WO2022089600A1 - Composé de sel double d'agent antimicrobien à base de flavonoïde glycoside amine organique, son procédé de préparation et son utilisation - Google Patents

Composé de sel double d'agent antimicrobien à base de flavonoïde glycoside amine organique, son procédé de préparation et son utilisation Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
double salt
baicalin
salt compound
group
salt
Prior art date
Application number
PCT/CN2021/127504
Other languages
English (en)
Chinese (zh)
Inventor
王化录
王鹿荧
Original Assignee
杭州拉林智能科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 杭州拉林智能科技有限公司 filed Critical 杭州拉林智能科技有限公司
Publication of WO2022089600A1 publication Critical patent/WO2022089600A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07C211/38—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 containing condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—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
    • 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
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Biotechnology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Neurology (AREA)
  • Pulmonology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé de sel double à base de flavonoïde glycoside et un agent antimicrobien amine organique. Le flavonoïde glycoside a une formule générale développée représentée par la formule suivante (1), dans laquelle R1-R9 sont chacun indépendamment choisis parmi -H, -OH, alkyle en C1-C6, alcoxy ou alkyle substitué, et au moins l'un parmi R1 et R2 est choisi parmi -OH. La présente invention concerne également un procédé de préparation du composé de sel double. La présente invention concerne en outre une composition pharmaceutique contenant une quantité thérapeutiquement efficace et son utilisation. En outre, la présente invention concerne également des nanoparticules double sel obtenues par nano-broyage du composé de sel double et leur utilisation.
PCT/CN2021/127504 2020-10-30 2021-10-29 Composé de sel double d'agent antimicrobien à base de flavonoïde glycoside amine organique, son procédé de préparation et son utilisation WO2022089600A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011195816.6 2020-10-30
CN202011195816 2020-10-30

Publications (1)

Publication Number Publication Date
WO2022089600A1 true WO2022089600A1 (fr) 2022-05-05

Family

ID=79014556

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/127504 WO2022089600A1 (fr) 2020-10-30 2021-10-29 Composé de sel double d'agent antimicrobien à base de flavonoïde glycoside amine organique, son procédé de préparation et son utilisation

Country Status (2)

Country Link
CN (1) CN113880898B (fr)
WO (1) WO2022089600A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105434454A (zh) * 2014-09-30 2016-03-30 复旦大学 一种治疗hbv耐药株感染的药物组合物
CN105878231A (zh) * 2015-01-26 2016-08-24 复旦大学 黄酮类化合物在制备抗hiv潜伏的治疗药物中的用途
CN106860866A (zh) * 2015-12-13 2017-06-20 复旦大学 一种抗hbv感染的宿主hnf因子抑制剂及其用途
CN111166887A (zh) * 2020-01-20 2020-05-19 哈尔滨商业大学 一种黄芩素与自噬抑制剂的药物组合物及其应用
CN113244212A (zh) * 2020-02-10 2021-08-13 中国医学科学院药物研究所 黄芩素在制备预防和/或治疗新型冠状病毒感染疾病的药物中的应用
CN113244211A (zh) * 2020-02-07 2021-08-13 中国科学院上海药物研究所 黄芩主要成分黄芩素、黄芩苷及其组合物在抗冠状病毒中的应用

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08208502A (ja) * 1995-02-06 1996-08-13 Tsumura & Co 抗エイズウイルス剤の効果増強剤
GB9820420D0 (en) * 1998-09-18 1998-11-11 Glaxo Group Ltd Antiviral combinations
EP1127572A3 (fr) * 2000-02-25 2003-05-02 Basf Aktiengesellschaft Utilisation de flavones dans le traitement de maladies induites par cyclooxygenase-2
AU2004206821C1 (en) * 2003-01-14 2009-10-01 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
CN100563641C (zh) * 2005-12-26 2009-12-02 山东轩竹医药科技有限公司 氨溴索或其盐和抗感染药物的组合物
EA015132B1 (ru) * 2005-12-28 2011-06-30 Закрытое Акционерное Общество "Мастерклон" Лекарственное средство для лечения вирусных инфекций
CN101797246B (zh) * 2009-10-30 2012-11-07 曲敬来 黄芩黄酮抗甲型流感病毒亚型感染的应用
CN101732417B (zh) * 2010-02-09 2011-11-09 曾建国 博落回总生物碱离子对混合物的制备方法和用途
CN103720650A (zh) * 2014-01-17 2014-04-16 中国药科大学 一种具有抗流感病毒作用的黄芩苷注射剂
EA033232B1 (ru) * 2015-04-24 2019-09-30 НОВИК, Анатолий Матвеевич Биологически активное вещество полифармакологического действия растительного происхождения

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105434454A (zh) * 2014-09-30 2016-03-30 复旦大学 一种治疗hbv耐药株感染的药物组合物
CN105878231A (zh) * 2015-01-26 2016-08-24 复旦大学 黄酮类化合物在制备抗hiv潜伏的治疗药物中的用途
CN106860866A (zh) * 2015-12-13 2017-06-20 复旦大学 一种抗hbv感染的宿主hnf因子抑制剂及其用途
CN111166887A (zh) * 2020-01-20 2020-05-19 哈尔滨商业大学 一种黄芩素与自噬抑制剂的药物组合物及其应用
CN113244211A (zh) * 2020-02-07 2021-08-13 中国科学院上海药物研究所 黄芩主要成分黄芩素、黄芩苷及其组合物在抗冠状病毒中的应用
CN113244212A (zh) * 2020-02-10 2021-08-13 中国医学科学院药物研究所 黄芩素在制备预防和/或治疗新型冠状病毒感染疾病的药物中的应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LI XIAOHUA , HUANG SHUNDE , YANG JIE: "Effects of baicalin combined with lamivudine on cellular immunity in the treatment of chronic hepatitis B", PHARMACOLOGY AND CLINICS OF CHINESE MATERIA MEDICA, vol. 31, no. 4, 15 August 2015 (2015-08-15), pages 218 - 220, XP055927172, DOI: 10.13412/j.cnki.zyyl.2015.04.069 *
ZHANG YUFENG; LYU CHUNMING; FONG SOPHIA YUI KAU; WANG QIAN; LI CHENRUI; HO NICOLAS JAMES; CHAN KAY SHEUNG; YAN XIAOYU; ZUO ZHONG: "Evaluation of potential herb-drug interactions between oseltamivir and commonly used anti-influenza Chinese medicinal herbs", JOURNAL OF ETHNOPHARMACOLOGY, vol. 243, 17 July 2019 (2019-07-17), IE , pages 1 - 10, XP085796383, ISSN: 0378-8741, DOI: 10.1016/j.jep.2019.112097 *

Also Published As

Publication number Publication date
CN113880898B (zh) 2023-07-25
CN113880898A (zh) 2022-01-04

Similar Documents

Publication Publication Date Title
TWI516499B (zh) 泰諾福韋（ｔｅｎｏｆｏｖｉｒ）亞拉芬醯胺（ａｌａｆｅｎａｍｉｄｅ）之半反式丁烯二酸鹽
US8349866B2 (en) High penetration prodrug compositions of 1H-imidazo[4,5-C]quinolin-4-amines and 1H-imidazo[4,5-C]quinolin-4-amine-related compounds
US20050187245A1 (en) Stable amorphous forms of montelukast sodium
JP2022031717A (ja) オキサチアジン様化合物を作製する方法
CN101723949A (zh) 用于治疗呼吸道合胞体病毒感染的多环试剂
CN107987020B (zh) 3,5-二芳基吡唑或3,4-二芳基吡唑类衍生物及其应用
WO2022089598A1 (fr) Composé de sel double de glycoside flavonoïde-amine organique neuroagoniste, son procédé de préparation et son application
US8859589B2 (en) Use of 4′-thio-2′-deoxynucleosides as anti orthopoxvirus agents
WO2022089589A1 (fr) Sel double de glycoside flavonoïde-organoamine inhibiteur de dpp-4, son procédé de préparation et application associée
WO2022089593A1 (fr) Composé de sel double d'un agent anti-tumoral à base de glycoside de flavone amine organique, son procédé de préparation et son utilisation
WO2022089600A1 (fr) Composé de sel double d'agent antimicrobien à base de flavonoïde glycoside amine organique, son procédé de préparation et son utilisation
US8664384B2 (en) N6-(ferrocenmethyl)quinazolin-2,4,6-triamina (H2) and the derivatives and prodrugs thereof as antileishmanial, antiprotozoal, antiparasitic and antimicrobial agents
CN109956975A (zh) 肝递送恩替卡韦前体药物核苷环磷酸酯化合物及应用
CN104804042A (zh) 核苷酸膦酸酯类化合物、其药物组合物、制备方法及用途
EP3242554A1 (fr) Synthèse concise de dérivés d'urée d'amphotéricine b
US11872224B2 (en) Amorphous solid dispersion formulation
WO2022089590A1 (fr) Composé de sel du complexe flavonoïde glycoside-inhibiteur de tyrosine kinase amine organique, son procédé de préparation et son utilisation
WO2005033279A2 (fr) Decouverte de nouveaux anesthesiques solubles cristallins
CN100364975C (zh) 一种抗呼吸道病毒的药物及用途
CN109956986A (zh) 肝递送吉西他滨前体药物核苷环磷酸酯化合物及应用
CN113797218A (zh) 药物组合物及其制备方法和应用
CN114075105B (zh) 富勒烯芳基多羧酸衍生物及其在抗冠状病毒感染中的应用
RU2255086C1 (ru) 1-метил-2-фенилтиометил-3-карбэтокси-4-диметиламинометил-5-окси-6- броминдола мезилат, обладающий противовирусной активностью, и фармацевтическая композиция с его использованием
CN116889557A (zh) 2,4-二叔丁基苯酚在制备抗人呼吸道合胞病毒药物中的应用
WO2023201072A1 (fr) Nouveaux composés de 6-azauridine en tant qu'agents antiviraux à large spectre

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21885326

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 25/10/2023)