WO2020107987A1 - Inhibiteur de erk comprenant de l'isoindoline, son procédé de préparation et son utilisation - Google Patents

Inhibiteur de erk comprenant de l'isoindoline, son procédé de préparation et son utilisation Download PDF

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WO2020107987A1
WO2020107987A1 PCT/CN2019/104110 CN2019104110W WO2020107987A1 WO 2020107987 A1 WO2020107987 A1 WO 2020107987A1 CN 2019104110 W CN2019104110 W CN 2019104110W WO 2020107987 A1 WO2020107987 A1 WO 2020107987A1
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compound
acid
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methanol
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徐云根
纪德重
张灵芝
朱启华
柏英
吴尧尧
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中国药科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • the present invention belongs to medicinal chemistry technology, and specifically relates to a class of ERK kinase inhibitors containing 6-(2-aminopyrimidin-4-yl)isoindolin-1-one structure, their preparation methods, and medicines containing these compounds Composition and its use in the preparation of anti-tumor drugs.
  • the mitogen-activated protein kinases (MAPKs) signal transduction pathway is an important signal pathway that transduces cell surface signals to the nucleus, which causes cell proliferation by affecting the transcription and regulation of genes in animal cells , Differentiation, transformation and apoptosis.
  • MAPKs signaling pathways have been found in mammalian cells, including extracellular signal-regulated kinases (ERK, Extracellular Regulated Proteins) and c-Jun N-terminal kinases (JNK/SAPK, c-Jun N-terminal Kinase/stress- activated protein), p38 kinase isozymes (p38A, p38B, p38C and p38D), ERK3/ERK4 and ERK5.
  • ERK extracellular signal-regulated kinases
  • JNK/SAPK c-Jun N-terminal kinases
  • JNK/SAPK c-Jun N-terminal Kinase/stress- activated protein
  • p38 kinase isozymes p38A, p38B, p38C and p38D
  • ERK3/ERK4 ERK5
  • the RAS-RAF-MEK-ERK signal transduction pathway (ERK pathway) is an evolutionarily conserved signaling cascade reaction pathway that can be transferred to cell surface receptor signals, thereby promoting cell proliferation and survival. Under normal physiological conditions, the ERK signaling pathway plays an important role in maintaining cell stability and regulating cell growth, and is strictly controlled by a multi-level feedback regulatory pathway.
  • BRAF inhibitors and MEK inhibitors have achieved great success in the field of anti-tumor, but with the development of clinical applications, it is found that whether BRAF inhibitors are used alone or in combination with MEK inhibitors, most The patient's condition will worsen again within one year (acquired resistance). In addition, about 10% to 15% of tumor patients with B-Raf V600E mutations are insensitive to BRAF inhibitors and MEK inhibitors (intrinsic resistance). Therefore, the problem of drug resistance of BRAF and MEK inhibitors has become a key scientific problem that needs to be solved at present.
  • ERK inhibitors will first block the re-activation of the MAPKs pathway exhibited by tumor cells resistant to BRAF and MEK inhibitors, overcoming existing drug resistance problems. Secondly, tumors inevitably develop drug resistance mutations through long-term targeted drug therapy. As mentioned above, a large number of BRAF and MEK mutations are mentioned. But so far, almost no mutations in ERK1/2 have been observed in tumor cells. At the same time, preclinical experimental results of ERK inhibitors show better effects than BRAF and MEK inhibitors. Therefore, inhibiting ERK is more effective than blocking its upstream kinase to block the signal transduction of the ERK pathway and overcome the resistance of tumor cells to BRAF inhibitors and MEK inhibitors.
  • the present invention provides an isoindolinone derivative containing 6-(2-aminopyrimidin-4-yl)isoindolin-1-one structure, and provides specific preparation of the derivative Method and pharmaceutical application for preparing ERK kinase inhibitor.
  • the present invention discloses an isoindolinone derivative represented by general formula I or a pharmaceutically acceptable salt thereof:
  • R 1 is selected from Wherein, X is selected from CH 2 , O, NH or CH-OH; R 4 is selected from H or C1-C6 alkyl, R 5 is selected from H, CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH or -CH 2 CH 2 CH 2 CH 2 OH; Y is selected from CH 2 , O, NH or S; R 6 is selected from F, Cl, Br, CH 3 , NH 2 or NHCOCH 3 ;
  • R 2 is H or -CH 2 OH
  • R 3 is selected from Wherein, R 7 is H, F, Cl, Br or OCH 3 , R 7 is mono-substituted, di-substituted or tri-substituted; R 8 is H or CH 3 .
  • R 1 is selected from
  • R 3 is selected from
  • R 2 is -CH 2 OH
  • the compound I or a pharmaceutically acceptable salt thereof includes chiral isomers:
  • the isoindolinone derivatives described in this application are selected from I-1 to I-28:
  • the above pharmaceutically acceptable salts are acid addition salts of compounds of general formula I, wherein the acids used for salt formation are: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid , Pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
  • the acids used for salt formation are: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid , Pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
  • the compound of the general formula (I) of the present invention can be prepared by the following method:
  • the compound IX is 1-methyl-1H-pyrazole-4-amine, 1-methyl-1H-pyrazole-3-amine, 4-aminotetrahydropyran, 4-aminocyclohexyl Alcohol, 4-aminopiperidine, 3-aminopyrrolidine, ethanolamine, cyclohexylamine, 3-amino-1-propanol, isopropylamine, 4-aminopyridine;
  • the solvent used is selected from sec-butanol, tert-butanol, ethanol , Tetrahydrofuran, ethyl acetate, methanol or a mixed solvent of any two or three of them, preferably sec-butanol;
  • the reaction temperature is selected from 90°C to 150°C, preferably 110°C to 130°C;
  • the reaction time is 4h to 48h, The reaction time is preferably 8h to 24h.
  • the compound VIII: compound IX (molar ratio) ratio is 1:1 to 1:20, preferably 1:1.5 to 1:3.
  • the second preparation method of the compound of general formula (I) includes the following steps:
  • R 3 stands for: Compound I
  • a configuration comprises:. S-configuration, R configuration and a mixture of two racemic configuration.
  • the process of preparing compound X from the reaction of compound VIII with tert-butyldimethylchlorosilane (TBSCl) the base used is selected from triethylamine, 4-dimethylaminopyridine, imidazole, sodium carbonate or potassium carbonate, preferably imidazole; reaction solvent Preferably ethyl acetate, tetrahydrofuran, chloroform, acetonitrile, methylene chloride, toluene, or a mixed solvent of any two or three of them, preferably methylene chloride; the temperature should be selected from 0°C to 50°C, preferably 30°C to 40°C ; The reaction time is selected from 1h to 12h, preferably 7h to 9h; Compound VIII: tert-butyldimethylchlorosilane (TBSCl) (molar ratio) The ratio is selected from 1:1 to 1:10, preferably 1:1.5 to 1 :2.
  • the process of preparing compound XI from compound X and IX through substitution reaction said compound IX is 2-aminothiazole, 2-aminooxazole, 1-methyl-5-aminotetrazole, 1-methyl-1H- 3-aminopyrazole or 1-methyl-1H-5-aminopyrazole;
  • the base used is selected from lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or sodium hydride, preferably bis (Trimethylsilyl) lithium amide;
  • the solvent used is tetrahydrofuran, N,N-dimethylformamide, dioxane, N-methylpyrrolidone or a mixed solvent of any two or three of them, preferably tetrahydrofuran And N,N-dimethylformamide;
  • the reaction temperature is selected from -80°C to 0°C, preferably -80°C to -25°C;
  • the reaction time is selected from 0.1h to 10h, preferably 1h to 3h;
  • the process of preparing compound I. A by removing the hydroxyl protecting group from compound XI to form a salt .
  • the deprotection reagent (A) used is selected from hydrogen chloride, hydrogen bromide, sulfuric acid or trifluoroacetic acid; the solvents are methanol, ethanol and methylene chloride , Acetone, ethyl acetate, tetrahydrofuran or a mixed solvent of any two; the reaction temperature is selected from 0°C to 50°C, preferably 0°C to 25°C; the reaction time is selected from 0.1h to 6h, preferably 1h to 3h.
  • the preparation method 1 of the key intermediate VIII in the preparation method of the general formula (I) of the present invention includes:
  • R 2 represents: H or -CH 2 OH
  • R 3 represents: Wherein R 7 represents H, F, Cl, Br or OCH 3 , R 7 may be mono-substituted, di-substituted or tri-substituted; R 8 represents H or CH 3 .
  • R 2 CH 2 OH
  • the configuration of compound VIII includes: S configuration, R configuration, and a mixed racemate of two configurations.
  • the catalyst used is selected from tetratriphenylphosphine palladium (Pd(PPh 3 ) 4 ), [1,1'-bis(diphenylphosphino ) Ferrocene) palladium dichloride (Pd(dppf)Cl 2 ), bistriphenylphosphine palladium dichloride (Pd(PPh3) 2 Cl 2 ), palladium acetate (Pd(OAc) 2 ) or (1, 1'-bis(diphenylphosphinoferrocene) nickel dichloride (NiCl 2 (dppf)), preferably tetratriphenylphosphine palladium (Pd(PPh 3 ) 4 ).
  • the base is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, sodium carbonate or potassium carbonate, preferably sodium carbonate;
  • the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate Glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, toluene, ethanol, water or a mixed solvent of any two or three of them, preferably a mixed solvent of toluene/methanol/water;
  • the reaction temperature is selected from 60°C ⁇ 120°C, preferably 70°C ⁇ 80°C;
  • reaction time is selected from 4h ⁇ 24h, preferably 7h ⁇ 10h;
  • compound II: compound III: catalyst: base (molar ratio) ratio is selected from 1:1:0.02:1 ⁇ 6 :1:0.2:6, preferably 1:1:0.03:1 ⁇ 1:1.05:0.1:2.
  • Oxidation of compound IV to prepare compound V The oxidant used is selected from m-CPBA, hydrogen peroxide, sodium hypochlorite, periodate, sodium periodate, potassium permanganate or tert-peroxide Butanol, preferably m-chloroperoxybenzoic acid; the reaction solvent is selected from tetrahydrofuran, acetone, methylene chloride, 1,4-dioxane or acetonitrile, preferably methylene chloride; the reaction temperature is selected from 10°C to 80°C, preferably 20°C to 30°C; reaction time is selected from 0.5h to 5h, preferably 1h to 2h; compound IV: oxidant (molar ratio) ratio is selected from 1:1 to 1:10, preferably 1:1.5 to 1:3.
  • the brominated reagent used is selected from N-bromosuccinimide (NBS) or liquid bromine, preferably N-bromosuccinimide;
  • the solvent is selected from benzene, Carbon tetrachloride, chloroform, acetonitrile, dichloromethane, methanol or toluene, preferably carbon tetrachloride;
  • the reaction temperature is selected from 50°C to 100°C, preferably 70°C to 90°C;
  • the reaction time is selected from 1h to 18h, preferably 4h ⁇ 7h;
  • Compound V: brominated reagent (molar ratio) is selected from 1:1 to 1:20, preferably 1:1 to 1:2.
  • the base used is selected from triethylamine, benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PyBop), N, N-diisopropylethylamine (DIEA), sodium carbonate or potassium carbonate, preferably triethylamine
  • the reaction solvent is selected from tetrahydrofuran, acetone, acetonitrile, methanol, methylene chloride, or a mixed solvent of any two, preferably acetonitrile
  • reaction The temperature is selected from 50°C to 100°C, preferably 60°C to 90°C;
  • the reaction time is selected from 1h to 24h, preferably 5h to 9h;
  • the compound VI: compound VII: base (molar ratio) ratio is selected from 1:1: 1 ⁇ 1:4:8, preferably 1:1:1 to 1:1.5:1.5.
  • the preparation method 2 of the key intermediate VIII in the preparation method of the general formula (I) of the present invention includes:
  • R 2 represents: H
  • R 3 represents: Wherein R 7 represents H, F, Cl, Br or OCH 3 , R 7 may be mono-substituted, di-substituted or tri-substituted; R 8 represents H or CH 3 .
  • the reaction is carried out under the conditions of adding a catalyst, a base and a reaction solvent, wherein the catalyst is selected from bis(triphenylphosphine) palladium dichloride, tetrakis(III) Phenylphosphine) palladium or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, preferably tetrakis(triphenylphosphine)palladium; base selected from sodium ethoxide, sodium acetate, potassium acetate , Potassium phosphate, sodium carbonate or potassium carbonate, preferably sodium carbonate; the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, 1,4-bis Oxyhexane, tetrahydrofuran, toluene, methanol, ethanol, water, or
  • the deprotection agent used is selected from hydrogen chloride, trifluoroacetic acid or boron trifluoride, preferably trifluoroacetic acid;
  • the reaction solvent is selected from tetrahydrofuran, acetone, dichloromethane, 1, 4-Dioxane or acetonitrile, preferably dichloromethane;
  • the reaction temperature is selected from 0°C to 50°C, preferably 20°C to 30°C;
  • the reaction time is selected from 0.5h to 6h, preferably 1h to 2h.
  • the process of preparing compound XVI by substitution reaction of compound XIV and compound XV the base used is selected from potassium carbonate, sodium carbonate, potassium phosphate, potassium acetate, potassium hydroxide, sodium hydride or sodium acetate, preferably sodium hydride; the reaction solvent is selected from Toluene, methanol, water, 1,4-dioxane, ethylene glycol dimethyl ether, or a mixed solvent of any three, preferably 1,4-dioxane; the reaction temperature is selected from 0°C to 120°C, preferably 50 °C ⁇ 80 °C; reaction time is selected from 3h to 24h, preferably 9h to 12h; compound XIV: compound XV: base (molar ratio) ratio is selected from 1:1:1 to 1:6:6, preferably 1:1 :1 ⁇ 1:1.2:1.5.
  • Oxidation reaction of compound XVI to prepare compound VIII The oxidant used is selected from m-CPBA, hydrogen peroxide, sodium hypochlorite, periodate, sodium periodate, potassium permanganate or tertiary peroxide Butanol, preferably m-chloroperoxybenzoic acid; the reaction solvent is selected from tetrahydrofuran, acetone, methylene chloride, 1,4-dioxane or acetonitrile, preferably methylene chloride; the reaction temperature is selected from 10°C to 80°C, preferably 20°C to 30°C; the reaction time is selected from 0.1h to 10h, preferably 1h to 2h; the compound IV: oxidant (molar ratio) ratio is selected from 1:1 to 1:6, preferably 1:1.5 to 1:3.
  • the invention also discloses a pharmaceutical composition, which contains the compound of the general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the compound can be added to a pharmaceutically acceptable carrier to make common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions, flavors, sweeteners, liquid or solid fillers or diluents can be added for common pharmaceutical use Accessories.
  • ERK kinase inhibitors are used to prepare drugs for treating malignant tumors.
  • the present invention discloses a new isoindolinone derivative represented by the general formula (I). Pharmacological experiments show that the compound I of the present invention can produce a good inhibitory effect on ERK kinase and can be used for preparation A medicine for treating malignant tumors with excessive activation of ERK pathway; the invention also discloses a preparation method of the isoindolinone derivatives.
  • Figure 1 is the experimental results of compound I-8 HCT116 nude mice xenografts.
  • the composition of the enzyme reaction system is as follows: 20 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij35, 0.02 mg/mL BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 10 ⁇ M ATP, kinase, kinase substrate; Add different concentrations of the compound to be screened to form a 50 ⁇ l reaction system, react at room temperature for 2h, then use the luciferase method to detect the ADP content in the system, and then react for 5min, on the MD-SpectraMax M5 multi-functional microplate reader The chemiluminescence signal is detected, and the intensity of the chemiluminescence signal is proportional to the inhibition of enzyme activity.
  • the detected chemiluminescence signal value is substituted into the formula:
  • Enzyme activity percentage (%) ⁇ (Lu drug-Lu background)/(Lu enzyme-Lu background) ⁇ x100%
  • Cells were subcultured for 10-15 generations, and the culture conditions were medium containing penicillin (final concentration 100U/mL), streptomycin (final concentration 100 ⁇ g/mL), 10% FBS (CT26, Colo-205, WM-266 -4: RPMI-1640; HCT116, HT29: McCoy's 5a; SW626: L-15), when the cells are fused to 90%, discard the old medium, wash the cells twice with 2mL PBS, add 2mL after discarding the PBS 0.25% (w/v) Trypsin-0.53 mM EDTA mixed digestion solution, observed under a microscope, about 30s, when the cells become round, quickly add 2mL of complete medium to stop the digestion, gently pipet to collect the cells. Centrifuge at 800 rpm, 4°C for 5 min, discard the supernatant, resuspend the cells in complete medium, culture in separate flasks, and change the medium the next day.
  • Log growth phase cells were seeded in 96-well plates at 1 ⁇ 105cells/well and cultured at 37°C under 5% CO 2 until the cells were 90% confluent, and incubated with serum-free L-15 medium for 2h Cell synchronization. Subsequently, the supernatant was discarded, and L-15 medium containing each compound (final dilution concentration of 1 nM, 10 nM, 100 nM, 500 nM, 1000 nM after compound addition) was added for incubation for 72 h. 4 h before the end of incubation, 20 ⁇ l of MTT solution was added to each well (5mg/mL).
  • Percentage of proliferation inhibitory activity (OD value administration-OD value background) / (OD value control-OD value background) x 100%
  • Some compounds with better ERK2 kinase inhibitory activity were selected and tested for human colon cancer cell line Colo-205 (BRAFV600E) and human melanoma cell WM-266-4 (BRAFV600D) containing RAS-RAF-MEK-ERK mutation ), anti-proliferative ability of human ovarian cancer cell SW-626 (KRASG12V) and human colon cancer cell HCT-116 (KRASG13D).
  • the experimental results showed (Table 2) that the test compounds showed a certain degree of proliferation inhibitory ability on the four cell lines, and the inhibitory activity was comparable to that of the positive drug BVD-523.
  • Subculture of cells the culture conditions are RPMI-1640 medium containing penicillin (final concentration 100U/mL), streptomycin (final concentration 100 ⁇ g/mL), 10% FBS, when the cells are confluent to 90%, discard Wash the cells twice with 2mL of PBS, discard the PBS, add 2mL of 0.25% (w/v) Trypsin-0.53mM EDTA mixed digestion solution, and observe under the microscope for about 30s. When the cells become round, add them quickly 2mL complete medium was used to stop the digestion, gently pipetting to collect the cells. Centrifuge at 800 rpm, 4°C for 5 min, discard the supernatant, resuspend the cells in complete medium, culture in separate flasks, and change the medium the next day.
  • Log growth phase cells were seeded in 96-well plates at 1 ⁇ 10 5 cells/well and cultured at 37°C under 5% CO 2 until the cells were 90% confluent and incubated with serum-free L-15 medium Synchronize the cells for 2h. Subsequently, the supernatant was discarded, and the RPMI-1640 medium containing each compound (10 nM, 100 nM, 1000 nM, 5000 nM, 10000 nM) was added for incubation for 72 h, and 4 ⁇ L of MTT solution (5 mg/mL) was added to each well before incubation for 4 h.
  • Negative control group 10 rats, intraperitoneal administration of saline containing 5% DMSO;
  • Group I-8 10 animals, the dosage is 50mg/kg;
  • BVD-523 group 10 animals, the dosage is 50mg/kg;
  • Mode of administration once a day, intragastric administration.
  • HCT116 cells were subcultured for 10-15 passages under 1640 medium containing penicillin (final concentration 100U/mL), streptomycin (final concentration 100 ⁇ g/mL), 10% FBS, when the cells were confluent to 90% , Discard the old culture medium, wash the cells twice with 2mL of PBS, add 2ml of 0.25% trypsin-0.02% EDTA mixed digestion solution after discarding the PBS, observe under the microscope, about 30s, when the cells become round, quickly add 2ml completely The medium is terminated for digestion, gently pipetting to collect the cells. Centrifuge at 800 rpm, 4°C for 5 min, discard the supernatant, resuspend the cells in complete medium, culture in separate flasks, and change the fluid the next day.
  • the statistical difference between the data groups was determined by one-way ANOVA and Tukey’s test. A P value of less than 0.05 was considered to be a significant difference.
  • compound I-8 and BVD-523 were able to significantly inhibit the increase in the volume and weight of transplanted tumors of HCT-116 nude mice (p ⁇ 0.05) after continuous oral administration at 50 mg/kg/day for 30 days.
  • the tumor suppression rate of I-8 is 71%, and the tumor suppression rate of BVD-523 is 54%, neither of which will affect the body weight of mice.
  • the experimental results show that the anti-tumor effect of I-8 at the dose of 50 mg/kg administered by gavage is superior to the positive drug BVD-523.

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Abstract

L'invention concerne un dérivé d'isoindoline, en particulier un composé contenant une structure de 6-(2-aminopyrimidin-4-yl)isoindolinon-1-one ; et un procédé de préparation du dérivé d'isoindoline. L'invention concerne en outre l'utilisation du dérivé d'isoindoline et d'un stéréoisomère, hydrate, solvate ou d'un cristal de celui-ci, ainsi qu'une composition comprenant le dérivé d'isoindoline ou un sel pharmaceutiquement acceptable de celui-ci et un véhicule pharmaceutiquement acceptable dans la préparation d'inhibiteurs de kinase ERK, et l'utilisation d'une composition pharmaceutique contenant de tels composés dans la préparation de médicaments antitumoraux.
PCT/CN2019/104110 2018-11-27 2019-09-03 Inhibiteur de erk comprenant de l'isoindoline, son procédé de préparation et son utilisation WO2020107987A1 (fr)

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CN201811424530.3A CN109608444B (zh) 2018-11-27 2018-11-27 含异吲哚啉酮的erk抑制剂及其制备方法与用途
CN201811424530.3 2018-11-27

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