WO2022089593A1 - Composé de sel double d'un agent anti-tumoral à base de glycoside de flavone amine organique, son procédé de préparation et son utilisation - Google Patents

Composé de sel double d'un agent anti-tumoral à base de glycoside de flavone amine organique, son procédé de préparation et son utilisation Download PDF

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WO2022089593A1
WO2022089593A1 PCT/CN2021/127477 CN2021127477W WO2022089593A1 WO 2022089593 A1 WO2022089593 A1 WO 2022089593A1 CN 2021127477 W CN2021127477 W CN 2021127477W WO 2022089593 A1 WO2022089593 A1 WO 2022089593A1
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double salt
salt compound
baicalin
preparation
double
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王化录
王鹿荧
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杭州拉林智能科技有限公司
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    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • 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

Definitions

  • the present application relates to the technical field of medicinal chemistry, in particular to a flavonoid glycoside-organic amine antitumor agent double salt compound and a preparation method and application thereof.
  • anti-tumor agents Due to the disadvantages of strong side effects and high cost in chemotherapy, radiotherapy and other treatments, there is an urgent need to develop anti-tumor agents with good therapeutic effects and less side effects.
  • Currently commonly used antitumor agents include nilotinib, pomalidomide, lenalidomide, dasatinib, imatinib, and ibrutinib.
  • the application provides a double salt compound, which is a double salt of a flavone glycoside and an organic amine antitumor agent, and the flavone glycoside has the general structural formula shown in formula (I):
  • R 1 to R 9 are each independently selected from -H, -OH, C 1 -C 6 alkyl, alkoxy or substituted alkyl, and at least one of R 1 and R 2 is -OH.
  • both R 1 and R 2 are selected from -OH.
  • the flavonoid glycoside is baicalin or baicalin.
  • the organic amine antitumor agent contains at least one amino group, each of which is independently selected from -NH 2 , -NR'H or -NR' 2 , and R' is an electron donating group.
  • the organic amine antineoplastic agent is nilotinib, dasatinib, imatinib, ibrutinib, pomalidomide, or lenalidomide.
  • the application also provides a preparation method of a double salt compound, comprising the following steps:
  • the flavonoid glycosides and the organic amine antitumor agent are respectively placed in a polar aprotic organic solvent to be mixed and dissolved to obtain a mixed solution;
  • the mixed solution is reacted to obtain a reaction solution
  • the solvent was removed from the reaction solution.
  • the polar aprotic organic solvent is at least one of N,N-dimethylformamide, dimethylsulfoxide, and acetonitrile.
  • the present application further provides a pharmaceutical composition, which contains a therapeutically effective amount of a double salt compound or its optical isomer, enantiomer, diastereomer, racemate, racemic mixture and pharmaceutically acceptable carrier, excipient or diluent.
  • the antitumor drug is used for the treatment of tumor diseases, and the tumor diseases are malignant lymphoma, leukemia, malignant gastrointestinal stromal tumor, myeloma or myelodysplastic syndrome.
  • a double salt nanoparticle is provided, wherein the double salt nanoparticle is obtained by nano-grinding the double salt compound.
  • the application of the double salt nanoparticles in the preparation of antitumor drugs is provided.
  • the antitumor drug is used for the treatment of tumor diseases, and the tumor diseases are malignant lymphoma, leukemia, malignant gastrointestinal stromal tumor, myeloma or myelodysplastic syndrome.
  • Organic amine antineoplastic agents are alkaline and can increase their stability and physical properties by forming salts with inorganic acids or small molecular organic acids, but these inorganic acids or small molecular organic acids cannot improve the pharmacological activity of antineoplastic agents .
  • the water solubility of flavonoid glycosides is poor, but its molecular structure contains carboxyl and phenolic hydroxyl groups, so it is easily soluble in alkalis and can form salts with inorganic bases and small molecular organic bases.
  • the present application enhances the water solubility of the flavonoid glycosides and improves the biological activity of the antitumor agent by forming a double salt of the amino group-containing organic amine antitumor agent with the flavone glycosides containing carboxyl and phenolic hydroxyl groups in the molecular structure.
  • the prepared double salt has high pharmacological activity and good druggability, can be used for the production of medicines for treating malignant tumor, and shows good anti-tumor effect.
  • Natural flavonoid glycosides have poor water solubility, but because of the presence of carboxyl and phenolic hydroxyl groups in the molecular structure, they are easily soluble in alkalis, so they form salts with small molecular organic bases to enhance their water solubility. Further, the double salt compound provided by the present application is ground by nano-grinding technology to reduce the particle size of the material so that the particle size reaches the nanometer level, so that the double salt compound has better water solubility.
  • Figures 1 to 11 are the H NMR spectra of the double salt compounds prepared in Examples 1 to 11 of the present application;
  • Figures 34 to 44 are DSC test charts of the double salt compounds prepared in Examples 1 to 11 of the present application.
  • alkoxy refers to a group having an -O-alkyl group, ie an alkyl group as defined above is attached to the core structure via an oxygen atom.
  • Suitable examples include, but are not limited to: methoxy (-O- CH3 or -OMe), ethoxy (-O- CH2CH3 or -OEt) and tert-butoxy (-OC( CH3 ) 3 or -OtBu).
  • “Pharmaceutically acceptable” refers to those ligands, materials, compositions and/or dosage forms suitable for administration to a patient within the scope of sound medical judgment and commensurate with a reasonable benefit/risk ratio.
  • Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch, potato starch and substituted or unsubstituted beta-cyclodextrins; (3) cellulose and derivatives thereof, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; Formulations such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyvalent Alcohols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers such as magnesium hydroxide and hydrogen
  • Substituted in reference to a group means that one or more hydrogen atoms attached to member atoms within the group are replaced by a substituent selected from the defined or suitable substituents.
  • the term “substituted” should be understood to include the implied condition that such substitution is consistent with the permissible valences of the substituted atoms and substituents and that the substitution results in a stable compound.
  • a group may contain one or more substituents, one or more of the member atoms within the group may be substituted.
  • a single member atom within the group may be substituted with more than one substituent, so long as the substitution is consistent with the permissible valence of the atom.
  • a "member atom” refers to an atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. The atoms that make up a substituent on a chain or ring are not member atoms in the chain or ring.
  • the application provides a double salt compound, which is a double salt of a flavone glycoside and an organic amine antitumor agent, and the flavone glycoside has the general structural formula shown in formula (I):
  • the carboxyl hydrogen in the gluconic acid unit and the phenolic hydroxyl hydrogen in the flavonoid unit in the flavonoid glycosides are located on both sides of the sugar ring, respectively.
  • the carboxyl hydrogen and the phenolic hydroxyl hydrogen on both sides of the sugar ring are converted to the same side, as shown in formula (II), forming a proton nest (as shown in the dashed box in formula (II)) proton structure), carboxyl oxygen electrons and nitrogen lone pair electrons.
  • the hydrogen proton and amine in the proton nest can form a very stable ammonium salt; from the analysis of molecular orbital theory, the empty orbital of hydrogen in the proton nest and the lone pair of electrons of amine can be perfectly combined; from quantum chemistry and quantum entanglement Theoretical analysis shows that hydrogen electrons in proton dens, carboxyl oxygen electrons and lone electron pairs of nitrogen in organic amines are entangled in the salt-forming region.
  • R 5 , R 6 , R 9 are all selected from -H.
  • R 7 , R 8 are each independently selected from -H or -OH.
  • R8 is selected from -H.
  • R7 is selected from -H.
  • the flavone glycosides are apigenin flavone glycosides, baicalin, scutellarin, chrysin flavone glycosides, or wogonin.
  • the flavone glycoside is baicalin or scutellarin.
  • baicalin The molecular structure of baicalin is shown in formula (I-II):
  • Nilotinib with molecular formula C 28 H 22 F 3 N 7 O, is a second-generation tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia.
  • the structural formula of nilotinib is as follows:
  • Dasatinib the molecular formula is C 22 H 28 ClN 7 O 3 S, is a polytyrosine kinase inhibitor, used for the treatment of chronic myeloid leukemia.
  • the structural formula of Dasatinib is as follows:
  • Imatinib molecular formula C 29 H 31 N 7 O, also belongs to tyrosine kinase inhibitor, is a small molecule protein kinase inhibitor.
  • tyrosine kinase inhibitor a small molecule protein kinase inhibitor.
  • the application also provides a preparation method of a double salt compound, comprising the following steps:
  • the flavonoid glycosides and the organic amine antitumor agent are respectively placed in a polar aprotic organic solvent in a molar ratio of 1:3 to 3:1 to be mixed and dissolved.
  • the molar ratio can also be 1:2, 1:1.5, 1:1, 1.5:1, or 2:1.
  • the polar aprotic organic solvent is at least one of N,N-dimethylformamide, dimethylsulfoxide, and acetonitrile.
  • the concentration of the organic amine antitumor agent in the second solution is 0.1 mol/L to 1.0 mol/L, optionally 0.33 mol/L.
  • the reaction temperature may be 30°C to 100°C, optionally 50°C to 70°C, and more optionally 70°C.
  • the purification also includes filtering the solution after beating, and further drying the filter cake after filtering.
  • the drying method can be freeze drying or vacuum drying.
  • the temperature of the vacuum drying may be 20°C to 60°C, optionally 30°C, and the drying time may be 8h to 48h, optionally 24h.
  • the freeze-drying temperature is less than 0°C, and the drying time can be 3h-12h, optionally 6h.
  • the application of the pharmaceutical composition involved in the present application in the drug for the treatment of tumor diseases in some embodiments, the application of the pharmaceutical composition involved in the present application in the drug for the treatment of tumor diseases.
  • the neoplastic disease comprises malignant lymphoma, leukemia, malignant gastrointestinal stromal tumor, myeloma, or myelodysplastic syndrome.
  • the present application further relates to a double salt nanoparticle, which is obtained by nano-grinding the double salt compound of any one of the above embodiments.
  • the average particle size of the double salt nanoparticles is 50 nm to 500 nm.
  • the mass ratio of the double salt compound and the suspending agent is 1000:(0.5-3).
  • the rotation speed of the grinding is 1000 rpm to 3000 rpm, and the grinding time is 20 minutes to 60 minutes.
  • the diameter of the working chamber of the nano-grinder used in the grinding is 85 mm. If the diameter of the working chamber of the nano-grinder changes, the speed should be adjusted accordingly.
  • the antitumor drug is used for the treatment of tumor diseases, and the tumor diseases are malignant lymphoma, leukemia, malignant gastrointestinal stromal tumor, myeloma or myelodysplastic syndrome.
  • the compounds of the present application useful in therapy according to the present application may be administered in the form of the original chemical compound, optionally in combination with one or more adjuvants, excipients, carriers, buffers, diluents and/or
  • the active ingredient is introduced into the pharmaceutical composition along with other conventional pharmaceutical excipients.
  • Such salts of the compounds of the present application may be anhydrous or solvated.
  • the application provides a medicament comprising a compound usable according to the application or a pharmaceutically acceptable derivative thereof and one or more pharmaceutically acceptable carriers and optionally other Therapeutic and/or prophylactic ingredients.
  • the carrier or carriers must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the recipient.
  • the compounds usable according to the present application can thus be placed in the form of medicaments and unit dosages thereof together with conventional auxiliaries, carriers or diluents.
  • Such forms include: solids, in particular tablets, filled capsules, powders and pellets; and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs and fillings therewith capsules, all forms for oral administration, suppositories for rectal administration and sterile injectable solutions for parenteral use.
  • These medicaments and unit dosage forms thereof may contain conventional ingredients in conventional proportions, with or without other active compounds or components, and such unit dosage forms may contain any suitable effective amount corresponding to the intended daily dosage range to be used. the active ingredient.
  • the compounds useful in accordance with the present application can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may include as active ingredient one or more compounds useful in accordance with the present application.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active ingredient is uniformly dispersed therein, eg, by stirring.
  • the molten homogeneous mixture is then poured into appropriately sized molds, allowed to cool and thereby solidify.
  • Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams containing in addition to the active ingredient suitable carriers known in the art agent or spray.
  • Liquid preparations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions.
  • liquid preparations for parenteral injection can be formulated as aqueous polyethylene glycol solutions.
  • the chemical compounds according to the present application may be formulated for parenteral administration (eg, by injection, eg, bolus injection or continuous infusion), and may be presented in unit dosage form in ampoules with an added preservative, Prefilled syringes, small volume infusions or in multi-dose containers.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
  • the drug is administered locally or systemically or by a combination of both routes.
  • 0.001% to 70% by weight of the compound alternatively 0.01% to 70% by weight of the compound, even more alternatively
  • the compounds of the present application are administered in formulations of the compounds.
  • a suitable amount of compound administered is in the range of 0.01 mg/kg body weight to 1 g/kg body weight.
  • compositions suitable for administration also include: lozenges comprising the active agent in a flavoured base (usually sucrose and acacia or tragacanth), lozenges comprising the active agent in an inert base such as gelatin and glycerol or sucrose and acacia Pastilles of the ingredients and mouthwashes containing the active ingredient in a suitable liquid carrier.
  • a flavoured base usually sucrose and acacia or tragacanth
  • lozenges comprising the active agent in an inert base such as gelatin and glycerol or sucrose and acacia Pastilles of the ingredients and mouthwashes containing the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are administered directly to the nasal cavity by conventional means such as with a dropper, pipette or spray.
  • Compositions may be presented in single or multiple dose form. In the latter case of a dropper or pipette, this can be accomplished by the patient administering a suitable predetermined volume of the solution or suspension. In the case of a nebulizer, this can be achieved, for example, by means of a metered atomizing spray pump.
  • Administration to the respiratory tract can also be accomplished by means of an aerosol with a suitable propellant such as a chlorofluorocarbon (CFC) (eg dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane), Carbon dioxide or other suitable gas provides the active ingredient in a pressurized pack.
  • a suitable propellant such as a chlorofluorocarbon (CFC) (eg dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane)
  • CFC chlorofluorocarbon
  • the aerosol may also conveniently contain a surfactant, such as lecithin.
  • the dose of the drug can be controlled by setting the metering valve.
  • the compounds In compositions intended for administration to the respiratory tract, including intranasal compositions, the compounds generally have a small particle size, eg, about 5 microns or less. Such particle sizes can be obtained by means known in the art, for example by micronization.
  • compositions suitable for sustained release of the active ingredient can be used.
  • the pharmaceutical formulations may optionally be presented in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are optional compositions.
  • Suitable formulations and ways of making them are also in, for example, "Arzneiformenlehre, Paul Heinz List, Ein Lehrbuch für Pharmazeuten,ticianliche Verlagsgesellschaft Stuttgart, 4. Auflage, 1985” or "The theory and practice of industrial pharmacy” by Lachman et al., Varghese Publishing House, 1987” or “Modern Pharmaceutics", edited by James S warbrick, 2nd edition”.
  • the DMF solution in which nilotinib was suspended was added into the DMF solution in which baicalin was suspended, and the reaction was stirred at 70° C. for 15 hours, and then concentrated to dryness under reduced pressure at 60° C. to obtain a crude product.
  • the crude product was slurried with 30 ml of ethyl acetate for 20 min, and then filtered to obtain a filter cake; the filter cake was divided into two equal parts, the first filter cake was suspended in 15 ml of water, freeze-dried for 6 h to remove the solvent, and the obtained Light yellow solid product, the solid product was 3.33 g, and the yield was 68.51%; the second filter cake was vacuum-dried at 30 °C for 24 h to obtain a light yellow solid product, the solid product was 3.37 g, and the yield was 69.06 %.
  • the double salt compounds were characterized by H NMR, IR, XRD and DSC.
  • the chemical shift of 1H NMR showed that the carboxyl hydrogen of baicalin formed salt with nilotinib-NH, and the infrared spectrum also showed this feature.
  • DSC test showed that the double salt compound had peaks at 122°C, 181°C and 203°C.
  • the physical properties, spectral characteristics and thermodynamic properties of the double salt compound were changed compared with those of the product obtained by simply mixing baicalin and nilotinib, and the obtained double salt compound was more soluble.
  • Nilotinib 5.30g (0.01mol) was suspended in 15ml DMF, and scutellarin 4.62g (0.01mol) was suspended in 30ml DMF.
  • the DMF solution in which nilotinib was suspended was added into the DMF solution in which baicalin was suspended, and the reaction was stirred at 70° C. for 15 hours, and then concentrated to dryness under reduced pressure at 60° C. to obtain a crude product.
  • the crude product was slurried with 30 ml of ethyl acetate for 20 min, and then filtered to obtain a filter cake; the filter cake was divided into two equal parts, the first filter cake was suspended in 15 ml of water, freeze-dried for 6 h to remove the solvent, and the obtained Light yellow solid product, the solid product was 3.28 g, and the yield was 66.10%; the second filter cake was vacuum-dried at 30° C. for 24 h to obtain a light yellow solid product, which was 3.30 g and the yield was 66.53 %.
  • the double salt compounds were characterized by H NMR, IR, XRD and DSC.
  • the chemical shift of 1H NMR showed that the carboxyl hydrogen of baicalin formed salt with nilotinib-NH, and the infrared spectrum also showed this feature.
  • DSC test showed that the double salt compound had peaks at 132°C, 183°C and 200°C.
  • the physical properties, spectral characteristics and thermodynamic properties of the double salt compound were changed compared with those of the product obtained by simply mixing baicalin and nilotinib, and the obtained double salt compound was more soluble.
  • the preparation method was basically the same as that of Example 1, except that 2.73 g (0.01 mol) of pomalidomide was used instead of nilotinib.
  • the baicalin pomalidomide salt obtained in the first part was 3.16 g, and the yield was 87.77%; the baicalin pomalidomide salt obtained in the second part was 3.20 g, and the yield was 89.01%.
  • the double salt compounds were characterized by H NMR, IR, XRD and DSC.
  • the chemical shift of 1H NMR showed that the carboxyl hydrogen of baicalin was salted with pomalidomide-NH 2 , and the infrared spectrum also showed this feature.
  • DSC test showed that the double salt compound had peaks at 187°C and 195°C.
  • the physical properties, spectral characteristics and thermodynamic properties of the double salt compound were changed compared with those of the product obtained by simply mixing baicalin and pomalidomide, and the obtained double salt compound was more soluble.
  • the preparation method was basically the same as that of Example 2, except that 2.73 g (0.01 mol) of pomalidomide was used instead of nilotinib.
  • the scutellarin pomalidomide salt obtained in the first portion was 3.29 g, and the yield was 89.52%; the scutellarin pomalidomide salt obtained in the second portion was 3.32 g, and the yield was 90.34%.
  • the preparation method was basically the same as that of Example 1, except that 2.59 g (0.01 mol) of lenalidomide was used instead of nilotinib.
  • the baicalin lenalidomide salt obtained in the first part is 2.40 g, and the yield is 68.21%; the baicalin lenalidomide salt obtained in the second part is 2.42 g, and the yield is 68.65%.
  • the double salt compounds were characterized by H NMR, IR, XRD and DSC.
  • the chemical shift of 1H NMR showed that the carboxyl hydrogen of baicalin was salted with lenalidomide-NH 2 , and the infrared spectrum also showed this feature.
  • DSC test showed that the double salt compound had peaks at 174°C, 189°C and 239°C. Compared with baicalin and lenalidomide, the physical properties, spectral characteristics and thermodynamic properties of the double salt compound were changed, and the obtained double salt compound was more soluble.
  • the preparation method was basically the same as that of Example 2, except that 2.59 g (0.01 mol) of lenalidomide was used instead of nilotinib.
  • the scutellarin lenalidomide salt obtained in the first part was 2.73 g, and the yield was 75.82%; the scutellarin lenalidomide salt obtained in the second part was 2.78 g, and the yield was 77.11%.
  • the double salt compounds were characterized by H NMR, IR, XRD and DSC.
  • the chemical shift of 1H NMR showed that the carboxyl hydrogen of baicalin was salted with lenalidomide-NH 2 , and the infrared spectrum also showed this feature.
  • DSC test showed that the double salt compound had peaks at 177°C, 196°C and 235°C.
  • the physical properties, spectral characteristics and thermodynamic properties of the double salt compound were changed compared with those of the product obtained by simply mixing baicalin and lenalidomide, and the obtained double salt compound was more soluble.
  • the preparation method was basically the same as that of Example 1, except that 4.88 g (0.01 mol) of dasatinib was used instead of nilotinib.
  • the baicalin dasatinib salt obtained in the first part is 1.82 g, and the yield is 39.05%; the baicalin dasatinib salt obtained in the second part is 1.82 g, and the yield is 39.05%.
  • the double salt compounds were characterized by H NMR, IR, XRD and DSC.
  • the chemical shift of 1H NMR showed that the carboxyl hydrogen of baicalin formed salt with dasatinib-N, and the infrared spectrum also showed this feature.
  • DSC test showed that the double salt compound had peaks at 197°C and 305°C. Compared with baicalin and dasatinib, the physical properties, spectral characteristics and thermodynamic properties of the double salt compound were changed, and the obtained double salt compound was more soluble.
  • the preparation method was basically the same as that of Example 2, except that 4.88 g (0.01 mol) of dasatinib was used instead of nilotinib.
  • the scutellarin dasatinib salt obtained in the first portion is 3.15 g, and the yield is 66.40%; the scutellarin dasatinib salt obtained in the second portion is 3.17 g, and the yield is 66.74%.
  • the double salt compounds were characterized by H NMR, IR, XRD and DSC.
  • the chemical shift of H NMR spectrum showed that the carboxyl hydrogen of baicalin formed salt with dasatinib-N, and the infrared spectrum also showed this feature.
  • DSC test showed that the double salt compound had peaks at 132°C, 205°C and 283°C.
  • the physical properties, spectral characteristics and thermodynamic properties of the double salt compound were changed compared with those of the product obtained by simply mixing baicalin and dasatinib, and the obtained double salt compound was more soluble.
  • the preparation method was basically the same as that of Example 1, except that 4.94 g (0.01 mol) of imatinib was used instead of nilotinib.
  • the baicalin imatinib salt obtained in the first part was 4.18 g, and the yield was 88.80%; the baicalin imatinib salt obtained in the second part was 4.20 g, and the yield was 89.17%.
  • the double salt compounds were characterized by H NMR, IR, XRD and DSC.
  • the chemical shift of 1H NMR showed that the carboxyl hydrogen of baicalin formed salt with imatinib-N, and the infrared spectrum also showed this feature.
  • DSC test showed that the double salt compound had peaks at 105°C, 198°C and 333°C. Compared with baicalin and imatinib, the physical properties, spectral characteristics and thermodynamic properties of the double salt compound were changed, and the obtained double salt compound was more soluble.
  • the preparation method was basically the same as that of Example 2, except that 4.94 g (0.01 mol) of imatinib was used instead of nilotinib.
  • the scutellarin imatinib salt obtained in the first part was 2.73 g, and the yield was 57.20%; the scutellarin imatinib salt obtained in the second part was 2.75 g, and the yield was 57.53%.
  • the double salt compounds were characterized by H NMR, IR, XRD and DSC.
  • the chemical shift of 1H NMR showed that the carboxyl hydrogen of baicalin formed salt with imatinib-N, and the infrared spectrum also showed this feature.
  • DSC test showed that the double salt compound had peaks at 131°C, 207°C and 325°C.
  • the physical properties, spectral characteristics and thermodynamic properties of the double salt compound were changed compared with those of the product obtained by simply mixing baicalin and imatinib, and the obtained double salt compound was more soluble.
  • the preparation method was basically the same as that of Example 1, except that 4.41 g (0.01 mol) of ibrutinib was used instead of nilotinib.
  • the scutellarin ibrutinib salt obtained in the first portion was 3.38 g, and the yield was 74.80%; the scutellarin ibrutinib salt obtained in the second portion was 3.41 g, and the yield was 75.53%.
  • the double salt compounds were characterized by H NMR, IR, XRD and DSC.
  • the chemical shift of 1H NMR showed that the carboxyl hydrogen of baicalin was salted with ibrutinib-NH 2 , and the infrared spectrum also showed this feature.
  • DSC test showed that the double salt compound had peaks at 114°C and 198°C. Compared with baicalin and imatinib, the physical properties, spectral characteristics and thermodynamic properties of the double salt compound were changed, and the obtained double salt compound was more soluble.
  • Embodiment 12 Double salt compound activity test
  • Each compound salt compound was prepared into different concentrations of the test articles, using tyrosine kinase kit, tyrosine kinase as the substrate, to determine the inhibitory effect of different concentrations of the test articles on tyrosine kinase activity, and calculate IC50, The calculation results are shown in Table 1.
  • Each compound salt compound was formulated into different concentrations of the test article, and the mouse spleen cells were used as test cells to determine the inhibition of different concentrations of the test article on the secretion activity of ⁇ -interferon, and IC50 was calculated. The calculation results are shown in Table 1. .
  • baicalin dasatinib double salt compound and scutellarin dasatinib compound salt compound on tyrosine kinase was higher than that of dasatinib on tyrosine kinase;
  • baicalin imatinib compound salt compound and baicalin imatinib compound salt compound on tyrosine kinase were higher than that of imatinib on tyrosine kinase;
  • baicalin-ibrutinib compound salt compound and baicalin-ibrutinib compound salt compound on tyrosine kinase were higher than that of ibrutinib on tyrosine kinase;
  • the inhibitory activity of baicalin pomalidomide double salt compound and scutellarin pomalidomide double salt compound on the secretion of ⁇ -interferon is higher than that of pomalidomide on the secretion of ⁇ -interferon;
  • baicalin lenalidomide double salt compound and baicalin lenalidomide compound salt compound on the secretion of ⁇ -interferon was higher than that of lenalidomide on the secretion of ⁇ -interferon.
  • baicalin nilotinib double salt compound 500 ml of water, 50 mg of Tween-20 as a suspending agent, 50 mg of hypromellose, and 50 mg of polyethylene glycol into a nano-grinder. , and milled at 2500 rpm for 40 minutes to obtain a nanosuspension of baicalin nilotinib double salt.
  • the obtained nanosuspension of baicalin and nilotinib double salt is dried in fluidized bed drying equipment, and the drying air inlet temperature is 65° C., and dried to a moisture content of about 3% to prepare baicalin and nilotinib double salt.
  • the solubility of the prepared baicalin-nilotinib double-salt compound at 20° C. for 10 minutes increased by 2.2 times.
  • the preparation method is basically the same as that of Example 13, except that the baicalin nilotinib double salt compound is replaced with the baicalin nilotinib double salt compound.
  • the particle size distribution of baicalin and nilotinib double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin-nilotinib double-salt nanoparticles have a 2.0-fold increase in solubility at 20° C. for 10 minutes.
  • the preparation method is basically the same as that of Example 13, except that the baicalin nilotinib double salt compound is replaced by the baicalin dasatinib double salt compound.
  • the particle size distribution of baicalin-dasatinib double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared baicalin-dasatinib double-salt nanoparticles have a 2.5-fold increase in solubility at 20° C. for 10 minutes.
  • the preparation method is basically the same as that of Example 15, except that the baicalin dasatinib double salt compound is replaced with the scutellarin dasatinib double salt compound.
  • the particle size distribution of scutellarin dasatinib double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin-dasatinib double-salt nanoparticles have a 2.5-fold increase in solubility at 20°C for 10 minutes compared to the scutellarin-dasatinib double-salt compound without nano-milling.
  • the preparation method is basically the same as that of Example 13, except that the baicalin nilotinib double salt compound is replaced with the baicalin imatinib double salt compound.
  • the particle size distribution of baicalin imatinib double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared baicalin-imatinib double-salt nanoparticles have a 1.5-fold increase in solubility at 20° C. for 10 minutes.
  • the preparation method is basically the same as that of Example 17, except that the baicalin imatinib double salt compound is replaced with the baicalin imatinib double salt compound.
  • the particle size distribution of baicalin imatinib double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin imatinib double salt nanoparticles have a 1.5-fold increase in solubility at 20°C for 10 minutes compared to the scutellarin imatinib double salt compound without nano-milling.
  • the preparation method is basically the same as that of Example 13, except that the baicalin nilotinib double salt compound is replaced by the baicalin ibrutinib double salt compound.
  • the particle size distribution of baicalin and ibrutinib double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared baicalin-ibrutinib double-salt nanoparticles had a 2.3-fold increase in solubility at 20°C for 10 minutes compared to the baicalin-ibrutinib double-salt compound without nano-milling.
  • the preparation method is basically the same as that of Example 19, except that the baicalin ibrutinib double salt compound is replaced with the baicalin ibrutinib double salt compound.
  • the particle size distribution of Scutellaria baicalensis ibrutinib compound salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin-ibrutinib double-salt nanoparticles have a 2.5-fold increase in solubility at 20° C. for 10 minutes compared to the scutellarin-ibrutinib double-salt compound without nano-milling.
  • the preparation method is basically the same as that of Example 13, except that the baicalin nilotinib double salt compound is replaced by the baicalin pomalidomide double salt compound.
  • the particle size distribution of baicalin and pomalidomide double salt nanoparticles is in the range of 50nm to 500nm.
  • the solubility of the prepared baicalin-pomalidomide double-salt compound at 20° C. for 10 minutes increased by 0.5 times.
  • the preparation method is basically the same as that of Example 20, except that the baicalin pomalidomide double salt compound is replaced by the scutellarin pomalidomide double salt compound.
  • the particle size distribution of baicalin pomalidomide double salt nanoparticles is in the range of 50nm to 500nm.
  • the solubility of the prepared scutellarin-pomalidomide double-salt compound at 20° C. for 10 minutes increased by 0.5 times.
  • the preparation method is basically the same as that of Example 13, except that the baicalin nilotinib double salt compound is replaced by the baicalin lenalidomide double salt compound.
  • the particle size distribution of baicalin lenalidomide double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared baicalin-lenalidomide double-salt nanoparticles have a 0.6-fold increase in solubility at 20° C. for 10 minutes.
  • Example 20 The preparation method of Example 20 is basically the same, except that the baicalin lenalidomide double salt compound is replaced with the baicalin lenalidomide double salt compound.
  • the particle size distribution of scutellarin lenalidomide double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin-lenalidomide double-salt nanoparticles have a 0.6-fold increase in solubility at 20°C for 10 minutes compared to the scutellarin-lenalidomide double-salt compound without nano-milling.
  • baicalin group The blank administration group, baicalin group, baicalin group, nilotinib group, imatinib group, dasatinib group, baicalin nilotinib compound salt nanosuspension group (baicalin group) were set up respectively.
  • Example 13 for the preparation method of the nilotinib double salt nanosuspension, and the scutellarin nilotinib double salt nanosuspension group (the preparation method of the scutellarin nilotinib double salt nanosuspension) was implemented with reference to Example 14), baicalin imatinib double salt nanosuspension group (baicalin imatinib double salt nanosuspension preparation method refers to Example 17), scutellarin imatinib double salt nanosuspension Liquid group (the preparation method of baicalin imatinib double salt nanosuspension refers to Example 18), baicalin dasatinib double salt nanosuspension group (baicalin dasatinib double salt nanosuspension For the preparation method, refer to Example 15), and the scutellarin dasatinib double salt nanosuspension group (for the preparation method of the scutellarin dasatinib double salt nanos
  • mice Balb/c nude mice, male, 6-8 weeks old. All mice had free access to food and water, and were kept at room temperature (23 ⁇ 2)°C.
  • Tumor cells K562 cell line, from NIH.
  • mice Leukemia tumor mice were established, and the qualified mice were randomly divided into groups of 10. The dosing schedule was as follows:
  • Blank administration group only normal saline was administered.
  • Baicalin group baicalin was formulated into a dosing solution with sterile PBS, and the dose was 21 mg/kg by gavage, once a day, for 21 consecutive days.
  • Baicalin group scutellarin was formulated into a dosing solution with sterile PBS, and the dose was 21 mg/kg by gavage, once a day, for 21 consecutive days.
  • Nilotinib group Nilotinib was formulated into a dosing solution with sterile PBS, and administered by gavage at a dose of 24 mg/kg, once a day, for 21 consecutive days.
  • Imatinib group Imatinib was formulated into a dosing solution with sterile PBS, and the dose was 16 mg/kg by gavage, once a day, for 21 consecutive days.
  • Dasatinib group Dasatinib was formulated into a dosing solution with sterile PBS, and the dose was 8 mg/kg by gavage, once a day, for 21 consecutive days.
  • Baicalin nilotinib compound salt nanosuspension group Baicalin nilotinib compound salt nanosuspension was used as the dosing solution, according to the dosage of 45 mg/kg, intragastrically, once a day, continuously for 21 day.
  • Baicalin and nilotinib compound salt nanosuspension group scutellarin and nilotinib compound salt nanosuspension as the dosing solution, according to the dosage of 45 mg/kg, gavage, once a day, continuously Medicine on the 21st.
  • Baicalin imatinib compound salt nanosuspension group Baicalin imatinib compound salt nanosuspension was used as a dosing solution, and the dosage was 30 mg/kg, intragastrically, once a day, for 21 consecutive times. day.
  • the scutellarin imatinib compound salt nanosuspension group the scutellarin imatinib compound salt nanosuspension was used as the dosing solution, and the dosage was 30 mg/kg by intragastric administration, once a day, continuously. Medicine on the 21st.
  • Baicalin dasatinib compound salt nanosuspension group Baicalin dasatinib compound salt nanosuspension was used as the dosing solution, and the dosage was 15 mg/kg, intragastrically, once a day, for 21 consecutive times. day.
  • the scutellarin dasatinib double salt nanosuspension group the scutellarin dasatinib double salt nanosuspension was used as the dosing solution, according to the dosage of 15 mg/kg, intragastrically, once a day, continuously given Medicine on the 21st.
  • the inhibition rate of the blank administration group was 0, the inhibition rate of the baicalin group (21 mg/kg) was 24%, the inhibition rate of the baicalin group (21 mg/kg) was 22%, and the inhibition rate of the nilotinib group (24 mg/kg) was 66%.
  • the blank administration group, the baicalin group, the baicalin group, the lenalidomide group, and the baicalin-lenalidomide double salt nanosuspension group (the preparation method of the baicalin-lenalidomide double salt nanosuspension) were set up respectively.
  • scutellarin lenalidomide double salt nanosuspension group (refer to Example 24 for the preparation method of scutellarin lenalidomide double salt nanosuspension).
  • mice Balb/c nude mice, male, 6-8 weeks old. All mice had free access to food and water, and were kept at room temperature (23 ⁇ 2)°C.
  • Tumor cells Ci-1 cell line, derived from NIH.
  • mice were established, and the qualified mice were randomly divided into groups of 10.
  • the dosing regimen was as follows:
  • Blank administration group only normal saline was administered.
  • Baicalin group baicalin was prepared into a dosing solution with sterile PBS, and the dose was 9.5 mg/kg by gavage, once a day, for 21 consecutive days.
  • Baicalin group scutellarin was formulated into a dosing solution with sterile PBS, and the dose was 9.5 mg/kg by gavage, once a day, for 21 consecutive days.
  • Lenalidomide group The dosing solution was prepared with sterile PBS lenalidomide, and the dosage was 5.5 mg/kg, administered by gavage, once a day, for 21 consecutive days.
  • Baicalin Lenalidomide Double Salt Nanosuspension Group Baicalin Lenalidomide Double Salt Nanosuspension was used as the dosing solution, and the dosage was 15 mg/kg, intragastrically, once a day, for 21 consecutive times. day.
  • Baicalin lenalidomide double salt nanosuspension group scutellarin lenalidomide double salt nanosuspension as the dosing solution, according to the dosage of 15 mg/kg, gavage, once a day, continuously Medicine on the 21st.
  • the inhibition rate of the blank administration group was 0, the inhibition rate of the baicalin group (9.5 mg/kg) was 22%, the inhibition rate of the baicalin group (9.5 mg/kg) was 22%, and the inhibition rate of the lenalidomide group (5.5 mg/kg) 66%, the inhibition rate of baicalin lenalidomide double salt nanosuspension group (15mg/kg) was 93%, and the inhibition rate of baicalin lenalidomide double salt nanosuspension group (15mg/kg) was 90%.
  • the blank administration group, the scutellarin group, the ibrutinib group, and the scutellarin-ibrutinib double-salt nanosuspension group (the preparation method of the scutellarin-ibrutinib double-salt nanosuspension) were set up respectively.
  • Example 20 The blank administration group, the scutellarin group, the ibrutinib group, and the scutellarin-ibrutinib double-salt nanosuspension group (the preparation method of the scutellarin-ibrutinib double-salt nanosuspension) were set up respectively.
  • Example 20 The blank administration group, the scutellarin group, the ibrutinib group, and the scutellarin-ibrutinib double-salt nanosuspension group (the preparation method of the scutellarin-ibrutinib double-salt nanosuspension) were set
  • mice Balb/c nude mice, male, 6-8 weeks old. All mice had free access to food and water, and were kept at room temperature (23 ⁇ 2)°C.
  • Tumor cells WSO-DLCL-2 cell line, derived from NIH.
  • the lymphoma mice were established, and the qualified mice were randomly divided into groups of 10.
  • the dosing regimen was as follows:
  • Blank administration group only normal saline was administered.
  • Baicalin group scutellarin was formulated into a dosing solution with sterile PBS, and the dose was 23 mg/kg by gavage, once a day, for 21 consecutive days.
  • Ibrutinib group The dosing solution was prepared with sterile PBS lenalidomide, and the dosage was 22 mg/kg, which was administered by gavage, once a day, for 21 consecutive days.
  • the scutellarin-ibrutinib complex salt nanosuspension group the scutellarin-ibrutinib complex salt nanosuspension was used as the dosing solution, and the dosage was 45 mg/kg, intragastrically, once a day, continuously given Medicine on the 21st.
  • the inhibition rate of the blank administration group was 0, the inhibition rate of the scutellarin group (23 mg/kg) was 24%, and the inhibition rate of the ibrutinib group (22 mg/kg) was 68%.
  • the inhibition rate of the group (45mg/kg) was 91%.

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Abstract

La présente invention relève du domaine technique de la chimie pharmaceutique, et concerne en particulier un composé de sel double d'un agent anti-tumoral à base de glycoside de flavone amine organique, son procédé de préparation et son utilisation. Dans le composé de sel double de l'agent anti-tumoral à base de glycoside de flavone amine organique préparé au moyen de la présente invention, le glycoside de flavone a une formule générale développée telle que représentée dans la formule (I), dans laquelle R1 à R9 sont indépendamment choisis parmi -H,-OH, alkyle en C1-C6, alcoxy ou alkyle substitué, et au moins l'un de R1 et R2 est -OH. La présente invention concerne également un procédé de préparation du composé de sel double. La présente invention concerne en outre une composition pharmaceutique contenant une quantité thérapeutiquement efficace du composé de sel double et son utilisation. Par ailleurs, la présente invention concerne également une nanoparticule de sel double obtenue par nano-broyage répété du composé de sel double, et son utilisation.
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CN113801181A (zh) 2021-12-17

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