WO2022089590A1 - Composé de sel du complexe flavonoïde glycoside-inhibiteur de tyrosine kinase amine organique, son procédé de préparation et son utilisation - Google Patents

Composé de sel du complexe flavonoïde glycoside-inhibiteur de tyrosine kinase amine organique, son procédé de préparation et son utilisation Download PDF

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WO2022089590A1
WO2022089590A1 PCT/CN2021/127471 CN2021127471W WO2022089590A1 WO 2022089590 A1 WO2022089590 A1 WO 2022089590A1 CN 2021127471 W CN2021127471 W CN 2021127471W WO 2022089590 A1 WO2022089590 A1 WO 2022089590A1
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cancer
double salt
baicalin
tyrosine kinase
salt compound
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PCT/CN2021/127471
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Chinese (zh)
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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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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the application relates to the technical field of medicinal chemistry, in particular to a flavonoid glycoside-organoamine tyrosine kinase inhibitor double salt compound and a preparation method and application thereof.
  • Tyrosine kinase inhibitors are a class of compounds that can inhibit the activity of tyrosine kinases. Tyrosine kinase inhibitors can be used as competitive inhibitors of the binding of adenosine triphosphate (ATP) to tyrosine kinases, and can also be used as tyrosine kinase inhibitors. Analogs, which block the activity of tyrosine kinases and inhibit cell proliferation, have been developed as several antitumor drugs, including gefitinib, erlotinib, pazopanib, osimertinib, lapatinib, etc.
  • ATP adenosine triphosphate
  • baicalin and baicalin are both flavonoid glycosides (flavonoid glycosides for short), which have rich pharmacological activities, such as improving antioxidant capacity by resisting lipid peroxidation, scavenging free radicals and superoxide anions, improving blood circulation and increasing blood flow.
  • Anti-platelet aggregation inhibit virus infection, enhance immunity, anti-cell hypoxia, neuroprotection, inhibit tumor cell growth, etc.
  • multi-target tyrosine kinase inhibitors in the treatment of patients with non-small cell lung cancer are inferior to other non-small cell lung cancer drugs in terms of efficacy and survival data. Therefore, the development of specific inhibitors with higher selectivity and activity, which can increase the efficacy and limit the toxicity, is expected to become a new method for the treatment of various malignant tumors such as non-small cell lung cancer.
  • the flavonoid glycoside-organoamine tyrosine kinase inhibitor double salt compound has higher inhibitory activity on tyrosine kinase.
  • a double salt compound which is a double salt of a flavonoid glycoside and an organic amine tyrosine kinase inhibitor, and the flavonoid glycoside has the general structural formula shown in the following formula (1):
  • 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 selected from -OH.
  • R 1 and R 2 are both selected from -OH.
  • the flavonoid glycoside is baicalin or baicalin.
  • the organic amine tyrosine kinase inhibitor contains at least one amino group, and the amino groups are each independently selected from -NH 2 , -NR'H or -NR' 2 , the R ' is an electron donating group.
  • the organic amine tyrosine kinase inhibitor is selected from any one of gefitinib, erlotinib, pazopanib, osimertinib and lapatinib.
  • this application also provides a kind of preparation method of described double salt compound, comprising the following steps:
  • the mixed solution is reacted to obtain a reaction solution
  • the solvent was removed from the reaction solution.
  • the polar aprotic organic solvent is one or more of N,N-dimethylformamide, dimethylsulfoxide or acetonitrile.
  • Another aspect of the present application further provides a pharmaceutical composition, which contains a therapeutically effective amount of the double salt compound or its optical isomer, enantiomer, diastereomer, racemate or racemate mixture, and a pharmaceutically acceptable carrier, excipient or diluent.
  • the application of the double salt compound or the pharmaceutical composition in the preparation of a tyrosine kinase inhibitor drug is provided.
  • the tyrosine kinase inhibitor drug is used for the treatment of malignant tumors
  • the malignant tumors include lung cancer, liver cancer, gastric cancer, esophagus cancer, cardia cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, laryngeal cancer, oropharyngeal cancer, brain tumor, glioma.
  • a double salt nanoparticle is provided, wherein the double salt nanoparticle is obtained by nano-grinding the double salt compound.
  • Another aspect of the present application provides the application of the double salt nanoparticles in the preparation of tyrosine kinase inhibitor drugs.
  • the tyrosine kinase inhibitor drug is used for the treatment of malignant tumors
  • the malignant tumors include lung cancer, liver cancer, gastric cancer, esophagus cancer, cardia cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, laryngeal cancer, oropharyngeal cancer, brain tumor, glioma or soft tissue sarcoma.
  • Organic amine tyrosine kinase inhibitors are alkaline and can form salts with inorganic acids or small-molecule organic acids to increase their stability and improve physical properties. Salts formed by small molecular organic acids and organic amine tyrosine kinase inhibitors cannot improve the biological activity of these drugs.
  • the compounds provided in this application use a specific structure of flavonoid glycosides and organic amine tyrosine kinase inhibitors to form double salts.
  • the molecular structure of the flavonoid glycosides contains carboxyl and phenolic hydroxyl groups, which can inhibit organic amine tyrosine kinase inhibitors.
  • the amine group in the agent is bonded, and the binding effect between the two is stronger than that of the general drug salt.
  • the double salt Compared with the organic amine tyrosine kinase inhibitor itself, the double salt exhibits higher inhibitory activity on tyrosine kinase, and thus has better effect on tumor inhibition.
  • Natural compounds such as flavonoid glycosides have poor water solubility, but because there are carboxyl groups and phenolic hydroxyl groups in the molecular structure, they are easily soluble in alkalis, and 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.
  • Fig. 1 ⁇ Fig. 4 is the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 1 of the application;
  • 5 to 8 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 2 of the application;
  • Figures 9 to 12 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 3 of the application;
  • 13 to 16 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 4 of the application;
  • 17 to 20 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 5 of the application;
  • 21 to 24 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 6 of the application;
  • 25 to 28 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 7 of the application;
  • 29 to 32 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 8 of the application;
  • 33 to 36 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 9 of the present application.
  • alkyl refers to a saturated hydrocarbon containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. Phrases containing this term, for example, "C 1 -C 6 alkyl” refers to an alkyl group containing 1 to 6 carbon atoms, and each occurrence may independently be a C 1 alkyl, C 2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl .
  • Suitable examples include, but are not limited to: methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n - propyl, -CH2CH2CH ) 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ) , 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 ) )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 ) CH 2 CH 2 CH 3 ), 2-p
  • 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).
  • Ammonia refers to a derivative of ammonia, non-limiting classes of amino groups include -NH2 , -N(alkyl) 2 , -NH(alkyl), -N(cycloalkyl) 2 , -NH(cycloalkane) base), -N(heterocyclyl) 2 , -NH(heterocyclyl), -N(aryl) 2 , -NH(aryl), -N(alkyl)(aryl), -N(alkane (heterocyclyl), -N(cycloalkyl)(heterocyclyl), -N(aryl)(heteroaryl), -N(alkyl)(heteroaryl), and the like.
  • “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.
  • “Pharmaceutically acceptable carrier, excipient or diluent” refers to a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • pharmaceutically acceptable carrier, excipient or diluent includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents compatible with pharmaceutical administration agents, isotonic and absorption delaying agents and the like.
  • Each carrier, excipient or diluent must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients in the formulation and not injurious to the patient.
  • 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 with a substituent selected from defined or suitable substituents.
  • substitution 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.
  • IC50 refers to the half-maximal inhibitory concentration of a compound relative to inhibition of a given activity, eg, neural receptors including acetylcholinesterase, NMDA receptors, sphingosine phosphate receptors. The smaller the IC50 value, the stronger the inhibitory activity of the compound for a given activity.
  • the application relates to a double salt compound, which is a double salt of a flavone glycoside and an organic amine tyrosine kinase inhibitor, and the flavone glycoside has the general structural formula shown in the following formula (1):
  • 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 selected from -OH.
  • the flavonoid glycosides, the carboxyl hydrogen in the gluconic acid unit in the molecular structure, and the phenolic hydroxyl hydrogen (the hydrogen in R 1 or R 2 ) in the flavonoid unit together form a hydrogen ion-rich region and are proton donors.
  • the nitrogen atom of the organic amine in the organic amine tyrosine kinase inhibitor contains a lone pair of electrons and is a proton acceptor. The two are combined to form the flavonoid glycoside-organoamine tyrosine kinase inhibitor double salt.
  • 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 (2), to form a proton nest (proton shown in the dotted box in formula 2). 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, carboxyl oxygen electrons in proton dens and lone electron pairs of nitrogen in organic amines are entangled in the salt-forming region.
  • the quantum entanglement formed during the salt formation continues to exist, which improves the biological activity of the double salt of the flavonoid glycoside-organic amine tyrosine kinase inhibitor.
  • both R 1 and R 2 are selected from -OH.
  • R3 is selected from -H or -OCH3 .
  • 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 -OH. In other embodiments, R7 is selected from -H.
  • the flavone glycoside can be any one of apigenin flavone glycoside, baicalin, scutellarin, chrysin flavone glycoside or wogonin, optionally, the flavone glycoside is baicalin or Baicalin.
  • the organic amine tyrosine kinase inhibitor contains at least one amino group, the amino groups are each independently selected from -NH 2 , -NR'H or -NR' 2 , and the R' is an electron donating group
  • R' is alkyl or alkoxy.
  • the organic amine tyrosine kinase inhibitor is selected from any one of gefitinib, erlotinib, pazopanib, osimertinib, and lapatinib.
  • Gefitinib an oral epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitor, inhibition of EGFR-TK can hinder tumor growth, metastasis and angiogenesis, and increase tumor cell apoptosis .
  • EGFR-TK oral epidermal growth factor receptor tyrosine kinase
  • the structural formula of gefitinib is as follows:
  • Erlotinib a targeted therapy drug, can specifically target tumor cells, inhibit the formation and growth of tumors, and inhibit the signaling pathway of human epidermal growth factor receptor (EGFR). Erlotinib inhibits tumor growth by inhibiting the activity of tyrosine kinases, one of the important intracellular components of EGFR. Erlotinib can be used for the third-line treatment of locally advanced or metastatic non-small cell lung cancer that has failed two or more chemotherapy regimens. The structural formula of erlotinib is shown below:
  • Pazopanib also known as pazopanib, is a vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR)-1 and -3, cytokine receptor (Kit), interleukin-2 receptor inducible T cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor A poly-tyrosine kinase inhibitor of somatic tyrosine kinase (c-Fms).
  • VGFR vascular endothelial growth factor receptor
  • VEGFR-2 VEGFR-2
  • VEGFR-3 platelet-derived growth factor receptor
  • FGFR fibroblast growth factor receptor
  • it cytokine receptor
  • Itk interleukin-2 receptor inducible T cell kinase
  • Lck leukocyte-specific protein
  • Pazopanib interferes with neovascularization required for survival and growth of recalcitrant tumors, targets vascular endothelial growth factor receptor (VEGFR), works by inhibiting neovascularization that supplies blood to tumors, and is suitable for advanced renal cells
  • Carcinoma a type of kidney cancer in which cancer cells are found in the kidney tubules
  • STS soft tissue sarcoma
  • NSCLC non-small cell lung cancer
  • Osimertinib is a potent and selective EGFR mutant inhibitor with IC50s of 12.92nM, 11.44nM and 493.8nM for exon 19-deleted EGFR, L858R/T790M EGFR and wild-type EGFR, respectively.
  • the molecular weight is 499.61, and the molecular formula is C 28 H 33 N 7 O 2 .
  • Osimertinib is a new drug for non-small cell advanced lung cancer, an oral drug for the treatment of patients with advanced non-small cell lung cancer (NSCLC).
  • NSCLC advanced non-small cell lung cancer
  • Lapatinib an oral small molecule epidermal growth factor (EGFR: ErbB-1, ErbB-2) tyrosine kinase inhibitor, chemical name N-[3-chloro-4-[(3-fluorobenzene yl)methoxy]phenyl]-6-[5-[(2-methanesulfonylethylamino)methyl]-2-furyl]quinazolin-4-amine, the molecular formula is C 29 H 26 Cl F N 4 O 4 S, molecular weight 581.05800.
  • Lapatinib is an anti-tumor drug.
  • lapatinib The structural formula of lapatinib is as follows:
  • the application also relates to a preparation method of a described double salt compound, comprising the following steps:
  • the molar ratio of the flavonoid glycoside and the organic amine tyrosine kinase inhibitor can be any ratio between 1:3 and 3:1, for example, it can also include 1:2, 1:1.5, 1:1, 1.5:1, 2:1, optional 1:1.
  • the polar aprotic organic solvent may be one or more of N,N-dimethylformamide, dimethylsulfoxide or acetonitrile.
  • step S10 there are various methods for mixing and dissolving the flavonoid glycoside, the organic amine tyrosine kinase inhibitor and the polar aprotic organic solvent to obtain a mixed solution.
  • the following steps can be included
  • the concentration of the flavonoid glycosides in the first solution is 0.1 mol/L to 1.0 mol/L, optionally 0.33 mol/L.
  • the concentration of the organic amine tyrosine kinase inhibitor 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 method for removing the solvent may be concentration under reduced pressure, and the temperature of the concentration under reduced pressure may be 40°C to 70°C, optionally 60°C.
  • Step S30 also includes a purification step.
  • the method of purification can be beating.
  • the solvent used in the beating can be ethyl acetate.
  • the dosage of ethyl acetate is 1:1 to 1:5 according to acid (baicalin or scutellarin) mol/L, and 1:3 is the best; the temperature of beating can be 5°C ⁇ 50°C, and 20 °C ⁇ 30°C, time is 20 minutes ⁇ 40 minutes.
  • 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 8 hours to 48 hours, optionally 24 hours.
  • the temperature of the freeze-drying is less than 0°C, and the drying time can be 3 hours to 12 hours, optionally 6 hours.
  • the present application relates to a compound containing a therapeutically effective amount of the above-mentioned double salt compound or its optical isomer, enantiomer, diastereomer, racemate or racemic mixture, and a pharmaceutically acceptable carrier , excipient or diluent composition.
  • the present application relates to the application of the double salt compound in the preparation of a tyrosine kinase inhibitor drug.
  • the tyrosine kinase inhibitor medicament prepared according to the double salt compound of the present application is used for the treatment of malignant tumors
  • the malignant tumors include lung cancer, liver cancer, gastric cancer, esophagus cancer, cardia cancer, colon cancer, rectal cancer Cancer, colorectal cancer, breast cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, laryngeal cancer, oropharyngeal cancer, brain tumor, glioma, soft tissue sarcoma, especially for the treatment of non-small cell lung cancer.
  • the application further relates to a method of treating a neurodegenerative disease, the method optionally comprising administering to a patient suffering from a neurodegenerative disease in need thereof an appropriate amount of a double salt as defined above, comprising a double salt according to the application composition of compounds.
  • the present application further relates to a double salt nanoparticle obtained by nano-milling the double salt compound of any of the above embodiments.
  • the average particle size of the double salt nanoparticles ranges from 50 nm to 500 nm.
  • the application also relates to a method for preparing the double salt nanoparticles, comprising:
  • the compound salt compound, the suspending agent and the solvent are mixed and ground by a nano-grinder.
  • the suspending agent is Tween, hypromellose, polyethylene glycol, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, fatty acid glycerides, polyol type nonionic Surfactant, polyoxyethylene type nonionic surface cleanser, poloxamer, vitamin E polyethylene glycol succinate, phospholipids, gelatin, xanthan gum, sodium lauryl sulfate and sodium deoxycholate one or more of them.
  • the suspending agent is a combination of Tween, hypromellose and polyethylene glycol.
  • the mass ratio of the double salt compound and the suspending agent is 1000:(0.5-3).
  • the rotation speed of the grinding is 2000 rpm to 3000 rpm, and the grinding time is 30 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 present application also relates to the application of the double salt nanoparticles in the preparation of tyrosine kinase inhibitor drugs.
  • the tyrosine kinase inhibitor drug is used for the treatment of malignant tumors
  • the malignant tumors include lung cancer, liver cancer, gastric cancer, esophagus cancer, cardia cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer , cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, laryngeal cancer, oropharyngeal cancer, brain tumor, glioma or soft tissue sarcoma.
  • 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 medicament of the present application may be suitable for oral, rectal, bronchial, nasal, topical, buccal, sublingual, transdermal, vaginal or parenteral (including dermal, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral) , intraocular injection or infusion), or in a form suitable for administration by inhalation or insufflation (including powder and liquid aerosol administration) or by sustained release systems.
  • sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compounds of the present application, which matrices may be in the form of shaped articles such as films or microcapsules.
  • 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.
  • pharmaceutically acceptable carriers can be solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material .
  • the carrier is a finely divided solid in admixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter Wait.
  • the term "preparation” is intended to include the formulation of the active compound with a coating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by and thus in association with a carrier.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.
  • 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.
  • solid form preparations that are intended to be converted shortly before use to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • these formulations can contain colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.
  • 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 active ingredient may be provided in dry powder form, eg, a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose, and polyvinylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose, and polyvinylpyrrolidone (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • Powder compositions may be presented in unit dosage forms, eg, capsules or cartridges such as gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • 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 with 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 Swarbrick, 2nd edition”.
  • the crude product was slurried with 30 ml of ethyl acetate at room temperature for 20 minutes, filtered, and the filter cake was divided into two equal parts.
  • the first part was suspended in 15 ml of water, and freeze-dried for 6 hours to remove the solvent to obtain a pale yellow solid product.
  • the second filter cake was dried under vacuum at 30°C for 24 hours to obtain a pale yellow solid product.
  • 3.74 g of baicalin gefitinib salt was obtained, and the yield was 83.70%.
  • 3.78 g of baicalin gefitinib salt was obtained, and the yield was 84.66%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figures 1 to 4. Compared with the simple mixture of baicalin and gefitinib, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin formed salt with gefitinib-N, and the infrared spectrum also showed this feature. The thermal weight loss showed that the product had peaks at 244°C and 260°C. Compared with baicalin and gefitinib, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has formed a salt.
  • Gefitinib 4.47 grams (0.01mol) was suspended in 15ml DMF, 4.62 grams (0.01mol) of scutellarin was added to 30ml DMF, the above-mentioned gefitinib DMF solution was added to the scutellarin DMF solution, and the reaction was stirred at 70°C For 15 hours, the reaction solution was 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 at room temperature for 20 minutes, filtered, and the filter cake was divided into two equal parts.
  • the first part was suspended in 15 ml of water, and freeze-dried for 6 hours to remove the solvent to obtain a pale yellow solid product.
  • the second filter cake was dried under vacuum at 30°C for 24 hours to obtain a pale yellow solid product.
  • the first part obtained 3.98 g of scutellarin gefitinib salt with a yield of 87.46%, and the second part obtained 4.10 g of scutellarin gefitinib salt with a yield of 90.20%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figures 5 to 8. Compared with the pure mixture of baicalin and gefitinib, the product is more soluble. The chemical shifts showed that the carboxyl hydrogen of baicalin was salted with gefitinib-N, and the infrared spectrum also showed this feature. The thermal weight loss showed that the product had a peak at 208°C. Compared with baicalin and gefitinib, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
  • the preparation method was basically the same as that of Example 1, except that 3.93 g (0.01 mol) of erlotinib was replaced by gefitinib.
  • the first part obtained 3.66 g of baicalin erlotinib salt with a yield of 87.17%, and the second part obtained 3.70 g of baicalin erlotinib salt with a yield of 88.20%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 9 to Figure 12. Compared with the simple mixture of baicalin and erlotinib, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin formed a salt with erlotinib-NH, and the infrared spectrum also showed this feature. The thermal weight loss showed that the product had peaks at 105°C, 194°C, and 245°C. Compared with baicalin and erlotinib, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has formed a salt.
  • the preparation method was basically the same as that of Example 2, except that 3.93 g (0.01 mol) of erlotinib was replaced by gefitinib.
  • the first part obtained 3.47 g of scutellarin erlotinib salt with a yield of 81.07%, and the second part obtained 3.52 g of scutellarin erlotinib salt with a yield of 82.34%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 13 to Figure 16. Compared with the simple mixture of baicalin and erlotinib, the product is more soluble. The chemical shifts showed that the carboxyl hydrogen of baicalin formed salt with erlotinib-NH, and the infrared spectrum also showed this feature. The thermal weight loss showed that the product had peaks at 168°C and 203°C. The XRD pattern shows that the product has characteristic diffraction peaks. Compared with baicalin and erlotinib, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has been formed into a salt.
  • the preparation method is basically the same as that of Example 1, except that gefitinib is replaced by pazopanib 4.38 g (0.01 mol).
  • the first part obtained 3.49 g of baicalin pazopanib salt with a yield of 78.88%, and the second part obtained 3.52 g of baicalin pazopanib salt with a yield of 79.38%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 17 to Figure 20. Compared with the simple mixture of baicalin and pazopanib, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin formed salt with pazopanib-NH, and the infrared spectrum also showed this feature. The thermal weight loss showed that the product had peaks at 200°C and 345°C. Compared with baicalin and pazopanib, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has formed a salt.
  • the preparation method was basically the same as that of Example 2, except that gefitinib was replaced by pazopanib 4.38 g (0.01 mol).
  • the first part obtained 2.54 g of scutellarin pazopanib salt with a yield of 56.54%, and the second part obtained 2.60 g of scutellarin pazopanib salt with a yield of 57.78%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 21 to Figure 24. Compared with the simple mixture of baicalin and pazopanib, the product is more soluble. The chemical shifts showed that the carboxyl hydrogen of baicalin formed salt with pazopanib-NH, and the infrared spectrum also showed this feature. The thermal weight loss showed that the product had peaks at 198°C and 320°C. Compared with baicalin and pazopanib, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
  • the preparation method was basically the same as that of Example 1, except that 5.96 g (0.01 mol) of osimertinib was replaced with gefitinib.
  • the first part obtained 4.30 g of baicalin osimertinib salt with a yield of 82.46%, and the second part obtained 4.35 g of baicalin osimertinib salt with a yield of 83.49%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 25 to Figure 28. Compared with the simple mixture of baicalin and osimertinib, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin formed a salt with osimertinib-N, and the infrared spectrum also showed this feature. The thermal weight loss showed that the product had wind at 154°C, 210°C, and 337°C. Compared with baicalin and osimertinib, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
  • the preparation method was basically the same as that of Example 1, except that 5.96 g (0.01 mol) of osimertinib was replaced with gefitinib.
  • the first part obtained 4.18 g of scutellarin osimertinib salt with a yield of 79.07%, and the second part obtained 4.22 g of scutellarin osimertinib salt with a yield of 79.77%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 29 to Figure 32. Compared with the pure mixture of baicalin and osimertinib, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin formed a salt with osimertinib-N, and the infrared spectrum also showed this feature. The thermal weight loss showed that the product had peaks at 154°C, 211°C, and 339°C. Compared with baicalin and osimertinib, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
  • the preparation method was basically the same as that of Example 2, except that 5.81 g (0.01 mol) of lapatinib was replaced with gefitinib.
  • the first part obtained 3.61 g of scutellarin lapatinib salt with a yield of 69.13%, and the second part obtained 3.64 g of scutellarin lapatinib salt with a yield of 69.80%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 33 to Figure 36. Compared with the simple mixture of baicalin and lapatinib, the product is more soluble. The chemical shift showed that the carboxyl hydrogen of baicalin formed salt with lapatinib-NH, and the infrared spectrum also showed this feature. The thermal weight loss showed that the product had peaks at 210°C and 266°C. Compared with baicalin and lapatinib, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has formed a salt.
  • Each compound salt compound was prepared into different concentrations of the test substance, and the tyrosine kinase kit was used to measure the inhibition of the test substance on tyrosine kinase activity, and IC50 was calculated.
  • baicalin erlotinib compound salt compound and Scutellaria baicalensis erlotinib compound salt compound on tyrosine kinase is stronger than that of erlotinib on tyrosine kinase;
  • baicalin pazopanib compound salt compound and baicalin pazopanib compound salt compound compound on tyrosine kinase is stronger than that of pazopanib on tyrosine kinase;
  • baicalin osimertinib double salt compound and baicalin osimertinib double salt compound on tyrosine kinase is stronger than that of osimertinib on tyrosine kinase;
  • baicalin and lapatinib compound salt on tyrosine kinase are stronger than that of lapatinib on tyrosine kinase.
  • baicalin and gefitinib double salt compound 1-10 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 baicalin gefitinib double salt nanosuspension.
  • baicalin and gefitinib double salt nano-suspension is dried in a fluidized bed drying equipment, and the drying air inlet temperature is 65° C., and is dried to a moisture content of about 3% to prepare the baicalin and gefitinib double salt nano-suspension.
  • the particle size distribution is in the range of 50nm to 500nm.
  • the prepared baicalin-gefitinib 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 11, except that the baicalin gefitinib double salt compound is replaced by the baicalin gefitinib double salt compound.
  • the particle size distribution of the nanoparticles of salicylic acid and gefitinib compound salt is in the range of 50nm to 500nm.
  • the prepared scutellarin-gefitinib double-salt nanoparticles had a 2.4-fold increase in solubility at 20°C for 10 minutes.
  • the preparation method is basically the same as that of Example 11, except that the baicalin gefitinib double salt compound is replaced by the baicalin erlotinib double salt compound.
  • the particle size distribution of baicalin-erlotinib double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared baicalin-erlotinib double-salt nanoparticles have a 1.8-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-erlotinib double salt compound is replaced with the baicalin-erlotinib double salt compound.
  • the particle size distribution of quinceline erlotinib double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin-erlotinib double-salt nanoparticles have a 2.0-fold increase in solubility at 20° C. for 10 minutes compared to the scutellarin-erlotinib double-salt compound without nano-milling.
  • the preparation method is basically the same as that of Example 11, except that the baicalin gefitinib double salt compound is replaced by the baicalin pazopanib double salt compound.
  • the particle size distribution of baicalin pazopanib double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared baicalin pazopanib double salt nanoparticles have a 2.2-fold increase in solubility at 20°C for 10 minutes compared to the baicalin pazopanib double salt compound without nano-milling.
  • the preparation method is basically the same as that of Example 15, except that the baicalin pazopanib double salt compound is replaced by the baicalin pazopanib double salt compound.
  • the particle size distribution of pazopanib double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin pazopanib double salt nanoparticles have a 2.2-fold increase in solubility at 20°C for 10 minutes compared to the scutellarin pazopanib double salt compound without nano-milling.
  • the preparation method is basically the same as that of Example 11, except that the baicalin gefitinib double salt compound is replaced by the baicalin osimertinib double salt compound.
  • the particle size distribution of baicalin osimertinib double salt nanoparticles is in the range of 50nm to 500nm.
  • the solubility of the prepared baicalin-osimertinib double-salt compound at 20° C. for 10 minutes increased by 2.4 times.
  • Example 17 The preparation method of Example 17 is basically the same, except that the baicalin osimertinib double salt compound is replaced with the baicalin osimertinib double salt compound.
  • the particle size distribution of quinceaside osimertinib double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin-osimertinib double-salt nanoparticles have a 2.2-fold increase in solubility at 20°C for 10 minutes compared to the scutellarin-osimertinib double-salt compound without nano-milling.
  • the preparation method is basically the same as that of Example 11, except that the baicalin gefitinib double salt compound is replaced with the baicalin lapatinib double salt compound.
  • the particle size distribution of quinceline lapatinib double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin lapatinib double salt nanoparticles have a 2.5-fold increase in solubility at 20° C. for 10 minutes compared to the scutellarin lapatinib double salt compound without nano-milling.
  • Example 20 Determination of in vivo anti-lung cancer tumor activity in animals
  • baicalin group baicalin group
  • gefitinib group gefitinib group
  • erlotinib baicalin-gefitinib double salt nanosuspension group
  • Example 11 for the preparation method of the nanosuspension, baicalin and gefitinib double salt nanosuspension group (refer to Example 12 for the preparation method of the scutellarin and nilotinib double salt nanosuspension), and baicalin Erlotinib double salt nanosuspension group (baicalin erlotinib double salt nanosuspension preparation method refers to Example 13), scutellarin erlotinib double salt nanosuspension group (scutellarin For the preparation method of erlotinib double salt nanosuspension, refer to Example 14).
  • mice Balb/c nude mice, male, 6-8 weeks old. All mice had free access to food and water, and were housed at room temperature (23 ⁇ 2)°C.
  • Tumor cells HCC827 cell line, derived from NIH.
  • Lung cancer tumor 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 The baicalin was formulated into a dosing solution with sterile PBS, and the dose was 38 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 38 mg/kg by gavage, once a day, for 21 consecutive days.
  • Gefitinib group Gefitinib was formulated into a dosing solution with sterile PBS, and the dosage was 38 mg/kg, administered by gavage, once a day, for 21 consecutive days.
  • Erlotinib group erlotinib was formulated into a dosing solution with sterile PBS, and the dosage was 15 mg/kg, administered by gavage, once a day, for 21 consecutive days.
  • Baicalin and gefitinib compound salt nanosuspension group Baicalin and gefitinib compound salt nanosuspension was used as a dosing solution, and the dosage was 75 mg/kg, intragastrically, once a day, for 21 consecutive times. day.
  • Baicalin and gefitinib double salt nanosuspension group scutellarin and gefitinib double salt nanosuspension as the dosing solution, according to the dosage of 75mg/kg, gavage, once a day, continuously Medicine on the 21st.
  • Baicalin-erlotinib complex salt nanosuspension group Baicalin-erlotinib complex salt nanosuspension was used as the dosing solution, according to the dosage of 35 mg/kg, intragastrically, once a day, continuously administered for 21 day.
  • the scutellarin-erlotinib double salt nanosuspension group the scutellarin-erlotinib double salt nanosuspension was used as the dosing solution, according to the dosage of 35 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 (38 mg/kg) was 24%, the inhibition rate of the baicalin group (38 mg/kg) was 28%, and the inhibition rate of the gefitinib group (38 mg/kg) was 66%.
  • Example 21 Determination of in vivo anti-renal cancer tumor activity in animals
  • 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 A498 cell line, derived from NIH.
  • Renal cancer tumor mice were established, and 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 The baicalin was prepared into a dosing solution with sterile PBS, and the dose was 33 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 33 mg/kg by gavage, once a day, for 21 consecutive days.
  • Pazopanib group Pazopanib was formulated into a dosing solution with sterile PBS, and the dose was 32 mg/kg by gavage, once a day, for 21 consecutive days.
  • Baicalin pazopanib compound salt nanosuspension group Baicalin pazopanib compound salt nanosuspension was used as a dosing solution, and the dosage was 65 mg/kg, intragastrically, once a day, for 21 consecutive times. day.
  • Baicalin pazopanib double salt nanosuspension group scutellarin pazopanib double salt nanosuspension was used as the dosing solution, according to the dosage of 75 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 (33 mg/kg) was 30%, the inhibition rate of the baicalin group (33 mg/kg) was 28%, and the inhibition rate of the pazopanib group (32 mg/kg) was 65%.
  • the inhibition rate of baicalin pazopanib nanosuspension group (65mg/kg) was 86%, and the inhibition rate of baicalin pazopanib nanosuspension group (65 mg/kg) was 91%.
  • 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 H1975 cell line, derived from NIH.
  • Lung cancer tumor 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 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 mg/kg by gavage, once a day, for 21 consecutive days.
  • Osimertinib group Osimertinib was formulated into a dosing solution with sterile PBS, and the dose was 11 mg/kg by gavage, once a day, for 21 consecutive days.
  • Baicalin osimertinib compound salt nanosuspension group Baicalin osimertinib compound salt nanosuspension was used as a dosing solution, and the dosage was 20 mg/kg, intragastrically, once a day, for 21 consecutive times. day.
  • the scutellarin osimertinib double salt nanosuspension group the scutellarin osimertinib double salt nanosuspension was used as the dosing solution, and the dosage was 20 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 (33 mg/kg) was 30%, the inhibition rate of the baicalin group (33 mg/kg) was 28%, and the inhibition rate of the osimertinib group (32 mg/kg) was 65%.
  • the inhibition rate of baicalin osimertinib nanosuspension group (65mg/kg) was 86%, and the inhibition rate of baicalin osimertinib nanosuspension group (65mg/kg) was 91%.
  • the blank administration group, the scutellarin group, the lapatinib group, and the scutellarin-lapatinib double salt nanosuspension group (the preparation method of the scutellarin and lapatinib double salt nanosuspension) were set up respectively.
  • Example 19 The blank administration group, the scutellarin group, the lapatinib group, and the scutellarin-lapatinib double salt nanosuspension group (the preparation method of the scutellarin and lapatinib double salt nanosuspension) were set up respectively. Example 19).
  • 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 BT474 cell line, derived from NIH.
  • mice Mammary tumor 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 The scutellarin was formulated into a dosing solution with sterile PBS, and the dose was 31 mg/kg by gavage, once a day, for 21 consecutive days.
  • Lapatinib group Lapatinib was formulated into a dosing solution with sterile PBS, and the dose was 39 mg/kg by gavage, once a day, for 21 consecutive days.
  • Baicalin-lapatinib double-salt nanosuspension group Baicalin-lapatinib double-salt nanosuspension was used as a dosing solution, and the dosage was 20 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 (31 mg/kg) was 25%, the inhibition rate of the lapatinib group (39 mg/kg) was 67%, and the scutellarin lapatinib nanosuspension group ( 20mg/kg) the inhibition rate was 90%.

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Abstract

La présente invention concerne un composé de sel du complexe d'un flavonoïde glycoside et d'un inhibiteur de tyrosine kinase amine organique. Le glycoside flavonoïde a une formule générale développée telle que représentée par la formule (1), dans laquelle chaque R1-R9 est indépendamment choisi parmi -H, -OH et alkyle en C1-C6, alcoxy ou alkyle substitué, et au moins l'un de R1 et R2 est choisi parmi -OH. La présente invention concerne également un procédé de préparation du composé de sel du complexe. En outre, la présente invention concerne également une composition pharmaceutique contenant une quantité thérapeutiquement efficace du composé et son utilisation et une nanoparticule de sel du complexe obtenue par nano-broyage du composé de sel du complexe et son utilisation. [Formule I]
PCT/CN2021/127471 2020-10-30 2021-10-29 Composé de sel du complexe flavonoïde glycoside-inhibiteur de tyrosine kinase amine organique, son procédé de préparation et son utilisation WO2022089590A1 (fr)

Applications Claiming Priority (2)

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