WO2024083183A1 - Sel et forme cristalline d'un dérivé phosphonyle et leur utilisation en médecine - Google Patents

Sel et forme cristalline d'un dérivé phosphonyle et leur utilisation en médecine Download PDF

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WO2024083183A1
WO2024083183A1 PCT/CN2023/125385 CN2023125385W WO2024083183A1 WO 2024083183 A1 WO2024083183 A1 WO 2024083183A1 CN 2023125385 W CN2023125385 W CN 2023125385W WO 2024083183 A1 WO2024083183 A1 WO 2024083183A1
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salt
formula
compound represented
compound
ray powder
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PCT/CN2023/125385
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English (en)
Chinese (zh)
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宫正
蒋西
蒋琦
胡健涌
范江
窦赢
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西藏海思科制药有限公司
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Publication of WO2024083183A1 publication Critical patent/WO2024083183A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system

Definitions

  • the present invention relates to the field of medicine, and in particular to a salt and a crystal form of a compound represented by formula (I) and a preparation method thereof, as well as a pharmaceutical composition and application thereof in medicine.
  • Epidermal growth factor receptor is a transmembrane protein tyrosine kinase that can act 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.).
  • PROTAC proteolysis targeting chimera
  • PROTAC technology By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology can be used to treat 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.).
  • PCT/CN2022/090243 describes a compound represented by formula (I), which is a Protacs small molecule with good EGFR inhibition and degradation activity.
  • the purpose of the present invention is to provide a pharmaceutically acceptable salt of a compound represented by formula (I), a crystal form thereof, and a preparation method thereof, a pharmaceutical composition thereof, and use thereof in preparing drugs for EGFR-related diseases such as cancer diseases.
  • the advantages of the compound represented by formula (I) or the pharmaceutically acceptable salt of its stereoisomer and its solvate and the crystalline or amorphous form of the compound represented by formula (I) include but are not limited to easy processing and crystallization, convenient handling, easy purification, easy industrialization, good fluidity, easy micronization, high solubility, good pharmacokinetic properties and good stability, and are suitable for preparing pharmaceutical preparations.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt of its stereoisomer and a solvate thereof.
  • the pharmaceutically acceptable salt is selected from maleate, 2-naphthalenesulfonate, 1,5-naphthalene disulfonate, fumarate, hydrohalide (preferably hydrobromide and hydrochloride), sulfate, phosphate, L-tartrate, citrate, L-malate, hippurate, D-glucuronate, glycolate, mucate, succinate, lactate, orotate, pamoate, glycinate, alanine, arginine, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetate, propionate, valerate, triphenylacetate, L-proline, ferulate, 2-hydroxyethanesulfonate, mandelate, nitrate, methanesulfonate, malonate, gentisate, salicylate, oxalate, or glutarate;
  • hydrohalide preferably hydrobromide and hydro
  • the pharmaceutically acceptable salt is selected from benzenesulfonate, L-malate, phosphate, sulfate, p-toluenesulfonate, hydrochloride, maleate, 2-naphthalenesulfonate, hydrobromide, methanesulfonate, citrate, mandelate, lactobionate, succinate, salicylate, 1,5-naphthalenedisulfonate, fumarate, nicotinate, hippurate, and oxalate;
  • the pharmaceutically acceptable salt is selected from the group consisting of methanesulfonate, maleate, 2-naphthalenesulfonate, oxalate;
  • the pharmaceutically acceptable salt is selected from the group consisting of mesylate;
  • the molar ratio of the compound represented by formula (I): the pharmaceutically acceptable salt is 1:0.5 to 1:3.5;
  • the molar ratio of the compound represented by formula (I): the pharmaceutically acceptable salt is 1:1, 1:2, 1:3;
  • the pharmaceutically acceptable salt is selected from a methanesulfonate salt, and the molar ratio of the compound represented by formula (I): methanesulfonic acid is 1:1, 1:2, 1:3;
  • the pharmaceutically acceptable salt is selected from a methanesulfonate salt, and the molar ratio of the compound represented by formula (I): methanesulfonic acid is 1:2;
  • the pharmaceutically acceptable salt is selected from maleate, and the molar ratio of the compound represented by formula (I): maleic acid is 1:2 or 1:1;
  • the pharmaceutically acceptable salt is selected from 2-naphthalenesulfonate, and the molar ratio of the compound represented by formula (I): 2-naphthalenesulfonic acid is 1:1, 1:2;
  • the pharmaceutically acceptable salt is selected from oxalates, and the molar ratio of the compound represented by formula (I): oxalic acid is 1:1;
  • the pharmaceutically acceptable salt is selected from benzenesulfonate, and the molar ratio of the compound represented by formula (I): benzenesulfonic acid is 1:1, 1:2 or 1:3;
  • the pharmaceutically acceptable salt is selected from L-malate, and the molar ratio of the compound represented by formula (I): L-malic acid is 1:2;
  • the pharmaceutically acceptable salt is selected from phosphates, and the molar ratio of the compound represented by formula (I): phosphoric acid is 1:1, 1:2;
  • the pharmaceutically acceptable salt is selected from sulfates, and the molar ratio of the compound represented by formula (I): sulfuric acid is 1:1, 1:2 or 1:3;
  • the pharmaceutically acceptable salt is selected from p-toluenesulfonate, and the molar ratio of the compound represented by formula (I): p-toluenesulfonic acid is 1:1, 1:2;
  • the pharmaceutically acceptable salt is selected from hydrochloride, and the molar ratio of the compound represented by formula (I): hydrochloric acid is 1:1, 1:2 or 1:3;
  • the pharmaceutically acceptable salt is selected from maleate salts, and the molar ratio of the compound represented by formula (I): maleic acid is 1:1, 1:2;
  • the pharmaceutically acceptable salt is selected from hydrobromide, and the molar ratio of the compound represented by formula (I): hydrobromic acid is 1:1, 1:2 or 1:3;
  • the pharmaceutically acceptable salt is selected from a methanesulfonate salt, and the molar ratio of the compound represented by formula (I): methanesulfonic acid is 1:1, 1:2 or 1:3;
  • the pharmaceutically acceptable salt is selected from citrate, and the molar ratio of the compound represented by formula (I): citric acid is 1:1, 1:2;
  • the pharmaceutically acceptable salt is selected from mandelate, and the molar ratio of the compound represented by formula (I): mandelic acid is 1:1, 1:2;
  • the pharmaceutically acceptable salt is selected from succinate, and the molar ratio of the compound represented by formula (I): succinic acid is 1:1, 1:2 or 1:3;
  • the pharmaceutically acceptable salt is selected from fumarate, and the molar ratio of the compound represented by formula (I): fumaric acid is 1:0.5, 1:2;
  • the pharmaceutically acceptable salt is selected from hippurate, and the molar ratio of the compound represented by formula (I): hippuric acid is 1:1;
  • the pharmaceutically acceptable salt is selected from salicylates, and the molar ratio of the compound represented by formula (I): salicylic acid is 1:1;
  • the pharmaceutically acceptable salt is selected from 1,5-dinaphthylidenesulfonate, and the molar ratio of the compound represented by formula (I): 1,5-dinaphthylidenesulfonic acid is 1:1, 1:2;
  • the pharmaceutically acceptable salt is selected from nicotinate, and the molar ratio of the compound represented by formula (I): nicotinic acid is 1:3;
  • the pharmaceutically acceptable salts described above are amorphous.
  • the present invention relates to a maleate crystalline form 1 of a compound represented by formula (I); in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2 ⁇ positions: 14.83° ⁇ 0.2°, 16.53° ⁇ 0.2°, 20.34° ⁇ 0.2°, 22.87° ⁇ 0.2°, and 23.92° ⁇ 0.2°; in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2 ⁇ positions: 4.77° ⁇ 0.2°, 6.75° ⁇ 0.2°, 8.80° ⁇ 0.2°, 14.83° ⁇ 0.2°, 16.53° ⁇ 0.2°, 20.34° ⁇ 0.2°, 22.87° ⁇ 0.2°, and 23.92° ⁇ 0.2°.
  • its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.77° ⁇ 0.2°, 6.75° ⁇ 0.2°, 8.80° ⁇ 0.2°, 10.97° ⁇ 0.2°, 14.83° ⁇ 0.2°, 16.53° ⁇ 0.2°, 16.97° ⁇ 0.2°, 18.68° ⁇ 0.2°, 20.34° ⁇ 0.2°, 21.08° ⁇ 0.2°, 22.87° ⁇ 0.2°, 23.92° ⁇ 0.2°, 24.61° ⁇ 0.2°; in some embodiments, Cu-K ⁇ radiation is used, and its X-ray powder diffraction pattern is shown in Figure 1.
  • the present invention relates to a dimaleate crystalline form 1 of a compound represented by formula (I); in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2 ⁇ positions: 4.18° ⁇ 0.2°, 8.24° ⁇ 0.2°, 18.40° ⁇ 0.2°, 20.48° ⁇ 0.2°, 21.96° ⁇ 0.2°; in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2 ⁇ positions: 4.18° ⁇ 0.2°, 8.24° ⁇ 0.2°, 18.40° ⁇ 0.2°, 18.80° ⁇ 0.2°, 20.48° ⁇ 0.2°, 21.96° ⁇ 0.2°, 23.66° ⁇ 0.2°, 24.34° ⁇ 0.2°; In some embodiments, Cu-K ⁇ radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.18° ⁇ 0.2°, 8.24° ⁇ 0.2°, 12.30
  • the present invention relates to a 2-naphthalenesulfonate salt crystal form 1 of a compound represented by formula (I); in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2 ⁇ positions: 5.82° ⁇ 0.2°, 17.52° ⁇ 0.2°, 20.13° ⁇ 0.2°, 21.16° ⁇ 0.2°, and 26.80° ⁇ 0.2°; in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2 ⁇ positions: 5.82° ⁇ 0.2°, 12.58° ⁇ 0.2°, 14.92° ⁇ 0.2°, 17.52° ⁇ 0.2°, 20.13° ⁇ 0.2°, 21.16° ⁇ 0.2°, 22.95° ⁇ 0.2°, 26.80 ° ⁇ 0.2°; in some embodiments, Cu-K ⁇ radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.82° ⁇ 0.2
  • the present invention relates to an oxalate crystal form 1 of a compound represented by formula (I); in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 19.69° ⁇ 0.2°, 20.07° ⁇ 0.2°, 23.75° ⁇ 0.2°, 24.45° ⁇ 0.2°, 26.82° ⁇ 0.2°; in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 13.79° ⁇ 0.2°, 17.86° ⁇ 0.2°, 19.69° ⁇ 0.2°, 20.07° ⁇ 0.2°, 23.75° ⁇ 0.2°, 24.45° ⁇ 0.2°, 24.82° ⁇ 0.2°, 26.82° ⁇ 0.2°, 27.07° ⁇ 0.2°; in some embodiments, Cu-K ⁇ radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.91° ⁇
  • the present invention relates to an amorphous dimethanesulfonate of a compound represented by formula (I), and its X-ray powder diffraction pattern is shown in FIG36 .
  • the present invention relates to a crystalline form 1 of a compound represented by formula (I); in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.03° ⁇ 0.2°, 15.35° ⁇ 0.2°, 19.43° ⁇ 0.2°, 19.88° ⁇ 0.2°; in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 2°, 5.03° ⁇ 0.2°, 8.03° ⁇ 0.2°, 13.25° ⁇ 0.2°, 14.57° ⁇ 0.2°, 14.88° ⁇ 0.2°, 15.35° ⁇ 0.2°, 19.43° ⁇ 0.2°, 19.88° ⁇ 0.2°, 23.83 ⁇ 0.2°, 24.71° ⁇ 0.2°, 26.44° ⁇ 0.2°, 29.93° ⁇ 0.2°; in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions:
  • the present invention relates to a method for preparing a pharmaceutically acceptable salt of a compound represented by formula (I), wherein the method comprises: a step of forming a salt using the compound represented by formula (I) and an acid; in some embodiments, the solvent used is selected from one or more of C1-6 halogenated alkane solvents, C2-6 ester solvents, C2-6 ether solvents, C1-6 alcohol solvents or water; in some embodiments, the solvent used is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, propanol, ether, tetrahydrofuran and water.
  • the present invention relates to a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of a crystalline or amorphous pharmaceutically acceptable salt of any one of the compounds represented by formula (I) above, and a pharmaceutically acceptable carrier or excipient.
  • the present invention relates to the use of a crystalline or amorphous pharmaceutically acceptable salt of any one of the compounds represented by formula (I) or the pharmaceutical composition described above in the preparation of a drug for treating diseases (preferably cancer) related to the inhibition or degradation of EGFR.
  • the present invention relates to the use of a crystalline or amorphous pharmaceutically acceptable salt of any one of the compounds represented by formula (I) or the pharmaceutical composition described above in the preparation of a drug for treating diseases (preferably cancer) related to the inhibition or degradation of EGFR.
  • the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation strength").
  • Effective amount or “therapeutically effective amount” as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition (e.g., cancer) being treated to some extent.
  • the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system.
  • an "effective amount” for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg, 4-500 mg, 5-500 mg, 6-500 mg, 10-500 mg g, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg,
  • examples of therapeutically effective amounts include, but are not limited to, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg.
  • a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of a pharmaceutically acceptable salt or cocrystal of the compound of the present invention, preferably 1-800 mg, wherein the disease is preferably a disease related to the inhibition or degradation of EGFR (preferably cancer).
  • a method for treating a disease in a mammal comprising administering a pharmaceutically acceptable salt or co-crystal of a compound of the present invention to a subject at a daily dose of 1-1000 mg/day
  • the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 25-400 mg/day, 50- 400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments, daily doses include but are not limited to 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200 mg/day, 300 mg/day, 320 mg/day, 400 mg/day, 480 mg/day, 600 mg/day, 640 mg/day
  • the present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a pharmaceutically acceptable salt or co-crystal of the compound of the present invention, and the amount of the pharmaceutically acceptable salt or co-crystal of the compound of the present invention is the same as that in the above-mentioned pharmaceutical composition.
  • the crystal form of the compound shown in formula (I) of the present invention has excellent physical properties, including but not limited to solubility, dissolution rate, light resistance, low hygroscopicity, high temperature resistance, and high humidity resistance.
  • the crystal form of the present invention can significantly reduce the filtration time, shorten the production cycle, and save costs during the preparation process.
  • the crystal form of the present invention also has good light stability, thermal stability, and wet stability, which can ensure the reliability of the crystal form during storage and transportation, thereby ensuring the safety of the preparation, and the crystal form does not need to be specially packaged to prevent the influence of light, temperature, and humidity, thereby reducing costs.
  • the crystal form will not be degraded due to the influence of light, high temperature, and high humidity, thereby improving the safety of the preparation and the effectiveness after long-term storage. Patients taking the crystal form will not worry about the photosensitivity reaction of the preparation due to exposure to sunlight.
  • the crystalline form of the compound represented by formula (I) of the present invention degrades very little or less when stored or transported at ambient temperature, has good thermal stability, can be stably maintained for a long time, and is suitable for standard preparation production processes.
  • the crystal form of the compound represented by formula (I) described in the present invention is suitable and convenient for mass preparation.
  • the preparation prepared using the aforementioned crystal form can reduce irritation and improve absorption, so that the problem of metabolic rate can be solved, toxicity can be significantly reduced, safety can be improved, and the quality and efficacy of the preparation can be effectively guaranteed.
  • the crystalline structure of the present invention can be analyzed using various analytical techniques known to those skilled in the art, including but not limited to, X-ray powder diffraction (XRD), ion chromatography (IC), differential scanning calorimetry (DSC) and/or thermogravimetric analysis (TGA), also known as thermogravimetry (TG).
  • XRD X-ray powder diffraction
  • IC ion chromatography
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • TG thermogravimetric analysis
  • crystal forms of the present invention are not limited to characteristic spectra that are completely identical to the characteristic spectra described in the accompanying drawings disclosed in the present invention, such as XRD, DSC, TGA, and any crystal forms having characteristic spectra that are substantially the same or essentially the same as those described in the accompanying drawings fall within the scope of the present invention.
  • the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compound of the present invention is characterized by a DSC pattern with a characteristic peak position, having substantially the same properties as the DSC pattern provided in the accompanying drawings of the present invention, with an error tolerance of ⁇ 3 ° C.
  • the terms "about” and “approximately” used herein generally refer to the numerical value of the variable and all numerical values of the variable within experimental error (e.g., within a 95% confidence interval for the mean value) or within ⁇ 10% of the specified numerical value, or a wider range.
  • amorphous refers to any solid material that is not ordered in three dimensions.
  • amorphous solids can be characterized by known techniques, including XRPD crystal diffraction analysis, differential scanning calorimetry (DSC), solid-state nuclear magnetic resonance (ssNMR) spectroscopy, or a combination of these techniques. As described below, the XRPD pattern produced by an amorphous solid has no obvious diffraction characteristic peaks.
  • crystalline form or “crystal” refers to any solid material that exhibits a three-dimensional ordering, in contrast to an amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.
  • seed crystals refer to the formation of crystal nuclei by adding insoluble additives in the crystallization method, which accelerates or promotes the growth of enantiomer crystals with the same crystal form or stereo configuration.
  • composition refers to a mixture of one or more compounds described herein or their physiologically/pharmaceutically acceptable salts and other components, wherein the other components include physiologically/pharmaceutically acceptable carriers and excipients.
  • carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the administered compound.
  • excipient refers to an inert substance added to a pharmaceutical composition to further enhance the administration of a compound.
  • the “IC 50" in the present invention refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
  • ether solvent refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms. Specific examples include but are not limited to: tetrahydrofuran, ethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether or 1,4-dioxane.
  • the "alcohol solvent” described in the present invention refers to a group derived from one or more "hydroxyl groups” replacing one or more hydrogen atoms on a "C 1-6 alkyl group", wherein the "hydroxyl group” and "C 1-6 alkyl group” are as defined above, and specific examples include but are not limited to: methanol, ethanol, isopropanol, n-propanol, isopentanol or trifluoroethanol.
  • ester solvent refers to a combination of a low-level organic acid containing 1 to 4 carbon atoms and a low-level alcohol containing 1 to 6 carbon atoms. Specific examples include but are not limited to: ethyl acetate, isopropyl acetate or butyl acetate.
  • keton solvent refers to a compound in which a carbonyl group (-C(O)-) is connected to two hydrocarbon groups.
  • ketones can be divided into aliphatic ketones, alicyclic ketones, aromatic ketones, saturated ketones and unsaturated ketones. Specific examples include but are not limited to: acetone, acetophenone, 4-methyl-2-pentanone.
  • nitrile solvent refers to a group derived from one or more "cyano” replacing one or more hydrogen atoms on a "C 1-6 alkyl".
  • the "cyano” and “C 1-6 alkyl” are as defined above, and specific examples include but are not limited to: acetonitrile or propionitrile.
  • halogenated hydrocarbon solvent refers to a group derived from one or more "halogen atoms” replacing one or more hydrogen atoms on a "C 1-6 alkyl group", wherein the "halogen atom” and "C 1-6 alkyl group” are as defined above, and specific examples include but are not limited to: dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride.
  • crystal of the present invention can be used interchangeably.
  • room temperature generally refers to 4-30°C, preferably refers to 20 ⁇ 5°C.
  • the drying temperature of the present invention is generally 20 to 100° C., preferably 25 to 70° C., and can be either normal pressure drying or reduced pressure drying (vacuum drying). Preferably, the drying is carried out under reduced pressure.
  • X-ray powder diffraction pattern refers to an experimentally observed diffraction pattern or a parameter, data or value derived therefrom.
  • An XRPD pattern is usually characterized by peak position (abscissa) and/or peak intensity (ordinate).
  • the "2 ⁇ or 2 ⁇ angle" described in the present invention refers to the diffraction angle
  • ⁇ is the Bragg angle, which is based on the peak position expressed in degrees (°) set in the X-ray diffraction experiment, and is usually the horizontal coordinate unit in the diffraction spectrum. If the incident beam forms an angle ⁇ with a certain lattice plane and the reflection is diffracted, the experimental setting needs to record the reflected beam at an angle of 2 ⁇ .
  • substantially the same means that representative peak positions and intensity variations are taken into account. For example, one skilled in the art will appreciate that peak positions (2 ⁇ ) will show some variation, typically up to 0.1 to 0.2 degrees, and that the instrument used to measure diffraction will also cause some variation. In addition, one skilled in the art will appreciate that relative peak intensities will vary due to instrumental differences as well as degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to one skilled in the art, and should be considered as only qualitative measurements.
  • the “differential scanning calorimetry or DSC” mentioned in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining a constant temperature of the sample, so as to characterize all physical and chemical changes related to thermal effects and obtain the phase change information of the sample.
  • Hygroscopic weight gain due to moisture absorption is less than 15% but not less than 2%;
  • weight gain due to moisture absorption is less than 2% but not less than 0.2%;
  • moisture gain is less than 0.2%.
  • the crystal form disclosed in the present invention can be prepared by the following common methods for preparing crystal forms:
  • the volatilization experiment is to evaporate the clear solution of the sample at different temperatures until the solvent is dry.
  • the slurry experiment is to stir the supersaturated solution of the sample (with insoluble solids) at a certain temperature in different solvent systems.
  • the anti-solvent test is to dissolve the sample in a good solvent, add an anti-solvent, stir the precipitated solid for a short time and then filter it immediately.
  • the cooling crystallization experiment is to dissolve a certain amount of sample into the corresponding solvent at high temperature, and then stir and crystallize directly at room temperature or low temperature.
  • the polymer template experiment is to add different types of polymer materials to the sample clear solution and leave it open at room temperature to evaporate until the solvent is dry.
  • the thermal method experiment is to treat the sample under certain thermal method crystallization conditions and cool it to room temperature.
  • the water vapor diffusion experiment is to place the sample in a certain humidity environment at room temperature.
  • FIG1 is an X-ray powder diffraction pattern of maleate salt form 1 of the compound represented by formula (I).
  • FIG2 is a thermogravimetric analysis spectrum of the maleate salt form 1 of the compound represented by formula (I).
  • FIG3 is a differential scanning calorimetry curve of maleate salt form 1 of the compound represented by formula (I).
  • FIG4 is an isothermal adsorption curve of maleate salt form 1 of the compound represented by formula (I).
  • FIG5 is a DVS spectrum of the maleate salt form 1 of the compound represented by formula (I).
  • FIG6 is an X-ray powder diffraction pattern of the dimaleate crystalline form 1 of the compound represented by formula (I).
  • FIG. 7 is a thermogravimetric analysis spectrum of the dimaleate crystal form 1 of the compound represented by formula (I).
  • FIG8 is a differential scanning calorimetry curve of the dimaleate crystal form 1 of the compound represented by formula (I).
  • FIG9 is an isothermal adsorption curve of the dimaleate crystal form 1 of the compound represented by formula (I).
  • FIG10 is a DVS spectrum of the dimaleate crystal form 1 of the compound represented by formula (I).
  • FIG11 is an X-ray powder diffraction pattern of 2-naphthalenesulfonic acid form 1 of the compound represented by formula (I).
  • FIG12 is a thermogravimetric analysis spectrum of 2-naphthalenesulfonic acid form 1 of the compound represented by formula (I).
  • FIG13 is a differential scanning calorimetry curve of 2-naphthalenesulfonic acid form 1 of the compound represented by formula (I).
  • FIG14 is an isothermal adsorption curve of 2-naphthalenesulfonic acid form 1 of the compound represented by formula (I).
  • FIG15 is a DVS spectrum of 2-naphthalenesulfonic acid form 1 of the compound represented by formula (I).
  • FIG16 is an X-ray powder diffraction pattern of oxalate crystal form 1 of the compound represented by formula (I).
  • FIG. 17 is a thermogravimetric analysis spectrum of the oxalate salt form 1 of the compound represented by formula (I).
  • FIG18 is a differential scanning calorimetry curve of the oxalate crystal form 1 of the compound represented by formula (I).
  • FIG19 is an X-ray powder diffraction pattern of the amorphous benzenesulfonate salt of the compound represented by formula (I).
  • FIG. 20 is an X-ray powder diffraction pattern of the amorphous triphenylsulfonate salt of the compound represented by formula (I).
  • FIG21 is an X-ray powder diffraction pattern of the amorphous di-L-malate salt of the compound represented by formula (I).
  • FIG. 22 is an X-ray powder diffraction pattern of the amorphous phosphate of the compound represented by formula (I).
  • FIG. 23 is an X-ray powder diffraction pattern of the amorphous diphosphate of the compound represented by formula (I).
  • FIG. 24 is an X-ray powder diffraction pattern of the amorphous sulfate salt of the compound represented by formula (I).
  • FIG25 is an X-ray powder diffraction pattern of the amorphous disulfate salt of the compound represented by formula (I).
  • FIG26 is an X-ray powder diffraction pattern of the amorphous trisulfate salt of the compound represented by formula (I).
  • FIG. 27 is an X-ray powder diffraction pattern of the amorphous di-p-toluenesulfonate salt of the compound represented by formula (I).
  • FIG28 is an X-ray powder diffraction pattern of the amorphous hydrochloride salt of the compound represented by formula (I).
  • FIG29 is an X-ray powder diffraction pattern of the amorphous dihydrochloride salt of the compound represented by formula (I).
  • FIG30 is an X-ray powder diffraction pattern of the amorphous trihydrochloride salt of the compound represented by formula (I).
  • FIG31 is an X-ray powder diffraction pattern of the amorphous di-2-naphthalenesulfonate salt of the compound represented by formula (I).
  • FIG32 is an X-ray powder diffraction pattern of the amorphous hydrobromide salt of the compound represented by formula (I).
  • FIG33 is an X-ray powder diffraction pattern of the amorphous dihydrobromide salt of the compound represented by formula (I).
  • FIG34 is an X-ray powder diffraction pattern of the amorphous trihydrobromide salt of the compound represented by formula (I).
  • FIG35 is an X-ray powder diffraction pattern of the amorphous methanesulfonate salt of the compound represented by formula (I).
  • FIG36 is an X-ray powder diffraction pattern of the amorphous dimesylate salt of the compound represented by formula (I).
  • FIG37 is an X-ray powder diffraction pattern of the amorphous trimesylate salt of the compound represented by formula (I).
  • FIG38 is an X-ray powder diffraction pattern of the amorphous mandelate salt of the compound represented by formula (I).
  • FIG39 is an X-ray powder diffraction pattern of the amorphous bimandelate salt of the compound represented by formula (I).
  • FIG40 is an X-ray powder diffraction pattern of the amorphous succinate salt of the compound represented by formula (I).
  • FIG41 is an X-ray powder diffraction pattern of the amorphous salicylate of the compound represented by formula (I).
  • FIG42 is an X-ray powder diffraction pattern of amorphous 1,5-naphthalene disulfonate of the compound represented by formula (I).
  • FIG43 is an X-ray powder diffraction pattern of amorphous di-1,5-naphthalene disulfonate of the compound represented by formula (I).
  • FIG44 is an X-ray powder diffraction pattern of the amorphous hemi-fumarate salt of the compound represented by formula (I).
  • Figure 45 is an X-ray powder diffraction pattern of the amorphous difumarate salt of the compound represented by formula (I).
  • FIG46 is an X-ray powder diffraction pattern of the amorphous trinicotinate salt of the compound represented by formula (I).
  • FIG47 is an X-ray powder diffraction pattern of the amorphous hippurate salt of the compound represented by formula (I).
  • Figure 48 is an X-ray powder diffraction pattern of Form 1 of the compound represented by formula (I).
  • FIG49 is a thermogravimetric analysis spectrum of Form 1 of the compound represented by formula (I).
  • Figure 50 is a differential scanning calorimetry curve of Form 1 of the compound represented by formula (I).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Eclipse Plus C18, 150 ⁇ 4.6mm).
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.
  • 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.
  • 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).
  • V sample is the reading of the drug treatment group
  • V vehicle control is The values are the average values of the solvent control group.
  • origin9.2 software nonlinear regression model was used to draw the S-shaped dose-survival rate curve and calculate the IC 50 value.
  • the compound has good proliferation inhibitory activity against NCI-H1975 (EGFR-L858R-T790M) cells, but poor proliferation inhibitory activity against A431 (EGFR-WT) cells, and has good selectivity.
  • 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 compound has good proliferation inhibitory activity on NCI-H1975 EGFR-L858R-T790M-C797S cells.
  • mice Male SD rats, about 220 g, 6-8 weeks old, 3 rats/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Intragastric administration solvent 0.5% MC (MC: methylcellulose)
  • Test Example 4 Beagle dog pharmacokinetic test
  • mice Male beagle dogs, about 8-11 kg, 3 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.
  • test method On the day of the test, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and were fed 4 hours after administration.

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Abstract

La présente invention concerne un sel pharmaceutiquement acceptable d'un composé tel que représenté par la formule (I) ou un stéréoisomère de celui-ci, un solvate et/ou une forme cristalline de celui-ci, son procédé de préparation, une composition pharmaceutique de celui-ci, et son utilisation en médecine.
PCT/CN2023/125385 2022-10-20 2023-10-19 Sel et forme cristalline d'un dérivé phosphonyle et leur utilisation en médecine WO2024083183A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021018009A1 (fr) * 2019-07-26 2021-02-04 贝达药业股份有限公司 Inhibiteur d'egfr, composition et procédé de préparation correspondant
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
WO2022228547A1 (fr) * 2021-04-30 2022-11-03 四川海思科制药有限公司 Dérivé de phosphonyle, et composition et application pharmaceutique de celui-ci
CN116003418A (zh) * 2021-10-22 2023-04-25 标新生物医药科技(上海)有限公司 Crbn e3连接酶配体化合物、基于该配体化合物开发的蛋白降解剂及它们的应用

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Publication number Priority date Publication date Assignee Title
WO2021018009A1 (fr) * 2019-07-26 2021-02-04 贝达药业股份有限公司 Inhibiteur d'egfr, composition et procédé de préparation correspondant
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
WO2022228547A1 (fr) * 2021-04-30 2022-11-03 四川海思科制药有限公司 Dérivé de phosphonyle, et composition et application pharmaceutique de celui-ci
CN116003418A (zh) * 2021-10-22 2023-04-25 标新生物医药科技(上海)有限公司 Crbn e3连接酶配体化合物、基于该配体化合物开发的蛋白降解剂及它们的应用

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Title
REN CHAOWEI, SUN NING, LIU HAIXIA, KONG YING, SUN RENHONG, QIU XING, CHEN JINJU, LI YAN, ZHANG JIANSHUI, ZHOU YUEDONG, ZHONG HUI, : "Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 64, no. 13, 8 July 2021 (2021-07-08), US , pages 9152 - 9165, XP055981658, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.1c00373 *

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