WO2024083184A1 - 一种egfr抑制剂的药物组合物 - Google Patents

一种egfr抑制剂的药物组合物 Download PDF

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WO2024083184A1
WO2024083184A1 PCT/CN2023/125386 CN2023125386W WO2024083184A1 WO 2024083184 A1 WO2024083184 A1 WO 2024083184A1 CN 2023125386 W CN2023125386 W CN 2023125386W WO 2024083184 A1 WO2024083184 A1 WO 2024083184A1
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alkyl
alkoxy
cycloalkyl
pharmaceutical composition
optionally substituted
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PCT/CN2023/125386
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English (en)
French (fr)
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李小平
关琳
刘祥东
傅灵
任东
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西藏海思科制药有限公司
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Publication of WO2024083184A1 publication Critical patent/WO2024083184A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical composition of a compound of formula (I) or its stereoisomers and pharmaceutically acceptable salts, a preparation method and medical use thereof.
  • Epidermal growth factor receptor is a transmembrane protein tyrosine kinase that acts as a receptor for EGF family members to trigger the EGFR signaling pathway in human epithelial cells, thereby regulating cell proliferation, invasion, metastasis, apoptosis and angiogenesis (Nat. Rev. Cancer, 2007, 7, 169-181; Expert Opin. Ther. Targets, 2012, 16, 15-31.).
  • EGFR gene Overexpression, mutation or amplification of the EGFR gene in the human body leads to abnormal increase in EGFR activity, which can lead to the occurrence of many malignant tumors such as esophageal cancer, glioblastoma, anal cancer, head and neck epithelial cancer, breast cancer, lung cancer, especially non-small cell lung cancer (NSCLC) (Cells, 2019, 8, 350-361.).
  • malignant tumors such as esophageal cancer, glioblastoma, anal cancer, head and neck epithelial cancer, breast cancer, lung cancer, especially non-small cell lung cancer (NSCLC) (Cells, 2019, 8, 350-361.).
  • NSCLC non-small cell lung cancer
  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • Such compounds can be recognized by the proteasome of the cell, causing the degradation of the target protein, and can effectively reduce the content of the target protein in the cell.
  • ligands that can bind to different target proteins By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology can be applied to the treatment of various diseases. This technology has also received widespread attention in recent years (ACS Chem. Biol. 2017, 12, 892-898; Drug Discovery Today Technol. 2019, 31, 15-27.).
  • Patent PCT/CN2022/090243 describes a class of compounds that have excellent inhibitory activity against NCI-H1975 (EGFR-L858R-T790M) and NCI-H1975 EGFR-L858R-T790M-C797S cells.
  • the object of the present invention is to provide a pharmaceutical composition of a compound of formula (I) or its stereoisomers or pharmaceutically acceptable salts, which has good dissolution performance and oral performance, a simple and stable preparation process, and a stable pharmaceutical preparation with few impurities and controllable quality.
  • the present invention provides a pharmaceutical composition comprising:
  • Active ingredient is a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof:
  • X is selected from N or CH
  • R 1 is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • R 2 is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclyl, 4- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • R 1 and R 2 are directly linked to form a C 5-6 carbocyclic ring or a 5- to 6-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • R 3 is selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • R 4 is selected from H, C 1-4 alkyl, C 1-4 alkoxy, -OC 3-6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • R 5 is selected from H, C 1-4 alkyl, C 1-4 alkoxy, -OC 3-6 cycloalkyl, C 3-6 cycloalkyl, 4 to 6 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • Cy1 or Cy2 is selected from a 4-6 membered nitrogen-containing heterocycle, and the Cy1 or Cy2 is optionally substituted by 1 to 2 R d ;
  • R d is selected from H, F, Cl, Br, I, OH, COOH, CN, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl or C 1-4 alkoxy;
  • R k1 is selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • p1 is selected from 0, 1, 2, 3 or 4;
  • p2 is selected from 0, 1, 2, 3 or 4;
  • n1 is selected from 0, 1 or 2;
  • the content of the active ingredient in the pharmaceutical composition is 1% to 80% w/w.
  • the active ingredient is present in the pharmaceutical composition in an amount of 5% to 60% w/w.
  • the active ingredient is present in the pharmaceutical composition in an amount of 10% to 50% w/w.
  • the active ingredient is present in the pharmaceutical composition in an amount of 10% to 30% w/w.
  • the content of the active ingredient in the pharmaceutical composition is 10% to 25% as a free base.
  • the compound of formula (I) in the compound of formula (I):
  • R 1 is selected from H, F, Cl, Br, CF 3 , methyl or ethyl
  • R 2 is selected from F, Cl, Br, CF 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, phenyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • R3 is selected from F, Cl, Br;
  • R4 is selected from methoxy, ethoxy, -O-cyclopropyl
  • R 5 is selected from H, methyl, ethyl, cyclopropyl, pyrazolyl, pyrrolyl, wherein the methyl, ethyl, cyclopropyl, pyrazolyl, pyrrolyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • Cy1 or Cy2 is independently selected from azetidinyl, azopentyl, azohexyl or piperazine, and the Cy1 and Cy2 are optionally substituted by 1 to 2 R d ;
  • Rd is selected from F, Cl, Br, I, OH, CN, methyl or ethyl
  • R k1 is selected from F, Cl, Br, I, OH, NH 2 , methyl, ethyl, methoxy or cyclopropyl, wherein the methyl, ethyl, methoxy or cyclopropyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl.
  • the compound of formula (I) is selected from one of the following structures:
  • the pharmaceutically acceptable salt of the compound of formula (I) is selected from hydrochloride, sulfate, methanesulfonate, benzenesulfonate.
  • the molar ratio of the compound of formula (I) to the pharmaceutically acceptable salt is selected from 1:1, 1:2, 1:3.
  • the active ingredient is Compound 1 and its pharmaceutically acceptable salts.
  • the active ingredient is the dimesylate salt of Compound 1.
  • the surfactant is selected from one or more of anionic surfactants, cationic surfactants, zwitterionic surfactants, nonionic surfactants, or polymeric surfactants.
  • the surfactant is selected from one or more of sodium C5-20 alkyl sulfate, sodium C5-20 alkyl sulfonate, polyethylene glycol, ethylene oxide-propylene oxide copolymer, polyethylene glycol ester, polysorbate, cyclodextrin, sodium dioctyl sulfosuccinate, and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
  • the surfactant is selected from one or more of sodium dodecyl sulfate (SLS), polyethylene glycol, poloxamer, polysorbate 80, vitamin E polyethylene glycol succinate (TPGS), ⁇ -cyclodextrin, sodium sulfobutyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sodium dioctyl sulfosuccinate, and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
  • SLS sodium dodecyl sulfate
  • TPGS vitamin E polyethylene glycol succinate
  • ⁇ -cyclodextrin sodium sulfobutyl- ⁇ -cyclodextrin
  • hydroxypropyl- ⁇ -cyclodextrin sodium dioctyl sulfosuccinate
  • the surfactant is selected from sodium dodecyl sulfate (SLS).
  • the weight ratio of active ingredient calculated as free base to surfactant is 1:1-1:10, 1:1-1:5, or 1:1-1:4.
  • the weight ratio of active ingredient calculated as free base to surfactant is 1:1 to 1:10.
  • the weight ratio of active ingredient calculated as free base to surfactant is 1:1 to 1:5.
  • the weight ratio of active ingredient calculated as free base to surfactant is 1:1 to 1:4.
  • the surfactant is selected from sodium lauryl sulfate (SLS), and the weight ratio of active ingredient calculated as free base to sodium lauryl sulfate is 1:1-1:10, 1:1-1:5 or 1:1-1:4.
  • SLS sodium lauryl sulfate
  • the pharmaceutical composition further contains one or more of a filler, a disintegrant, and a binder.
  • the filler is selected from one or more of lactose, anhydrous calcium hydrogen phosphate, maltodextrin, microcrystalline cellulose, microcrystalline cellulose colloidal silicon dioxide co-processed product, and mannitol.
  • the filler is selected from lactose, microcrystalline cellulose and colloidal silicon dioxide co-process.
  • the disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch.
  • the binder is selected from one or more of povidone, copovidone, and cellulose derivatives;
  • the cellulose derivative is selected from hydroxypropyl cellulose, hypromellose.
  • the pharmaceutical composition comprises Compound 1 or a pharmaceutically acceptable salt thereof, and a surfactant.
  • the pharmaceutical composition comprises the dimesylate salt of Compound 1, a surfactant.
  • the pharmaceutical composition includes Compound 1 or a pharmaceutically acceptable salt thereof, and SLS.
  • the pharmaceutical composition comprises the dimesylate salt of Compound 1, SLS.
  • the pharmaceutical composition comprises Compound 1 or a pharmaceutically acceptable salt thereof, a surfactant, a filler, a disintegrant, and a binder.
  • the pharmaceutical composition includes the dimesylate salt of Compound 1, a surfactant, a filler, a disintegrant, and a binder.
  • the content of Compound 1 in the pharmaceutical composition is 1% to 80% w/w.
  • the content of Compound 1 in the pharmaceutical composition is 5% to 60% w/w.
  • the content of Compound 1 in the pharmaceutical composition is 10% to 50% w/w.
  • the content of Compound 1 in the pharmaceutical composition is 10% to 30% w/w.
  • the content of Compound 1 in the pharmaceutical composition is 10% to 40% w/w.
  • the content of Compound 1 in the pharmaceutical composition is 10% to 25% w/w.
  • the content of Compound 1 in the pharmaceutical composition is 10%-15% w/w, 20-25% w/w.
  • the content of dimesylate salt of Compound 1 in the pharmaceutical composition is 1% to 80% w/w.
  • the content of dimesylate salt of Compound 1 in the pharmaceutical composition is 5% to 60% w/w.
  • the content of dimesylate salt of Compound 1 in the pharmaceutical composition is 10% to 50% w/w.
  • the content of dimesylate salt of Compound 1 in the pharmaceutical composition is 10% to 40% w/w.
  • the content of dimesylate salt of Compound 1 in the pharmaceutical composition is 10% to 30% w/w.
  • the content of dimesylate salt of Compound 1 in the pharmaceutical composition is 12% to 30% w/w.
  • the dimesylate salt of Compound 1 is present in the pharmaceutical composition in an amount of 12%-17% w/w, 24-30% w/w.
  • the content of dimesylate salt of Compound 1 in the pharmaceutical composition is 12% to 25% w/w.
  • the pharmaceutical composition includes dimesylate salt of Compound 1, SLS, lactose, microcrystalline cellulose colloidal silicon dioxide co-process, hypromellose, croscarmellose sodium.
  • the pharmaceutical composition includes dimethanesulfonate of Compound 1, SLS, lactose, co-processed microcrystalline cellulose colloidal silicon dioxide, hypromellose, and cross-linked sodium carboxymethyl cellulose, and the content of dimethanesulfonate of Compound 1 in the pharmaceutical composition is 10% to 30% w/w.
  • the present invention relates to a pharmaceutical preparation, which contains any one of the above-mentioned pharmaceutical compositions.
  • the amount of active ingredient in a unit preparation is 1 mg to 800 mg calculated as a free base.
  • the amount of active ingredient in a unit preparation is selected from 5 mg, 10 mg, 20 mg, 25 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 160 mg, 200 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg calculated as free base.
  • the pharmaceutical preparation is in the form of a tablet, a granule, a capsule, a dry suspension, an oral solution, a soft capsule, and an emulsion.
  • the present invention relates to the use of any one of the above-mentioned pharmaceutical compositions or pharmaceutical preparations in the preparation of drugs for treating and inhibiting or degrading EGFR-related diseases.
  • the disease is cancer.
  • the disease is lung cancer.
  • the compound of general formula (I) can be prepared by the method of PCT/CN2022/090243.
  • “Pharmaceutically acceptable salt” refers to salts that are safe, non-toxic and neither biologically nor otherwise undesirable and include salts thereof that are pharmaceutically acceptable for veterinary as well as human pharmaceutical use and possess the desired pharmacological activity.
  • Steps refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.
  • heterocyclyl optionally substituted with alkyl means that the alkyl group may but need not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl group and instances where the heterocyclyl group is not substituted with alkyl group.
  • “Surfactant” refers to an amphiphilic molecule including a non-polar hydrophobic portion, such as a straight or branched hydrocarbon or fluorocarbon chain containing 8-18 carbon atoms connected to a polar or ionic portion (hydrophilic), the hydrophilic portion can be nonionic, ionic or zwitterionic and accompanied by a counterion.
  • Non-limiting examples include anionic surfactants (such as alkyl sulfonates, fatty acid salts, sulfates), cationic surfactants (such as quaternary ammonium salts, amine salts), zwitterionic surfactants (such as betaines, amino acids, imidazolines), nonionic surfactants (such as polyoxyethylenes, fatty alcohol polyoxyethylene ethers, fatty alcohol polyoxyethylene esters, alkylphenol polyoxyethylene ethers, glycerol fatty acid esters, sorbitan fatty acid esters), polymeric surfactants (such as ethylene oxide-propylene oxide copolymers, ethylene oxide-polyoxypropylene block copolymers), and cyclodextrins.
  • anionic surfactants such as alkyl sulfonates, fatty acid salts, sulfates
  • cationic surfactants such as quaternary ammonium salts, amine salts
  • SLS sodium lauryl sulfate
  • TPGS vitamin E polyethylene glycol succinate
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • SBE- ⁇ -CD sodium sulfobutyl- ⁇ -cyclodextrin
  • Eudragit L100 methacrylic acid-methyl methacrylate copolymer
  • Eudragit L100-55 methacrylic acid-ethyl acrylate copolymer
  • HPMCP Hydroxypropyl methylcellulose phthalate
  • Soluplus Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer
  • HPMCAS Hydroxypropyl methylcellulose acetate succinate
  • HPC Hydroxypropylcellulose
  • PVP-VA Copovidone
  • PVA Polyvinyl alcohol
  • 1G (130 g, 0.19 mmol) was dissolved in a mixture of THF (1.3 L) and water (400 mL), and ammonium chloride (51 g, 0.95 mmol) and zinc powder (62 g, 0.95 mmol) were added. The temperature was slowly raised to 40-60 °C for reaction for 1-2 hours. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with 1 L of DCM. The organic phases were combined, and the organic phases were washed with 0.5 L of ammonia water and 0.5 L of saturated brine in sequence. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain 1H as a yellow solid.
  • 2C (0.31 g, 0.62 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (0.71 g, 6.2 mmol) was added at room temperature, stirred for 1 h, and concentrated under reduced pressure. 20 mL of dichloromethane was added to the residue, and saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8-9, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2D (0.24 g, yield: 97%).
  • the concentrate was further purified by preparative liquid phase (instrument: waters 2767 preparative chromatographic column: SunFire@Prep C18 (19 mm ⁇ 150 mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% TFA)), and the prepared product was lyophilized.
  • the obtained solid was dissolved in 20 mL of dichloromethane, saturated sodium bicarbonate solution (50 mL) was added, and the organic layer was dried over anhydrous sodium sulfate after separation, and concentrated under reduced pressure to obtain compound 2 (40 mg, yield: 13%).
  • Test Example 1 Proliferation Inhibitory Activity of NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) Cells
  • NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells were purchased from ATCC, and the culture medium was RPMI1640 + 10% FBS and DMEM + 10% FBS, respectively, and cultured in a 37 ° C, 5% CO 2 incubator. On the first day, NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells in the exponential growth phase were collected, and live cells were counted using an automatic cell analyzer (countstar).
  • the cell suspension was adjusted with culture medium and plated on a 96-well cell culture plate, with 1000 NCI-H1975 (EGFR-L858R-T790M) cells per well and 3000 A431 cells per well.
  • the culture medium was aspirated, and 90 ⁇ L of fresh culture medium and 10 ⁇ L of different concentrations of compounds were added to each well, with a final DMSO concentration of 0.1% per well.
  • the cells were cultured in an incubator at 37°C and 5% CO 2 for 72 hours.
  • CTG solution promega, G7572
  • 50 ⁇ L of CTG solution pre-melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes before measuring the fluorescence signal value with a microplate reader (PHERAstar FSX).
  • Cell viability was calculated using the formula V sample /V vehicle control x 100%, where V sample was the reading of the drug-treated group and V vehicle control was the average value of the solvent control group.
  • V sample was the reading of the drug-treated group and V vehicle control was the average value of the solvent control group.
  • origin9.2 software a nonlinear regression model was used to draw a S-shaped dose-survival curve and calculate the IC 50 value.
  • the compounds of the present invention have good proliferation inhibitory activity against NCI-H1975 (EGFR-L858R-T790M) cells; have poor proliferation inhibitory activity against A431 (EGFR-WT) cells, and have good selectivity, as described in Table 1.
  • Test Example 2 Proliferation Inhibitory Activity on Cells NCI-H1975 EGFR-L858R-T790M-C797S
  • Cells NCI-H1975 EGFR-L858R-T790M-C797S were cultured in a 37°C, 5% CO 2 incubator in RPMI1640+10% FBS+100 ⁇ g/mL hygromycin. Cells in the exponential growth phase were collected, and the cell suspension was adjusted to an appropriate concentration with a medium without hygromycin and plated on a 96-well plate with a density of 1500 cells/well and a volume of 90 ⁇ L. 10 ⁇ L of compounds of different concentrations were added, and a solvent control group of cells plus DMSO was set up, and the concentration of DMSO was 0.1%. The cell culture plate was placed in a 37°C, 5% CO 2 incubator for 72 hours.
  • the compounds of the present invention such as Compounds 1 to 8, have good proliferation inhibitory activity on NCI-H1975EGFR-L858R-T790M-C797S cells, as shown in Table 2.
  • This study administered the test substance to ICR mice by single-dose intravenous and oral gavage, determined the concentration of the test substance in mouse plasma, and evaluated the pharmacokinetic characteristics and bioavailability of the test substance in mice.
  • mice Male ICR mice, 20-25 g. Purchased from Beijing Huafukang Biotechnology Co., Ltd., Laboratory Animal Production License No.: SCXK (Beijing) 2019-0008; or Chengdu Dashuo Laboratory Animal Co., Ltd. (SCXK (Sichuan) 2020-030); or Hunan Slake Jingda Laboratory Animal Co., Ltd. (SCXK (Xiang) 2019-0004).
  • mice On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration, and food was resumed 4 hours after administration.
  • Test Example 5 EGFR protein degradation activity in cells H1975-EGFR-T790M-L858R-C797S
  • Protein sample preparation NCI-H1975 EGFR-L858R-T790M-C797S cells were cultured in a 37°C, 5% CO 2 incubator in a medium containing RPMI1640 + 10% FBS + 100 ⁇ g/mL hygromycin. Cells in the exponential growth phase were collected, and the cell suspension was adjusted to an appropriate concentration using a medium without hygromycin and plated on a 6-well plate at a density of 350,000 cells/well with a plate volume of 2 mL. The cells were cultured overnight in a 37°C, 5% CO 2 incubator. The next day, Add different concentrations of compounds and set up DMSO control wells to ensure that the DMSO concentration in all wells is 0.1%.
  • Western detection Add 20 ⁇ g protein sample to each well, perform polyacrylamide gel electrophoresis and transfer to membrane. After transfer, add diluted anti-EGFR (CST, Cat.4267S) and NADPH (Kangchen, Cat.KC-5G4) antibodies and incubate overnight at 4°C. After washing the membrane, add diluted goat anti-rabbit (Licor, Cat.926-32211) and goat anti-mouse (Licor, Cat.926-68070) antibodies and incubate in the dark for 45 minutes. Scan and detect with far-infrared imaging system (Odyssey) at 700nm and 800nm wavelengths.
  • Odyssey far-infrared imaging system
  • EGFR compound is the fluorescence value of EGFR protein after compound incubation
  • EGFR vehicle is the fluorescence value of EGFR protein in the DMSO control group. Origin9.2 software was used to calculate the DC 50 value of the drug concentration when the expression of EGFR protein relative to the DMSO control group was 50%.
  • EGFR% EGFR compound / EGFR vehicle ⁇ 100% Formula (3)
  • the compounds of the present invention have good degradation activity. Specifically, compound 1 has a degradation activity DC 50 ⁇ 100 nM for EGFR protein in NCI-H1975 EGFR-L858R-T790M-C797S cells.
  • Prescriptions 1-6 were added with other conventional excipients in the art, such as fillers, binders and disintegrants, and granulated with a hydropropyl methylcellulose aqueous solution, dried at 60°C to a moisture content of 2.0-4.0%, granulated, and compressed into tablets according to different specifications (100 mg, 100 mg, 20 mg, 20 mg, 10 mg) to prepare different tablets.
  • the dissolution and release determination method Method 0931, Part 4, General Rules, 2020 Edition of the Chinese Pharmacopoeia
  • different tablets were subjected to dissolution curve investigation in a pH 6.8 buffer solution containing 0.5% sodium dodecyl sulfate, and the rotation speed was 75 rpm. The results showed that the use of surfactants in the prescription greatly improved the dissolution rate of the tablet samples.
  • results As shown in Table 4, the type of filler in the prescription has an effect on the dissolution rate of the sample.
  • the dissolution rate of the water-soluble filler prescription is faster, and its dosage has no significant effect on the dissolution rate; the dissolution rate of the water-insoluble filler prescription is slower, and as its dosage increases, the sample dissolves faster.
  • the preparation samples prepared in the above examples of the present invention were orally administered to male Beagle dogs (3 dogs for each preparation) once, and venous blood was collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours.
  • the bioavailability was calculated using the area under the curve obtained by plotting the plasma concentration of compound 1 as a function of time.
  • test results show that the preparations prepared according to different prescriptions have good oral bioavailability.

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Abstract

一种药物组合物及其药物制剂，药物组合物包括式(I)化合物或其立体异构体、药学上可接受的盐和表面活性剂。药物组合物和药物制剂的制备方法及其用于制备治疗癌症如肺癌的药物中的应用。

Description

一种EGFR抑制剂的药物组合物 技术领域
本发明涉及一种式(I)化合物或其立体异构体、药学上可接受的盐的药物组合物及其制备方法和医药用途。
背景技术
表皮生长因子受体(EGFR)是一种跨膜蛋白酪氨酸激酶，可作为EGF家族成员触发人类上皮细胞中EGFR信号通路的受体，从而调节细胞增殖，侵袭，转移，凋亡和血管生成(Nat.Rev.Cancer,2007,7,169-181；Expert Opin.Ther.Targets,2012,16,15-31.)。人体内EGFR基因的过度表达、突变或扩增致使EGFR活性异常增加，会导致许多恶性肿瘤如食道癌、胶质母细胞瘤、肛门癌、头颈部上皮癌、乳腺癌、肺癌、特别是非小细胞肺癌(NSCLC)的产生(Cells,2019,8,350-361.)。
PROTAC(proteolysis targeting chimera)分子是一类能够同时结合靶向蛋白和E3泛素连接酶的双功能化合物，此类化合物能够被细胞的蛋白酶体识别，引起靶向蛋白的降解，能够有效地降低靶向蛋白在细胞中的含量。通过在PROTAC分子引入能结合不同靶向蛋白的配体，使PROTAC技术应用于各种疾病的治疗成为可能，该技术近年来同时得到了广泛的关注(ACS Chem.Biol.2017,12,892-898；Drug Discovery Today Technol.2019,31,15-27.)。
PCT/CN2022/090243专利中记载一类化合物，这类化合物对NCI-H1975(EGFR-L858R-T790M)和NCI-H1975 EGFR-L858R-T790M-C797S细胞具有优异的抑制活性。
发明内容
本发明的目的在于提供一种式(I)化合物或其立体异构体、药学上可接受的盐的药物组合物，具有良好的溶出性能和口服性能，制剂工艺简单、稳定，所得到的药物制剂稳定、杂质少、质量可控。
本发明提供一种药物组合物，包括：
a)活性成分，活性成分为式(I)化合物或其立体异构体、药学上可接受的盐：
X选自N或CH；
R1选自H、卤素、C1-4烷基、C1-4烷氧基，所述的烷基或烷氧基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
R2选自H、卤素、C1-4烷基、C1-4烷氧基、C3-6碳环基、4至6元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
作为选择，R1与R2直接连接形成C5-6碳环或者5至6元杂环，所述的碳环或者杂环任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
R3选自卤素、C1-4烷基、C1-4烷氧基，所述的烷基或烷氧基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
R4选自H、C1-4烷基、C1-4烷氧基、-O-C3-6环烷基，所述的烷基、烷氧基或环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
R5选自H、C1-4烷基、C1-4烷氧基、-O-C3-6环烷基、C3-6环烷基、4至6元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
Cy1或Cy2选自4-6元含氮杂环，所述的Cy1或Cy2任选被1至2个Rd取代；
Rd选自H、F、Cl、Br、I、OH、COOH、CN、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基；
Rk1选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基，所述的烷基、烷氧基或环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
p1选自0、1、2、3或4；
p2选自0、1、2、3或4；
n1选自0、1或2；
b)表面活性剂；
其中，活性成分在药物组合物中的含量为1％～80％w/w。
在一些实施方案中，活性成分在药物组合物中的含量为5％～60％w/w。
在一些实施方案中，活性成分在药物组合物中的含量为10％～50％w/w。
在一些实施方案中，活性成分在药物组合物中的含量为10％～30％w/w。
在一些实施方案中，活性成分以游离碱计在药物组合物中的含量为10％～25％。在一些实施方案中，式(I)化合物中：
R1选自H、F、Cl、Br、CF3、甲基或乙基；
R2选自F、Cl、Br、CF3、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、苯基，所述的甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、苯基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
R3选自F、Cl、Br；
R4选自甲氧基、乙氧基、-O-环丙基；
R5选自H、甲基、乙基、环丙基、吡唑基、吡咯基，所述的甲基、乙基、环丙基、吡唑基、吡咯基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
Cy1或Cy2各自独立的选自氮杂环丁基、氮杂环戊基、氮杂环己基或哌嗪，所述的Cy1、Cy2任选被1至2个Rd取代；
Rd选自F、Cl、Br、I、OH、CN、甲基或乙基；
Rk1选自F、Cl、Br、I、OH、NH2、甲基、乙基、甲氧基或环丙基，所述的甲基、乙基、甲氧基或环丙基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代。
在一些实施方案中，式(I)化合物选自如下结构之一：

在一些实施方案中，式(I)化合物的药学上可接受的盐选自盐酸盐、硫酸盐、甲磺酸盐、苯磺酸盐。
在一些实施方案中，式(I)化合物与药学上可接受的盐摩尔比选自1:1、1:2、1:3。
在一些实施方案中，活性成分为化合物1及其药学上可接受的盐。
在一些实施方案中，活性成分为化合物1的二甲磺酸盐。
在一些实施方案中，表面活性剂选自阴离子表面活性剂、阳离子表面活性剂、两性离子表面活性剂、非离子型表面活性剂或聚合物表面活性剂中的一种或多种。
在一些实施方案中，表面活性剂选自C5-20烷基硫酸钠、C5-20烷基磺酸钠、聚乙二醇、环氧乙烷-环氧丙烷共聚物、聚乙二醇酯、聚山梨酯、环糊精、丁二酸二辛酯磺酸钠、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物中的一种或多种。
在一些实施方案中，表面活性剂选自十二烷基硫酸钠(SLS)、聚乙二醇、泊洛沙姆、聚山梨酯80、维生素E琥珀酸聚乙二醇酯(TPGS)、β-环糊精、磺丁基-β-环糊精钠、羟丙基-β-环糊精、丁二酸二辛酯磺酸钠、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物中的一种或多种。
在一些实施方案中，表面活性剂选自十二烷基硫酸钠(SLS)。
在一些实施方案中，以游离碱计的活性成分与表面活性剂的重量比为1:1-1:10、1:1-1:5或1:1-1:4。
在一些实施方案中，以游离碱计的活性成分与表面活性剂的重量比为1:1-1:10。
在一些实施方案中，以游离碱计的活性成分与表面活性剂的重量比为1:1-1:5。
在一些实施方案中，以游离碱计的活性成分与表面活性剂的重量比为1:1-1:4。
在一些实施方案中，表面活性剂选自十二烷基硫酸钠(SLS)，以游离碱计的活性成分与十二烷基硫酸钠的重量比为1:1-1:10、1:1-1:5或1:1-1:4。
在一些实施方案中，药物组合物中进一步含有填充剂、崩解剂、黏合剂中的一种或几种。
在一些实施方案中，填充剂选自乳糖、无水磷酸氢钙、麦芽糊精、微晶纤维素、微晶纤维素胶态二氧化硅共处理物、甘露醇中的一种或多种。
在一些实施方案中，填充剂选自乳糖、微晶纤维素胶态二氧化硅共处理物。
在一些实施方案中，崩解剂选自交联聚维酮、低取代羟丙纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或多种。
在一些实施方案中，黏合剂选自聚维酮、共聚维酮、纤维素衍生物中的一种或多种；
在一些实施方案中，纤维素衍生物选自羟丙纤维素、羟丙甲纤维素。
在特定的实施方案中，药物组合物包括化合物1或其药学上可接受的盐、表面活性剂。
在特定的实施方案中，药物组合物包括化合物1的二甲磺酸盐、表面活性剂。
在特定的实施方案中，药物组合物包括化合物1或其药学上可接受的盐、SLS。
在特定的实施方案中，药物组合物包括化合物1的二甲磺酸盐、SLS。
在特定的实施方案中，药物组合物包括化合物1或其药学上可接受的盐、表面活性剂、填充剂、崩解剂、黏合剂。
在特定的实施方案中，药物组合物包括化合物1的二甲磺酸盐、表面活性剂、填充剂、崩解剂、黏合剂。
在特定的实施方案中，化合物1在药物组合物中的含量为1％～80％w/w。
在特定的实施方案中，化合物1在药物组合物中的含量为5％～60％w/w。
在特定的实施方案中，化合物1在药物组合物中的含量为10％～50％w/w。
在特定的实施方案中，化合物1在药物组合物中的含量为10％～30％w/w。
在特定的实施方案中，化合物1在药物组合物中的含量为10％～40％w/w。
在特定的实施方案中，化合物1在药物组合物中的含量为10％～25％w/w。
在特定的实施方案中，化合物1在药物组合物中的含量为10％-15％w/w、20-25％ w/w。
在特定的实施方案中，化合物1的二甲磺酸盐在药物组合物中的含量为1％～80％w/w。
在特定的实施方案中，化合物1的二甲磺酸盐在药物组合物中的含量为5％～60％w/w。
在特定的实施方案中，化合物1的二甲磺酸盐在药物组合物中的含量为10％～50％w/w。
在特定的实施方案中，化合物1的二甲磺酸盐在药物组合物中的含量为10％～40％w/w。
在特定的实施方案中，化合物1的二甲磺酸盐在药物组合物中的含量为10％～30％w/w。
在特定的实施方案中，化合物1的二甲磺酸盐在药物组合物中的含量为12％～30％w/w。
在特定的实施方案中，化合物1的二甲磺酸盐在药物组合物中的含量为12％-17％w/w、24-30％w/w。
在特定的实施方案中，化合物1的二甲磺酸盐在药物组合物中的含量为12％～25％w/w。
在特定的实施方案中，药物组合物包括化合物1的二甲磺酸盐、SLS、乳糖、微晶纤维素胶态二氧化硅共处理物、羟丙甲纤维素、交联羧甲基纤维素钠。
在特定的实施方案中，药物组合物包括化合物1的二甲磺酸盐、SLS、乳糖、微晶纤维素胶态二氧化硅共处理物、羟丙甲纤维素、交联羧甲基纤维素钠，化合物1的二甲磺酸盐在药物组合物中的含量为10％～30％w/w。
本发明涉及一种药物制剂，药物制剂中含有前述任一项药物组合物。
在一些实施方案中，单位制剂中活性成分的量以游离碱计算为1mg～800mg。
在一些实施方案中，单位制剂中活性成分的量以游离碱计算选自5mg、10mg、20mg、25mg、50mg、60mg、80mg、100mg、120mg、160mg、200mg、400mg、500mg、600mg、700mg、800mg。
在一些实施方案中，药物制剂的制剂形式选自片剂、颗粒剂、胶囊剂、干混悬剂、口服溶液、软胶囊、乳剂。
本发明涉及上述任一项药物组合物或者药物制剂在用于制备治疗与抑制或降解EGFR相关疾病的药物中的应用。
在一些实施方案中，疾病为癌症。
在一些实施方案中，疾病为肺癌。
通式(I)化合物可以通过PCT/CN2022/090243的方法制备得到。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
“药学上可接受的盐”是指安全、无毒的并且既不在生物学上也不再其它方面不合乎需要，并且包括其对于兽医使用以及人类药物使用上药学可接受的，并且具有所期望的药理学活性的盐。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。
“表面活性剂”是指包括非极性疏水部分的两亲性分子，例如与极性或离子部分(亲水)相连的含有8-18个碳原子的直或分支的碳氢化合物或碳氟化合物链，亲水性部分可以是非离子的、离子的或两性离子的并且伴有抗衡离子。非限制性实施例包括阴离子表面活性剂(如烷基磺酸盐、脂肪酸盐、硫酸酯盐)、阳离子表面活性剂(如季铵盐、胺盐)、两性离子表面活性剂(如甜菜碱类、氨基酸类、咪唑啉类)、非离子型表面活性剂(如聚氧乙烯类、脂肪醇聚氧乙烯醚类、脂肪醇聚氧乙烯酯类、烷基酚聚氧乙烯醚类、甘油脂肪酸酯、山梨醇脂肪酸酯)、聚合物表面活性剂(如环氧乙烷-环氧丙烷共聚物、环氧乙烯-聚氧丙烯嵌段共聚物)、环糊精。
具体实施方式
以下结合实施例说明本发明要解决的技术问题、技术方案及有益效果。应当理解，此处所描述的具体实施例仅用于解释本发明，并不用于限定本发明。
SLS：十二烷基硫酸钠；TPGS：维生素E琥珀酸聚乙二醇酯；HP-β-CD：羟丙基β-环糊精；SBE-β-CD：磺丁基-β-环糊精钠；
Eudragit L100：甲基丙烯酸-甲基丙烯酸甲酯共聚物；
Eudragit L100-55：甲基丙烯酸-丙烯酸乙酯共聚物；
HPMCP：邻苯二甲酸羟丙甲纤维素酯；
Soluplus:聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物；
HPMCAS:醋酸羟丙甲纤维素琥珀酸酯
HPC：羟丙纤维素；PVP-VA：共聚维酮；PVA：聚乙烯醇
实施例1：化合物的化学制备例
1.1化合物1的制备
第一步：1C的制备
将1A(16g,56.45mmol)和1B(14.8g,59.27mmol)溶于DMSO(200mL)中，加入碳酸钾(23.5g,0.17mol)，120℃搅拌反应4小时，反应液冷却至室温，加入300mL水，有黄色固体析出，抽滤，滤饼水洗3次，二氯甲烷将滤饼复溶，无水硫酸钠干燥，减压浓缩，柱层析纯化(流动相：二氯甲烷/甲醇(V/V)＝50/1-15/1)得到1C(22g，收率：76％)。
第四步：1E的制备
将1C(400g,0.78mol)、1D(158g,1.24mol)溶于1,4-二氧六环(1.6L)和水(0.4L)混合溶剂，加入碳酸钾(216g,1.56mol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(38g,0.047mol)，氮气置换3次，90℃搅拌反应过夜，反应完全后，减压浓缩后加入500mL乙酸乙酯稀释反应液，水洗3次，饱和氯化钠洗涤1次，有机相经无水硫酸钠干燥后减压浓缩得到1E粗品，加入PE/EA＝3/1混合液(1600mL)打浆 30分钟，抽滤，滤饼减压浓缩得到1E(377g，收率：94％)。
LCMS m/z＝515.3[M+H]+
第五步：1F的制备
将1E(377g,0.73mol)溶于甲醇(600mL)中，加入氯化氢-二氧六环溶液(4mol/L，2.5L)，室温下搅拌反应60min，减压浓缩得到粗品，粗品中加入水2.5L和浓盐酸500mL，乙酸乙酯(1.5L*2)萃取，水相用氢氧化钠溶液调节pH至13，二氯甲烷(1.5L*2)萃取，合并有机相并用无水硫酸钠干燥，抽滤，滤液减压浓缩得后加入PE/MTBE混合溶液(v/v＝1/1,1.2L)打浆，抽滤，滤饼减压浓缩干得1F(256g，收率：85％)。
第六步：1G的制备
将1F(120g，0.29mol)溶于DMSO(600mL)中，依次加入2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(80g,0.29mmol)和二异丙基乙胺(112g,0.87mmol)，100℃反应过夜。加入2.0L水，析出固体，抽滤，滤饼用200mL二氯甲烷溶解、萃取，有机相用无水硫酸钠干燥后，减压浓缩，用硅胶柱层析纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-10/1)得到1G(186g，收率：96％)。
第七步：1H的制备
将1G(130g,0.19mmol)溶于THF(1.3L)和水(400mL)的混合液中，加入氯化铵(51g，0.95mmol)和锌粉(62g，0.95mmol)，缓慢升温至40-60℃反应1-2小时，反应液冷却至室温，过滤，滤饼用1L的DCM洗涤，合并有机相，有机相用依次用0.5L氨水和0.5L饱和食盐水洗涤，无水硫酸钠干燥后减压浓缩，得到1H，黄色固体。
LCMS m/z＝641.3[M+H]+
第八步：化合物1的制备
将1H(80g,126mmol)和1M(51g,126mmol)溶于DMF(500mL)中，加入对甲苯磺酸一水合物(48g,252mmol)，100℃反应过夜。冷却至室温，缓慢加入800mL的饱和碳酸氢钠水溶液，抽滤，滤饼用二氯甲烷溶解、萃取，有机相用无水硫酸钠干燥后，减压浓缩，用硅胶柱层析纯化(二氯甲烷/甲醇(V/V)＝100/1-100/4),柱层析得到64g化合物1(64g，收率：50％)。
通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物1的化学位移5.12(dd,J＝12.9,5.4Hz,1H)为38号位置的—CH峰，2.70(s,6H)的峰为甲磺酸的峰，其比例 为1:6，故可解析得到化合物1与甲磺酸的比例为1:2。
1.2化合物2的制备
第一步：2C的制备
将2A(1.23g,4.57mmol)，2B(0.96g,3.80mmol)和碳酸钾(1.58g,11.41mmol)混合溶于DMSO(20mL)中，120℃搅拌过夜。冷却至室温，加入50mL水和50mL乙酸乙酯萃取，有机层减压浓缩，残留物柱层析纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-20/1)得到2C(970mg，收率：62％)。
LCMS m/z＝501.5[M+H]+。
第二步：2D的制备
将2C(0.31g,0.62mmol)溶于二氯甲烷(10mL)，室温下加入三氟乙酸(0.71g,6.2mmol)，搅拌1h，减压浓缩，残留物加入20mL二氯甲烷，加入饱和碳酸氢钠水溶液，调节pH＝8-9，用二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，得到2D(0.24g，收率：97％)。
LCMS m/z＝401.2[M+H]+。
第三步：2E的制备
将2D(1.0g,2.50mmol)溶于DMSO(20mL)中，依次加入2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(828mg,3.00mmol)和碳酸氢钠(692mg,8.24mmol)，100℃搅拌5h。冷却至室温，加入30mL水，过滤，滤饼减压干燥后，用硅胶柱层 析纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-20/1)得到2E(0.90g，收率：55％)。
LCMS m/z＝657.3[M+H]+。
第四步：2F的制备
将2E(0.90g,1.37mmol)溶于乙醇/水(20mL，3:1)中，依次加入铁粉(375mg，6.71mmol)，氯化铵(361mg，6.75mmol)，氮气保护，80℃搅拌1h。冷却至室温，减压抽滤，滤液减压浓缩后，粗品用硅胶柱层析纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-20/1)得到2F(700mg，收率：82％)。
LCMS m/z＝627.3[M+H]+。
第五步：化合物2的制备
将2F(200mg,0.32mmol)和2G(180mg,0.46mmol)溶于DMF(10mL)中，加入对甲苯磺酸一水合物(160mg,0.84mmol)，氮气保护下100℃搅拌16h。冷却至室温，加入10mL饱和碳酸氢钠水溶液和20mL二氯甲烷分层，有机层减压浓缩。将浓缩液进一步制备液相纯化(仪器：waters 2767制备色谱柱：SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.1％TFA))，将制备所得冻干。将所得固体溶于20mL二氯甲烷，加入饱和碳酸氢钠溶液(50mL)，萃取，分液后有机层用无水硫酸钠干燥，减压浓缩，得到化合物2(40mg，收率：13％)。
LCMS m/z＝491.7[(M+2H)/2]+。
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),11.06(s,1H),8.55-8.41(m,1H),8.28(s,1H),8.11(s,1H),8.03(s,1H),7.88(s,1H),7.76-7.65(m,2H),7.65-7.51(m,3H),7.46(t,2H),7.41-7.33(m,2H),7.31-7.11(m,2H),6.85(s,1H),5.08(dd,1H),3.80(s,3H),3.77(s,3H),3.53-3.39(m,4H),3.19-3.05(m,2H),2.97-2.83(m,1H),2.74-2.51(m,8H),2.36-2.22(m,1H),2.08-1.92(m,1H),1.89-1.74(m,8H),1.67-1.53(m,2H)。
化合物3-8参考化合物1的制备方法得到。

实施例2：化合物1的二甲磺酸盐的制备
20g化合物1加入至有机溶剂中，加入甲基磺酸4.21g(2.2eq)升温至55℃搅拌1-2h。降温至40℃左右，保持内温搅拌1-2h，随后降温至20℃左右，抽滤，干燥得21.18g化合物1的二甲磺酸盐。
实施例3：生物活性测试
测试例1：NCI-H1975(EGFR-L858R-T790M)和A431(EGFR-WT)细胞的增殖抑制活性
NCI-H1975(EGFR-L858R-T790M)和A431(EGFR-WT)细胞购自于ATCC，培养基分别为RPMI1640+10％FBS和DMEM+10％FBS，于37℃，5％CO2孵箱中培养。第一天，收集处于指数生长期的NCI-H1975(EGFR-L858R-T790M)和A431(EGFR-WT)细胞，用自动细胞分析仪(countstar)进行活细胞计数。用培养基将细胞悬液调整后铺板96孔细胞培养板，NCI-H1975(EGFR-L858R-T790M)细胞每孔1000个，A431细胞每孔3000个。第二天，吸去培养基，每孔加入90μL新鲜培养基和10μL不同浓度化合物，每孔DMSO终浓度为0.1％。于37℃，5％CO2孵箱中培养72小时。药物处理72小时后，每孔加入50μL预先融化并平衡到室温的CTG溶液(promega，G7572)，用微孔板震荡器混匀2min，于室温放置10min后用酶标仪(PHERAstar FSX)测定荧光信号值。
细胞存活率用公式Vsample/Vvehicle control x100％计算。其中Vsample为药物处理组的读数，Vvehicle control为溶剂对照组的平均值。应用origin9.2软件,使用非线性回归模型绘制S型剂量-存活率曲线并计算IC50值。
表1对NCI-H1975(EGFR-L858R-T790M)与A431(EGFR-WT)细胞的增殖抑制活性结果
结论：本发明化合物例如化合物1至化合物8对NCI-H1975(EGFR-L858R-T790M)细胞具有良好的增殖抑制活性；对A431(EGFR-WT)细胞增殖抑制活性差，具有良好的选择性，具体的如表1所述。
测试例2:对细胞NCI-H1975 EGFR-L858R-T790M-C797S的增殖抑制活性
细胞NCI-H1975 EGFR-L858R-T790M-C797S培养于37℃，5％CO2孵箱中，培养基为RPMI1640+10％FBS+100μg/mL潮霉素。收集处于指数生长期的细胞，用不含潮霉素的培养基将细胞悬液调整到适当浓度后铺板96孔板，铺板密度为1500个/孔，体积90μL。加入10μL不同浓度的化合物，并设置细胞加DMSO的溶媒对照组，DMSO的浓度均为0.1％。细胞培养板置于37℃，5％CO2孵箱中培养72小时。培养结束后，按照CellTiter-Glo试剂盒(Promega，G7572)操作说明，每孔加入50μL预先融化并平衡到室温的CTG溶液，用微孔板震荡器混匀2min，于室温放置10min后用酶标仪(Envision2104)测定荧光信号值。细胞存活率(Surviving cells％)数据采用式(2)处理，并使用GraphPad Prism 5.0软件，使用非线性回归模型绘制S型剂量-存活率曲线并计算IC50值。其中Vsample为药物处理组的读数，Vvehicle control为对照组的读数。
Surviving cells％＝Vsample/Vvehicle control x100％  (式2)
表2对细胞NCI-H1975 EGFR-L858R-T790M-C797S的增殖抑制活性

结论：本发明化合物例如化合物1至化合物8对细胞NCI-H1975EGFR-L858R-T790M-C797S具有良好的增殖抑制活性，具体的如表2所示。
测试例3：小鼠药代动力学测试
实验目的：本试验通过单剂量静脉和灌胃给予受试物于ICR小鼠，测定小鼠血浆中受试物的浓度，评价受试物在小鼠体内药代特征和生物利用度。
试验动物：雄性ICR小鼠，20～25g。购自北京华阜康生物科技股份有限公司，实验动物生产许可证号：SCXK(京)2019-0008；或者成都达硕实验动物有限公司(SCXK(川)2020-030)；或湖南斯莱克景达实验动物有限公司(SCXK(湘)2019-0004)。
试验方法：试验当天，ICR小鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h恢复给食。
表3给药信息
取样：于给药前及给药后异氟烷麻醉经眼眶取血，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。采集血浆时间点：0,5min,15min,30min,1,2,4,6,8,24h；
分析检测前，所有样品存于-80℃。用LC-MS/MS对样品进行定量分析。
结论：本发明化合物例如化合物1至化合8在大鼠体内具有良好的吸收性能，例如化合物1大鼠灌胃10mg/kg后，AUC(ng.h.mL-1)＝144575，T1/2(h)＝18，化合物2大鼠灌胃10mg/kg后，AUC(ng.h.mL-1)＝51014。
测试例5：对细胞H1975-EGFR-T790M-L858R-C797S中EGFR蛋白降解活性
蛋白样品制备：细胞NCI-H1975 EGFR-L858R-T790M-C797S培养于37℃，5％CO2孵箱中，培养基为RPMI1640+10％FBS+100μg/mL潮霉素。收集处于指数生长期的细胞，用不含潮霉素的培养基将细胞悬液调整到适当浓度后铺板6孔板，铺板密度为350000个/孔，铺板体积2mL，过夜培养于37℃、5％CO2培养箱中。第二天， 加入不同浓度的化合物并设置DMSO对照孔，确保所有孔的DMSO浓度均为0.1％。将6孔板置于37℃、5％CO2培养箱中培养48h后，加入30μL含有蛋白酶抑制剂(碧云天，Cat.P0013B)的RIPA裂解液(碧云天，Cat.P0013B)，冰上裂解30min。于4℃，13000转/分钟离心20分钟，收集蛋白上清样品，用BCA法进行蛋白定量，制备Western Blot检测样品。
Western检测：每孔加入20μg蛋白样品，聚丙烯酰胺凝胶电泳并转膜。转膜结束后加入稀释后的抗EGFR(CST，Cat.4267S)和NADPH(Kangchen，Cat.KC-5G4)抗体，4℃过夜孵育。洗膜后加入稀释后的羊抗兔(Licor，Cat.926-32211)和羊抗鼠(Licor，Cat.926-68070)抗体，避光孵育45min。用远红外成像系统(Odyssey)在700nm和800nm波长下扫描检测。
根据式(3)计算不同浓度化合物孵育后，细胞中EGFR蛋白相对与DMSO对照组的表达量。其中EGFRcompound为化合物孵育后EGFR蛋白的荧光值，EGFRvehicle为DMSO对照组EGFR蛋白的荧光值。使用Origin9.2软件计算EGFR蛋白相对DMSO对照组表达量为50％时的药物浓度DC50值。
EGFR％＝EGFRcompound/EGFRvehicle×100％式(3)
结论：本发明化合物例如化合物1至化合8具有良好的降解活性，具体的如化合物1对细胞NCI-H1975 EGFR-L858R-T790M-C797S中EGFR蛋白降解活性DC50<100nM.
实施例4：组合物
4.1表面活性剂筛选

将处方1-6增加本领域常规的其它辅料，例如填充剂、粘合剂与崩解剂等，以羟丙甲纤维素水溶液湿法制粒，60℃干燥至水分2.0～4.0％，整粒，按照不同规格(100mg、100mg、20mg、20mg、10mg压片，制备得到不同的片剂。照溶出度与释放度测定法(中国药典2020年版四部通则0931第二法)，将不同片剂在含0.5％十二烷基硫酸钠的pH6.8缓冲液中进行溶出曲线考察转速均为75rpm。结果表明：处方中表面活性剂的使用，大大改善了片剂样品的溶出速率。
4.2不同处方实施例
将处方13～15在含0.5％十二烷基硫酸钠的pH6.8缓冲液中进行溶出曲线考察， 结果见表4：
表4处方13～15的溶出结果
结果：由表4可知，处方中填充剂的种类对样品的溶出速率存在影响。水溶性填充剂处方溶出速率较快，且其用量对溶出速率无明显影响；水不溶性填充剂处方溶出速率较慢，随着其用量增加，样品溶出较快。
生物测试例
将本发明前述实施例制备得到制剂样品单次给与雄性Beagle犬口服(每个制剂3只)，于0、0.25、0.5、1、2、4、6、8、10、12、24、48h时取静脉血，以化合物1血浆浓度作为时间的函数所做的点得到的曲线下面积计算生物利用度。
试验结果表明，根据不同处方制备得到的制剂均具有较好的口服生物利用度。

Claims (12)

  1. 一种药物组合物，包括：
    a)活性成分，活性成分为式(I)化合物或其立体异构体、药学上可接受的盐：
    X选自N或CH；
    R1选自H、卤素、C1-4烷基、C1-4烷氧基，所述的烷基或烷氧基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
    R2选自H、卤素、C1-4烷基、C1-4烷氧基、C3-6碳环基、4至6元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
    作为选择，R1与R2直接连接形成C5-6碳环或者5至6元杂环，所述的碳环或者杂环任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
    R3选自卤素、C1-4烷基、C1-4烷氧基，所述的烷基或烷氧基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
    R4选自H、C1-4烷基、C1-4烷氧基、-O-C3-6环烷基，所述的烷基、烷氧基或环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
    R5选自H、C1-4烷基、C1-4烷氧基、-O-C3-6环烷基、C3-6环烷基、4至6元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
    Cy1或Cy2选自4-6元含氮杂环，所述的Cy1或Cy2任选被1至2个Rd取代；
    Rd选自H、F、Cl、Br、I、OH、COOH、CN、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基；
    Rk1选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基，所述的烷基、烷氧基或环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
    p1选自0、1、2、3或4；
    p2选自0、1、2、3或4；
    n1选自0、1或2；
    b)表面活性剂；
    其中，活性成分在药物组合物中的含量为1％～80％w/w，优选为5％～60％w/w，更优选为10％～50％w/w。
  2. 根据权利要求1所述的药物组合物，其中，
    R1选自H、F、Cl、Br、CF3、甲基或乙基；
    R2选自F、Cl、Br、CF3、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、苯基，所述的甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、苯基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
    R3选自F、Cl、Br；
    R4选自甲氧基、乙氧基、-O-环丙基；
    R5选自H、甲基、乙基、环丙基、吡唑基、吡咯基，所述的甲基、乙基、环丙基、吡唑基、吡咯基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
    Cy1或Cy2各自独立的选自氮杂环丁基、氮杂环戊基、氮杂环己基或哌嗪，所述的Cy1、Cy2任选被1至2个Rd取代；
    Rd选自F、Cl、Br、I、OH、CN、甲基或乙基；
    Rk1选自F、Cl、Br、I、OH、NH2、甲基、乙基、甲氧基或环丙基，所述的甲基、乙基、甲氧基或环丙基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代。
  3. 根据权利要求1所述的口服药物组合物，式(I)化合物选自如下结构之一：
  4. 根据权利要求1所述的药物组合物，式(I)化合物的药学上可接受的盐选自盐酸盐、硫酸盐、甲磺酸盐、苯磺酸盐。
  5. 根据权利要求4所述的药物组合物，式(I)化合物与药学上可接受的盐摩尔比选自1:1、1:2、1:3。
  6. 根据权利要求1所述的药物组合物，所述的表面活性剂选自阴离子表面活性剂、阳离子表面活性剂、两性离子表面活性剂、非离子型表面活性剂或聚合物表面活性剂中的一种或多种，优选C5-20烷基硫酸钠、C5-20烷基磺酸钠、聚乙二醇、环氧乙烷-环氧丙烷共聚物、聚乙二醇酯、聚山梨酯、环糊精、丁二酸二辛酯磺酸钠、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物中的一种或多种优选地，所述的表面活性剂选自十二烷基硫酸钠(SLS)、聚乙二醇、泊洛沙姆、聚山梨酯80、维生素E琥珀酸聚乙二醇酯(TPGS)、β-环糊精、磺丁基-β-环糊精钠、羟丙基-β-环糊精、丁二酸二辛酯磺酸钠、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物中的一种或多种。
  7. 根据权利要求1所述的药物组合物，药物组合物中进一步含有填充剂、崩解剂、黏合剂中的一种或几种，
    优选地，所述的填充剂选自乳糖、无水磷酸氢钙、麦芽糊精、微晶纤维素、微晶 纤维素胶态二氧化硅共处理物、甘露醇中的一种或多种；
    所述的崩解剂选自交联聚维酮、低取代羟丙纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或多种；
    所述的黏合剂选自聚维酮、共聚维酮、纤维素衍生物中的一种或多种；所述纤维素衍生物选自羟丙纤维素、羟丙甲纤维素。
  8. 一种药物制剂，该药物制剂中含有权利要求1至7任一项所述的药物组合物。
  9. 根据权利要求8所述的药物制剂，单位制剂中活性成分的量以游离碱计算为1mg～800mg，优选为5mg、10mg、20mg、25mg、50mg、60mg、80mg、100mg、120mg、160mg、200mg、400mg、500mg、600mg、700mg、800mg。
  10. 根据权利要求8所述的药物制剂，该药物制剂的制剂形式选自片剂、颗粒剂、胶囊剂、干混悬剂、口服溶液、软胶囊、乳剂。
  11. 权利要求1-7任意一项所述的药物组合物或者权利要求8-9任意一项所述的药物制剂在用于制备治疗与抑制或降解EGFR相关疾病的药物中的应用。
  12. 根据权利要求11所述的应用，所述的疾病为癌症，优选肺癌。
PCT/CN2023/125386 2022-10-20 2023-10-19 一种egfr抑制剂的药物组合物 WO2024083184A1 (zh)

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Publication number Priority date Publication date Assignee Title
CN107613978A (zh) * 2015-05-28 2018-01-19 正大天晴药业集团股份有限公司 Mek抑制剂的药物组合物及其制备方法
CN108653231A (zh) * 2017-04-01 2018-10-16 北京赛林泰医药技术有限公司 含有布鲁顿酪氨酸激酶抑制剂的组合物及其制备方法
WO2020236083A1 (en) * 2019-05-22 2020-11-26 Agency For Science, Technology And Research Oral formulations, methods of manufacture and uses thereof
CN114805303A (zh) * 2021-01-20 2022-07-29 海思科医药集团股份有限公司 一种具有降解egfr双功能分子及其组合物和药学上的应用
WO2022194269A1 (zh) * 2021-03-19 2022-09-22 上海齐鲁制药研究中心有限公司 新型egfr降解剂

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107613978A (zh) * 2015-05-28 2018-01-19 正大天晴药业集团股份有限公司 Mek抑制剂的药物组合物及其制备方法
CN108653231A (zh) * 2017-04-01 2018-10-16 北京赛林泰医药技术有限公司 含有布鲁顿酪氨酸激酶抑制剂的组合物及其制备方法
WO2020236083A1 (en) * 2019-05-22 2020-11-26 Agency For Science, Technology And Research Oral formulations, methods of manufacture and uses thereof
CN114805303A (zh) * 2021-01-20 2022-07-29 海思科医药集团股份有限公司 一种具有降解egfr双功能分子及其组合物和药学上的应用
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