Scanning mode: ⁇ /2 ⁇ , scanning range: 3-48°.
  • DSC is differential scanning calorimetry: METTLER TOLEDO DSC3+ was used for the measurement, the heating rate was 10°C/min, 25-350°C, and the nitrogen purging rate was 50mL/min.
  • TGA thermogravimetric analysis: METTLER TOLEDO TGA2 was used for detection, the heating rate was 10°C/min, the specific temperature range was referred to the corresponding map, and the nitrogen purging rate was 50mL/min.
  • DVS dynamic moisture adsorption: using Surface Measurement Systems advantage 2, the humidity starts from 50%, the inspection humidity range is 0%-95%, and the step is 10%.
  • the judgment standard is that the mass change within 360min is less than 0.002%, and the cycle is repeated twice. .
  • the structure of metabolite 14 is as follows:
  • compound 1c (9.97 g, 38.7 mmol) was dissolved in tetrahydrofuran (80 mL), and LDA (13.5 mL, 2M solution in tetrahydrofuran and n-hexane) was added dropwise at -78°C. After the dropwise addition, the mixture was stirred at -78°C for 1 hour. Compound 1d (8.8 g, 35.07 mmol) was added dropwise at -78°C, and stirring was continued at -78°C for 9 hours.
  • intermediate 4a The synthetic procedure of intermediate 4a is shown in intermediate 3e, wherein the compound dimethyl-d 6 -amine hydrochloride is replaced with methyl-d 3 -amine hydrochloride to prepare the aforementioned intermediate 4a.
  • 0.2nM recombinantly expressed full-length SHP2 (aa 1-593), 0.5nM activating polypeptide IRS1 with double phosphorylation site (sequence: H2N-LN(pY)IDLDLY(dPEG8)LST(pY)ASINFQK-amide ) and a series of concentrations of test compounds (final concentrations of 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 0.03 ⁇ M, 0.01 ⁇ M, 0.003 ⁇ M, 0.001 ⁇ M, 0.0003 ⁇ M, 0.0001 ⁇ M, 0.00003 ⁇ M M)
  • Add phosphatase reaction solution 60mM HEPES, pH 7.5 0.005% Brij-35, 75mM NaCl, 75mM KCl, 1mM EDTA, 5mM DTT
  • reaction substrate DiFMUP with a final concentration of 30 ⁇ M was added and reacted at room temperature for 30 minutes, and then the phosphatase reaction was terminated with 5 ⁇ L of reaction stop solution (60 mM HEPES, pH 7.5, 0.2% SDS). Read the fluorescence value of Ex358nm/Em455 on a fluorescence plate reader MD SpectraMax.
  • the IC50 value of the compound was calculated by the four-parameter logit method.
  • x represents the logarithmic form of the compound concentration
  • A, B, C and D are four parameters. Different concentrations correspond to different inhibition rates of phosphatase activity, and an inverse curve is made, and the IC 50 of the inhibitor is calculated from the curve.
  • the IC50 of the compound was calculated with Primer premier 6.0.
  • Example number IC50 (nM) Example number IC50 (nM) SHP099 79 1 1.7 2 2.1 3 4.5 5 4.8 6 4.7
  • Test Example 2 In vitro metabolic stability experiment of rat liver microsomes
  • the compound concentration in the reaction system was determined by LC/MS/MS to calculate the intrinsic clearance of the test compound and to evaluate the in vitro metabolic stability in rat liver microsomes.
  • Reactions were terminated at 0.5, 5, 10, 15, 20, and 30 minutes by transferring 20 ⁇ L of the incubation system to a stop plate containing 100 ⁇ L of cold stop solution, and vortexed for 2 minutes.
  • the stop plate was centrifuged at 4000 rpm for 20 minutes, then left to stand at 4°C for 30 minutes, and then centrifuged at 4000 rpm for 20 minutes.
  • the obtained sample was quantified by ion chromatogram, and the residual ratio was calculated based on the peak area of the test compound or positive control.
  • the slope k was determined by linear regression of the natural log value of the residual rate against incubation time using Microsoft Excel.
  • Rats were used as test animals, and the drug concentration in plasma at different time points was determined by LC/MS/MS method after the rats were given the compounds of the present invention by gavage.
  • the pharmacokinetic behavior of the compound of the present invention in rats was studied, and its pharmacokinetic characteristics were evaluated.
  • Rats were administered the compounds of the present invention by gavage, and 0.2 mL of blood was collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and placed in a test tube containing EDTA-K2 at 4°C, 4000 rpm Plasma was separated by centrifugation for 5 minutes and stored at -75°C.
  • Determination of the content of the test compound in rat plasma after oral administration of drugs of different concentrations take 50 ⁇ L of rat plasma at each time after administration, add 200 ⁇ L of acetonitrile solution of internal standard dexamethasone (50 ng/mL), vortex Mixed for 30 seconds, centrifuged at 4°C, 4700 rpm for 15 minutes, the supernatant of the plasma sample was diluted three times with water, and 2.0 ⁇ L was taken for LC/MS/MS analysis.
  • the rat pharmacokinetic parameters of the compounds of the present invention are shown in Table 3 below.
  • Test Example 4 Pharmacokinetic experiment in cynomolgus monkeys
  • the LC/MS/MS method was used to determine the drug concentration in the plasma of the cynomolgus monkeys at different times after intragastric administration of the compounds of the present invention.
  • the pharmacokinetic behavior of the compounds of the present invention in cynomolgus monkeys was studied, and their pharmacokinetic characteristics were evaluated.
  • Oral administration Weigh a certain amount of medicine, add 0.5% mass hypromellose, 0.1% volume Tween 80 and 99.4% volume water to prepare a 1 mg/mL white suspension.
  • the cynomolgus monkeys were fasted overnight and then intragastrically administered at a dose of 5 mg/kg.
  • Cynomolgus monkeys were administered the compound of the present invention by gavage, and 0.2 mL of blood was collected from peripheral veins at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and placed in a test tube containing EDTA-K2 at 2-8 °C, Plasma was separated by centrifugation at 2000 rpm for 10 minutes and stored at -75°C.
  • Determination of the content of the test compound in the plasma of cynomolgus monkeys after oral administration of different concentrations of drugs take 55 ⁇ L of cynomolgus monkey plasma at each time after administration, add 200 ⁇ L of acetonitrile solution of internal standard verapamil or dexamethasone, Vortex for 30 seconds, centrifuge at 3900 rpm for 15 minutes at 4°C, and the supernatant of the plasma sample was diluted three times with water, and 15 ⁇ L was taken for LC/MS/MS analysis.
  • the cynomolgus monkey pharmacokinetic parameters of the compounds of the present invention are shown in Table 4 below.
  • the apparent permeability coefficient (P app ) of the analyzed drugs was determined by liquid chromatography tandem mass spectrometry (LC/MS/MS) by the Caco-2 cell model.
  • HBSS 25 mM HEPES, pH 7.4, containing 50 ⁇ M quinidine
  • HBSS 25 mM HEPES, pH 7.4, containing 50 ⁇ M quinidine
  • CR is the concentration of the compound to be tested at the basal end (the superscript "120” or “45” is the sampling time, unit: minutes)
  • CD is the concentration of the compound to be tested at the top end (the superscript "120” or “45” is the sampling time, Unit: minutes)
  • Area is the membrane surface area (0.33 em 2 )
  • time is the total transit time (75 x 60 seconds).
  • 150-donor pooled human liver microsomes purchased from Corning, Cat. No. 452117) were used to assess representative substrate metabolic responses of the five major human CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5). Determination of different concentrations of test compounds for phenacetin (CYP1A2), diclofenac sodium (CYP2C9), S-mephentoin (CYP2C19), bufurolol hydrochloride by liquid chromatography tandem mass spectrometry (LC/MS/MS) Effects of salt (2D6) and midazolam (CYP3A4/5) on metabolic responses.
  • test compound concentration of 0.1, 0.3, 1, 3, 10, 30 ⁇ mol/L or positive compound or blank control and mixed human liver microsomes (0.2mg/mL) in a reaction system of 200 ⁇ L (100mmol/L phosphate buffer, pH 7.4, containing 0.3% by volume respectively) DMSO, 0.6% acetonitrile, 0.1% methanol) were incubated at 37°C for 5 minutes.
  • Peak area ratio metabolite peak area/internal standard peak area
  • Residual activity ratio (%) peak area ratio of the test compound group / peak area ratio of the blank group
  • CYP median inhibitory concentration (IC 50 ) was calculated by Excel XLfit 5.3.1.3.
  • the fifth step adopts methanol-dichloromethane solvent system column chromatography, and rotary evaporation obtains a solid, which is detected by X-ray powder diffraction. It is defined as Form A; TGA spectrum ( Figure 3) shows that Form A loses 1.33% in the range of 25-260 °C, and the DSC spectrum ( Figure 4) shows that Form A has an endothermic peak with a peak It is 241.49°C; the X-ray powder diffraction comparison chart before and after DVS shows that the crystal form before and after DVS does not change, as shown in Figure 5.
  • the preparation process of crystal form A includes the step of solid-liquid separation, and the crystal form is determined by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in Figure 12, and its characteristic peak positions are shown in Table 15, which is defined as the H crystal form; the TGA spectrum shows that the H crystal form has a weight loss of 3.64% between 25-60 °C; the DSC spectrum shows that the H crystal form There are three endothermic peaks, the peaks are 50.81 °C, 67.63 °C, 243.52 °C, and there is one exothermic peak, the peak is 190.16 °C.
  • crystal form A The stability of crystal form A, crystal form F, crystal form G and crystal form H were respectively placed at 25°C, 60% RH and 40°C, 75% RH, 5°C and -20°C under nitrogen-filled conditions.
  • Example 18 Study on the wettability of crystal form A, crystal form F, crystal form G and crystal form H

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Abstract

La présente divulgation porte sur une forme cristalline d'un dérivé pyrimido-hétérocyclique azoté à cinq chaînons et son procédé de préparation. La présente divulgation porte plus particulièrement sur différentes formes cristallines du composé représenté dans la formule (I) et son procédé de préparation. Les formes cristallines du composé de formule (I) selon la présente divulgation présentent une bonne stabilité et peuvent être mieux utilisées pour un traitement clinique.
PCT/CN2021/141214 2020-12-25 2021-12-24 Forme cristalline d'un dérivé pyrimido-hétérocyclique azoté à cinq chaînons et son procédé de préparation WO2022135568A1 (fr)

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WO2023060253A1 (fr) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Inhibiteurs de ras
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques

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CN110446709A (zh) * 2017-01-23 2019-11-12 锐新医药公司 作为变构shp2抑制剂的二环化合物
CN111153901A (zh) * 2018-11-07 2020-05-15 如东凌达生物医药科技有限公司 一类含氮稠杂环类shp2抑制剂化合物、制备方法和用途
WO2020108590A1 (fr) * 2018-11-30 2020-06-04 上海拓界生物医药科技有限公司 Pyrimidine et dérivé hétérocycle pentagonal de nitrogène, leur procédé de préparation et applications médicales
CN111433205A (zh) * 2017-12-15 2020-07-17 锐新医药公司 作为变构shp2抑制剂的多环化合物
WO2020259679A1 (fr) * 2019-06-28 2020-12-30 上海拓界生物医药科技有限公司 Dérivé hétérocyclique azoté à cinq chaînons de pyrimidine, son procédé de préparation et son utilisation pharmaceutique

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CN110446709A (zh) * 2017-01-23 2019-11-12 锐新医药公司 作为变构shp2抑制剂的二环化合物
CN111433205A (zh) * 2017-12-15 2020-07-17 锐新医药公司 作为变构shp2抑制剂的多环化合物
CN110156786A (zh) * 2018-02-13 2019-08-23 上海青煜医药科技有限公司 嘧啶并环化合物及其制备方法和应用
CN111153901A (zh) * 2018-11-07 2020-05-15 如东凌达生物医药科技有限公司 一类含氮稠杂环类shp2抑制剂化合物、制备方法和用途
WO2020108590A1 (fr) * 2018-11-30 2020-06-04 上海拓界生物医药科技有限公司 Pyrimidine et dérivé hétérocycle pentagonal de nitrogène, leur procédé de préparation et applications médicales
WO2020259679A1 (fr) * 2019-06-28 2020-12-30 上海拓界生物医药科技有限公司 Dérivé hétérocyclique azoté à cinq chaînons de pyrimidine, son procédé de préparation et son utilisation pharmaceutique

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023060253A1 (fr) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Inhibiteurs de ras
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques

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