WO2022089600A1 - Flavonoid glycoside-organic amine antimicrobial agent double salt compound, preparation method therefor and application thereof - Google Patents

Flavonoid glycoside-organic amine antimicrobial agent double salt compound, preparation method therefor and application thereof Download PDF

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WO2022089600A1
WO2022089600A1 PCT/CN2021/127504 CN2021127504W WO2022089600A1 WO 2022089600 A1 WO2022089600 A1 WO 2022089600A1 CN 2021127504 W CN2021127504 W CN 2021127504W WO 2022089600 A1 WO2022089600 A1 WO 2022089600A1
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double salt
baicalin
salt compound
group
salt
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PCT/CN2021/127504
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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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    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
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    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
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    • A61P31/12—Antivirals
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    • A—HUMAN NECESSITIES
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
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    • C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

  • the present application relates to the technical field of medicinal chemistry, in particular to a flavonoid glycoside-organic amine antimicrobial double salt compound and a preparation method and application thereof.
  • Antimicrobial agent refers to a drug that inhibits or kills pathogenic microorganisms, thereby hindering their growth and reproduction. According to the object of action, it can be divided into three categories: the first category, antibacterial drugs (referred to as antibacterial drugs), including drugs that can inhibit or kill bacteria, mycoplasma, chlamydia, rickettsia, spirochetes and other pathogenic bacteria, according to different sources of drugs, Antibacterial drugs can be divided into antibiotics and synthetic antibacterial drugs.
  • the second category, antifungal drugs are primarily used to inhibit fungal growth and/or kill fungi.
  • the third category is antiviral drugs.
  • antiviral drugs are all clinically effective anti-microbial infection drugs for microbial infectious diseases such as influenza, hepatitis B, malaria and other microbial infections, especially viruses sexually transmitted diseases.
  • 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.
  • the flavonoid glycoside-organic amine antimicrobial double salt compound has higher inhibitory activity on pathogenic microorganisms.
  • a double salt compound which is the double salt of a flavone glycoside and an organic amine antimicrobial agent, 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.
  • R 1 and R 2 are both selected from -OH.
  • the flavonoid glycoside is baicalin or baicalin.
  • the organic amine antimicrobial agent contains at least one amino group, and the amino groups are each independently selected from the group consisting of -NH 2 , -NR'H or -NR' 2 , and the R' is to give electronic group.
  • the organic amine antimicrobial agent is selected from any one of amantadine, lamivudine, oseltamivir, hydroxychloroquine and chloroquine.
  • 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 antimicrobial drug is used for the treatment of a viral disease, the viral disease being influenza virus, hepatitis B virus, malaria, rheumatoid arthritis, lupus erythematosus or neurodegenerative disease.
  • 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 antimicrobial drugs is provided.
  • the antimicrobial drug is used for the treatment of viral diseases
  • the viral diseases are excessive immune responses caused by influenza virus, hepatitis B virus, malaria, rheumatoid arthritis, lupus erythematosus, and microbial infections. or neurodegenerative diseases.
  • Organic amine antimicrobial agents are alkaline and can form salts with inorganic acids or small-molecule organic acids to increase their stability and improve physical properties. Salts of acids with organic amine antimicrobials do not enhance the biological activity of these drugs.
  • the double salt compound provided by the present application adopts flavonoid glycosides with a specific structure and organic amine antimicrobial agents to form double salts. Base bonding, the binding effect between the two is stronger than the general drug salt formation. Compared with the organic amine antimicrobial itself, the double salt exhibits higher inhibitory activity against pathogenic microorganisms.
  • 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).
  • Amino refers to a derivative of ammonia.
  • Non-limiting classes of amino groups include -NH2 , -N(alkyl) 2 , -NH(alkyl), -N(cycloalkyl) 2 , -NH(cycloalkyl) ), -N(heterocyclyl) 2 , -NH(heterocyclyl), -N(aryl) 2 , -NH(aryl), -N(alkyl)(aryl), -N(alkyl) )(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.
  • 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.
  • IC50 refers to the half-maximal inhibitory concentration of a compound relative to inhibition of a given activity, eg, influenza A virus, DNA polymerase, RNA polymerase. 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 antimicrobial agent, 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 antimicrobial agent contains a lone pair of electrons and is a proton acceptor. The two are combined to form the flavonoid glycoside-organic amine antimicrobial 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 in proton dens, carboxyl oxygen electrons and lone electron pairs of nitrogen in organic amines are entangled in the salt-forming region.
  • the organic acids and organic After the bases are dissociated from each other the quantum entanglement formed during the salt formation continues to exist, which improves the biological activity of the flavonoid glycoside-organic amine antimicrobial double salt.
  • 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 antimicrobial agent 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 antimicrobial agent is selected from any one of amantadine, lamivudine, oseltamivir, hydroxychloroquine and chloroquine.
  • Amantadine with the molecular formula C 12 H 21 N, is an excitatory amino acid (NMDA) receptor inhibitor used for the treatment of moderate to severe Alzheimer's dementia.
  • NMDA excitatory amino acid
  • Lamivudine also known as 3-TC, is a nucleoside analog, an antiviral drug, which has a competitive inhibitory effect on the synthesis and elongation of viral DNA chains.
  • the structural formula of lamivudine is as follows:
  • Oseltamivir is a specific inhibitor that acts on neuraminidase. It inhibits the action of neuraminidase and can inhibit the mature influenza virus from leaving the host cell, thereby inhibiting the spread of influenza virus in the human body. to the treatment of influenza.
  • the structural formula of oseltamivir is as follows:
  • Hydroxychloroquine is a 4-aminoquinoline derivative antimalarial drug with similar action and mechanism to chloroquine.
  • the structural formula of hydroxychloroquine is as follows:
  • Chloroquine a drug mainly used to control malaria symptoms, is also used as an anti-amebic drug. It also has a certain effect on certain autoimmune diseases, such as rheumatoid arthritis, lupus erythematosus, and nephrotic syndrome.
  • the structural formula of chloroquine 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 antimicrobial agent 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 antimicrobial agent 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 antimicrobial 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 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 application relates to the use of the double salt compound in the preparation of an antimicrobial drug.
  • the antimicrobial medicament prepared according to the double salt compound of the present application is used for the treatment of a viral disease, the viral disease being influenza virus, hepatitis B virus, malaria, rheumatoid arthritis, lupus erythematosus or neurodegeneration sexually transmitted diseases.
  • a viral disease being influenza virus, hepatitis B virus, malaria, rheumatoid arthritis, lupus erythematosus or neurodegeneration sexually transmitted diseases.
  • 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 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 present application also relates to the application of the double salt nanoparticles in the preparation of antimicrobial drugs.
  • the antimicrobial drug is used for the treatment of a viral disease, the viral disease being an excessive immune response caused by influenza virus, hepatitis B virus, malaria, rheumatoid arthritis, lupus erythematosus, microbial infection-like diseases, or neurodegenerative diseases.
  • 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, in addition to the active ingredient, coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweetening agents, dispersing agents, thickening agents, 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 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.
  • 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.
  • 2.65 g of baicalin amantadine salt was obtained, and the yield was 80.88%.
  • 2.68 g of baicalin amantadine salt was obtained, and the yield was 89.78%.
  • 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 adamantane, the product is more soluble, and the chemical shift of the hydrogen NMR spectrum shows that The carboxyl hydrogen of baicalin forms a salt with amantadine-NH 2 , and the infrared spectrum also exhibits this feature. The thermal weight loss shows that the product has peaks at 149 °C and 195 °C. The XRD pattern shows that the product has characteristic diffraction peaks. Compared with baicalin and adamantane, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has been formed into a salt.
  • 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 2.32 g of scutellarin amantadine salt with a yield of 75.57%, and the second part obtained 2.36 g of scutellarin amantadine salt with a yield of 77.05%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figures 5 to 8. Compared with the simple mixture of baicalin and adamantane, the product is more soluble, and the chemical shift of the hydrogen NMR spectrum is It shows that the carboxyl hydrogen of baicalin forms a salt with amantadine-NH 2 , and the infrared spectrum also presents this feature. The thermal weight loss shows that the product has peaks at 185 °C, 204 °C and 205 °C. Compared with baicalin and adamantane, 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 amantadine is replaced by 2.29 g (0.01 mol) of lamivudine.
  • the first part obtained 3.03 g of baicalin lamivudine salt with a yield of 89.85%, and the second part obtained 3.08 g of baicalin lamivudine salt with a yield of 91.26%.
  • 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 pure mixture of baicalin and lamivudine, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin formed a salt with lamivudine-NH 2 , and the infrared spectrum also showed this feature, and the thermal weight loss showed that the product had peaks at 187°C and 261°C. Compared with baicalin and lamivudine, the physical properties, spectral characteristics and thermodynamic properties of the product have all changed, indicating that it has become a salt.
  • the preparation method is basically the same as that of Example 2, except that amantadine is replaced by 2.29 g (0.01 mol) of lamivudine.
  • the first part obtained 3.12 g of scutellarin lamivudine salt with a yield of 90.25%, and the second part obtained 3.15 g of scutellarin lamivudine salt with a yield of 91.17%.
  • 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 lamivudine, the product is more soluble. The chemical shift shows that the carboxyl hydrogen of baicalin forms a salt with lamivudine-NH 2 , and the infrared spectrum also shows this feature. The thermal weight loss shows that the product has peaks at 193 °C and 293 °C. The XRD pattern shows that the product has characteristic diffraction peaks. Compared with baicalin and lamivudine, the physical properties, spectral characteristics and thermodynamic properties of the product have all changed, indicating that it has become a salt.
  • the preparation method is basically the same as that of Example 1, except that amantadine is replaced with oseltamivir 3.12 g (0.01 mol).
  • the first part obtained 3.12 g of baicalin oseltamivir salt with a yield of 82.36%, and the second part obtained 3.18 g of baicalin oseltamivir salt with a yield of 83.90%.
  • 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 oseltamivir, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin formed a salt with oseltamivir-NH 2 , and the infrared spectrum also showed this feature, and the thermal weight loss showed that the product had a peak at 190 °C. Compared with baicalin and oseltamivir, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
  • the preparation method is basically the same as that of Example 2, except that amantadine is replaced by oseltamivir 3.12 g (0.01 mol).
  • the first part obtained 3.23 g of scutellarin oseltamivir salt with a yield of 83.58%, and the second part obtained 3.26 g of scutellarin oseltamivir salt with a yield of 84.24%.
  • 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 oseltamivir, the product is more soluble. The chemical shifts showed that the carboxyl hydrogen of baicalin formed a salt with oseltamivir-NH 2 , and the infrared spectrum also showed this feature. The thermal weight loss showed that the product had peaks at 192°C and 338°C. Compared with baicalin and oseltamivir, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
  • the preparation method is basically the same as that of Example 1, except that amantadine is replaced by 3.36 g (0.01 mol) of hydroxychloroquine.
  • the first part obtained 3.51 g of baicalin hydroxychloroquine salt with a yield of 89.72%, and the second part obtained 3.55 g of baicalin hydroxychloroquine salt with a yield of 90.79%.
  • 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 hydroxychloroquine, the product is more soluble, and the chemical shift of the hydrogen NMR spectrum shows that The carboxyl hydrogen of baicalin forms a salt with hydroxychloroquine-N, and the infrared spectrum also exhibits this feature. The thermal weight loss shows that the product has peaks at 200 °C and 277 °C. Compared with baicalin and hydroxychloroquine, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
  • the preparation method is basically the same as that of Example 2, except that amantadine is replaced by 3.36 g (0.01 mol) of hydroxychloroquine.
  • the first part obtained 3.27 grams of scutellarin hydroxychloroquine salt with a yield of 82.05%, and the second part obtained 3.28 grams of scutellarin hydroxychloroquine salt with a yield of 82.21%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 29 to Figure 32.
  • the product is more soluble, and the chemical shift of the hydrogen NMR spectrum is It shows that the carboxyl hydrogen of baicalin forms a salt with hydroxychloroquine-N, and the infrared spectrum also shows this feature, and the thermal weight loss shows that the product has a peak at 206 °C.
  • the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
  • the preparation method is basically the same as that of Example 2, except that amantadine is replaced by 3.20 g (0.01 mol) of chloroquine.
  • the first part obtained 3.38 grams of scutellarin chloroquine salt with a yield of 86.57%
  • the second part obtained 3.38 grams of scutellarin chloroquine salt with a yield of 86.57%.
  • 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 chloroquine, the product is more soluble, and the chemical shift of the hydrogen NMR spectrum shows that The carboxyl hydrogen of baicalin forms salt with -N of chloroquine, and the infrared spectrum also shows this feature. The thermal weight loss shows that the product has peaks at 205°C and 343°C. Compared with baicalin and chloroquine, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
  • Each compound salt compound was formulated into different concentrations of the test article, and the hamster kidney cells were used as the test cells to determine the inhibitory activity of the test article on the viability of influenza A virus-infected cells, and calculate the IC50.
  • Each double salt compound was prepared into different concentrations of the test article, the inhibitory activity of the test article on DNA polymerase activity was determined, and the IC50 was calculated.
  • Each compound salt compound was prepared into different concentrations of the test article, the inhibitory activity of the test article on RNA polymerase activity was determined, and IC50 was calculated.
  • the inhibitory activity of baicalin amantadine double salt compound and baicalin amantadine double salt compound to influenza A virus is stronger than the inhibitory activity of amantadine to influenza A virus;
  • baicalin oseltamivir compound salt compound and scutellarin oseltamivir compound salt compound against influenza A virus is stronger than that of oseltamivir against influenza A virus;
  • baicalin lamivudine compound salt compound and baicalin lamivudine compound salt compound on DNA polymerase is stronger than that of lamivudine on DNA polymerase;
  • the inhibitory activity of baicalin hydroxychloroquine double salt compound and scutellarin hydroxychloroquine double salt compound on DNA polymerase and RNA polymerase is stronger than that of hydroxychloroquine on DNA polymerase;
  • the inhibitory activity of scutellarin chloroquine double salt compound on DNA polymerase is stronger than that of chloroquine on DNA polymerase and RNA polymerase.
  • baicalin amantadine 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. Grinding at 2000 rpm for 40 minutes to obtain a nanosuspension of baicalin amantadine double salt.
  • baicalin amantadine double salt compound nanosuspension is dried in a 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 amantadine double salt nanoparticles. , particle size distribution in the range of 50nm ⁇ 500nm.
  • the prepared baicalin amantadine double salt nanoparticles have a 1.5-fold increase in solubility at 20° C. for 10 minutes.
  • Example 11 The preparation method of Example 11 is basically the same, except that the baicalin amantadine double salt compound is replaced by the baicalin amantadine double salt compound.
  • the particle size distribution of the pycnogenol amantadine double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin amantadine double salt nanoparticles have a 1.3-fold increase in solubility at 20°C for 10 minutes compared to the scutellarin amantadine double salt compound without nano-milling.
  • the preparation method is basically the same as that of Example 11, except that the baicalin amantadine double salt compound is replaced by the baicalin oseltamivir double salt compound.
  • the particle size distribution of baicalin and oseltamivir double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared baicalin-oseltamivir double-salt nanoparticles have a 0.8-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-oseltamivir double-salt compound is replaced with the scutellarin-oseltamivir double-salt compound.
  • the particle size distribution of quinceaside oseltamivir double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin-oseltamivir double-salt nanoparticles have a 1.0-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 amantadine double salt compound is replaced by the baicalin lamivudine double salt compound.
  • the particle size distribution of baicalin lamivudine double salt nanoparticles is in the range of 50nm to 500nm.
  • the solubility of the prepared baicalin-lamivudine double-salt compound at 20° C. for 10 minutes increased by 1.2 times.
  • the preparation method is basically the same as that of Example 15, except that the baicalin lamivudine double salt compound is replaced with the baicalin lamivudine double salt compound.
  • the particle size distribution of pycnogenol lamivudine double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin-lamivudine double-salt nanoparticles have a 1.0-fold increase in solubility at 20° C. for 10 minutes compared to the scutellarin-lamivudine double-salt compound without nano-milling.
  • Example 11 The preparation method of Example 11 is basically the same, except that the baicalin amantadine double salt compound is replaced by the baicalin hydroxychloroquine double salt compound.
  • the particle size distribution of baicalin hydroxychloroquine double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared baicalin-hydroxychloroquine double-salt nanoparticles have a 1.0-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 hydroxychloroquine double salt compound is replaced with the scutellarin hydroxychloroquine double salt compound.
  • the particle size distribution of the quinoside hydroxychloroquine double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin-hydroxychloroquine double-salt nanoparticles have a 1.0-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 amantadine double salt compound is replaced with the scutellarin chloroquine double salt compound.
  • the particle size distribution of the quinoside chloroquine double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin-chloroquine double-salt nanoparticles have a 1.0-fold increase in solubility at 20°C for 10 minutes.
  • baicalin group baicalin group, amantadine group, oseltamivir group, baicalin amantadine double salt nanosuspension group (baicalin amantadine double salt nanosuspension group) were set up respectively.
  • the scutellarin amantadine double salt nanosuspension group for the preparation method of the scutellarin amantadine double salt nanosuspension, refer to Example 12
  • baicalin and oseltamivir complex Salt nanosuspension group the preparation method of baicalin oseltamivir double salt nanosuspension preparation method refers to Example 13
  • scutellarin oseltamivir double salt nanosuspension group scutellarin oseltamivir complex For the preparation method of the salt nanosuspension, refer to Example 14).
  • mice C57BL/6J mouse, female, body weight 20g, 6-8 weeks old. All mice had free access to food and water, and were kept at room temperature (23 ⁇ 2)°C.
  • mice were established to infect mice with influenza mouse lung-adapted strains, 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 45 mg/kg, administered by gavage, once a day, for 7 consecutive days.
  • Baicalin group scutellarin was formulated into a dosing solution with sterile PBS, and the dose was 45 mg/kg by intragastric administration, once a day, for 7 consecutive days.
  • Amantadine group amantadine was prepared into a dosing solution with sterile PBS, and the dose was 15 mg/kg by gavage, once a day, for 7 consecutive days.
  • Oseltamivir group Oseltamivir was formulated into a dosing solution with sterile PBS, and the dosage was 16 mg/kg, administered by gavage, once a day, for 7 consecutive days.
  • Baicalin amantadine compound salt nanosuspension group Baicalin amantadine nanosuspension was used as a dosing solution, according to the dosage of 45 mg/kg, intragastrically, once a day, for 7 consecutive days.
  • Baicalin amantadine double salt nanosuspension group scutellarin amantadine nanosuspension was used as a dosing solution, according to the dosage of 45 mg/kg, intragastrically, once a day, for 7 consecutive days.
  • Baicalin oseltamivir compound salt nanosuspension group Baicalin oseltamivir nanosuspension was used as a dosing solution, according to the dosage of 28 mg/kg, intragastrically, once a day, for 7 consecutive days.
  • Baicalin oseltamivir compound salt nanosuspension group scutellarin oseltamivir nanosuspension as the dosing solution, according to the dosage of 28 mg/kg, gavage, once a day, continuous administration for 7 day.
  • the average lung index inhibition rate was 49.8%
  • the average lung index inhibition rate was 46.6%
  • the amantadine group (15mg/kg) averaged lung index inhibition rate was 62.6%.
  • oseltamivir group (12mg/kg) average lung index inhibition rate was 73.2%
  • baicalin amantadine compound salt nanosuspension group (45mg/kg) lung index inhibition rate was 86.8%
  • scutellarin amantadine The average lung index inhibition rate of the compound salt nanosuspension group (45mg/kg) was 83.6%
  • the average lung index of the baicaleside oseltamivir compound nanosuspension group (28mg/kg) was 88.8%
  • the average lung index was 88.8%.
  • the average lung index inhibition rate in the Tasvir compound salt nanosuspension group (28 mg/kg) was 89.4%.
  • the blank administration group, the baicalin group, the baicalin group, the lamivudine group, and the baicalin-lamivudine compound salt nanosuspension group were set up respectively (the preparation method of the baicalin-lamivudine nanosuspension was implemented with reference to the Example 15), scutellarin lamivudine double salt nanosuspension group (refer to Example 16 for the preparation method of scutellarin lamivudine nanosuspension).
  • a mouse negative transfection group was established.
  • mice C57BL/6J mouse, male, body weight 20g, 6-8 weeks old. All mice had free access to food and water, and were kept at room temperature (23 ⁇ 2)°C.
  • Hepatitis B virus DNA plasmid name pAAV/HBV1.2, from NIH.
  • Negative transfection group 10 mice were not granulated and transfected, and were only given normal saline.
  • mice transfected with HBV DNA plasmid were randomly divided into groups, 10 mice in each group, and the dosage 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 30 mg/kg by gavage, once a day, for 14 consecutive days.
  • Baicalin group scutellarin was formulated into a dosing solution with sterile PBS, and the dose was 30 mg/kg by gavage, once a day, for 14 consecutive days.
  • Lamivudine group amantadine was prepared into a dosing solution with sterile PBS, and the dosage was 15 mg/kg by gavage, once a day, for 14 consecutive days.
  • Baicalin lamivudine compound salt nanosuspension group Baicalin lamivudine compound salt nanosuspension was used as the dosing solution, according to the dosage of 45 mg/kg, gavage, once a day, for 14 consecutive administrations day.
  • Baicalin lamivudine compound salt nanosuspension group Baicalin lamivudine compound salt nanosuspension was used as the dosing solution, according to the dosage of 45 mg/kg, intragastrically, once a day, continuously given Medicine on the 14th.
  • mice transaminase was divided by the transaminase value of the blank administration group), and the results were as follows:
  • the mean value of transaminase in the blank administration group was 100%, the relative mean value of transaminase in the baicalin group (dose 30mg/kg) was 84%, the relative mean value of transaminase in the baicalin group (dose 30mg/kg) was 82%, and the lamivudine group (dose 15mg/kg) )
  • the relative mean value of transaminase was 63%, the relative mean value of transaminase in the baicalin lamivudine compound salt nanosuspension group (dose 45mg/kg) was 22%, and the baicalin lamivudine compound salt nanosuspension group (dose 45mg/kg) kg) transaminase relative mean 23%.
  • baicalin group Compared with the blank administration group, baicalin group, baicalin group, lamivudine group, baicalin lamivudine compound salt nanosuspension group and baicalin lamivudine compound salt nanosuspension group
  • baicalin lamivudine compound salt nanosuspension group Compared with the blank administration group, baicalin group, baicalin group, lamivudine group, baicalin lamivudine compound salt nanosuspension group and baicalin lamivudine compound salt nanosuspension group.
  • Example 22 Determination of in vivo anti-inflammatory activity in animals
  • a blank control group, a baicalin group, a baicalin group, a hydroxychloroquine group, and a baicalin-hydroxychloroquine double salt nanosuspension group were set respectively (the preparation method of the baicalin-hydroxychloroquine double salt nanosuspension was referred to in Example 17), and the wild Baicalin hydroxychloroquine double salt nanosuspension group (refer to Example 18 for the preparation method of scutellarin hydroxychloroquine double salt nanosuspension).
  • a negative administration group was established.
  • mice C57BL/6J mouse, male, body weight 20g, 6-8 weeks old. All mice had free access to food and water, and were kept at room temperature (23 ⁇ 2)°C.
  • Negative control group 10 mice without any treatment, only given normal saline.
  • the inflammatory diseased mice were randomly divided into groups of 10, and 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 dosage was 29 mg/kg, administered by gavage, once a day, for 3 consecutive days.
  • Baicalin group scutellarin was formulated into a dosing solution with sterile PBS, and the dose was 29 mg/kg by gavage, once a day, for 3 consecutive days.
  • Hydroxychloroquine group Hydroxychloroquine was prepared into a dosing solution with sterile PBS, and the dose was 21 mg/kg by gavage, once a day, for 3 consecutive days.
  • Baicalin-Hydroxychloroquine Double Salt Nanosuspension Group Baicalin-Hydroxychloroquine Double Salt Nanosuspension was used as a dosing solution, and the dose was 50 mg/kg by intragastric administration, once a day, for 3 consecutive days.
  • Scutellarin and hydroxychloroquine double salt nanosuspension group As a dosing solution, scutellarin and hydroxychloroquine double salt nanosuspension was administered by intragastric administration at a dose of 50 mg/kg, once a day, for 3 consecutive days.
  • the inflammatory cytokines in the blank administration group were about 3 times that of the negative control group, and the average value of inflammatory cytokines in the blank administration group was 100%.
  • the relative mean that is, the inflammatory cytokine value of each group of mice divided by the inflammatory cytokine value of the blank administration group, the results are as follows:
  • the mean value of inflammatory cytokines in the blank administration group was 100%, the relative mean value of inflammatory cytokines in the baicalin group (dose 29mg/kg) was 92%, the relative mean value of inflammatory cytokines in the baicalin group (dose 29mg/kg) was 90%, and the hydroxychloroquine group ( The relative mean of inflammatory cytokines at a dose of 21mg/kg) was 54%, the relative mean of inflammatory cytokines in the baicalin-hydroxychloroquine compound salt nanosuspension group (dose of 50mg/kg) was 32%, and the scutellarin-hydroxychloroquine compound salt nanosuspension group (Dose 50mg/kg) The relative mean of inflammatory cytokines was 33%.
  • baicalin group Compared with the blank administration group, baicalin group, scutellarin group, and hydroxychloroquine group, there were significant differences in inflammatory cytokines between the baicalin hydroxychloroquine double salt nanosuspension group and the scutellarin hydroxychloroquine double salt nanosuspension group.

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Abstract

The present application relates to a double salt compound of flavonoid glycoside and an organic amine antimicrobial agent. The flavonoid glycoside has a structural general formula represented by the following formula (1), wherein R1-R9 are each independently selected from among -H, -OH, C1-C6 alkyl, alkoxy or substituted alkyl, and at least one among R1 and R2 is selected from -OH. The present application also relates to a preparation method for the double salt compound. The present application further relates to a pharmaceutical composition containing a therapeutically effective amount and an application thereof. Furthermore, the present application also relates to double salt nanoparticles obtained by nano-grinding the double salt compound and an application thereof.

Description

黄酮苷-有机胺类抗微生物剂复盐化合物及其制备方法和应用Flavonoid glycoside-organic amine antimicrobial agent double salt compound and preparation method and application thereof
相关申请Related applications
本申请要求于2020年10月30日提交中国专利局、申请号为2020111958166发明名称为“黄酮苷-有机胺类抗微生物剂复盐及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application claims the priority of the Chinese patent application filed on October 30, 2020, with the application number of 2020111958166 and the invention titled "flavonoid glycoside-organic amine antimicrobial agent double salt and its preparation method and application". The entire contents of this application are incorporated by reference.
技术领域technical field
本申请涉及药物化学技术领域，特别是一种黄酮苷-有机胺类抗微生物剂复盐化合物及其制备方法和应用。The present application relates to the technical field of medicinal chemistry, in particular to a flavonoid glycoside-organic amine antimicrobial double salt compound and a preparation method and application thereof.
背景技术Background technique
抗微生物剂是指一种抑制或杀伤致病微生物，从而使其生长、繁殖受阻碍的药物。按照作用对象可以分为三类：第一类，抗细菌药(简称抗菌药)，包括能抑制或杀灭细菌、支原体、衣原体、立克次体、螺旋体等病原菌的药物，根据药物来源不同，抗菌药又可分为抗生素类和人工合成抗菌药。第二类，抗真菌药，主要用于抑制真菌生长和/或杀死真菌。第三类，抗病毒药，抗病毒感染的途径很多，如直接抑制或杀灭病毒、干扰病毒吸附、阻止病毒穿入细胞、抑制病毒生物合成、抑制病毒释放或增强宿主抗病毒能力等。抗病毒药物的作用主要是通过影响病毒复制周期的某个环节而实现的。金刚烷胺、拉米夫定、奥司他韦、羟氯喹、氯喹等都是临床有效的抗微生物感染的药物，用于微生物感染性疾病如流感、乙肝、疟疾及其他微生物感染，尤其是病毒性感染疾病。Antimicrobial agent refers to a drug that inhibits or kills pathogenic microorganisms, thereby hindering their growth and reproduction. According to the object of action, it can be divided into three categories: the first category, antibacterial drugs (referred to as antibacterial drugs), including drugs that can inhibit or kill bacteria, mycoplasma, chlamydia, rickettsia, spirochetes and other pathogenic bacteria, according to different sources of drugs, Antibacterial drugs can be divided into antibiotics and synthetic antibacterial drugs. The second category, antifungal drugs, are primarily used to inhibit fungal growth and/or kill fungi. The third category is antiviral drugs. There are many ways to resist viral infection, such as directly inhibiting or killing viruses, interfering with viral adsorption, preventing viruses from penetrating cells, inhibiting viral biosynthesis, inhibiting virus release or enhancing host antiviral capabilities. The effect of antiviral drugs is mainly achieved by affecting a certain link in the viral replication cycle. Amantadine, lamivudine, oseltamivir, hydroxychloroquine, chloroquine, etc. are all clinically effective anti-microbial infection drugs for microbial infectious diseases such as influenza, hepatitis B, malaria and other microbial infections, especially viruses sexually transmitted diseases.
黄芩苷和野黄芩苷都是黄酮类糖苷(简称黄酮苷)，具有丰富的药理活性，例如通过抗脂质过氧化提高抗氧化能力，清除自由基和超氧阴离子作用，改善血液循环增加血流量，抗血小板聚集，抑制病毒感染，增强免疫力，抗细胞缺氧，神经保护，抑制肿瘤细胞生长等。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.
此外，针对难溶性药物，如何提高其溶解度，加快溶解速度，增加血药浓度也是亟待解决的问题。In addition, for poorly soluble drugs, how to improve their solubility, speed up the dissolution rate, and increase the blood drug concentration are also problems to be solved urgently.
发明内容SUMMARY OF THE INVENTION
基于此，有必要提供一种黄酮苷-有机胺类抗微生物剂复盐化合物及其制备方法和应用。相比于有机胺类抗微生物剂本身，该黄酮苷-有机胺类抗微生物剂复盐化合物对致病微生物具有更高的抑制活性。Based on this, it is necessary to provide a flavonoid glycoside-organic amine antimicrobial double salt compound and its preparation method and application. Compared with the organic amine antimicrobial itself, the flavonoid glycoside-organic amine antimicrobial double salt compound has higher inhibitory activity on pathogenic microorganisms.
本申请一方面，提供一种复盐化合物，为黄酮苷与有机胺类抗微生物剂的复盐，所述黄酮苷具有如下 式(1)所示的结构通式：One aspect of the present application provides a double salt compound, which is the double salt of a flavone glycoside and an organic amine antimicrobial agent, and the flavone glycoside has the general structural formula shown in the following formula (1):
Figure PCTCN2021127504-appb-000001
Figure PCTCN2021127504-appb-000001
其中，R 1～R 9各自独立地选自-H、-OH、C 1～C 6烷基、烷氧基或取代烷基，且R 1和R 2中至少有一个选自-OH。 Wherein, 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.
在其中一个实施例中，R 1和R 2均选自-OH。 In one embodiment, R 1 and R 2 are both selected from -OH.
在其中一个实施例中，所述黄酮苷为黄芩苷或野黄芩苷。In one embodiment, the flavonoid glycoside is baicalin or baicalin.
在其中一个实施例中，所述有机胺类抗微生物剂中含有至少一个氨基，所述氨基各自独立地选自包括-NH 2、-NR’H或-NR’ 2，所述R’为给电子基团。 In one embodiment, the organic amine antimicrobial agent contains at least one amino group, and the amino groups are each independently selected from the group consisting of -NH 2 , -NR'H or -NR' 2 , and the R' is to give electronic group.
在其中一个实施例中，所述有机胺类抗微生物剂选自金刚烷胺、拉米夫定、奥司他韦、羟氯喹和氯喹中的任意一种。In one embodiment, the organic amine antimicrobial agent is selected from any one of amantadine, lamivudine, oseltamivir, hydroxychloroquine and chloroquine.
本申请一方面，还提供一种所述的复盐化合物的制备方法，包括以下步骤：On the one hand, this application also provides a kind of preparation method of described double salt compound, comprising the following steps:
将所述黄酮苷、所述有机胺类抗微生物剂和极性非质子有机溶剂混合溶解得到混合溶液；mixing and dissolving the flavonoid glycosides, the organic amine antimicrobial agent and the polar aprotic organic solvent to obtain a mixed solution;
将所述混合溶液进行反应，得到反应液；以及The mixed solution is reacted to obtain a reaction solution; And
将所述反应液除去溶剂。The solvent was removed from the reaction solution.
在其中一个实施例中，所述极性非质子有机溶剂为N,N-二甲基甲酰胺、二甲基亚砜或乙腈中的一种或多种。In one embodiment, the polar aprotic organic solvent is one or more of N,N-dimethylformamide, dimethylsulfoxide or acetonitrile.
本申请另一方面，进一步提供一种药物组合物，其中含有治疗有效量的所述的复盐化合物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，以及药学上可接受的载体、赋形剂或稀释剂。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.
本申请再一方面，提供所述的复盐化合物或所述的药物组合物在制备抗微生物药物中的应用。In yet another aspect of the present application, there is provided an application of the double salt compound or the pharmaceutical composition in the preparation of an antimicrobial drug.
在其中一个实施例中，所述抗微生物药物用于病毒疾病的治疗，所述病毒疾病为流感病毒、乙肝病毒、疟疾、类风湿性关节炎、红斑狼疮或神经退行性疾病。In one embodiment, the antimicrobial drug is used for the treatment of a viral disease, the viral disease being influenza virus, hepatitis B virus, malaria, rheumatoid arthritis, lupus erythematosus or neurodegenerative disease.
本申请又一方面，提供了一种复盐纳米颗粒，所述复盐纳米颗粒由所述复盐化合物经纳米研磨得到。In another aspect of the present application, a double salt nanoparticle is provided, wherein the double salt nanoparticle is obtained by nano-grinding the double salt compound.
本申请还一方面，提供所述复盐纳米颗粒在制备抗微生物药物中的应用。In another aspect of the present application, the application of the double salt nanoparticles in the preparation of antimicrobial drugs is provided.
在其中一个实施例中，所述抗微生物药物用于病毒疾病的治疗，所述病毒疾病为流感病毒、乙肝病毒、疟疾、类风湿性关节炎、红斑狼疮、微生物感染类疾病引起的过度免疫反应或神经退行性疾病。In one embodiment, the antimicrobial drug is used for the treatment of viral diseases, and the viral diseases are excessive immune responses caused by influenza virus, hepatitis B virus, malaria, rheumatoid arthritis, lupus erythematosus, and microbial infections. or neurodegenerative diseases.
与现有技术相比较，本申请具有如下有益效果：Compared with the prior art, the present application has the following beneficial effects:
有机胺类抗微生物剂呈碱性，可以与无机酸或小分子有机酸成盐，以增加其稳定性和提升物理性能，但是现有技术中一般用于药物成盐的无机酸或小分子有机酸与有机胺类抗微生物剂所形成的盐并不能提高这些药物的生物活性。而本申请提供的复盐化合物，采用特定结构的黄酮苷与有机胺类抗微生物剂形成复盐，该黄酮苷的分子结构中含有羧基和酚羟基，可与有机胺类抗微生物剂中的胺基键合，二者之间的结合作用强于一般的药物成盐。该复盐相比于有机胺类抗微生物剂本身，表现出对致病微生物更高的抑制活性。Organic amine antimicrobial agents are alkaline and can form salts with inorganic acids or small-molecule organic acids to increase their stability and improve physical properties. Salts of acids with organic amine antimicrobials do not enhance the biological activity of these drugs. The double salt compound provided by the present application adopts flavonoid glycosides with a specific structure and organic amine antimicrobial agents to form double salts. Base bonding, the binding effect between the two is stronger than the general drug salt formation. Compared with the organic amine antimicrobial itself, the double salt exhibits higher inhibitory activity against pathogenic microorganisms.
黄酮苷这类天然化合物水溶解性较差，但是因为分子结构中有羧基和酚羟基，易溶于碱，和小分子有机碱成盐，增强其水溶性。进一步地，本申请提供的复盐化合物通过纳米研磨技术进行研磨，减小物料粒径，使其粒径达到纳米级，可以使复盐化合物具有更好的水溶性。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.
附图说明Description of drawings
图1～图4为本申请实施例1制备的复盐化合物的核磁共振氢谱、红外光谱、DSC测试图以及XRD图；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;
图5～图8为本申请实施例2制备的复盐化合物的核磁共振氢谱、红外光谱、DSC测试图以及XRD图；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;
图9～图12为本申请实施例3制备的复盐化合物的核磁共振氢谱、红外光谱、DSC测试图以及XRD图；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;
图13～图16为本申请实施例4制备的复盐化合物的核磁共振氢谱、红外光谱、DSC测试图以及XRD图；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;
图17～图20为本申请实施例5制备的复盐化合物的核磁共振氢谱、红外光谱、DSC测试图以及XRD图；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;
图21～图24为本申请实施例6制备的复盐化合物的核磁共振氢谱、红外光谱、DSC测试图以及XRD图；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;
图25～图28为本申请实施例7制备的复盐化合物的核磁共振氢谱、红外光谱、DSC测试图以及XRD图；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;
图29～图32为本申请实施例8制备的复盐化合物的核磁共振氢谱、红外光谱、DSC测试图以及XRD图；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;
图33～图36为本申请实施例9制备的复盐化合物的核磁共振氢谱、红外光谱、DSC测试图以及XRD图。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.
具体实施方式Detailed ways
以下结合具体实施例对本申请进行进一步详细的说明。本申请可以以许多不同的形式来实现，并不限于本文所描述的实施方式。相反地，提供这些实施方式的目的是使对本申请公开内容理解更加透彻全面。The present application will be further described in detail below with reference to specific embodiments. The application may be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that a thorough and complete understanding of the present disclosure is provided.
除非另有定义，本文所使用的所有的技术和科学术语与属于本申请的技术领域的技术人员通常理解的含义相同。本文中在本申请的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本申请。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this application belongs. The terms used herein in the specification of the application are for the purpose of describing specific embodiments only, and are not intended to limit the application. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
本文中使用的缩写和符号与化学和生物学领域的技术人员通常使用的这类缩写和符号一致。具体地，在实施例和整个说明书中可能使用以下缩写。Abbreviations and symbols used herein are consistent with such abbreviations and symbols commonly used by those skilled in the chemical and biological arts. Specifically, the following abbreviations may be used in the examples and throughout the specification.
DMF(N,N-二甲基甲酰胺)     DSC(示差扫描量热法)DMF(N,N-Dimethylformamide) DSC (Differential Scanning Calorimetry)
术语和定义Terms and Definitions
除非另外说明或存在矛盾之处，本文中使用的术语或短语具有以下含义：Unless otherwise stated or otherwise contradicted, terms or phrases used herein have the following meanings:
术语“烷基”是指包含伯(正)碳原子、或仲碳原子、或叔碳原子、或季碳原子、或其组合的饱和烃。包含该术语的短语，例如，“C 1～C 6烷基”是指包含1～6个碳原子的烷基，每次出现时，可以互相独立地为C 1烷基、C 2烷基、C 3烷基、C 4烷基、C 5烷基或C 6烷基。合适的实例包括但不限于：甲基(Me、-CH 3)、乙基(Et、-CH 2CH 3)、1-丙基(n-Pr、n-丙基、-CH 2CH 2CH 3)、2-丙基(i-Pr、i-丙基、-CH(CH 3) 2)、1-丁基(n-Bu、n-丁基、-CH 2CH 2CH 2CH 3)、2-甲基-1-丙基(i-Bu、i-丁基、-CH 2CH(CH 3) 2)、2-丁基(s-Bu、s-丁基、-CH(CH 3)CH 2CH 3)、2-甲基-2-丙基(t-Bu、t-丁基、-C(CH 3) 3)、1-戊基(n-戊基、-CH 2CH 2CH 2CH 2CH 3)、2-戊基(-CH(CH 3)CH 2CH 2CH 3)、3-戊基(-CH(CH 2CH 3) 2)、2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)、3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)、3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)、2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)、1-己基(-CH 2CH 2CH 2CH 2CH 2CH 3)、2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)、3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))、2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)、3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)、4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)、3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)、2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)、2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)、和3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3。 The term "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-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2- Butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl ( -CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2- Methyl-2-pentyl (-C( CH3 )2CH2CH2CH3), 3 -methyl- 2 -pentyl (-CH( CH3 ) CH ( CH3 ) CH2CH3 ) , 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ) , 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), and 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 .
术语“烷氧基”是指具有-O-烷基的基团，即如上所定义的烷基经由氧原子连接至母核结构。包含该术语 的短语，例如，“C 1～C 6烷氧基”是指烷基部分包含1～6个碳原子，每次出现时，可以互相独立地为C 1烷氧基、C 2烷氧基、C 3烷氧基、C 4烷氧基、C 5烷氧基或C 6烷氧基。合适的实例包括但不限于：甲氧基(-O-CH 3或-OMe)、乙氧基(-O-CH 2CH 3或-OEt)和叔丁氧基(-O-C(CH 3) 3或-OtBu)。 The term "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. Phrases containing this term, for example, "C 1 -C 6 alkoxy" means that the alkyl moiety contains 1 to 6 carbon atoms, and each occurrence may independently be C 1 alkoxy, C 2 alkoxy oxy, C 3 alkoxy, C 4 alkoxy, C 5 alkoxy or C 6 alkoxy. 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).
“氨基”是指氨的衍生物氨基的非限制性类型包括-NH 2、-N(烷基) 2、-NH(烷基)、-N(环烷基) 2、-NH(环烷基)、-N(杂环基) 2、-NH(杂环基)、-N(芳基) 2、-NH(芳基)、-N(烷基)(芳基)、-N(烷基)(杂环基)、-N(环烷基)(杂环基)、-N(芳基)(杂芳基)、-N(烷基)(杂芳基)等。 "Amino" refers to a derivative of ammonia. Non-limiting classes of amino groups include -NH2 , -N(alkyl) 2 , -NH(alkyl), -N(cycloalkyl) 2 , -NH(cycloalkyl) ), -N(heterocyclyl) 2 , -NH(heterocyclyl), -N(aryl) 2 , -NH(aryl), -N(alkyl)(aryl), -N(alkyl) )(heterocyclyl), -N(cycloalkyl)(heterocyclyl), -N(aryl)(heteroaryl), -N(alkyl)(heteroaryl), and the like.
“药学上可接受的”指在合理医学判断范围内适于施用患者且与合理益处/风险比相称的那些配体、材料、组合物和/或剂型。"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.
“药学上可接受的载体、赋形剂或稀释剂”指药学上可接受的材料、组合物或媒剂，例如液体或固体填充剂、稀释剂、赋形剂、溶剂或囊封材料。如本文所用，语言“药学上可接受的载体、赋形剂或稀释剂”包括与药物施用相容的缓冲剂、注射用无菌水、溶剂、分散介质、包衣、抗细菌剂及抗真菌剂、等渗剂及吸收延迟剂及诸如此类。在与配制物中其他成分兼容且对患者无害的意义上，每种载体、赋形剂或稀释剂必须为“药学上可接受的”。合适的实例包括但不限于：(1)糖，例如乳糖、葡萄糖及蔗糖；(2)淀粉，例如玉米淀粉、马铃薯淀粉及经取代或未经取代的β-环糊精；(3)纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素及乙酸纤维素；(4)粉状黄蓍胶；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，例如可可脂及栓剂蜡；(9)油类，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油；(10)二醇，例如丙二醇；(11)多元醇，例如甘油、山梨醇、甘露醇及聚乙二醇；(12)酯类，例如油酸乙酯及月桂酸乙酯；(13)琼脂；(14)缓冲剂，例如氢氧化镁及氢氧化铝；(15)海藻酸；(16)无热原水；(17)等渗盐水；(18)林格氏溶液；(19)乙醇；(20)磷酸盐缓冲液；及(21)药物配制物中所采用的其他无毒兼容物质。"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. As used herein, the language "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 (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) pharmaceutical formulation other non-toxic compatible substances used in the product.
涉及基团的“取代”指与基团内的成员原子附接的一个或多个氢原子由选自所限定或适合的取代基中的取代基替代。应理解术语“取代的”包括下述隐含条件：这种取代应与取代的原子和取代基的允许化合价一致并且取代导致稳定的化合物。当陈述基团可以含有一个或多个取代基时，该基团内的一个或多个成员原子可以被取代。另外，只要这种取代与原子的允许化合价一致，该基团内的单个成员原子就可以由多于一种取代基取代。“成员原子”指的是形成链或环的一个原子或多个原子。在链中以及环内存在多于一个成员原子的情况下，每个成员原子与该链或环中的相邻成员原子共价结合。组成链或环上的取代基的原子不是该链或环中的成员原子。"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. 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. When it is stated that a group may contain one or more substituents, one or more of the member atoms within the group may be substituted. In addition, 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.
术语“IC 50”指的是化合物相对于给定活性例如A型流感病毒、DNA聚合酶、RNA聚合酶的抑制的半最大抑制浓度。IC 50值越小，说明化合物对给定活性的抑制活性越强。 The term " IC50 " refers to the half-maximal inhibitory concentration of a compound relative to inhibition of a given activity, eg, influenza A virus, DNA polymerase, RNA polymerase. The smaller the IC50 value, the stronger the inhibitory activity of the compound for a given activity.
化合物compound
在一个方面，本申请涉及一种复盐化合物，为黄酮苷与有机胺类抗微生物剂的复盐，所述黄酮苷具有如下式(1)所示的结构通式：In one aspect, the application relates to a double salt compound, which is a double salt of a flavone glycoside and an organic amine antimicrobial agent, and the flavone glycoside has the general structural formula shown in the following formula (1):
Figure PCTCN2021127504-appb-000002
Figure PCTCN2021127504-appb-000002
其中，R 1～R 9各自独立地选自-H、-OH、C 1～C 6烷基、烷氧基或取代烷基，且R 1和R 2中至少有一个选自-OH。 Wherein, 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.
所述黄酮苷，分子结构中葡萄糖酸单元中的羧基氢、黄酮单元中的酚羟基氢(R 1或R 2中的氢)，共同形成了氢离子丰富区域，是质子供体。所述有机胺类抗微生物剂中有机胺的氮原子含有孤对电子，是质子受体。二者结合，形成所述黄酮苷-有机胺类抗微生物剂复盐。由于空间位阻的原因，所述黄酮苷中葡萄糖酸单元中的羧基氢和黄酮单元中的酚羟基氢分别位于糖环的两侧。当其与有机胺结合时，位于糖环两侧的所述羧基氢和所述酚羟基氢转变为同侧，如式(2)所示，形成质子窝(如式2虚线框所示的质子结构)、羧基氧电子和氮孤对电子的微环境。从价键理论分析，质子窝中氢质子和胺可形成很稳定的铵盐；从分子轨道理论分析，质子窝中氢的空轨道与胺的孤对电子可以完美结合；从量子化学及量子纠缠理论分析，质子窝中氢电子、羧基氧电子以及有机胺中氮的孤电子对在成盐区域实现缠绕，因为量子纠缠的存在，黄酮苷-有机胺类抗微生物剂复盐的有机酸和有机碱互相解离后，其成盐期间形成的量子纠缠继续存在，提高了黄酮苷-有机胺类抗微生物剂复盐的生物活性。 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 antimicrobial agent contains a lone pair of electrons and is a proton acceptor. The two are combined to form the flavonoid glycoside-organic amine antimicrobial double salt. Due to steric hindrance, 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. When it is combined with an organic amine, 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. From the analysis of valence bond theory, 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. Because of the existence of quantum entanglement, the organic acids and organic After the bases are dissociated from each other, the quantum entanglement formed during the salt formation continues to exist, which improves the biological activity of the flavonoid glycoside-organic amine antimicrobial double salt.
Figure PCTCN2021127504-appb-000003
Figure PCTCN2021127504-appb-000003
可选的，所述R 1和R 2均选自-OH。 Optionally, both R 1 and R 2 are selected from -OH.
在一些实施例中，R 3选自-H或-OCH 3。 In some embodiments, R3 is selected from -H or -OCH3 .
在一些实施例中，R 5、R 6、R 9均选自-H。 In some embodiments, R 5 , R 6 , R 9 are all selected from -H.
在一些实施例中，R 7、R 8各自独立地选自-H或-OH。 In some embodiments, R 7 , R 8 are each independently selected from -H or -OH.
在一些实施例中，R 8选自-H。 In some embodiments, R8 is selected from -H.
在一些实施例中，R 7选自-OH。在另一些实施例中，R 7选自-H。在一些实施例中，所述黄酮苷可以为芹菜素黄酮苷、黄芩苷、野黄芩苷、白杨素黄酮苷或汉黄芩苷中的任意一种，可选的，所述黄酮苷为黄芩苷或野黄芩苷。 In some embodiments, R7 is selected from -OH. In other embodiments, R7 is selected from -H. In some embodiments, 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.
所述黄芩苷的分子结构式如下式(1-1)所示：The molecular structural formula of the baicalin is shown in the following formula (1-1):
Figure PCTCN2021127504-appb-000004
Figure PCTCN2021127504-appb-000004
所述野黄芩苷的分子结构式如下式(1-2)所示：The molecular structural formula of the baicalin is shown in the following formula (1-2):
Figure PCTCN2021127504-appb-000005
Figure PCTCN2021127504-appb-000005
所述有机胺类抗微生物剂中含有至少一个氨基，所述氨基各自独立地选自-NH 2、-NR’H或-NR’ 2，所述R’为给电子基团。 The organic amine antimicrobial agent 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.
在一些实施例中，R’为烷基或烷氧基。在一些实施例中，所述有机胺类抗微生物剂选自金刚烷胺、拉米夫定、奥司他韦、羟氯喹和氯喹中的任意一种。In some embodiments, R' is alkyl or alkoxy. In some embodiments, the organic amine antimicrobial agent is selected from any one of amantadine, lamivudine, oseltamivir, hydroxychloroquine and chloroquine.
金刚烷胺，分子式为C 12H 21N，属于兴奋性氨基酸(NMDA)受体抑制剂，用于治疗中重度至重度阿尔茨海默型痴呆。金刚烷胺的结构式如下所示： Amantadine, with the molecular formula C 12 H 21 N, is an excitatory amino acid (NMDA) receptor inhibitor used for the treatment of moderate to severe Alzheimer's dementia. The structural formula of amantadine is shown below:
Figure PCTCN2021127504-appb-000006
Figure PCTCN2021127504-appb-000006
拉米夫定，又称3-TC，是核苷类似物、抗病毒药物，对病毒DNA链的合成和延长有竞争性抑制作用。拉米夫定的结构式如下所示：Lamivudine, also known as 3-TC, is a nucleoside analog, an antiviral drug, which has a competitive inhibitory effect on the synthesis and elongation of viral DNA chains. The structural formula of lamivudine is as follows:
Figure PCTCN2021127504-appb-000007
Figure PCTCN2021127504-appb-000007
奥司他韦，是一种作用于神经氨酸酶的特异性抑制剂，其抑制神经氨酸酶的作用，可以抑制成熟的流感病毒脱离宿主细胞，从而抑制流感病毒在人体内的传播以起到治疗流行性感冒的作用。奥司他韦的结构式如下所示：Oseltamivir is a specific inhibitor that acts on neuraminidase. It inhibits the action of neuraminidase and can inhibit the mature influenza virus from leaving the host cell, thereby inhibiting the spread of influenza virus in the human body. to the treatment of influenza. The structural formula of oseltamivir is as follows:
Figure PCTCN2021127504-appb-000008
Figure PCTCN2021127504-appb-000008
羟氯喹，为4-氨基喹啉衍生物类抗疟药，作用和机制与氯喹类似。羟氯喹的结构式如下所示：Hydroxychloroquine is a 4-aminoquinoline derivative antimalarial drug with similar action and mechanism to chloroquine. The structural formula of hydroxychloroquine is as follows:
Figure PCTCN2021127504-appb-000009
Figure PCTCN2021127504-appb-000009
氯喹，主要用于控制疟疾症状的药物，也可用作抗阿米巴药物。对某些自身免疫性疾病，如类风湿关节炎、红斑狼疮、肾病综合症等亦有一定的作用。氯喹的结构式如下所示：Chloroquine, a drug mainly used to control malaria symptoms, is also used as an anti-amebic drug. It also has a certain effect on certain autoimmune diseases, such as rheumatoid arthritis, lupus erythematosus, and nephrotic syndrome. The structural formula of chloroquine is as follows:
Figure PCTCN2021127504-appb-000010
Figure PCTCN2021127504-appb-000010
在一个方面，本申请还涉及一种所述的复盐化合物的制备方法，包括以下步骤：In one aspect, the application also relates to a preparation method of a described double salt compound, comprising the following steps:
S10，将所述黄酮苷、所述有机胺类抗微生物剂和极性非质子有机溶剂混合溶解得到混合溶液；S10, the flavonoid glycosides, the organic amine antimicrobial agent and the polar aprotic organic solvent are mixed and dissolved to obtain a mixed solution;
S20，将所述混合溶液进行反应，得到反应液；以及S20, the mixed solution is reacted to obtain a reaction solution; And
S30，将所述反应液除去溶剂。S30, the solvent is removed from the reaction solution.
所述黄酮苷和所述有机胺类抗微生物剂的摩尔比可以为1:3～3:1之间的任意比值，例如还可以包括1:2、1:1.5、1:1、1.5:1、2:1，可选为1:1。The molar ratio of the flavonoid glycoside and the organic amine antimicrobial agent 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.
所述极性非质子有机溶剂可以为N,N-二甲基甲酰胺、二甲基亚砜或乙腈中的一种或多种。The polar aprotic organic solvent may be one or more of N,N-dimethylformamide, dimethylsulfoxide or acetonitrile.
步骤S10中将所述黄酮苷、所述有机胺类抗微生物剂和极性非质子有机溶剂混合溶解得到混合溶液的方法可以有多种。可选的，可以包括以下步骤In step S10, there are various methods for mixing and dissolving the flavonoid glycoside, the organic amine antimicrobial agent and the polar aprotic organic solvent to obtain a mixed solution. Optionally, the following steps can be included
S11，将所述黄酮苷溶于所述极性非质子有机溶剂中，得到第一溶液；S11, dissolving the flavonoid glycosides in the polar aprotic organic solvent to obtain a first solution;
S12，将所述有机胺类抗微生物剂溶于所述极性非质子有机溶剂中，得到第二溶液；S12, dissolving the organic amine antimicrobial agent in the polar aprotic organic solvent to obtain a second solution;
S13，将所述第一溶液和所述第二溶液混合，得到所述混合溶液。S13, mixing the first solution and the second solution to obtain the mixed solution.
所述第一溶液中所述黄酮苷的浓度为0.1mol/L～1.0mol/L，可选为0.33mol/L。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.
所述第二溶液中所述有机胺类抗微生物剂的浓度为0.1mol/L～1.0mol/L，可选为0.33mol/L。The concentration of the organic amine antimicrobial agent in the second solution is 0.1 mol/L to 1.0 mol/L, optionally 0.33 mol/L.
所述混合溶液进行反应的步骤中，反应温度可以为30℃～100℃，可选为50℃～70℃，更可选为70℃。In the step of reacting the mixed solution, the reaction temperature may be 30°C to 100°C, optionally 50°C to 70°C, and more optionally 70°C.
所述除去溶剂的方法可为减压浓缩，所述减压浓缩的温度可以为40℃～70℃，可选为60℃。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.
步骤S30还包括提纯的步骤。所述提纯的方法可以为打浆。所述打浆使用的溶剂可以为乙酸乙酯。乙酸乙酯用量按酸(黄芩苷或野黄芩苷)mol/L以1:1至1:5为宜，以1:3最佳；打浆的温度可以为5℃～50℃，可选为20℃～30℃，时间为20分钟～40分钟。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℃～50℃, and 20 ℃～30℃, time is 20 minutes～40 minutes.
所述提纯还包括将打浆之后的溶液进行过滤，过滤后的滤饼进一步干燥。所述干燥的方法可以为冷冻干燥或真空干燥。所述真空干燥的温度可以为20℃～60℃，可选为30℃，干燥时间可以为8小时～48小时，可选为24小时。所述冷冻干燥的温度为小于0℃，干燥时间可以为3小时～12小时，可选为6小时。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.
在一个方面，本申请涉及含有治疗有效量的上述的复盐化合物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，以及药学上可接受的载体、赋形剂或稀释剂的组合物。In one aspect, 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.
在一个方面，本申请涉及所述的复盐化合物在制备抗微生物剂药物中的应用。In one aspect, the application relates to the use of the double salt compound in the preparation of an antimicrobial drug.
在一些实施方式中，根据本申请的复盐化合物制备的抗微生物剂药物用于病毒疾病的治疗，所述病毒疾病为流感病毒、乙肝病毒、疟疾、类风湿性关节炎、红斑狼疮或神经退行性疾病。In some embodiments, the antimicrobial medicament prepared according to the double salt compound of the present application is used for the treatment of a viral disease, the viral disease being influenza virus, hepatitis B virus, malaria, rheumatoid arthritis, lupus erythematosus or neurodegeneration sexually transmitted diseases.
在一个方面，本申请进一步涉及治疗神经退行性疾病的方法，所述方法可选包括对需要其的患有神经退行性疾病的患者给药适合量的如上所限定的包括根据本申请的复盐化合物的组合物。In one aspect, 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.
在一个方面，本申请进一步涉及一种复盐纳米颗粒，所述复盐纳米颗粒由上述任一实施方式的复盐化合物经纳米研磨得到。In one aspect, the present application further relates to a double salt nanoparticle obtained by nano-milling the double salt compound of any of the above embodiments.
在一些实施例中，所述复盐纳米颗粒的平均粒径为50nm～500nm。In some embodiments, the average particle size of the double salt nanoparticles ranges from 50 nm to 500 nm.
在一个方面，本申请还涉及所述复盐纳米颗粒的制备方法，包括：In one aspect, the application also relates to a method for preparing the double salt nanoparticles, comprising:
将所述复盐化合物、助悬剂和溶剂混合后经纳米研磨机研磨制成。The compound salt compound, the suspending agent and the solvent are mixed and ground by a nano-grinder.
在一些实施例中，所述助悬剂为吐温、羟丙甲纤维素、聚乙二醇、羟丙基纤维素、甲基纤维素、聚乙烯吡咯烷酮、脂肪酸甘油酯、多元醇型非离子表面活性剂、聚氧乙烯型非离子表面洁性剂、泊洛沙姆、维生素E聚乙二醇琥珀酸酯、磷脂、明胶、黄原胶、十二烷基硫酸钠和脱氧胆酸纳中的一种或几种。In some embodiments, 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.
在一些可选实施例中，所述助悬剂为吐温、羟丙甲纤维和聚乙二醇的组合物。In some alternative embodiments, the suspending agent is a combination of Tween, hypromellose and polyethylene glycol.
在一些实施例中，所述复盐化合物和所述助悬剂的质量比为1000：(0.5～3)。In some embodiments, the mass ratio of the double salt compound and the suspending agent is 1000:(0.5-3).
在一些实施例中，所述研磨的转速为1000rpm～3000rpm，所述研磨的时间为20分钟～60分钟。所述研磨使用的纳米研磨机工作腔直径为85mm。如纳米研磨机工作腔直径有变化，应相应调节转速。In some embodiments, 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.
在一个方面，进一步，本申请还涉及所述复盐纳米颗粒在制备抗微生物药物中的应用。In one aspect, further, the present application also relates to the application of the double salt nanoparticles in the preparation of antimicrobial drugs.
在一些实施例中，所述抗微生物药物用于病毒疾病的治疗，所述病毒疾病为流感病毒、乙肝病毒、疟疾、类风湿性关节炎、红斑狼疮、微生物感染类疾病引起的过度免疫反应或神经退行性疾病。In some embodiments, the antimicrobial drug is used for the treatment of a viral disease, the viral disease being an excessive immune response caused by influenza virus, hepatitis B virus, malaria, rheumatoid arthritis, lupus erythematosus, microbial infection-like diseases, or neurodegenerative diseases.
给药和配制品Administration and Formulations
含有本申请的化合物、其活性代谢产物或同分异构体的药物的生产及其应用可以根据熟知的制药方法进行。The production of medicaments containing the compounds of the present application, their active metabolites or isomers and their use can be carried out according to well known methods of pharmacy.
虽然根据本申请可用于治疗的本申请的化合物可以以原始化学化合物的形式给药，但是可选地是与一种或多种助剂、赋形剂、载体、缓冲剂、稀释剂和/或其他常规药物辅料一起将活性成分在药物组合物中引入。本申请的化合物的这类盐可以是无水的或溶剂化的。Although 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.
在可选实施方式中，本申请提供药物，其包括根据本申请可用的化合物或其药学上可接受的衍生物以及用于其的一种或多种药学上可接受的载体和可选地其他治疗性和/或预防性成分。该一种或多种载体必须是在与配制品的其他成分相容的且对其受体无害的意义上是“可接受的”。In an alternative embodiment, 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.
本申请的药物可以是适用于口服、直肠、支气管、鼻腔、局部、口腔、舌下、经皮、阴道或肠胃外(包括皮肤、皮下、肌内、腹膜内、静脉内、动脉内、脑内、眼内注射或输注)给药的那些药物，或者为适用于通过吸入或吹气给药(包括粉末和液体气雾剂给药)或通过缓释体系给药的形式的那些药物。缓释体系的适合示例包括含有本申请的化合物的固体疏水聚合物的半渗透基质，该基质可以是成形物品的形式，例如膜或微胶囊。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. Suitable examples of 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.
根据本申请可用的化合物与常规助剂、载体或稀释剂一起可以因此被放置成药物及其单位剂量的形式。这样的形式包括：固体，特别地为片剂、填充胶囊、粉剂和药丸(pellet)形式；以及液体，特别地为含水或非水溶液剂、悬浮剂、乳剂、万能药(elixir)和用其装填的胶囊，用于口服的所有形式，用于直肠给药的栓剂以及用于肠胃外使用的无菌注射溶液。这些药物和其单位剂量形式可以在有或没有其他活性化合物或组成部分的情况下包括常规比例的常规成分，且这种单位剂量形式可以含有与待使用的预期日常剂量范围相应的任何适合有效量的活性成分。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.
根据本申请可用的化合物可以以各种各样的口服和肠胃外剂量形式给药。对本领域技术人员而言明显的是，以下剂量形式可以包括一种或多种根据本申请可用的化合物作为活性成分。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.
对于由根据本申请可用的化合物制备药物，药学上可接受的载体可以是固体的或液体的。固体形式制剂包括粉剂、片剂、丸剂、胶囊、扁囊剂(cachet)、栓剂和可分散颗粒剂。固体载体可以是还可以用作稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩解剂或包膜材料(encapsulating material)的一种或多种物质。For the preparation of medicaments from 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 .
在粉剂中，载体是与粉碎的活性组分混合的粉碎固体。在片剂中，活性组分与具有必要的结合能力的载体以适合的比例混合，并压缩成所需形状和大小。适合的载体是碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。术语“制剂”意在包括具有包膜材料作为载体的活性化合物配制品，提供其中活性组分在有或没有载体的情况下被载体包围并因此与其结合的胶囊。类似地，包括扁囊剂和锭剂(lozenge)。片剂、粉剂、胶囊、丸剂、扁囊剂和锭剂可以用作适用于口服给药的固体形式。In powders, the carrier is a finely divided solid in admixture with the finely divided active component. In tablets, 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. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.
为了制备栓剂，首先熔化低熔点蜡，诸如脂肪酸甘油酯或可可脂的混合物，并使活性组分均匀地分散在其中，如通过搅拌。然后将熔化的均匀混合物倒入大小适中的模具中，允许其冷却并从而凝固。适用于阴道给药的组合物可以表现为除活性成分之外还含有本领域中已知的适当载体的阴道栓(pessary)、止血塞(tampon)、霜剂、凝胶剂、糊剂、泡沫剂或喷剂。液体制剂包括溶液剂、悬浮剂和乳剂，例如水或水-丙二醇溶液。例如，肠胃外注射液体制剂可以配制为含水聚乙二醇溶液。To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and 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. For example, liquid preparations for parenteral injection can be formulated as aqueous polyethylene glycol solutions.
因此，根据本申请的化学化合物可以配制用于肠胃外给药(例如，通过注射，例如推注(bolus injection) 或持续输注)，且可以以单位剂量形式存在于具有添加防腐剂的安瓿、预填装注射器、小体积输注或在多剂量容器中。组合物可以采取下述形式，诸如悬浮剂、溶液剂或者含油或含水载体(vehicle)中的乳剂，且可以含有配制剂(formulation agent)，诸如悬浮剂、稳定剂和/或分散剂。可替选地，活性成分可以是通过无菌固体的无菌分离或通过溶液冻干获得的粉末形式，用于在使用前与适合的载体例如无菌无热原水复配(constitution)。Thus, 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. Alternatively, 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.
可以通过将活性组分溶解在水中并根据需要加入适合的着色剂、调味剂、稳定剂和增稠剂来制备适用于口服使用的含水溶液。可以通过用粘性材料诸如天然或合成胶、树脂、甲基纤维素、羧甲基纤维素钠或其他熟知的悬浮剂将粉碎的活性组分分散在水中来制备适用于口服使用的含水悬浮剂。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.
还包括预期在使用前不久转化为液体形式制剂用于口服给药的固体形式制剂。这样的液体形式包括溶液剂、悬浮剂和乳剂。除活性组分外，这些制剂还可以含有着色剂、调味剂、稳定剂、缓冲剂、人工和天然甜味剂、分散剂、增稠剂、增溶剂等。Also included are solid form preparations that are intended to be converted shortly before use to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These formulations can contain, in addition to the active ingredient, coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweetening agents, dispersing agents, thickening agents, solubilizers, and the like.
在本申请的一种实施方式中，局部地或全身地或通过两种途径组合地施用药物。In one embodiment of the present application, the drug is administered locally or systemically or by a combination of both routes.
对于给药，在一种实施方式中，可以在含有按重量0.001％至70％的化合物，可选地按重量0.01％至70％的化合物，甚至更可选地按重量0.1％至70％的化合物的配制品中给药本申请的化合物。在一种实施方式中，所给药的化合物的适合量在0.01mg/kg体重至1g/kg体重的范围内。For administration, in one embodiment, 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. In one embodiment, a suitable amount of compound administered is in the range of 0.01 mg/kg body weight to 1 g/kg body weight.
适用于给药的组合物还包括：在调味基质(通常为蔗糖和阿拉伯胶或黄蓍胶)中包括活性剂的锭剂、在惰性基质(如明胶和甘油或蔗糖和阿拉伯胶)中包括活性成分的软锭剂(pastille)以及在适合的液体载体中包括活性成分的漱口剂(mouthwash)。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.
溶液剂或悬浮剂通过常规手段例如用滴管、移液管或喷雾器直接给药至鼻腔。组合物可以提供为单或多剂量形式。在滴管或移液管的后一种情况中，可以由给药适合的预定体积的溶液或悬浮液的患者来实现。在喷雾器的情况下，可以例如通过计量雾化喷雾泵来实现。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 a metered atomizing spray pump.
对呼吸道的给药也可以通过气雾剂的方式实现，其中用合适的推进剂诸如含氯氟烃(CFC)(例如二氯二氟甲烷、三氯氟甲烷或二氯四氟乙烷)、二氧化碳或其它合适的气体在加压包装中提供活性组分。该气雾剂还可以方便地含有表面活性剂，如卵磷脂。药物的剂量可以通过设置计量阀来控制。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. The aerosol may also conveniently contain a surfactant, such as lecithin. The dose of the drug can be controlled by setting the metering valve.
可替选地，该活性成分可以提供为干粉形式，例如化合物在合适的粉末基质诸如乳糖、淀粉、诸如羟丙基甲基纤维素的淀粉衍生物以及聚乙烯吡咯烷酮(PVP)中的粉末混合物。方便地，粉末载体会在鼻腔内形成凝胶。粉末组合物可以以单位剂量形式存在，例如，如明胶的胶囊或药筒(cartridges)，或者是粉末可以通过吸入器从其给药的泡罩包装(blister pack)。Alternatively, 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). Conveniently, 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.
在包括鼻内组合物的预期向呼吸道给药的组合物中，化合物一般具有小粒径，例如大约5微米或以下。 这样的粒径可以通过本领域中已知的手段例如通过微粉化获得。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.
在需要时，可以使用适于使活性成分缓释的组合物。When desired, compositions suitable for sustained release of the active ingredient can be used.
药物制剂可选为单位剂量形式。在这种形式中，制剂被细分为含有合适量的活性组分的单位剂量。单位剂量形式可以是包装的制剂，该包装含有分立的制剂量，诸如小瓶或安瓿中的包装片剂、胶囊和粉剂。而且，单位剂量形式可以是胶囊、片剂、扁囊剂或锭剂本身，或者其可以是合适数量的这些剂量形式中任意一种的包装形式。用于口服给药的片剂或胶囊和用于静脉内给药和持续输注的液体是可选的组合物。The pharmaceutical formulations may optionally be presented in unit dosage form. In such 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. Also, 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.
关于配制和给药的技术的其他详细信息可见于最新版的“Remington's Pharmaceutical Sciences(雷明顿药物科学)(Maack Publishing Co.Easton,Pa.)和Remington:The science and practice of pharmacy“,Lippincott Williams and Wilkins。Additional details on techniques for formulation and administration can be found in the latest editions of "Remington's Pharmaceutical Sciences (Maack Publishing Co. Easton, Pa.) and Remington: The science and practice of pharmacy", Lippincott Williams and Wilkins.
适合配制品和制造它们的方式也在例如Lachman等人著写的“Arzneiformenlehre,Paul Heinz List,EinLehrbuchfürPharmazeuten,WissenschaftlicheVerlagsgesellschaft Stuttgart,4.Auflage,1985”或”The theory and practice of industrial pharmacy”,Varghese Publishing House,1987”或“Modern Pharmaceutics”,James Swarbrick编辑，第2版”中公开。Suitable formulations and ways of making them are also found in, for example, "Arzneiformenlehre, Paul Heinz List, Ein Lehrbuchfür Pharmazeuten, Wissenschaftliche 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".
以下为具体实施例The following are specific examples
下文参照以下实施例进一步描述本申请，实施例意在说明而并不限制本申请的范围。除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。实施例中未注明具体条件的实验方法，按照常规条件，例如文献、书本中所述的条件或者生产厂家推荐的方法实现。The application is further described below with reference to the following examples, which are intended to illustrate but not limit the scope of the application. Unless otherwise stated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods. The experimental methods for which specific conditions are not indicated in the examples are realized according to conventional conditions, such as conditions described in literatures, books or methods recommended by manufacturers.
实施例1 黄芩苷金刚烷胺盐的制备Example 1 Preparation of Baicalin Amantadine Salt
金刚烷胺1.51克(0.01mol)悬浮于15ml DMF中，黄芩苷4.46克(0.01mol)加入到30mlDMF中，上述金刚烷胺DMF溶液加入到黄芩苷DMF溶液中，70℃搅拌反应15小时，反应液60℃减压浓缩至干，得到粗产物。1.51 grams (0.01mol) of amantadine was suspended in 15ml DMF, 4.46 grams (0.01mol) of baicalin was added to 30ml DMF, the above-mentioned amantadine DMF solution was added to the baicalin DMF solution, and the reaction was stirred at 70°C for 15 hours. The liquid was concentrated to dryness under reduced pressure at 60°C to obtain a crude product.
粗产物于室温条件下用30ml乙酸乙酯打浆20分钟，过滤，滤饼均分为两等份，第一份悬浮于15ml水中，冷冻干燥6小时除去溶剂，得到淡黄色固体产物。第二份滤饼30℃真空干燥24小时，得到淡黄色固体产物。第一份得到黄芩苷金刚烷胺盐2.65克，收率80.88％。第二份得到黄芩苷金刚烷胺盐2.68克，收率89.78％。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. In the first portion, 2.65 g of baicalin amantadine salt was obtained, and the yield was 80.88%. In the second part, 2.68 g of baicalin amantadine salt was obtained, and the yield was 89.78%.
产物通过核磁氢谱、红外光谱、DSC以及XRD进行结构表征测试，结果如图1～图4所示，相较于黄芩苷和金刚烷的单纯混合物，产物更易溶解，核磁共振氢谱化学位移显示黄芩苷的羧基氢与金刚烷胺-NH 2成盐，红外光谱同样呈现这一特征，热失重显示产物149℃、195℃处有峰。XRD图谱显示产物具有特征衍射峰。产物的物理性质、光谱特征、热力学性质相较于黄芩苷和金刚烷都发生了改变，说明其已成盐。 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 adamantane, the product is more soluble, and the chemical shift of the hydrogen NMR spectrum shows that The carboxyl hydrogen of baicalin forms a salt with amantadine-NH 2 , and the infrared spectrum also exhibits this feature. The thermal weight loss shows that the product has peaks at 149 °C and 195 °C. The XRD pattern shows that the product has characteristic diffraction peaks. Compared with baicalin and adamantane, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has been formed into a salt.
实施例2 野黄芩苷金刚烷胺盐的制备Example 2 Preparation of scutellarin amantadine salt
金刚烷胺1.51克(0.01mol)悬浮于15ml DMF中，野黄芩苷4.62克(0.01mol)加入到30mlDMF中，上述金刚烷胺DMF溶液加入到黄芩苷DMF溶液中，70℃搅拌反应15小时，反应液60℃减压浓缩至干，得到粗产物。1.51 grams (0.01mol) of amantadine were suspended in 15ml DMF, 4.62 grams (0.01mol) of baicalin was added to 30ml DMF, the above-mentioned amantadine DMF solution was added to the baicalin 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.
粗产物于室温条件下用30ml乙酸乙酯打浆20分钟，过滤，滤饼均分为两等份，第一份悬浮于15ml水中，冷冻干燥6小时除去溶剂，得到淡黄色固体产物。第二份滤饼30℃真空干燥24小时，得到淡黄色固体产物。第一份得到野黄芩苷金刚烷胺盐2.32克，收率75.57％，第二份得到野黄芩苷金刚烷胺盐2.36克，收率77.05％。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 2.32 g of scutellarin amantadine salt with a yield of 75.57%, and the second part obtained 2.36 g of scutellarin amantadine salt with a yield of 77.05%.
产物通过核磁氢谱、红外光谱、DSC以及XRD进行结构表征测试，结果如图5～图8所示，相较于野黄芩苷和金刚烷的单纯混合物，产物更易溶解，核磁共振氢谱化学位移显示野黄芩苷的羧基氢与金刚烷胺-NH 2成盐，红外光谱同样呈现这一特征，热失重显示产物185℃、204℃、205℃处有峰。产物的物理性质、光谱特征、热力学性质相较于野黄芩苷和金刚烷都发生了改变，说明其已成盐。 The product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figures 5 to 8. Compared with the simple mixture of baicalin and adamantane, the product is more soluble, and the chemical shift of the hydrogen NMR spectrum is It shows that the carboxyl hydrogen of baicalin forms a salt with amantadine-NH 2 , and the infrared spectrum also presents this feature. The thermal weight loss shows that the product has peaks at 185 ℃, 204 ℃ and 205 ℃. Compared with baicalin and adamantane, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has been formed into a salt.
实施例3 黄芩苷拉米夫定的制备Example 3 Preparation of Baicalin Lamivudine
与实施例1的制备方法基本相同，不同之处在于，将金刚烷胺替换为拉米夫定2.29克(0.01mol)。The preparation method is basically the same as that of Example 1, except that amantadine is replaced by 2.29 g (0.01 mol) of lamivudine.
第一份得到黄芩苷拉米夫定盐3,03克，收率89.85％，第二份得到黄芩苷拉米夫定盐3.08克，收率91.26％。The first part obtained 3.03 g of baicalin lamivudine salt with a yield of 89.85%, and the second part obtained 3.08 g of baicalin lamivudine salt with a yield of 91.26%.
产物通过核磁氢谱、红外光谱、DSC以及XRD进行结构表征测试，结果如图9～图12所示，相较于黄芩苷和拉米夫定的单纯混合物，产物更易溶解，核磁共振氢谱化学位移显示黄芩苷的羧基氢与拉米夫定-NH 2成盐，红外光谱同样呈现这一特征，热失重显示产物187℃、261℃处有峰。产物的物理性质、光谱特征、热力学性质相较于黄芩苷和拉米夫定都发生了改变，说明其已成盐。 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 pure mixture of baicalin and lamivudine, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin formed a salt with lamivudine-NH 2 , and the infrared spectrum also showed this feature, and the thermal weight loss showed that the product had peaks at 187°C and 261°C. Compared with baicalin and lamivudine, the physical properties, spectral characteristics and thermodynamic properties of the product have all changed, indicating that it has become a salt.
实施例4 野黄芩苷拉米夫定的制备Example 4 Preparation of scutellarin lamivudine
与实施例2的制备方法基本相同，不同之处在于，将金刚烷胺替换为拉米夫定2.29克(0.01mol)。The preparation method is basically the same as that of Example 2, except that amantadine is replaced by 2.29 g (0.01 mol) of lamivudine.
第一份得到野黄芩苷拉米夫定盐3.12克，收率90.25％，第二份得到野黄芩苷拉米夫定盐3.15克，收率91.17％。The first part obtained 3.12 g of scutellarin lamivudine salt with a yield of 90.25%, and the second part obtained 3.15 g of scutellarin lamivudine salt with a yield of 91.17%.
产物通过核磁氢谱、红外光谱、DSC以及XRD进行结构表征测试，结果如图13～图16所示，相较于野黄芩苷和拉米夫定的单纯混合物，产物更易溶解，核磁共振氢谱化学位移显示野黄芩苷的羧基氢与拉米夫定-NH 2成盐，红外光谱同样呈现这一特征，热失重显示产物193℃、293℃处有峰。XRD图谱显示产物具有特征衍射峰。产物的物理性质、光谱特征、热力学性质相较于野黄芩苷和拉米夫定都发生了改变，说明其已成盐。 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 lamivudine, the product is more soluble. The chemical shift shows that the carboxyl hydrogen of baicalin forms a salt with lamivudine-NH 2 , and the infrared spectrum also shows this feature. The thermal weight loss shows that the product has peaks at 193 ℃ and 293 ℃. The XRD pattern shows that the product has characteristic diffraction peaks. Compared with baicalin and lamivudine, the physical properties, spectral characteristics and thermodynamic properties of the product have all changed, indicating that it has become a salt.
实施例5 黄芩苷奥司他韦的制备Example 5 Preparation of baicalin and oseltamivir
与实施例1的制备方法基本相同，不同之处在于，将金刚烷胺替换为奥司他韦3.12克(0.01mol)。The preparation method is basically the same as that of Example 1, except that amantadine is replaced with oseltamivir 3.12 g (0.01 mol).
第一份得到黄芩苷奥司他韦盐3.12克，收率82.36％，第二份得到黄芩苷奥司他韦盐3.18克，收率83.90％。The first part obtained 3.12 g of baicalin oseltamivir salt with a yield of 82.36%, and the second part obtained 3.18 g of baicalin oseltamivir salt with a yield of 83.90%.
产物通过核磁氢谱、红外光谱、DSC以及XRD进行结构表征测试，结果如图17～图20所示，相较于黄芩苷和奥司他韦的单纯混合物，产物更易溶解，核磁共振氢谱化学位移显示黄芩苷的羧基氢与奥司他韦-NH 2成盐，红外光谱同样呈现这一特征，热失重显示产物190℃处有峰。产物的物理性质、光谱特征、热力学性质相较于黄芩苷和奥司他韦都发生了改变，说明其已成盐。 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 oseltamivir, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin formed a salt with oseltamivir-NH 2 , and the infrared spectrum also showed this feature, and the thermal weight loss showed that the product had a peak at 190 °C. Compared with baicalin and oseltamivir, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
实施例6 野黄芩苷奥司他韦的制备Example 6 Preparation of scutellarin oseltamivir
与实施例2的制备方法基本相同，不同之处在于，将金刚烷胺替换为奥司他韦3.12克(0.01mol)。The preparation method is basically the same as that of Example 2, except that amantadine is replaced by oseltamivir 3.12 g (0.01 mol).
第一份得到野黄芩苷奥司他韦盐3.23克，收率83.58％，第二份得到野黄芩苷奥司他韦盐3.26克，收率84.24％。The first part obtained 3.23 g of scutellarin oseltamivir salt with a yield of 83.58%, and the second part obtained 3.26 g of scutellarin oseltamivir salt with a yield of 84.24%.
产物通过核磁氢谱、红外光谱、DSC以及XRD进行结构表征测试，结果如图21～图24所示，相较于野黄芩苷和奥司他韦的单纯混合物，产物更易溶解，核磁共振氢谱化学位移显示野黄芩苷的羧基氢与奥司他韦-NH 2成盐，红外光谱同样呈现这一特征，热失重显示产物192℃、338℃处有峰。产物的物理性质、光谱特征、热力学性质相较于野黄芩苷和奥司他韦都发生了改变，说明其已成盐。 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 oseltamivir, the product is more soluble. The chemical shifts showed that the carboxyl hydrogen of baicalin formed a salt with oseltamivir-NH 2 , and the infrared spectrum also showed this feature. The thermal weight loss showed that the product had peaks at 192℃ and 338℃. Compared with baicalin and oseltamivir, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
实施例7 黄芩苷羟氯喹的制备The preparation of embodiment 7 baicalin hydroxychloroquine
与实施例1的制备方法基本相同，不同之处在于，将金刚烷胺替换为羟氯喹3.36克(0.01mol)。The preparation method is basically the same as that of Example 1, except that amantadine is replaced by 3.36 g (0.01 mol) of hydroxychloroquine.
第一份得到黄芩苷羟氯喹盐3.51克，收率89.72％，第二份得到黄芩苷羟氯喹盐3.55克，收率90.79％。The first part obtained 3.51 g of baicalin hydroxychloroquine salt with a yield of 89.72%, and the second part obtained 3.55 g of baicalin hydroxychloroquine salt with a yield of 90.79%.
产物通过核磁氢谱、红外光谱、DSC以及XRD进行结构表征测试，结果如图25～图28所示，相较于黄芩苷和羟氯喹的单纯混合物，产物更易溶解，核磁共振氢谱化学位移显示黄芩苷的羧基氢与羟氯喹-N成盐，红外光谱同样呈现这一特征，热失重显示产物200℃、277℃处有峰。产物的物理性质、光谱特征、热力学性质相较于黄芩苷和羟氯喹都发生了改变，说明其已成盐。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 hydroxychloroquine, the product is more soluble, and the chemical shift of the hydrogen NMR spectrum shows that The carboxyl hydrogen of baicalin forms a salt with hydroxychloroquine-N, and the infrared spectrum also exhibits this feature. The thermal weight loss shows that the product has peaks at 200 °C and 277 °C. Compared with baicalin and hydroxychloroquine, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
实施例8 野黄芩苷羟氯喹的制备Example 8 Preparation of scutellarin hydroxychloroquine
与实施例2的制备方法基本相同，不同之处在于，将金刚烷胺替换为羟氯喹3.36克(0.01mol)。The preparation method is basically the same as that of Example 2, except that amantadine is replaced by 3.36 g (0.01 mol) of hydroxychloroquine.
第一份得到野黄芩苷羟氯喹盐3.27克，收率82.05％，第二份得到野黄芩苷羟氯喹盐3.28克，收率82.21％。The first part obtained 3.27 grams of scutellarin hydroxychloroquine salt with a yield of 82.05%, and the second part obtained 3.28 grams of scutellarin hydroxychloroquine salt with a yield of 82.21%.
产物通过核磁氢谱、红外光谱、DSC以及XRD进行结构表征测试，结果如图29～图32所示，相较于野黄芩苷和羟氯喹的单纯混合物，产物更易溶解，核磁共振氢谱化学位移显示野黄芩苷的羧基氢与羟氯喹 -N成盐，红外光谱同样呈现这一特征，热失重显示产物206℃处有峰。产物的物理性质、光谱特征、热力学性质相较于野黄芩苷和羟氯喹都发生了改变，说明其已成盐。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 simple mixture of baicalin and hydroxychloroquine, the product is more soluble, and the chemical shift of the hydrogen NMR spectrum is It shows that the carboxyl hydrogen of baicalin forms a salt with hydroxychloroquine-N, and the infrared spectrum also shows this feature, and the thermal weight loss shows that the product has a peak at 206 °C. Compared with baicalin and hydroxychloroquine, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
实施例9 野黄芩苷氯喹的制备The preparation of embodiment 9 scutellarin chloroquine
与实施例2的制备方法基本相同，不同之处在于，将金刚烷胺替换为氯喹3.20克(0.01mol)。The preparation method is basically the same as that of Example 2, except that amantadine is replaced by 3.20 g (0.01 mol) of chloroquine.
第一份得到野黄芩苷氯喹盐3.38克，收率86.57％，第二份得到野黄芩苷氯喹盐3.38克，收率86.57％。The first part obtained 3.38 grams of scutellarin chloroquine salt with a yield of 86.57%, and the second part obtained 3.38 grams of scutellarin chloroquine salt with a yield of 86.57%.
产物通过核磁氢谱、红外光谱、DSC以及XRD进行结构表征测试，结果如图33～图36所示，相较于野黄芩苷和氯喹的单纯混合物，产物更易溶解，核磁共振氢谱化学位移显示野黄芩苷的羧基氢与氯喹的-N成盐，红外光谱同样呈现这一特征，热失重显示产物205℃、343℃处有峰。产物的物理性质、光谱特征、热力学性质相较于野黄芩苷和氯喹都发生了改变，说明其已成盐。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 chloroquine, the product is more soluble, and the chemical shift of the hydrogen NMR spectrum shows that The carboxyl hydrogen of baicalin forms salt with -N of chloroquine, and the infrared spectrum also shows this feature. The thermal weight loss shows that the product has peaks at 205°C and 343°C. Compared with baicalin and chloroquine, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
实施例10 活性测试Example 10 Activity test
1、抗病毒活性测定方法1. Determination method of antiviral activity
将各复盐化合物分别配制成不同浓度的供试品，以地鼠肾细胞为试验用细胞，测定供试品对A型流感病毒感染细胞活力的抑制活性，计算IC50。Each compound salt compound was formulated into different concentrations of the test article, and the hamster kidney cells were used as the test cells to determine the inhibitory activity of the test article on the viability of influenza A virus-infected cells, and calculate the IC50.
2、抗DNA聚合酶活性测定2. Anti-DNA polymerase activity assay
将各复盐化合物分别配制成不同浓度的供试品，测定供试品对DNA聚合酶活性的抑制活性，计算IC50。Each double salt compound was prepared into different concentrations of the test article, the inhibitory activity of the test article on DNA polymerase activity was determined, and the IC50 was calculated.
3、抗RNA聚合酶活性测定3. Anti-RNA polymerase activity assay
将各复盐化合物分别配制成不同浓度的供试品，测定供试品对RNA聚合酶活性的抑制活性，计算IC50。Each compound salt compound was prepared into different concentrations of the test article, the inhibitory activity of the test article on RNA polymerase activity was determined, and IC50 was calculated.
各复盐化合物的药物活性如表2所示：The pharmaceutical activity of each double salt compound is shown in Table 2:
表2Table 2
活性成分名称Active ingredient name 靶点target IC50(nM)IC50(nM)
金刚烷胺Amantadine A型流感病毒Influenza A virus 27002700
黄芩苷金刚烷胺盐Baicalin amantadine salt A型流感病毒Influenza A virus 13001300
野黄芩苷金刚烷胺盐Baicalin amantadine salt A型流感病毒Influenza A virus 12501250
奥司他韦Oseltamivir A型流感病毒Influenza A virus 320320
黄芩苷奥司他韦盐Baicalin Oseltamivir Salt A型流感病毒 Influenza A virus 180180
野黄芩苷奥司他韦盐Baicalin Oseltamivir Salt A型流感病毒Influenza A virus 185185
黄芩苷Baicalin A型流感病毒Influenza A virus 大于5000greater than 5000
野黄芩苷Baicalin A型流感病毒Influenza A virus 大于5000greater than 5000
拉米夫定Lamivudine DNA聚合酶DNA polymerase 8.48.4
黄芩苷拉米夫定盐Baicalin Lamivudine Salt DNA聚合酶DNA polymerase 6.16.1
野黄芩苷拉米夫定盐Baicalin Lamivudine Salt DNA聚合酶DNA polymerase 6.06.0
羟氯喹Hydroxychloroquine DNA聚合酶DNA polymerase 15.015.0
黄芩苷羟氯喹盐Baicalin Hydroxychloroquine Salt DNA聚合酶DNA polymerase 12.012.0
野黄芩苷羟氯喹盐Scutellarin Hydroxychloroquine Salt DNA聚合酶DNA polymerase 11.811.8
氯喹Chloroquine DNA聚合酶DNA polymerase 18.018.0
野黄芩苷氯喹盐Scutellarin Chloroquine Salt DNA聚合酶DNA polymerase 12.512.5
黄芩苷Baicalin DNA聚合酶DNA polymerase 大于100greater than 100
野黄芩苷Baicalin DNA聚合酶DNA polymerase 大于100greater than 100
羟氯喹Hydroxychloroquine RNA聚合酶RNA polymerase 36.8036.80
黄芩苷羟氯喹盐Baicalin Hydroxychloroquine Salt RNA聚合酶RNA polymerase 22.4022.40
野黄芩苷羟氯喹盐Scutellarin Hydroxychloroquine Salt RNA聚合酶RNA polymerase 24.6024.60
氯喹Chloroquine RNA聚合酶RNA polymerase 40.8040.80
野黄芩苷氯喹盐Scutellarin Chloroquine Salt RNA聚合酶RNA polymerase 26.8026.80
黄芩苷Baicalin RNA聚合酶RNA polymerase 大于100greater than 100
野黄芩苷Baicalin RNA聚合酶RNA polymerase 大于100greater than 100
由表2可知，黄芩苷金刚烷胺复盐化合物、野黄芩苷金刚烷胺复盐化合物对A型流感病毒的抑制活性比金刚烷胺对A型流感病毒的抑制活性强；As shown in Table 2, the inhibitory activity of baicalin amantadine double salt compound and baicalin amantadine double salt compound to influenza A virus is stronger than the inhibitory activity of amantadine to influenza A virus;
黄芩苷奥司他韦复盐化合物、野黄芩苷奥司他韦复盐化合物对A型流感病毒的抑制活性比奥司他韦对A型流感病毒的抑制活性强；The inhibitory activity of baicalin oseltamivir compound salt compound and scutellarin oseltamivir compound salt compound against influenza A virus is stronger than that of oseltamivir against influenza A virus;
黄芩苷拉米夫定复盐化合物、野黄芩苷拉米夫定复盐化合物对DNA聚合酶的抑制活性比拉米夫定对DNA聚合酶的抑制活性强；The inhibitory activity of baicalin lamivudine compound salt compound and baicalin lamivudine compound salt compound on DNA polymerase is stronger than that of lamivudine on DNA polymerase;
黄芩苷羟氯喹复盐化合物、野黄芩苷羟氯喹复盐化合物对DNA聚合酶、RNA聚合酶的抑制活性比羟氯喹对DNA聚合酶的抑制活性强；The inhibitory activity of baicalin hydroxychloroquine double salt compound and scutellarin hydroxychloroquine double salt compound on DNA polymerase and RNA polymerase is stronger than that of hydroxychloroquine on DNA polymerase;
野黄芩苷氯喹复盐化合物对DNA聚合酶的抑制活性比氯喹对DNA聚合酶、RNA聚合酶的抑制活性强。The inhibitory activity of scutellarin chloroquine double salt compound on DNA polymerase is stronger than that of chloroquine on DNA polymerase and RNA polymerase.
实施例11 黄芩苷金刚烷胺复盐纳米颗粒的制备Example 11 Preparation of Baicalin Amantadine Double Salt Nanoparticles
1、向纳米研磨机中，加入黄芩苷金刚烷胺复盐化合物50克，水500毫升，助悬剂吐温-20 50毫克，羟丙甲纤维素50毫克，聚乙二醇6000 50毫克，以2000rpm转速研磨40分钟，得到黄芩苷金刚烷胺复盐的纳米混悬液。1. Add 50 g of baicalin amantadine 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. Grinding at 2000 rpm for 40 minutes to obtain a nanosuspension of baicalin amantadine double salt.
2、得到的黄芩苷金刚烷胺复盐化合物纳米混悬液在流化床干燥设备干燥，干燥进风温度65℃，干燥至水分含量3％左右，制备得到黄芩苷金刚烷胺复盐纳米颗粒，粒径分布在50nm～500nm范围内。2. The obtained baicalin amantadine double salt compound nanosuspension is dried in a 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 amantadine double salt nanoparticles. , particle size distribution in the range of 50nm ~ 500nm.
制备得到的黄芩苷金刚烷胺复盐纳米颗粒相比未经纳米研磨的黄芩苷金刚烷胺复盐化合物，在10分钟20℃的溶解度增加了1.5倍。Compared with the baicalin amantadine double salt compound without nano-milling, the prepared baicalin amantadine double salt nanoparticles have a 1.5-fold increase in solubility at 20° C. for 10 minutes.
实施例12 野黄芩苷金刚烷胺复盐纳米颗粒的制备Example 12 Preparation of scutellarin amantadine double salt nanoparticles
与实施例11的制备方法基本相同，不同之处在于，将黄芩苷金刚烷胺复盐化合物替换为野黄芩苷金刚烷胺复盐化合物。野芩苷金刚烷胺复盐纳米颗粒粒径分布在50nm～500nm范围内。The preparation method of Example 11 is basically the same, except that the baicalin amantadine double salt compound is replaced by the baicalin amantadine double salt compound. The particle size distribution of the pycnogenol amantadine double salt nanoparticles is in the range of 50nm to 500nm.
制备得到的野黄芩苷金刚烷胺复盐纳米颗粒相比未经纳米研磨的野黄芩苷金刚烷胺复盐化合物，在10分钟20℃的溶解度增加了1.3倍。The prepared scutellarin amantadine double salt nanoparticles have a 1.3-fold increase in solubility at 20°C for 10 minutes compared to the scutellarin amantadine double salt compound without nano-milling.
实施例13 黄芩苷奥司他韦复盐纳米颗粒的制备Example 13 Preparation of Baicalin Oseltamivir Double Salt Nanoparticles
与实施例11的制备方法基本相同，不同之处在于，将黄芩苷金刚烷胺复盐化合物替换为黄芩苷奥司他韦复盐化合物。黄芩苷奥司他韦复盐纳米颗粒粒径分布在50nm～500nm范围内。The preparation method is basically the same as that of Example 11, except that the baicalin amantadine double salt compound is replaced by the baicalin oseltamivir double salt compound. The particle size distribution of baicalin and oseltamivir double salt nanoparticles is in the range of 50nm to 500nm.
制备得到的黄芩苷奥司他韦复盐纳米颗粒相比未经纳米研磨的黄芩苷奥司他韦复盐化合物，在10分钟20℃的溶解度增加了0.8倍。Compared with the baicalin-oseltamivir double-salt compound without nano-grinding, the prepared baicalin-oseltamivir double-salt nanoparticles have a 0.8-fold increase in solubility at 20° C. for 10 minutes.
实施例14 野黄芩苷奥司他韦复盐纳米颗粒的制备Example 14 Preparation of scutellarin oseltamivir double salt nanoparticles
与实施例13的制备方法基本相同，不同之处在于，将黄芩苷奥司他韦复盐化合物替换为野黄芩苷奥司他韦复盐化合物。野芩苷奥司他韦复盐纳米颗粒粒径分布在50nm～500nm范围内。The preparation method is basically the same as that of Example 13, except that the baicalin-oseltamivir double-salt compound is replaced with the scutellarin-oseltamivir double-salt compound. The particle size distribution of quinceaside oseltamivir double salt nanoparticles is in the range of 50nm to 500nm.
制备得到的野黄芩苷奥司他韦复盐纳米颗粒相比未经纳米研磨的野黄芩苷奥司他韦复盐化合物，在10分钟20℃的溶解度增加了1.0倍。Compared with the scutellarin-oseltamivir double-salt compound without nano-grinding, the prepared scutellarin-oseltamivir double-salt nanoparticles have a 1.0-fold increase in solubility at 20°C for 10 minutes.
实施例15 黄芩苷拉米夫定复盐纳米颗粒的制备Example 15 Preparation of Baicalin Lamivudine Double Salt Nanoparticles
与实施例11的制备方法基本相同，不同之处在于，将黄芩苷金刚烷胺复盐化合物替换为黄芩苷拉米夫定复盐化合物。黄芩苷拉米夫定复盐纳米颗粒粒径分布在50nm～500nm范围内。The preparation method is basically the same as that of Example 11, except that the baicalin amantadine double salt compound is replaced by the baicalin lamivudine double salt compound. The particle size distribution of baicalin lamivudine double salt nanoparticles is in the range of 50nm to 500nm.
制备得到的黄芩苷拉米夫定复盐纳米颗粒相比未经纳米研磨的黄芩苷拉米夫定复盐化合物，在10分钟20℃的溶解度增加了1.2倍。Compared with the baicalin-lamivudine double-salt compound prepared without nano-milling, the solubility of the prepared baicalin-lamivudine double-salt compound at 20° C. for 10 minutes increased by 1.2 times.
实施例16 野黄芩苷拉米夫定复盐纳米颗粒的制备Example 16 Preparation of scutellarin lamivudine double salt nanoparticles
与实施例15的制备方法基本相同，不同之处在于，将黄芩苷拉米夫定复盐化合物替换为野黄芩苷拉米夫定复盐化合物。野芩苷拉米夫定复盐纳米颗粒粒径分布在50nm～500nm范围内。The preparation method is basically the same as that of Example 15, except that the baicalin lamivudine double salt compound is replaced with the baicalin lamivudine double salt compound. The particle size distribution of pycnogenol lamivudine double salt nanoparticles is in the range of 50nm to 500nm.
制备得到的野黄芩苷拉米夫定复盐纳米颗粒相比未经纳米研磨的野黄芩苷拉米夫定复盐化合物，在10分钟20℃的溶解度增加了1.0倍。The prepared scutellarin-lamivudine double-salt nanoparticles have a 1.0-fold increase in solubility at 20° C. for 10 minutes compared to the scutellarin-lamivudine double-salt compound without nano-milling.
实施例17 黄芩苷羟氯喹复盐纳米颗粒的制备Example 17 Preparation of Baicalin Hydroxychloroquine Double Salt Nanoparticles
与实施例11的制备方法基本相同，不同之处在于，将黄芩苷金刚烷胺复盐化合物替换为黄芩苷羟氯 喹复盐化合物。黄芩苷羟氯喹复盐纳米颗粒粒径分布在50nm～500nm范围内。The preparation method of Example 11 is basically the same, except that the baicalin amantadine double salt compound is replaced by the baicalin hydroxychloroquine double salt compound. The particle size distribution of baicalin hydroxychloroquine double salt nanoparticles is in the range of 50nm to 500nm.
制备得到的黄芩苷羟氯喹复盐纳米颗粒相比未经纳米研磨的黄芩苷羟氯喹复盐化合物，在10分钟20℃的溶解度增加了1.0倍。Compared with the baicalin-hydroxychloroquine double-salt compound without nano-grinding, the prepared baicalin-hydroxychloroquine double-salt nanoparticles have a 1.0-fold increase in solubility at 20° C. for 10 minutes.
实施例18 野黄芩苷羟氯喹复盐纳米颗粒的制备Example 18 Preparation of scutellarin hydroxychloroquine double salt nanoparticles
与实施例17的制备方法基本相同，不同之处在于，将黄芩苷羟氯喹复盐化合物替换为野黄芩苷羟氯喹复盐化合物。野芩苷羟氯喹复盐纳米颗粒粒径分布在50nm～500nm范围内。The preparation method is basically the same as that of Example 17, except that the baicalin hydroxychloroquine double salt compound is replaced with the scutellarin hydroxychloroquine double salt compound. The particle size distribution of the quinoside hydroxychloroquine double salt nanoparticles is in the range of 50nm to 500nm.
制备得到的野黄芩苷羟氯喹复盐纳米颗粒相比未经纳米研磨的野黄芩苷羟氯喹复盐化合物，在10分钟20℃的溶解度增加了1.0倍。Compared with the scutellarin-hydroxychloroquine double-salt compound without nano-grinding, the prepared scutellarin-hydroxychloroquine double-salt nanoparticles have a 1.0-fold increase in solubility at 20° C. for 10 minutes.
实施例19 野黄芩苷氯喹复盐纳米颗粒的制备Example 19 Preparation of scutellarin chloroquine double salt nanoparticles
与实施例17的制备方法基本相同，不同之处在于，将黄芩苷金刚烷胺复盐化合物替换为野黄芩苷氯喹复盐化合物。野芩苷氯喹复盐纳米颗粒粒径分布在50nm～500nm范围内。The preparation method is basically the same as that of Example 17, except that the baicalin amantadine double salt compound is replaced with the scutellarin chloroquine double salt compound. The particle size distribution of the quinoside chloroquine double salt nanoparticles is in the range of 50nm to 500nm.
制备得到的野黄芩苷氯喹复盐纳米颗粒相比未经纳米研磨的野黄芩苷氯喹复盐化合物，在10分钟20℃的溶解度增加了1.0倍。Compared with the scutellarin-chloroquine double-salt compound without nano-grinding, the prepared scutellarin-chloroquine double-salt nanoparticles have a 1.0-fold increase in solubility at 20°C for 10 minutes.
实施例20 动物在体抗流感活性测定Example 20 Determination of in vivo anti-influenza activity in animals
分别设置空白给药组，黄芩苷组，野黄芩苷组，金刚烷胺组，奥司他韦组，黄芩苷金刚烷胺复盐纳米混悬液组(黄芩苷金刚烷胺复盐纳米混悬液制备方法参照实施例11)，野黄芩苷金刚烷胺复盐纳米混悬液组(野黄芩苷金刚烷胺复盐纳米混悬液制备方法参照实施例12)，黄芩苷奥司他韦复盐纳米混悬液组(黄芩苷奥司他韦复盐纳米混悬液制备方法参照实施例13)，野黄芩苷奥司他韦复盐纳米混悬液组(野黄芩苷奥司他韦复盐纳米混悬液制备方法参照实施例14)。The blank administration group, baicalin group, baicalin group, amantadine group, oseltamivir group, baicalin amantadine double salt nanosuspension group (baicalin amantadine double salt nanosuspension group) were set up respectively. For the preparation method of the liquid, refer to Example 11), the scutellarin amantadine double salt nanosuspension group (for the preparation method of the scutellarin amantadine double salt nanosuspension, refer to Example 12), baicalin and oseltamivir complex Salt nanosuspension group (the preparation method of baicalin oseltamivir double salt nanosuspension preparation method refers to Example 13), scutellarin oseltamivir double salt nanosuspension group (scutellarin oseltamivir complex For the preparation method of the salt nanosuspension, refer to Example 14).
1、试验细胞及动物1. Test cells and animals
小鼠：C57BL/6J鼠，雌性，体重20g,6-8周龄。所有小鼠均自由取食和饮水，在室温(23±2)℃条件下饲养。Mice: C57BL/6J mouse, female, body weight 20g, 6-8 weeks old. All mice had free access to food and water, and were kept at room temperature (23±2)℃.
2、试验方法2. Test method
建立流感鼠肺适应株感染小鼠，并将合格小鼠随机分组，每组10只，给药方案如下：Mice were established to infect mice with influenza mouse lung-adapted strains, and the qualified mice were randomly divided into groups of 10. The dosing schedule was as follows:
空白给药组：仅给予生理盐水。Blank administration group: only normal saline was administered.
黄芩苷组：用无菌PBS将黄芩苷配制成给药溶液，按照45mg/kg给药量，灌胃，每日一次，连续给药7日。Baicalin group: baicalin was formulated into a dosing solution with sterile PBS, and the dose was 45 mg/kg, administered by gavage, once a day, for 7 consecutive days.
野黄芩苷组：用无菌PBS将野黄芩苷配制成给药溶液，按照45mg/kg给药量，灌胃，每日一次，连续给药7日。Baicalin group: scutellarin was formulated into a dosing solution with sterile PBS, and the dose was 45 mg/kg by intragastric administration, once a day, for 7 consecutive days.
金刚烷胺组：用无菌PBS将金刚烷胺配制成给药溶液，按照15mg/kg给药量，灌胃，每日一次，连续给药7日。Amantadine group: amantadine was prepared into a dosing solution with sterile PBS, and the dose was 15 mg/kg by gavage, once a day, for 7 consecutive days.
奥司他韦组：用无菌PBS将奥司他韦配制成给药溶液，按照16mg/kg给药量，灌胃，每日一次，连续给药7日。Oseltamivir group: Oseltamivir was formulated into a dosing solution with sterile PBS, and the dosage was 16 mg/kg, administered by gavage, once a day, for 7 consecutive days.
黄芩苷金刚烷胺复盐纳米混悬液组：黄芩苷金刚烷胺纳米混悬液作为给药溶液，按照45mg/kg给药量，灌胃，每日一次，连续给药7日。Baicalin amantadine compound salt nanosuspension group: Baicalin amantadine nanosuspension was used as a dosing solution, according to the dosage of 45 mg/kg, intragastrically, once a day, for 7 consecutive days.
野黄芩苷金刚烷胺复盐纳米混悬液组：野黄芩苷金刚烷胺纳米混悬液作为给药溶液，按照45mg/kg给药量，灌胃，每日一次，连续给药7日。Baicalin amantadine double salt nanosuspension group: scutellarin amantadine nanosuspension was used as a dosing solution, according to the dosage of 45 mg/kg, intragastrically, once a day, for 7 consecutive days.
黄芩苷奥司他韦复盐纳米混悬液组：黄芩苷奥司他韦纳米混悬液作为给药溶液，按照28mg/kg给药量，灌胃，每日一次，连续给药7日。Baicalin oseltamivir compound salt nanosuspension group: Baicalin oseltamivir nanosuspension was used as a dosing solution, according to the dosage of 28 mg/kg, intragastrically, once a day, for 7 consecutive days.
野黄芩苷奥司他韦复盐纳米混悬液组：野黄芩苷奥司他韦纳米混悬液作为给药溶液，按照28mg/kg给药量，灌胃，每日一次，连续给药7日。Baicalin oseltamivir compound salt nanosuspension group: scutellarin oseltamivir nanosuspension as the dosing solution, according to the dosage of 28 mg/kg, gavage, once a day, continuous administration for 7 day.
给药结束后，处死小鼠，解刨肺，计算每组小鼠均肺指数抑制率(肺指数＝肺重g/体重g*100％；均肺指数抑制率＝(空白给药组肺指数均值-各药物治疗组肺指数均值)/空白给药组肺指数均值)，结果如下：After the administration, the mice were sacrificed, the lungs were dissected, and the average lung index inhibition rate of each group of mice was calculated (lung index=lung weight g/body weight g*100%; average lung index inhibition rate=(blank administration group lung index) Mean value - the mean value of lung index in each drug treatment group) / the mean value of lung index in blank administration group), the results are as follows:
黄芩苷组(剂量45mg/kg)均肺指数抑制率49.8％，野黄芩苷组(剂量45mg/kg)均肺指数抑制率46.6％，金刚烷胺组(15mg/kg)均肺指数抑制率62.6％，奥司他韦组(12mg/kg)均肺指数抑制率73.2％，黄芩苷金刚烷胺复盐纳米混悬液组(45mg/kg)肺指数抑制率86.8％，野黄芩苷金刚烷胺复盐纳米混悬液组(45mg/kg)均肺指数抑制率83.6％，黄芩苷奥司他韦复盐纳米混悬液组(28mg/kg)均肺指数均值88.8％，野黄芩苷奥司他韦复盐纳米混悬液组(28mg/kg)均肺指数抑制率89.4％。In the baicalin group (dose 45mg/kg), the average lung index inhibition rate was 49.8%, in the baicalin group (dose 45mg/kg), the average lung index inhibition rate was 46.6%, and the amantadine group (15mg/kg) averaged lung index inhibition rate was 62.6%. %, oseltamivir group (12mg/kg) average lung index inhibition rate was 73.2%, baicalin amantadine compound salt nanosuspension group (45mg/kg) lung index inhibition rate was 86.8%, scutellarin amantadine The average lung index inhibition rate of the compound salt nanosuspension group (45mg/kg) was 83.6%, the average lung index of the baicaleside oseltamivir compound nanosuspension group (28mg/kg) was 88.8%, and the average lung index was 88.8%. The average lung index inhibition rate in the Tasvir compound salt nanosuspension group (28 mg/kg) was 89.4%.
实施例21 动物在体抗乙肝活性测定Example 21 Determination of in vivo anti-hepatitis B activity in animals
分别设置空白给药组，黄芩苷组，野黄芩苷组，拉米夫定组，黄芩苷拉米夫定复盐纳米混悬液组(黄芩苷拉米夫定纳米混悬液制备方法参照实施例15)，野黄芩苷拉米夫定复盐纳米混悬液组(野黄芩苷拉米夫定纳米混悬液制备方法参照实施例16)。另外设立小鼠阴性转染组。The blank administration group, the baicalin group, the baicalin group, the lamivudine group, and the baicalin-lamivudine compound salt nanosuspension group were set up respectively (the preparation method of the baicalin-lamivudine nanosuspension was implemented with reference to the Example 15), scutellarin lamivudine double salt nanosuspension group (refer to Example 16 for the preparation method of scutellarin lamivudine nanosuspension). In addition, a mouse negative transfection group was established.
1、试验细胞及动物1. Test cells and animals
小鼠：C57BL/6J鼠，雄性，体重20g,6-8周龄。所有小鼠均自由取食和饮水，在室温(23±2)℃条件下饲养。Mice: C57BL/6J mouse, male, body weight 20g, 6-8 weeks old. All mice had free access to food and water, and were kept at room temperature (23±2)℃.
乙肝病毒DNA质粒：名称pAAV/HBV1.2，源自NIH。Hepatitis B virus DNA plasmid: name pAAV/HBV1.2, from NIH.
2、试验方法2. Test method
阴性转染组：未做制粒转染小鼠10只，仅给予生理盐水。Negative transfection group: 10 mice were not granulated and transfected, and were only given normal saline.
将质粒导入小鼠肝脏，建立乙肝病毒转染小鼠。将乙肝病毒DNA质粒转染小鼠随机分组，每组10只，给药方案如下：The plasmid was introduced into mouse liver to establish hepatitis B virus-transfected mice. Mice transfected with HBV DNA plasmid were randomly divided into groups, 10 mice in each group, and the dosage regimen was as follows:
空白给药组：仅给予生理盐水。Blank administration group: only normal saline was administered.
黄芩苷组：用无菌PBS将黄芩苷配制成给药溶液，按照30mg/kg给药量，灌胃，每日一次，连续给药14日。Baicalin group: The baicalin was formulated into a dosing solution with sterile PBS, and the dose was 30 mg/kg by gavage, once a day, for 14 consecutive days.
野黄芩苷组：用无菌PBS将野黄芩苷配制成给药溶液，按照30mg/kg给药量，灌胃，每日一次，连续给药14日。Baicalin group: scutellarin was formulated into a dosing solution with sterile PBS, and the dose was 30 mg/kg by gavage, once a day, for 14 consecutive days.
拉米夫定组：用无菌PBS将金刚烷胺配制成给药溶液，按照15mg/kg给药量，灌胃，每日一次，连续给药14日。Lamivudine group: amantadine was prepared into a dosing solution with sterile PBS, and the dosage was 15 mg/kg by gavage, once a day, for 14 consecutive days.
黄芩苷拉米夫定复盐纳米混悬液组：黄芩苷拉米夫定复盐纳米混悬液作为给药溶液，按照45mg/kg给药量，灌胃，每日一次，连续给药14日。Baicalin lamivudine compound salt nanosuspension group: Baicalin lamivudine compound salt nanosuspension was used as the dosing solution, according to the dosage of 45 mg/kg, gavage, once a day, for 14 consecutive administrations day.
野黄芩苷拉米夫定复盐纳米混悬液组：野黄芩苷拉米夫定复盐纳米混悬液作为给药溶液，按照45mg/kg给药量，灌胃，每日一次，连续给药14日。Baicalin lamivudine compound salt nanosuspension group: Baicalin lamivudine compound salt nanosuspension was used as the dosing solution, according to the dosage of 45 mg/kg, intragastrically, once a day, continuously given Medicine on the 14th.
给药结束后，取血测定转氨酶数值，测定空白给药组转氨酶约为阴性转染组的5倍，以空白给药组转氨酶均值为100％，计算每组小鼠转氨酶相对均值(即每组小鼠转氨酶除以空白给药组转氨酶值)，结果如下：After the administration, blood was taken to measure the transaminase value, and the transaminase of the blank administration group was about 5 times that of the negative transfection group. The mouse transaminase was divided by the transaminase value of the blank administration group), and the results were as follows:
空白给药组转氨酶均值100％，黄芩苷组(剂量30mg/kg)转氨酶相对均值84％，野黄芩苷组(剂量30mg/kg)转氨酶相对均值82％，拉米夫定组(剂量15mg/kg)转氨酶相对均值63％，黄芩苷拉米夫定复盐纳米混悬液组(剂量45mg/kg)转氨酶相对均值22％，野黄芩苷拉米夫定复盐纳米混悬液组(剂量45mg/kg)转氨酶相对均值23％。相比较空白给药组、黄芩苷组、野黄芩苷组、拉米夫定组，黄芩苷拉米夫定复盐纳米混悬液组和野黄芩苷拉米夫定复盐纳米混悬液组转氨酶差异明显，而且转氨酶趋于正常。The mean value of transaminase in the blank administration group was 100%, the relative mean value of transaminase in the baicalin group (dose 30mg/kg) was 84%, the relative mean value of transaminase in the baicalin group (dose 30mg/kg) was 82%, and the lamivudine group (dose 15mg/kg) ) The relative mean value of transaminase was 63%, the relative mean value of transaminase in the baicalin lamivudine compound salt nanosuspension group (dose 45mg/kg) was 22%, and the baicalin lamivudine compound salt nanosuspension group (dose 45mg/kg) kg) transaminase relative mean 23%. Compared with the blank administration group, baicalin group, baicalin group, lamivudine group, baicalin lamivudine compound salt nanosuspension group and baicalin lamivudine compound salt nanosuspension group The differences in transaminases were obvious, and transaminases tended to be normal.
实施例22 动物在体抗炎症活性测定Example 22 Determination of in vivo anti-inflammatory activity in animals
分别设置空白对照组，黄芩苷组，野黄芩苷组，羟氯喹组，黄芩苷羟氯喹复盐纳米混悬液组(黄芩苷羟氯喹复盐纳米混悬液制备方法参照实施例17)，野黄芩苷羟氯喹复盐纳米混悬液组(野黄芩苷羟氯喹复盐纳米混悬液制备方法参照实施例18)。另外设立阴性给药组。A blank control group, a baicalin group, a baicalin group, a hydroxychloroquine group, and a baicalin-hydroxychloroquine double salt nanosuspension group were set respectively (the preparation method of the baicalin-hydroxychloroquine double salt nanosuspension was referred to in Example 17), and the wild Baicalin hydroxychloroquine double salt nanosuspension group (refer to Example 18 for the preparation method of scutellarin hydroxychloroquine double salt nanosuspension). In addition, a negative administration group was established.
1、试验细胞及动物1. Test cells and animals
小鼠：C57BL/6J鼠，雄性，体重20g,6-8周龄。所有小鼠均自由取食和饮水，在室温(23±2)℃条件下饲养。Mice: C57BL/6J mouse, male, body weight 20g, 6-8 weeks old. All mice had free access to food and water, and were kept at room temperature (23±2)℃.
2、试验方法2. Test method
阴性对照组：未做任何处理的小鼠10只，仅给予生理盐水。Negative control group: 10 mice without any treatment, only given normal saline.
建立炎症患病小鼠。将炎症患病小鼠随机分组，每组10只，给药方案如下：Establishment of inflammatory diseased mice. The inflammatory diseased mice were randomly divided into groups of 10, and the dosing regimen was as follows:
空白给药组：仅给予生理盐水。Blank administration group: only normal saline was administered.
黄芩苷组：用无菌PBS将黄芩苷配制成给药溶液，按照29mg/kg给药量，灌胃，每日一次，连续给药3日。Baicalin group: baicalin was prepared into a dosing solution with sterile PBS, and the dosage was 29 mg/kg, administered by gavage, once a day, for 3 consecutive days.
野黄芩苷组：用无菌PBS将野黄芩苷配制成给药溶液，按照29mg/kg给药量，灌胃，每日一次，连续给药3日。Baicalin group: scutellarin was formulated into a dosing solution with sterile PBS, and the dose was 29 mg/kg by gavage, once a day, for 3 consecutive days.
羟氯喹组：用无菌PBS将羟氯喹配制成给药溶液，按照21mg/kg给药量，灌胃，每日一次，连续给药3日。Hydroxychloroquine group: Hydroxychloroquine was prepared into a dosing solution with sterile PBS, and the dose was 21 mg/kg by gavage, once a day, for 3 consecutive days.
黄芩苷羟氯喹复盐纳米混悬液组：黄芩苷羟氯喹复盐纳米混悬液作为给药溶液，按照50mg/kg给药量，灌胃，每日一次，连续给药3日。Baicalin-Hydroxychloroquine Double Salt Nanosuspension Group: Baicalin-Hydroxychloroquine Double Salt Nanosuspension was used as a dosing solution, and the dose was 50 mg/kg by intragastric administration, once a day, for 3 consecutive days.
野黄芩苷羟氯喹复盐纳米混悬液组：野黄芩苷羟氯喹复盐纳米混悬液作为给药溶液，按照50mg/kg给药量，灌胃，每日一次，连续给药3日。Scutellarin and hydroxychloroquine double salt nanosuspension group: As a dosing solution, scutellarin and hydroxychloroquine double salt nanosuspension was administered by intragastric administration at a dose of 50 mg/kg, once a day, for 3 consecutive days.
给药结束后，取血测定炎症细胞因子，测定空白给药组炎症细胞因子约为阴性对照组的3倍，以空白给药组炎症细胞因子均值为100％，计算每组小鼠炎症细胞因子相对均值(即每组小鼠炎症细胞因子值除以空白给药组炎症细胞因子值)，结果如下：After the administration, blood was taken to measure inflammatory cytokines, the inflammatory cytokines in the blank administration group were about 3 times that of the negative control group, and the average value of inflammatory cytokines in the blank administration group was 100%. The relative mean (that is, the inflammatory cytokine value of each group of mice divided by the inflammatory cytokine value of the blank administration group), the results are as follows:
空白给药组炎症细胞因子均值100％，黄芩苷组(剂量29mg/kg)炎症细胞因子相对均值92％，野黄芩苷组(剂量29mg/kg)炎症细胞因子相对均值90％，羟氯喹组(剂量21mg/kg)炎症细胞因子相对均值54％，黄芩苷羟氯喹复盐纳米混悬液组(剂量50mg/kg)炎症细胞因子相对均值32％，野黄芩苷羟氯喹复盐纳米混悬液组(剂量50mg/kg)炎症细胞因子相对均值33％。相比较空白给药组、黄芩苷组、野黄芩苷组、羟氯喹组，黄芩苷羟氯喹复盐纳米混悬液组和野黄芩苷羟氯喹复盐纳米混悬液组炎症细胞因子差异明显。The mean value of inflammatory cytokines in the blank administration group was 100%, the relative mean value of inflammatory cytokines in the baicalin group (dose 29mg/kg) was 92%, the relative mean value of inflammatory cytokines in the baicalin group (dose 29mg/kg) was 90%, and the hydroxychloroquine group ( The relative mean of inflammatory cytokines at a dose of 21mg/kg) was 54%, the relative mean of inflammatory cytokines in the baicalin-hydroxychloroquine compound salt nanosuspension group (dose of 50mg/kg) was 32%, and the scutellarin-hydroxychloroquine compound salt nanosuspension group (Dose 50mg/kg) The relative mean of inflammatory cytokines was 33%. Compared with the blank administration group, baicalin group, scutellarin group, and hydroxychloroquine group, there were significant differences in inflammatory cytokines between the baicalin hydroxychloroquine double salt nanosuspension group and the scutellarin hydroxychloroquine double salt nanosuspension group.
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity, all possible combinations of the technical features in the above-described embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be regarded as the scope described in this specification.
以上所述实施例仅表达了本申请的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本申请构思的前提下，还可以做出若干变形和改进，这些都属于本申请的保护范围。因此，本申请专利的保护范围应以所附权利要求为准。The above-mentioned embodiments only represent several embodiments of the present application, and the descriptions thereof are specific and detailed, but should not be construed as a limitation on the scope of the invention patent. It should be pointed out that for those skilled in the art, without departing from the concept of the present application, several modifications and improvements can be made, which all belong to the protection scope of the present application. Therefore, the scope of protection of the patent of the present application shall be subject to the appended claims.

Claims (13)

  1. 一种复盐化合物，其特征在于，为黄酮苷与有机胺类抗微生物剂的复盐，所述黄酮苷具有如下式(1)所示的结构通式：A double salt compound is characterized in that it is a double salt of a flavonoid glycoside and an organic amine antimicrobial agent, and the flavonoid glycoside has the general structural formula shown in the following formula (1):
    Figure PCTCN2021127504-appb-100001
    Figure PCTCN2021127504-appb-100001
    其中，R 1～R 9各自独立地选自-H、-OH、C 1～C 6烷基、烷氧基或取代烷基，且R 1和R 2中至少有一个选自-OH。 Wherein, 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.
  2. 根据权利要求1所述的复盐化合物，其特征在于，R 1和R 2均选自-OH。 The double salt compound according to claim 1, wherein R 1 and R 2 are both selected from -OH.
  3. 根据权利要求1或2所述的复盐化合物，其特征在于，所述黄酮苷为黄芩苷或野黄芩苷。The double salt compound according to claim 1 or 2, wherein the flavonoid glycoside is baicalin or scutellarin.
  4. 根据权利要求1所述的复盐化合物，其特征在于，所述有机胺类抗微生物剂中含有至少一个氨基，所述氨基各自独立地选自包括-NH 2、-NR’H或-NR’ 2，所述R’为给电子基团。 The double salt compound according to claim 1, wherein the organic amine antimicrobial agent contains at least one amino group, and the amino groups are independently selected from the group consisting of -NH 2 , -NR'H or -NR' 2 , the R' is an electron donating group.
  5. 根据权利要求1所述的复盐化合物，其特征在于，所述有机胺类抗微生物剂选自金刚烷胺、拉米夫定、奥司他韦、羟氯喹和氯喹中的任意一种。The double salt compound according to claim 1, wherein the organic amine antimicrobial agent is selected from any one of amantadine, lamivudine, oseltamivir, hydroxychloroquine and chloroquine.
  6. 一种权利要求1～5任一项所述的复盐化合物的制备方法，其特征在于，包括以下步骤：A preparation method of the double salt compound according to any one of claims 1 to 5, characterized in that, comprising the following steps:
    将所述黄酮苷、所述有机胺类抗微生物剂和极性非质子有机溶剂混合溶解得到混合溶液；mixing and dissolving the flavonoid glycosides, the organic amine antimicrobial agent and the polar aprotic organic solvent to obtain a mixed solution;
    将所述混合溶液进行反应，得到反应液；以及The mixed solution is reacted to obtain a reaction solution; And
    将所述反应液除去溶剂。The solvent was removed from the reaction solution.
  7. 根据权利要求1所述的复盐化合物的制备方法，其特征在于，所述极性非质子有机溶剂为N,N-二甲基甲酰胺、二甲基亚砜或乙腈中的一种或多种。The method for preparing a double salt compound according to claim 1, wherein the polar aprotic organic solvent is one or more of N,N-dimethylformamide, dimethyl sulfoxide or acetonitrile kind.
  8. 一种药物组合物，其中含有治疗有效量的权利要求1～5任一项所述的复盐化合物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，以及药学上可接受的载体、赋形剂或稀释剂。A pharmaceutical composition comprising a therapeutically effective amount of the double salt compound according to any one of claims 1 to 5 or its optical isomer, enantiomer, diastereomer, racemate or racemate mixture, and a pharmaceutically acceptable carrier, excipient or diluent.
  9. 权利要求1～5任一项所述的复盐化合物或权利要求8所述的药物组合物在制备抗微生物药物中的应 用。Application of the double salt compound according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 8 in the preparation of antimicrobial drugs.
  10. 根据权利要求9所述的药物组合物，其特征在于，所述抗微生物药物用于病毒疾病的治疗，所述病毒疾病为流感病毒、乙肝病毒、疟疾、类风湿性关节炎、红斑狼疮或神经退行性疾病。The pharmaceutical composition according to claim 9, wherein the antimicrobial drug is used for the treatment of viral diseases, and the viral diseases are influenza virus, hepatitis B virus, malaria, rheumatoid arthritis, lupus erythematosus or neurological disease Degenerative disease.
  11. 一种复盐纳米颗粒，其特征在于，由权利要求1～5任一项所述的复盐化合物经纳米研磨得到。A double salt nanoparticle, characterized in that, it is obtained by nano-grinding the double salt compound according to any one of claims 1 to 5.
  12. 权利要求11所述的复盐纳米颗粒在制备抗微生物药物中的应用。The application of the compound salt nanoparticles of claim 11 in the preparation of antimicrobial medicines.
  13. 根据权利要求12所述的应用，其特征在于，所述抗微生物药物用于病毒疾病的治疗，所述病毒疾病为流感病毒、乙肝病毒、疟疾、类风湿性关节炎、红斑狼疮、微生物感染类疾病引起的过度免疫反应或神经退行性疾病。The application according to claim 12, wherein the antimicrobial drug is used for the treatment of viral diseases, and the viral diseases are influenza virus, hepatitis B virus, malaria, rheumatoid arthritis, lupus erythematosus, microbial infection Excessive immune response or neurodegenerative disease caused by disease.
PCT/CN2021/127504 2020-10-30 2021-10-29 Flavonoid glycoside-organic amine antimicrobial agent double salt compound, preparation method therefor and application thereof WO2022089600A1 (en)

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