WO2022111578A1 - 一类星状棘蛋白靶向的抗呼吸道感染病毒的双功能化合物及其盐类的制备方法和应用 - Google Patents

一类星状棘蛋白靶向的抗呼吸道感染病毒的双功能化合物及其盐类的制备方法和应用 Download PDF

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WO2022111578A1
WO2022111578A1 PCT/CN2021/133118 CN2021133118W WO2022111578A1 WO 2022111578 A1 WO2022111578 A1 WO 2022111578A1 CN 2021133118 W CN2021133118 W CN 2021133118W WO 2022111578 A1 WO2022111578 A1 WO 2022111578A1
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compound
virus
metabolite
hydrate
stereoisomer
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English (en)
French (fr)
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徐峻
郝梦娇
张毓婷
陈浩
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深圳市三启药物开发有限公司
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Priority to EP21897078.8A priority Critical patent/EP4253394A1/en
Priority to JP2023531584A priority patent/JP2023550193A/ja
Publication of WO2022111578A1 publication Critical patent/WO2022111578A1/zh
Priority to US18/323,272 priority patent/US20230322837A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/88—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/64—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with oxygen atoms directly attached in position 8

Definitions

  • the invention relates to the fields of drug design and medicinal chemistry, and more particularly, to a preparation method and application of a bifunctional compound targeting a class of stellate spike proteins against respiratory virus infection and salts thereof.
  • the main idea of current mainstream antiviral drug research is to obtain target molecules (mainly proteins) related to virus replication, design or screen their inhibitors, and clarify the mode of action of receptors and ligand molecules, and then specific drugs can be found.
  • Modern technology allows us to obtain structural data of drug targets quickly, and drug repurposing strategies can also shorten the time to select drug candidates.
  • most pharmacists are looking for target-specific drugs for the new coronavirus.
  • the main targets are pathogenic: spike protein (S protein), E protein (envelope protein), M membrane protein, N-nucleocapsid protein, and various enzymes involved in viral replication; also have host-specific targets such as ACE2.
  • an object of the present invention is to provide a novel compound that has significant anti-coronavirus spike protein targeting and has a certain broad spectrum.
  • the compounds provided by the present invention and their salts are combined with the spike protein on the surface of the virus particle containing spike protein that causes respiratory tract infection at orthotopic and allosteric sites, so that the spike protein on the surface of the virus particle cannot interact with the receptor protein of the host cell. (eg, angiotensin-converting enzyme 2, or neuraminidase), thereby rendering the virus unable to infect humans.
  • one aspect of the present invention provides a compound or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, metabolite or prodrug thereof.
  • the compound has at least one of the following basic units:
  • R is a monosaccharide or a derivative thereof, an aromatic ring, at least one of the monosaccharide or a derivative thereof and an aromatic ring is optionally substituted with at least one substituent selected from amino and carboxyl,
  • n an integer from 1 to 6
  • Each X is attached to the backbone atom of R,
  • Each X may be the same or different, and each independently has the following structure:
  • R' represents an optionally substituted six-membered aromatic ring, coumarin, isocoumarin, flavonoid, isoflavone and glucosamine,
  • n an integer from 1 to 3
  • Each X' is the same or different and is each independently attached to a ring atom of R',
  • X' represents QH or QC(O)R"
  • Q represents -O-, -N-, -SO 2 -;
  • R" represents a monosaccharide group.
  • the inventors of the present invention are based on the characteristics that coronaviruses (such as SARS, MERS, SARS-CoV-2, etc.) and influenza viruses have a common mechanism in the fusion of virus-host cell membranes, that is, through the spine protein on the surface and the surface of the host cell.
  • ACE2 or neuraminidase binds to infect host cells.
  • the star-shaped small molecule compound has at least one of the aforementioned basic units.
  • Such molecules and their salts bind to orthotopic binding sites, such as RBD domains or allosteric sites, to viruses containing spike proteins or viruses with spike proteins on their surfaces, thereby preventing the invasion of coronaviruses or other viruses that express spike proteins on their surfaces. host cells, preventing viral infection from occurring.
  • such molecules and their salts interact with vitamin K-dependent proteins in the human body, inhibit the expression of vitamin K and inhibit blood coagulation in the human body, thereby treating vascular embolism caused by coronavirus and producing pneumonia caused by severe viral infection. curative effect.
  • the compound when X' represents QC(O)R", the compound contains a plurality of the basic units, wherein one of two adjacent basic units passes through the QC(O) in X' ) is attached to a carbon or oxygen atom of the backbone of R in another of said basic units whose recursion level does not exceed 2 in said compound.
  • R represents a monosaccharide group
  • the compound contains a plurality of the basic units, wherein one of two adjacent basic units passes through
  • the monosaccharide group in X' is attached to a carbon atom or atoms of R in another said base unit, said base unit in said compound having a recursion level of no more than 2.
  • the inventors of the present invention creatively designed a class of star-shaped molecules (including a plurality of the basic units) and their salts, targeting the pulmonary infection-causing viruses (such as coronavirus and influenza virus) containing spine proteins, and using spine protein as a target.
  • This spine-like protein invades host cells.
  • Molecular dynamics simulations were used to screen natural product-like star-like stellates that could dock with the orthotopic or allosteric sites of the spike protein and mediate the formation of homologous or heterologous k-polymers (k>1) of the spike protein.
  • the small molecule library was prepared by chemical synthesis, and each molecule underwent a molecular dynamics simulation experiment with a time course of 100 nanoseconds to select the hit compounds.
  • R is a monosaccharide or a derivative thereof, an aromatic ring, and the monosaccharide or a derivative thereof or an aromatic ring is optionally substituted by at least one substituent selected from amino and carboxyl;
  • R' represents an optionally substituted six-membered aromatic ring, coumarin, flavonoid, isoflavone,
  • Q represents -O-, -N-.
  • the monosaccharide or its derivative is selected from glucose, gluconic acid, and glucosamine, and the aromatic ring is selected from a C 4 -C 20 aromatic ring.
  • the aromatic ring is selected from phenyl, chromone, and isoflavone.
  • R' represents an optionally substituted six-membered aromatic ring, coumarin, flavonoid,
  • the basic unit in the compound is selected from one of the following structures:
  • R is the glucosamine skeleton, n is equal to 3, and the X group is at the 2, 3, and 4 positions of the glucosamine skeleton; in the X group, Q is O, and in R', m is equal to 3, and the X' group is between , Para, X' is hydroxyl.
  • R is chromone, n is equal to 3, X group is in the 5, 6, and 8 positions of chromone; in X group, Q is O, in R', m is equal to 3, X' group is between, In the para position, X' is a hydroxyl group.
  • R is isoflavone, n is equal to 4, X group is in the 5, 6, 8, 4' positions of isoflavone; in X group, Q is O, in R', m is equal to 3, X' group is in between , Para, X' is hydroxyl.
  • Compound 5 The divalent calcium salt of Compound 1.
  • R is the gluconic acid skeleton, n is equal to 3, and the X group is at the 2, 3, and 4 positions of the gluconic acid amine skeleton; in the X group, Q is O, and in R', m is equal to 3, and the X' group is between, In the para position, X' is a hydroxyl group; the carboxyl group of the compound forms a salt with zinc.
  • Compound 7 is the metabolite of compound 6.
  • R is 3-deoxygluconic acid skeleton, n is equal to 2, X group is at the 2 and 4 positions of 3-deoxygluconic acid skeleton; in X group, Q is O, in R', m is equal to 3, X' The base is in the meta or para position, and X' is a hydroxyl group; the carboxyl group of the compound forms a salt with sodium.
  • a second aspect of the present invention provides a pharmaceutical composition.
  • the pharmaceutical composition comprises the compound of the first aspect or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, metabolite or prodrug thereof.
  • the pharmaceutical composition provided by the present invention can be used to treat or prevent diseases caused by virus infection of host cells, and the virus is a virus with spike protein on the surface, and at the same time, the pharmaceutical composition of the present invention can inhibit the elevation of vitamin K; and inhibit lung Vascular embolism.
  • the dosage form of the pharmaceutical composition is selected from powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections, sprays, aerosols, and powders, preferably For nasal spray.
  • the third aspect of the present invention provides the use of the compound described in the first aspect or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, metabolite or prodrug thereof in the preparation of a medicament for the following at least one of:
  • the virus is a virus with spike protein on the surface;
  • the viruses include coronaviruses and influenza viruses.
  • the coronavirus includes SARS, MERS, and SARS-CoV-2.
  • the diseases include new coronary pneumonia, influenza A, and influenza B.
  • the second object of the present invention is to provide a compound having a therapeutic effect on novel coronavirus pneumonia.
  • the third object of the present invention is to provide the preparation method of the bifunctional compound and its salts.
  • the bifunctional compound means that the compound prevents the invasion of virus particles to host cells, and the metabolites of these compounds and their salts in vivo further inhibit the expression level of vitamin K, thereby treating such viruses invading host cells in the lungs. resulting in vascular embolism.
  • the fourth aspect of the present invention provides the use of a medicament in preventing and/or treating diseases caused by virus infection of host cells.
  • the medicament comprises the compound described in the first aspect or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, metabolite or prodrug thereof and/or described in the second aspect
  • the viruses include coronaviruses and influenza viruses.
  • the coronavirus includes SARS, MERS, and SARS-CoV-2.
  • a fifth aspect of the present invention provides the use of a medicament for reducing vitamin K levels in patients with high vitamin K levels.
  • the medicament comprises the compound described in the first aspect or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, metabolite or prodrug thereof and/or described in the second aspect pharmaceutical composition.
  • the sixth aspect of the present invention provides the use of a medicament in preventing and/or treating pulmonary vascular embolism.
  • the medicament comprises the compound described in the first aspect or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, metabolite or prodrug thereof and/or described in the second aspect pharmaceutical composition.
  • a seventh aspect of the present invention provides a method for preventing and/or treating diseases caused by virus infection of host cells.
  • the method comprises administering the pharmaceutical composition of the second aspect to a patient having or suspected of having a disease caused by infection of a host cell by the virus, wherein the virus is a virus having a spike protein on the surface .
  • the diseases include new coronary pneumonia, influenza A, and influenza B.
  • the viruses include coronaviruses and influenza viruses.
  • the coronavirus includes SARS, MERS, and SARS-CoV-2.
  • An eighth aspect of the present invention provides a method for reducing vitamin K levels.
  • the method comprises administering the pharmaceutical composition of the second aspect to a patient in need of reducing vitamin K levels.
  • the ninth aspect of the present invention provides a method for preventing and/or treating pulmonary vascular embolism.
  • the method comprises administering the pharmaceutical composition of the second aspect to a patient suffering from or suspected of suffering from the pulmonary vascular embolic disease.
  • the lead compound (star molecule) of the present invention is a pathogen-targeted drug (target is spike protein), and has good pathogenic specificity; and because it not only binds to the RBD domain of spike protein, but also binds to the multiplex of spike protein. Site binding, so it has broad-spectrum anti-coronavirus and influenza virus activity, which is a feature that other antiviral drugs are difficult to have;
  • the lead compound of the present invention is metabolized into coumarins (warfarin analogs) anticoagulant natural products in the body, so it has a therapeutic effect on severe new coronary pneumonia; many antiviral compounds can only prevent effect; and the compound provided by the present invention has two purposes;
  • the molecules of the lead compound of the present invention designed according to the structural characteristics of the spine protein are subjected to virtual screening by the molecular dynamics simulation technology based on supercomputing, and finally confirmed by biological experiments;
  • the best active lead compound provided by the present invention is derived from the "old drug new use” of natural products. Historically, it has been used as a "universal antidote” together with activated carbon and magnesium oxide, and can be used orally and externally to treat cold sores and Fever blisters, diaper rash, prickly heat, sore throat, swollen tonsils, rash, chronic diarrhea, dysentery, hematuria, arthralgia, persistent cough, and cancer are also used as flavorings in food and beverages; therefore, have a high clinical safety.
  • the lead compound of the present invention is widely distributed in medicinal plants, has abundant resources, and is easy to modify the activity by chemical synthesis, thereby further improving the druggability.
  • Figures 1-6 show the preparation routes for synthesizing compounds 1-6 in some embodiments provided by the present invention
  • Figure 7 shows the activity of compounds 4 and 6 in inhibiting virus infection of host cells at three different virus titers, wherein, at each virus titer, the bar graphs represent DMSO, compound 4 10 ⁇ L, compound 4 from left to right, respectively The percentage of infected cells after treatment with 20 ⁇ L, 10 ⁇ L of compound 5, and 20 ⁇ L of compound 5;
  • Figure 8 shows the results of transmission electron microscopy experiments that compounds 4 and 6 at three different virus titers inhibit virus infection of host cells.
  • Figure 9 shows the changes in the fluorescence intensity of the viruses in the host cells that inhibit the virus infection of the host cells by compounds 4 and 6 under three different virus titers
  • Figure 10 shows the anticoagulant activity of compound 6 metabolites.
  • Stereoisomers refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, etc. .
  • a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
  • Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to an association in which the solvent molecule is water.
  • the term "pharmaceutically acceptable salt” means suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergy, etc., within the scope of sound medical judgment, and with reasonable benefit/risk than commensurate with those salts.
  • Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharm. Sci. 66:1-19,1977. These salts can be prepared in situ during the final isolation and purification of the compounds of the present disclosure, or separately by reacting the free base group with a suitable organic acid.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyric acid Salt, camphorate, camphorsulfonate, carbonate, chloride, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, fumarate , Glucoheptonate, Glycerophosphate, Hemisulfate, Heptanoate, Caproate, Hydrobromide, Hydrochloride, Hydroiodide, 2-Hydroxyethanesulfonate, Lacturonate, Lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, Oxalate, Palmitate, Pamoate, Pec
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine , dimethylamine, trimethylamine, triethylamine, ethylamine, etc.
  • prodrug is a pharmacological substance that is administered in an inactive (or significantly less active) form and subsequently metabolized in vivo to an active metabolite. Getting more drug to the desired target at lower doses is often the rationale behind the use of prodrugs and this is often attributed to better absorption, distribution, metabolism and/or excretion (ADME) properties. Prodrugs are often designed to improve oral bioavailability because gastrointestinal malabsorption is often the limiting factor. Additionally, the use of a prodrug strategy can increase the selectivity of a drug to its intended target, thereby reducing the potential for off-target effects.
  • One of the adjacent two said basic units is connected to the backbone atom of R in the other said basic unit through a monosaccharide group in X'" means that in X' in one of the adjacent two said basic units The hydroxyl group in the monosaccharide group is esterified with the carboxyl group on the backbone atom of R in the other basic unit, thereby connecting the two basic units.
  • the medicament in the present invention can be prepared in various dosage forms, including but not limited to powder, tablet, granule, capsule, solution, emulsion, suspension, injection, spray, aerosol, powder aerosol, preferably For nasal spray.
  • the drug in the present invention can use various pharmaceutically acceptable adjuvants/excipients, including but not limited to solvents, solubilizers, binders, stabilizers, antioxidants, pH adjusters, according to needs and common knowledge in the pharmaceutical field. , flavoring agents, etc.
  • the present invention provides a class of stellate spike protein-targeted compounds and salts thereof, the structures of which are:
  • R is a monosaccharide or an aminated monosaccharide or a monosaccharide carboxyl group, or the skeleton of an aromatic ring.
  • X 1-n are multiple substituents on the R skeleton, and X i and X i+1 may be the same or different, but the total number of substituents on R does not exceed 6.
  • R' ⁇ six-membered aromatic ring, coumarin, flavonoids, isoflavones, glucosamine ⁇ ;
  • R" ⁇ R(X) n , monosaccharide group ⁇
  • spike protein spike protein
  • somatic proteins eg, angiotensin-converting enzyme 2, or neuraminidase
  • R is a monosaccharide or an aminated monosaccharide or a monosaccharide carboxyl group, or the backbone of an aromatic ring.
  • X 1-n are multiple substituents on the R skeleton, and X i and X i+1 may be the same or different, but the total number of substituents on R does not exceed 6.
  • Such molecules and their salts are broken down into metabolites in the human body, including 3,4,5-trihydroxybenzoic acid glycoside polymers, polyhydroxycoumarin glycoside polymers, and polyhydroxyflavonoid glycoside polymers; this The metabolites inhibit the expression level of vitamin K in the human body, prevent platelet aggregation, and thus treat vascular embolism caused by coronavirus.
  • R is a monosaccharide or an aminated monosaccharide or a monosaccharide carboxyl group, or the backbone of an aromatic ring.
  • X 1-n are multiple substituents on the R skeleton, and X i and X i+1 may be the same or different, but the total number of substituents on R does not exceed 6.
  • the preparation method of this type of compound is characterized in that: carrying out an esterification reaction between polyhydroxybenzoic acid and monosaccharide at room temperature, and then condensing with polyhydroxybenzoic acid, flavonoids, and coumarin to obtain star-shaped molecules, such molecules Its salts bind to the orthotopic binding site of the new coronavirus or the virus with the spine protein on the surface, such as the RBD domain or allosteric site, thereby preventing the coronavirus or other viruses expressing the spine protein on the surface from invading host cells and preventing virus infection happened.
  • R is a monosaccharide or an aminated monosaccharide or a monosaccharide carboxyl group, or the backbone of an aromatic ring.
  • X 1-n are multiple substituents on the R skeleton, and X i and X i+1 may be the same or different, but the total number of substituents on R does not exceed 6.
  • the preparation method of this type of compound is characterized in that: carrying out an esterification reaction between polyhydroxybenzoic acid and monosaccharide at room temperature, and then condensing with polyhydroxybenzoic acid, flavonoids and coumarin to obtain star-shaped molecules, such molecules and its salts bind to viruses containing spine proteins or viruses with spine proteins on the surface at orthotopic binding sites, such as RBD domains or allosteric sites, thereby preventing coronaviruses or other viruses expressing spine proteins from invading host cells, Prevent viral infections from occurring.
  • R 1 is a monosaccharide or an aminated monosaccharide or a monosaccharide carboxyl group, or an aromatic ring.
  • X 1-n are multiple substituents on the R skeleton, and X i and X i+1 may be the same or different, but the total number of substituents on R does not exceed 6.
  • the preparation method of this kind of compound is that polyhydroxybenzoic acid and monosaccharide are esterified at room temperature, and then condensed with polyhydroxybenzoic acid, flavonoids and coumarin to obtain star-shaped molecules, such molecules and their salts. It interacts with vitamin K-dependent proteins in the human body, inhibits the expression of vitamin K and inhibits blood coagulation in humans, thereby treating vascular embolism caused by coronavirus, and has curative effects on pneumonia caused by severe viral infection.
  • typical star compound type embodiments are as follows:
  • the present invention provides the preparation method of the bifunctional compound that targets the star-shaped spike protein-containing virus that causes pulmonary infection, comprising the following steps:
  • Embodiments of the present invention are described in detail below.
  • the embodiments described below are exemplary, only for explaining the present invention, and should not be construed as limiting the present invention. If no specific technique or condition is indicated in the examples, the technique or condition described in the literature in the field or the product specification is used.
  • the reagents or instruments used without the manufacturer's indication are conventional products that can be obtained from the market.
  • H1299 human lung cancer cells were cultured in RPMI-1640 10% fetal bovine serum, 37°C 5% CO 2 saturated humidity incubator.
  • Figure 7 shows the activity of compounds 4 and 6 in inhibiting virus infection of host cells at three different virus titers, where, at each virus titer, the bar graphs are from left to right respectively Indicates the percentage of infected cells after treatment with DMSO, compound 4 10 ⁇ L, compound 4 20 ⁇ L, compound 6 10 ⁇ L, and compound 5 20 ⁇ L;
  • Figure 8 shows the transmission electron microscope of compounds 4 and 6 inhibiting virus infection of host cells at three different virus titers Experimental results.
  • Figures 7-9 Under different virus titers, star compounds 4 and 6 can significantly inhibit virus infection of cells at a concentration of 20 ⁇ M; among them, star compound 4 can also significantly inhibit virus infection at a concentration of 10 ⁇ M cell.
  • the coagulation process is a complex process involving a series of coagulation factors. It is mainly divided into two types: "intrinsic coagulation pathway” and “extrinsic coagulation pathway”.
  • the zymogen time (PT) and thrombin time (TT) were used to evaluate the anticoagulant effect.
  • the APTT kit, PT kit, and TT kit were pre-warmed at 37°C for 2 minutes before use.
  • New Zealand rabbits were taken, anaesthetized with chloral hydrate, blood was collected by cardiac puncture, blood was collected in anticoagulation tubes containing 1/10 volume of 3.8% sodium citrate, centrifuged at 3000 rpm for 15 min, and the supernatant was collected to obtain platelet-poor plasma, which was refrigerated. Save in spare.
  • the compound was taken and prepared into a stock solution with a concentration of 10 mM in DMSO, and the sample to be tested was diluted with physiological saline during the assay, so that the final concentrations of the assay were 50 ⁇ M, 12.5 ⁇ M, 3.13 ⁇ M, 0.78 ⁇ M, 0.20 ⁇ M, and 0.05 ⁇ M.
  • the volume of the samples to be tested for each concentration was 50 ⁇ L, and the same volume of physiological saline solution was used as the negative control.
  • APTT determination Take 100 ⁇ L of plasma and mix with 50 ⁇ L of the sample to be tested, preheat at 37°C for 2 minutes, then add 50 ⁇ L of APTT reagent to it, continue to incubate at 37°C for 3 minutes, add 50 ⁇ L of 0.025mol/L CaCl
  • the coagulation analyzer detects and records the coagulation time.
  • PT determination Take 50 ⁇ L of plasma and mix with 20 ⁇ L of the sample to be tested respectively, preheat at 37°C for 2 minutes, add evenly, incubate at 37°C for 3 minutes, add 100 ⁇ L of PT reagent, mix well and detect, and record the coagulation time.
  • TT determination Take 100 ⁇ L of the prepared plasma and 50 ⁇ L of the mixture to be tested, mix well, preheat at 37°C for 2 min, add 50 ⁇ L of TT reagent to the mixture, detect, and record the instrument measurement results.
  • One-way analysis of variance was used for comparison among multiple groups; for pairwise comparison of means between groups, Dunnett's multiple comparisons test method was used when the variance was homogeneous; Dunnett's T3 multiple comparisons test method was used when the variance was unequal.
  • P ⁇ 0.05 means the difference is statistically significant. **** p ⁇ 0.0001, *** p ⁇ 0.001, ** p ⁇ 0.01, * p ⁇ 0.05.
  • the star compound 6 can inhibit the plasma coagulation effect in a dose-dependent manner.

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Abstract

种具有显著抗新冠病毒的棘蛋白靶向且具有一定广谱性的星状化合物。此类分子及其盐类具有至少一个R（x）„基本单元，其与含棘蛋白的病毒或表面有棘蛋白的病毒在正位结合位点，如MD域或者别构位点结合，从而阻止冠状病毒或者表面表达棘蛋白的其它病毒入侵宿主细胞，阻止病毒感染的发生。并且此类分子及其盐类与人体内维生素K依赖性蛋白相互作用，抑制维生素K的表达而抑制人体内的血液凝聚，从而治疗冠状病毒导致的血管栓塞，产生对重症病毒感染引起的肺炎的疗效。

Description

一类星状棘蛋白靶向的抗呼吸道感染病毒的双功能化合物及其盐类的制备方法和应用
优先权信息
本申请请求2020年11月25日向中国国家知识产权局提交的、专利申请号为202011341469.3的专利申请的优先权和权益，并且通过参照将其全文并入此处。
技术领域
本发明涉及药物设计和药物化学领域，更具体地，涉及一类星状棘蛋白靶向的抗呼吸道病毒感染的双功能化合物及其盐类的制备方法和应用。
背景技术
新冠肺炎(COVID-19)已经成为全球性健康挑战，由于是新发现的病毒，还没有特效药物或疫苗被批准用于治疗。目前，很多努力都集中在从老药中筛选针对病毒生命周期的关键酶的抑制剂。虽然给予老药新用特殊通道，目前发表的临床试验结果有待观察。
当前主流抗病毒药物研究的主要思路是：获取与病毒复制有关的靶分子(主要是蛋白质)，设计或筛选它们的抑制剂，厘清受体与配体分子的作用模式，就能找到特效药。现代技术使我们能很快获得药物靶标的结构数据，药物再利用策略也能缩短遴选候选药物的时间。在小分子药物研究领域，大部分药学家都在寻找针对新冠病毒的靶向特异性药物，主要靶标有针对病原的：棘蛋白(S蛋白)、E蛋白(包膜蛋白)、M膜蛋白、N核衣壳蛋白，以及与病毒复制有关的各种酶；也有针对宿主的靶标如ACE2。然而，野生动物携带近50万种可能感染人的病毒，不可能对每一种病毒都开发特异性靶向药物。病毒疫情的爆发性以及病毒的高变异性，使得简单的靶向药物难以及时响应疫情防治的需求，因为很容易因为RNA病毒的快速变异而失效。除了开发周期较长之外，简单靶向抗病毒药物的主要问题是：
(1)由于病毒快速变异而产生抗药性，
(2)感染后期的重症病人因炎症风暴或血管栓塞而危及生命，此时特异性抗病毒药物往往没有疗效。
发明内容
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。为此，本发明的一个目的在于提供一种新的具有显著抗新冠病毒的棘蛋白靶向且具有一定广谱性的化合物。本 发明提供的化合物及其盐类与含棘蛋白的引起呼吸道感染的病毒颗粒表面的棘蛋白在正位和别构位点上结合，造成病毒颗粒表面的棘蛋白不能与宿主细胞的受体蛋白(如，血管紧张素转换酶2，或神经氨酸酶)结合，从而导致病毒不能感染人类。
为此，本发明一方面提供一种化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药。根据本发明的实施例，所述化合物具有至少一个下列基本单元：
R(X) n，
其中，
R为单糖或其衍生物、芳香环，所述单糖或其衍生物和芳香环中的至少之一任选被至少一个选自氨基和羧基的取代基取代，
n表示1～6的整数，
每个X均与R的骨架原子相连，
每个X可以相同或者不同，并且分别独立地具有下列结构：
～QC(O)-R’((X’) m)
其中，
R’表示任选取代的六员芳环、香豆素、异香豆素、黄酮、异黄酮和氨糖，
m表示1～3的整数，
每个X’相同或者不同并且分别独立地与R’的环原子相连，
X’表示QH或QC(O)R”；
Q表示-O-、-N-、-SO 2-；
R”表示单糖基。
本发明的发明人根据冠状病毒(如SARS、MERS，SARS-CoV-2等)和流感病毒在病毒-宿主细胞膜融合方面具有共同的机制的特点，即通过其表面的棘蛋白与宿主细胞表面的ACE2酶或神经氨酸酶结合而感染宿主细胞。提出解决靶向抗病毒药物产生抗药性等问题的新方法：
1)以棘蛋白靶标结构为基础，设计和筛选与棘蛋白的正位和别构位点结合的小分子，从而兼具靶向性和抗冠状病毒广谱性的优点；
2)为了治疗新冠病毒引发的新冠肺炎，寻求既能抑制棘蛋白靶标又能阻止血栓形成的抗凝血小分子。
经过in silico，in vitro，in vivo的实验证实，发明人创造性的发现了具有上述双功能的星状小分子。该星状小分子化合物具有至少一个前述的基本单元。此类分子及其盐类与含棘蛋白的病毒或表面有棘蛋白的病毒在正位结合位点，如RBD域或者别构位点结合，从而阻止冠状病毒或者表面表达棘蛋白的其它病毒入侵宿主细胞，阻止病毒感染的发生。并且 此类分子及其盐类与人体内维生素K依赖性蛋白相互作用，抑制维生素K的表达而抑制人体内的血液凝聚，从而治疗冠状病毒导致的血管栓塞，产生对重症病毒感染引起的肺炎的疗效。
根据本发明的实施例，当X’表示QC(O)R”时，所述化合物含有多个所述基本单元，其中，相邻两个所述基本单元之一通过X’中的QC(O)与另一所述基本单元中的R的骨架的碳或氧原子相连，所述化合物中所述基本单元的递归层次不超过2。
根据本发明的实施例，当X’表示QC(O)R”时，R”表示单糖基，所述化合物含有多个所述基本单元，其中，相邻两个所述基本单元之一通过X’中的单糖基与另一所述基本单元中的R的碳原子或原子相连，所述化合物中所述基本单元的递归层次不超过2。
本发明发明人创造性的设计一类星状分子(包含多个所述基本单元)及其盐类，以含棘蛋白的引起肺部感染的病毒(如冠状病毒和流感病毒)为对象，以棘蛋白为靶标。该类棘蛋白入侵宿主细胞。采用分子动力学模拟方法，筛选能与棘蛋白正位或别构位点进行多点对接、介导棘蛋白形成同源或异源k-聚合体(k>1)的类天然产物的星状分子。通过化学合成制备获得小分子库，每种分子经历了100纳秒时程的分子动力学模拟实验，遴选出苗头化合物。这些苗头化合物经过细胞水平的实验验证，荧光探针表明这类分子及其盐类的确阻止了病毒颗粒对宿主细胞的入侵。这些化合物及其盐类在体内的代谢物进一步抑制维生素K的表达水平，从而治疗此类病毒入侵肺部宿主细胞而导致的血管栓塞。
根据本发明的实施例，R为单糖或其衍生物、芳香环，所述单糖或其衍生物或芳香环任选被至少一个选自氨基和羧基的取代基取代；
R’表示任选取代的六员芳环、香豆素、黄酮、异黄酮，
Q表示-O-、-N-。
根据本发明的实施例，所述单糖或其衍生物选自葡萄糖、葡萄糖酸、葡萄糖酸胺，所述芳香环选自C 4-C 20的芳香环。
根据本发明的实施例，所述芳香环选自苯基、色原酮、异黄酮。
根据本发明的实施例，R’表示任选取代的六员芳环、香豆素、黄酮，
Q表示-O-。
根据本发明的实施例，所述化合物中具有的基本单元选自如下结构之一：
Figure PCTCN2021133118-appb-000001
Figure PCTCN2021133118-appb-000002
化合物1：当R为苯基，n等于2，X基团在对位；在X基中，Q为O，R’中，m等于3，X’基在间、对位，X’为羟基。
化合物2：R为葡萄糖酸胺骨架，n等于3，X基在葡萄糖酸胺骨架2、3、4位；在X基中，Q为O，R’中，m等于3，X’基在间、对位，X’为羟基。
化合物3：R为色原酮，n等于3，X基在色原酮的5、6、8位；在X基中，Q为O，R’中，m等于3，X’基在间、对位，X’为羟基。
化合物4：R为异黄酮，n等于4，X基在异黄酮的5、6、8，4’位；在X基中，Q为O，R’中，m等于3，X’基在间、对位，X’为羟基。
化合物5：化合物1的二价钙盐。
化合物6：R为葡萄糖酸骨架，n等于3，X基在葡萄糖酸胺骨架2、3、4位；在X基中，Q为O，R’中，m等于3，X’基在间、对位，X’为羟基；化合物羧基与锌形成盐。
化合物7：是化合物6的代谢物。化合物7中，R为3-脱氧葡萄糖酸骨架，n等于2，X基在3-脱氧葡萄糖酸骨架2、4位；在X基中，Q为O，R’中，m等于3，X’基在间、对位，X’为羟基；化合物羧基与钠形成盐。
本发明第二方面提供一种药物组合物。根据本发明的实施例，所述药物组合物包含第一方面所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药。
本发明提供的药物组合物能够用于治疗或者预防病毒感染宿主细胞引起的疾病，所述病毒为表面具有棘蛋白的病毒，同时本发明的药物组合物能够抑制维生素K的升高；和抑制肺部血管栓塞。
根据本发明的实施例，所述药物组合物的剂型选自散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂、注射剂、喷雾剂、气雾剂、粉雾剂，优选为喷鼻剂。
本发明第三方面提供第一方面所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药在制备药物中的用途，所述药物用于下列的至少之一：
治疗或者预防病毒感染宿主细胞引起的疾病，优选地，所述病毒为表面具有棘蛋白的 病毒；
抑制维生素K的升高；和
抑制肺部血管栓塞。
根据本发明的实施例，所述病毒包括冠状病毒和流感病毒。
根据本发明的实施例，所述冠状病毒包括SARS、MERS、SARS-CoV-2。
根据本发明的实施例，所述疾病包括新冠肺炎、甲型流感、乙型流感。
本发明的目的之二在于提供一种对新冠肺炎具有治疗作用的化合物。
本发明的目的之三在于提供所述双功能化合物及其盐类的制备方法。
所述双功能化合物是指所述化合物阻止病毒颗粒对宿主细胞的入侵，并且这些化合物及其盐类在体内的代谢物进一步抑制维生素K的表达水平，从而治疗此类病毒入侵肺部宿主细胞而导致的血管栓塞。
本发明第四方面提供药物在预防和/或治疗病毒感染宿主细胞引起的疾病中的用途。根据本发明的实施例，所述药物包含第一方面所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药和/或第二方面所述的药物组合物，其中，所述病毒为表面具有棘蛋白的病毒，所述疾病包括新冠肺炎、甲型流感、乙型流感。
根据本发明的实施例，所述病毒包括冠状病毒和流感病毒。
根据本发明的实施例，所述冠状病毒包括SARS、MERS、SARS-CoV-2。
本发明第五方面提供药物在降低维生素K偏高患者中维生素K水平中的用途。根据本发明的实施例，所述药物包含第一方面所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药和/或第二方面所述的药物组合物。
本发明第六方面提供药物在预防和/或治疗肺部血管栓塞疾病中的用途。根据本发明的实施例，所述药物包含第一方面所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药和/或第二方面所述的药物组合物。
本发明第七方面提供一种预防和/或治疗病毒感染宿主细胞引起的疾病的方法。根据本发明的实施例，所述方法包括向患有或疑似患有所述病毒感染宿主细胞引起的疾病的患者施用第二方面所述的药物组合物，所述病毒为表面具有棘蛋白的病毒。
根据本发明的实施例，所述疾病包括新冠肺炎、甲型流感、乙型流感。
根据本发明的实施例，所述病毒包括冠状病毒和流感病毒。
根据本发明的实施例，所述冠状病毒包括SARS、MERS、SARS-CoV-2。
本发明第八方面提供一种降低维生素K水平的方法。根据本发明的实施例，所述方法包括向有降低维生素K水平需求的患者施用第二方面所述的药物组合物。
本发明第九方面提供一种预防和/或治疗肺部血管栓塞疾病的方法。根据本发明的实施例，所述方法包括向患有或疑似患有所述肺部血管栓塞疾病的患者施用第二方面所述的药物组合物。
与现有技术相比，本发明技术先进性概述如下：
1、本发明的先导化合物(星状分子)是病原体靶向药物(靶标为棘蛋白)，有很好的病原特异性；又因为它不仅与棘蛋白的RBD域结合，还与棘蛋白的多位点结合，因此具有广谱抗冠状病毒和流感病毒的活性，这是其它抗病毒药物难以具备的特色；
2、本发明的先导化合物在完成抗病毒使命后，在体内代谢成香豆素类(华法林类似物)抗凝血天然产物，因此，对重症新冠肺炎有治疗作用；很多抗病毒化合物只有预防作用；而本发明提供的的化合物兼备两种用途；
3、本发明的先导化合物根据棘蛋白结构特色设计的分子，通过基于超级计算的分子动力学模拟技术进行虚拟筛选，最后通过生物实验验证确定；
4、本发明提供的活性最佳的先导化合物源自天然产物的“老药新用途”，历史上，它与活性炭和氧化镁一起用作“万能解毒剂”，可以口服和外用治疗冷疮和发热水泡、尿布疹、痱子、喉咙痛、扁桃体肿痛、皮疹、慢性腹泻、痢疾、血尿、关节痛、持续咳嗽和癌症，在食品和饮料中也被用作调味剂；因此，具有很高的临床安全性。
5、本发明的先导化合物广泛分布于药用植物，资源丰沛，易于通过化学合成修饰对活性，进一步提高成药性。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1～6显示了本发明提供的一些实施方案中合成化合物1-6的制备路线图；
图7显示了三种不同病毒滴度下的化合物4与6抑制病毒感染宿主细胞的活性，其中，在每个病毒滴度下，柱状图自左至右分别表示DMSO、化合物4 10μL、化合物4 20μL、化合物5 10μL、化合物5 20μL处理后，感染细胞的百分数；
图8显示了三种不同病毒滴度下的化合物4与6抑制病毒感染宿主细胞的透射电镜实验结果。实验细胞：A549；病毒感染时间：48h；病毒滴度：10^9TU/mL；铺板细胞数：5*10^4/孔；病毒量：MOI＝20(1*10^6TU)；
图9显示了三种不同病毒滴度下的化合物4与6抑制病毒感染宿主细胞的病毒在宿主细胞内荧光强度变化；
图10显示了化合物6的代谢物抗凝血活性。
发明详细描述
下面结合具体实施例和附图进一步说明本发明的内容，但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下，对本发明方法、步骤或条件所作的简单修改或替换，均属于本发明的范围；若未特别指明，实施例中所用的技术手段为本领域技术人员所熟知的常规手段。
术语
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
如本文所用，术语“药学上可接受的盐”表示在合理的医学判断范围内适用于与人和动物的组织接触而没有过度的毒性、刺激性、变态反应等，并且与合理的受益/风险比相称的那些盐。药学上可接受的盐是本领域公知的。例如，S.M.Berge等人在J.Pharm.Sci.66:1-19,1977中详细描述了药学上可接受的盐。这些盐可以在本公开化合物的最终分离和纯化过程中原位制备，或者通过使游离碱基团与合适的有机酸反应而分开制备。代表性的酸加成盐包括乙酸盐、己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、碳酸盐、氯化物、柠檬酸盐、环戊烷丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、氢溴酸盐、盐酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十一酸盐、戊酸盐等。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁等，以及无毒铵、季铵和胺阳离子，包括但不限于铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。
“前药”是一种药理学物质，其以无活性(或显著较低的活性)形式施用，并随后在体内代谢为活性代谢物。以较低剂量使更多药物到达所需靶标通常是使用前药背后的基本原理 并且这通常归因于更好的吸收、分布、代谢和/或排泄(ADME)性质。前药通常设计成用于改善口服生物利用度，因为胃肠道吸收不良通常是限制因素。另外，使用前药策略可以增加药物对其预期靶标的选择性，从而降低脱靶效应的可能性。
“相邻两个所述基本单元之一通过X’中的单糖基与另一所述基本单元中的R的骨架原子相连”是指邻两个所述基本单元之一中的X’中的单糖基内的羟基与另一所述基本单元中的R的骨架原子上的羧基发生酯化反应，从而将两个基本单元相连。
“所述化合物中所述基本单元的递归层次不超过2”。
本发明中的药物可以制备为各种剂型，包括但不限于散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂、注射剂、喷雾剂、气雾剂、粉雾剂，优选为喷鼻剂。
本发明中的药物可以根据需要和药剂领域常识使用各种药学上可接受的各种辅料/赋形剂，包括但不限于溶剂、增溶剂、粘合剂、稳定剂、抗氧化剂、pH调节剂、矫味剂等。
根据本发明的一些具体的实施例，本发明提供一类星状棘蛋白靶向的化合物及其盐类，其结构为：
R(X) n,n＝1～6
其中，R为单糖或氨基化单糖或单糖羧基、或芳香环的骨架。X 1-n为R骨架上的多个取代基，X i与X i+1之间可以相同，也可以不同，但是R上的取代基总数不超过6。
X的结构如下所示：
～QC(O)-R’((X’) m),m＝1～3
R’＝{六员芳环，香豆素，黄酮，异黄酮，氨糖}；
Q＝{-O-,-N-，-SO 2-},X’＝{QH,QC(O)R”}
R”＝{R(X) n,单糖基}
此类分子及其盐类与含棘蛋白的引起呼吸道感染的病毒颗粒表面的棘蛋白(棘蛋白)在正位和别构位点上结合，造成病毒颗粒表面的棘蛋白不能与宿主细胞的受体蛋白(如，血管紧张素转换酶2，或神经氨酸酶)结合，从而不能感染人类。
根据本发明的一些具体的实施例，R为单糖或氨基化单糖或单糖羧基、或芳香环的骨架。X 1-n为R骨架上的多个取代基，X i与X i+1之间可以相同，也可以不同，但是R上的取代基总数不超过6。X的结构定义为～QC(O)-R’((X’) m),m＝1～3；R’定义为{六员芳环，香豆素，异香豆素，黄酮和异黄酮}；Q＝{-O-,-N-},X’＝{QH,QC(O)R”}；R”定义为{R(X) n,单糖基}，n＝1～6。
此类分子及其盐类在人体内分解为代谢物，包括3,4,5-三羟基苯甲酸苷多聚物、多羟基香豆素苷多聚物、多羟基黄酮苷多聚物；此类代谢物在人体内抑制维生素K的表达水平，阻止血小板聚集，从而治疗冠状病毒导致的血管栓塞。
根据本发明的一些具体的实施例，R为单糖或氨基化单糖或单糖羧基、或芳香环的骨架。X 1-n为R骨架上的多个取代基，X i与X i+1可以相同，也可以不同，但是R上的取代基总数不超过6。X的结构定义为～QC(O)-R’((X’) m),m＝1～3；R’定义为{六员芳环，香豆素，黄酮}；Q＝{-O-,-N-},X’＝{Q)H,QC(O)R”}；R”定义为{R(X) n,单糖基}，n＝1～6。此类化合物制备方法，其特征在于：将多羟基苯甲酸与单糖在室温条件下进行酯化反应，然后再与多羟基苯甲酸、黄酮、香豆素缩合得到得到星状分子，此类分子及其盐类与新冠病毒或表面有棘蛋白的病毒在正位结合位点，如RBD域或者别构位点结合，从而阻止冠状病毒或者表面表达棘蛋白的其它病毒入侵宿主细胞，阻止病毒感染的发生。
根据本发明的一些具体的实施例，R为单糖或氨基化单糖或单糖羧基、或芳香环的骨架。X 1-n为R骨架上的多个取代基，X i与X i+1之间可以相同，也可以不同，但是R上的取代基总数不超过6。X的结构定义为～QC(O)-R’((X’) m),m＝1～3；R’定义为{六员芳环，香豆素，黄酮}；Q＝{-O-,-N-},X’＝{QH,QC(O)R”}；R”定义为{R(X) n,单糖基}，n＝1～6。此类化合物制备方法，其特征在于：将多羟基苯甲酸与单糖在室温条件下进行酯化反应，然后再与多羟基苯甲酸、黄酮、香豆素缩合得到得到星状分子，此类分子及其盐类与含棘蛋白的病毒或表面有棘蛋白的病毒在正位结合位点，如RBD域或者别构位点结合，从而阻止冠状病毒或者表面表达棘蛋白的其它病毒入侵宿主细胞，阻止病毒感染的发生。
根据本发明的一些具体的实施例，R 1为单糖或氨基化单糖或单糖羧基、或芳香环。X 1-n为R骨架上的多个取代基，X i与X i+1之间可以相同，也可以不同，但是R上的取代基总数不超过6。X的结构定义为～QC(O)-R’((X’) m),m＝1～3；R’定义为{六员芳环，香豆素，黄酮}；Q＝{-O-,-N-},X’＝{QH,QC(O)R”}；R”定义为{R(X) n,单糖基}，n＝1～6。此类化合物制备方法，将多羟基苯甲酸与单糖在室温条件下进行酯化反应，然后再与多羟基苯甲酸、黄酮、香豆素缩合得到得到星状分子，此类分子及其盐类与人体内维生素K依赖性蛋白相互作用，抑制维生素K的表达而抑制人体类的血液凝聚，从而治疗冠状病毒导致的血管栓塞，产生对重症病毒感染引起的肺炎的疗效。
根据本发明的一些具体的实施例，典型星状化合物类型实施方案如下：
Figure PCTCN2021133118-appb-000003
根据本发明的一些实施例，本发明提供所述的星状靶向含棘蛋白的引起肺部感染的病毒的双功能化合物的制备方法，包括如下步骤：
Figure PCTCN2021133118-appb-000004
星状靶向含棘蛋白的引起肺部感染的病毒的双功能化合物的合成路线如上所示。含有羧酸基团的酚类原料(R 1-COOH)加入到二氯甲烷(可以使用DMF，吡啶，四氢呋喃等代替)中，同时加入二环己基碳二亚胺(DCC)和4-二甲氨基吡啶(DMAP)，室温搅拌0.5h。随后加入含有保护基团或没有保护基团的糖、带有羟基的芳香环、带有羟基的脂肪链(R 2-OH)，室温或加热条件下搅拌8h。使用乙酸乙酯或二氯甲烷萃取，取有机层，旋干有机溶剂，柱层析分离纯化后得到所需分子。
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1 化合物1的合成
3,4,5-三苄氧基苯甲酸(2.2mmol)，二环己基碳二亚胺(DCC，2.2mmol)和4-二甲氨基吡啶(DMAP，0.2mmol)，加入到二氯甲烷中，同时加入室温搅拌0.5h。随后加入1,4-苯二酚(1mmol)，室温条件下搅拌8h。随后使用乙酸乙酯萃取，取有机层，旋干有机溶剂，柱层析分离纯化后得到中间体。中间体与钯碳(60mg)加入甲醇中，抽干空气后充入氢气，室温下搅拌2h，过滤去除钯碳，有机层旋干。柱层析得到化合物1，总收率62.4％。化合物 1合成过程如图1所示。
实施例2 化合物2的合成
3,4,5-三苄氧基苯甲酸(3.3mmol)，二环己基碳二亚胺(DCC，3.3mmol)和4-二甲氨基吡啶(DMAP，0.3mmol)，加入到二氯甲烷中，同时加入室温搅拌0.5h。随后加入2-(6-(benzyloxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)acetamide(1mmol)，室温条件下搅拌8h。随后使用乙酸乙酯萃取，取有机层，旋干有机溶剂，柱层析分离纯化后得到中间体。中间体与钯碳(100mg)加入甲醇中，抽干空气后充入氢气，室温下搅拌2h，过滤去除钯碳，有机层旋干。柱层析得到化合物2，总收率53.5％。化合物2合成过程如图2所示。
实施例3 化合物3的合成
3,4,5-三苄氧基苯甲酸(3.3mmol)，二环己基碳二亚胺(DCC，3.3mmol)和4-二甲氨基吡啶(DMAP，0.3mmol)，加入到二氯甲烷中，同时加入室温搅拌0.5h。随后加入5,6,8-trihydroxy-4H-chromen-4-one(1mmol)，室温条件下搅拌8h。随后使用乙酸乙酯萃取，取有机层，旋干有机溶剂，柱层析分离纯化后得到中间体。中间体与钯碳(100mg)加入甲醇中，抽干空气后充入氢气，室温下搅拌2h，过滤去除钯碳，有机层旋干。柱层析得到化合物3，总收率61.2％。化合物3合成过程如图3所示。
实施例4 化合物4的合成
3,4,5-三苄氧基苯甲酸(4.4mmol)，二环己基碳二亚胺(DCC，4.4mmol)和4-二甲氨基吡啶(DMAP，0.4mmol)，加入到二氯甲烷中，同时加入室温搅拌0.5h。随后加入5,6,8-trihydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one(1mmol)，室温条件下搅拌8h。随后使用乙酸乙酯萃取，取有机层，旋干有机溶剂，柱层析分离纯化后得到中间体。中间体与钯碳(120mg)加入甲醇中，抽干空气后充入氢气，室温下搅拌2h，过滤去除钯碳，有机层旋干。柱层析得到化合物4，总收率76.3％。化合物4合成过程如图4所示。
实施例5 化合物5的合成
化合物1(1mmol)与碳酸氢钙(1mmol)加入到叔丁醇中，室温下搅拌12h，随后旋干溶剂，得到所需的化合物5，总收率98.9％。化合物5合成过程如图5所示。
实施例6 化合物6的合成
3,4,5-三苄氧基苯甲酸(3.3mmol)，二环己基碳二亚胺(DCC，3.3mmol)和4-二甲氨基吡啶(DMAP，0.3mmol)，加入到二氯甲烷中，同时加入室温搅拌0.5h。随后加入2-(6-(benzyloxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)acetic acid(1mmol)，室温条件下搅拌8h。随后使用乙酸乙酯萃取，取有机层，旋干有机溶剂，柱层析分离纯化后得到中间体。中间体与钯碳(100mg)加入甲醇中，抽干空气后充入氢气，室温下搅拌2h，过滤去除钯碳，有机层旋干。柱层析得到另一中间体b。中间体b与氢氧化锌加入叔丁醇中，室温下搅拌2h，随后旋干溶剂，得到化合物6，总收率49.8％。化合物6合成过程如图6所示。
实施例7 实施例1～6所得化合物的抗冠状病毒入侵实验
实验材料及试剂
H1299人肺癌细胞，RPMI-1640 10％胎牛血清，37℃ 5％CO 2饱和湿度培养箱中培养。
RPMI-1640+10％胎牛血清
PBS(Life Science Products&Services)
Trypsin-EDTA Solution(Gibco)
24孔板(Corning)
Lentivirus-NC病毒液(GenePharma，1×10 9TU/mL)
病毒侵染实验原理和步骤
1.将状态良好的H1299消化后重悬，取适量细胞接种至24孔板中，37℃培养箱中过夜；
2.取阴性对照病毒，按MOI 5、10、20与1640培养基混合稀释，总体积约500μL，并加入终浓度5μg/mL Polybrene；
3.吸去24孔板中原培养基，换入阴性对照病毒梯度稀释液，37℃培养箱中培养；
4、24h后吸去阴性对照病毒稀释液，换入500μL新鲜培养基，37℃培养箱中培养；
5、48h于荧光倒置显微镜下观察并记录结果，结果如图7-9所示，。
结果如图7-9所示：图7显示了三种不同病毒滴度下的化合物4与6抑制病毒感染宿主细胞的活性，其中，在每个病毒滴度下，柱状图自左至右分别表示DMSO、化合物4 10μL、化合物4 20μL、化合物6 10μL、化合物5 20μL处理后，感染细胞的百分数；图8显示了三种不同病毒滴度下的化合物4与6抑制病毒感染宿主细胞的透射电镜实验结果。实验细胞：A549；病毒感染时间：48h；病毒滴度：10^9TU/mL；铺板细胞数：5*10^4/孔；病毒量：MOI＝20(1*10^6TU)；图9显示了三种不同病毒滴度下的化合物4与6抑制病毒感染宿主细胞的病毒在宿主细胞内荧光强度变化；
图7-9所示：不同病毒滴度下，星状化合物4和6在20μM浓度下均能明显抑制病毒侵 染细胞；其中，星状化合物4在10μM浓度下，亦能明显抑制病毒侵染细胞。
实施例8 实施例1～6所得的化合物代谢物抗凝血实验研究
1.实验原理。
凝血过程是由一系列凝血因子共同参与的复杂过程，主要分为“内源性凝血途径”和“外源性凝血途径”两种，实验室通常采用部分活化凝血酶原时间(APTT)、凝血酶原时间(PT)和凝血酶时间(TT)来评价抗凝血效果。
2.试剂准备
2.1抗凝血实验试剂准备
APTT试剂盒、PT试剂盒、TT试剂盒，使用前37℃预温2min。
3.操作步骤
3.1抗凝血实验步骤
3.1.1血浆的制备
取新西兰兔，水合氯醛麻醉后，采用心脏穿刺法取血，以含有1/10体积3.8％枸橼酸钠抗凝管收集血液，3000rpm离心15min，收集上清液，获得贫血小板血浆，冰箱中保存备用。
3.1.2待测样品配制
取化合物，用DMSO制备成浓度为10mM的母液，测定时采用生理盐水对待测样品进行稀释，使检测终浓度为50μM，12.5μM，3.13μM，0.78μM，0.20μM，0.05μM。每个浓度待测样品体积为50μL，并以相同体积的生理盐水溶液最为阴性对照。
3.1.3检测方法
APTT测定：取血浆100μL与分别与待测样品50μL混匀，于37℃预热2min，随后向其中添加APTT试剂50μL，37℃继续孵育3min，加入0.025mol/L的CaCl2 50μL，于全自动血凝分析仪检测，记录凝固时间。
PT测定：取血浆50μL与分别与待测样品20μL混匀，于37℃预热2min后，加入匀，37℃保温3min，加入PT试剂100μL，混匀后检测，记录凝固时间。
TT测定：取制备好的100μL血浆与待测样品混合液50μL混匀，于37℃预热2min后，向混合液中加入TT试剂50μL，检测，并记录仪器测定结果。
3.1.4统计学方法
采用单因素方差分析(One-Way ANOVA)进行多组间比较；组间均数两两比较，方差齐时采用Dunnett's multiple comparisons test法；方差不齐时采用Dunnett's T3 multiple  comparisons test法。P<0.05为差异有统计学意义。 ****p<0.0001， ***p<0.001， **p<0.01， *p<0.05。
利用上述方法检测化合物6对体外对抗凝血指标APTT、PT、TT的影响，结果如表1和图10所示。
化合物6在50.00μL、12.50μL、3.13μL、0.78μL、0.20μL、0.05μL不同剂量梯度下的凝血指标APTT、PT、TT评价中，星状化合物6能够剂量依耐性的抑制血浆凝血作用。
表1 化合物6体外对抗凝血指标APTT、PT、TT的影响
Figure PCTCN2021133118-appb-000005
组别 APTT/s PT/s TT/s
生理盐水 21.24±1.04 10.96±0.39 23.00±0.10
化合物6 50.00(μM) 106.51±0.94 **** 16.66±0.45 *** 38.87±0.77 **
化合物6 12.50(μM) 75.11±2.58 *** 13.73±0.17 * 28.89±0.68 *
化合物6 3.13(μM) 37.72±1.83 ** 12.83±0.19 * 25.25±0.27 **
化合物6 0.78(μM) 26.84±0.79 * 10.54±0.37 23.95±0.07 **
化合物6 0.20(μM) 24.03±1.05 10.11±0.30 22.90±0.09
化合物6 0.05(μM) 20.12±0.09 9.76±0.85 23.35±0.31
备注：与生理盐水组相比， ****p<0.0001， ***p<0.001， **p<0.01， *p<0.05。
实施例9 实施例1～6所得的化合物外用制剂学实验研究
取0.4毫克至17.0毫克图1-6所述的最终产物按常规加入0.85至0.9克氯化钠，1.0至1.9毫克枸橼酸，按常规注入100毫升蒸馏水，按常规喷鼻剂制法得到喷鼻剂。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的， 不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (20)

  1. 一种化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药，其特征在于，所述化合物具有至少一个下列基本单元：
    R(X) n，
    其中，
    R为单糖或其衍生物、芳香环，所述单糖或其衍生物和芳香环中的至少之一任选被至少一个选自氨基和羧基的取代基取代，
    n表示1～6的整数，
    每个X均与R的骨架原子相连，
    每个X可以相同或者不同，并且分别独立地具有下列结构：
    ～QC(O)-R’((X’) m)
    其中，
    R’表示任选取代的六员芳环、香豆素、异香豆素、黄酮、异黄酮和氨糖，
    m表示1～3的整数，
    每个X’相同或者不同并且分别独立地与R’的环原子相连，
    X’表示QH或QC(O)R”；
    Q表示-O-、-N-、-SO 2-；
    R”表示单糖基。
  2. 根据权利要求1所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药，其特征在于，当X’表示QC(O)R”时，所述化合物含有多个所述基本单元，其中，相邻两个所述基本单元之一通过X’中的QC(O)与另一所述基本单元中的R的骨架原子相连，所述化合物中所述基本单元的递归层次不超过2。
  3. 根据权利要求1所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药，其特征在于，当X’表示QC(O)R”时，R”表示单糖基，所述化合物含有多个所述基本单元，其中，相邻两个所述基本单元之一通过X’中的单糖基与另一所述基本单元中的R的骨架原子相连，所述化合物中所述基本单元的递归层次不超过2。
  4. 根据权利要求1-3中任一项所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药，其特征在于，
    R为单糖或其衍生物、芳香环，所述单糖或其衍生物或芳香环任选被至少一个选自氨基和羧基的取代基取代；
    R’表示任选取代的六员芳环、香豆素、黄酮、异黄酮，
    Q表示-O-、-N-。
  5. 根据权利要求4所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药，其特征在于，所述单糖或其衍生物选自葡萄糖、葡萄糖酸、葡萄糖酸胺，所述芳香环选自C 4-C 20的芳香环。
  6. 根据权利要求5所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药，其特征在于，所述芳香环选自苯基、色原酮、异黄酮。
  7. 根据权利要求6所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药，其特征在于，
    R’表示任选取代的六员芳环、香豆素、黄酮，
    Q表示-O-。
  8. 权利要求1所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药，其特征在于，所述化合物中具有的基本单元选自如下结构之一：
    Figure PCTCN2021133118-appb-100001
    Figure PCTCN2021133118-appb-100002
  9. 一种药物组合物，其特征在于，所述药物组合物包含权利要求1-8中任一项所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药。
  10. 根据权利要求9所述的药物组合物，其特征在于，所述药物组合物的剂型选自散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂、注射剂、喷雾剂、气雾剂、粉雾剂，优选为喷鼻剂。
  11. 权利要求1-8中任一项所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药在制备药物中的用途，所述药物用于下列的至少之一：
    治疗或者预防病毒感染宿主细胞引起的疾病，优选地，所述病毒为表面具有棘蛋白的病毒；
    抑制维生素K的升高；和
    抑制肺部血管栓塞。
  12. 根据权利要求11所述的用途，其特征在于，所述病毒包括冠状病毒和流感病毒。
  13. 根据权利要求12所述的用途，其特征在于，所述冠状病毒包括SARS、MERS、SARS-CoV-2。
  14. 根据权利要求11所述的用途，其特征在于，所述疾病包括新冠肺炎、甲型流感、 乙型流感。
  15. 药物在预防和/或治疗病毒感染宿主细胞引起的疾病中的用途，其特征在于，所述药物包含权利要求1-8中任一项所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药和/或权利要求9或10所述的药物组合物，其中，所述病毒为表面具有棘蛋白的病毒，所述疾病包括新冠肺炎、甲型流感、乙型流感；
    任选地，所述病毒包括冠状病毒和流感病毒；
    任选地，所述冠状病毒包括SARS、MERS、SARS-CoV-2。
  16. 药物在降低维生素K偏高患者中维生素K水平中的用途，其特征在于，所述药物包含权利要求1-8中任一项所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药和/或权利要求9或10所述的药物组合物。
  17. 药物在预防和/或治疗肺部血管栓塞疾病中的用途，其特征在于，所述药物包含权利要求1-8中任一项所述的化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐、代谢物或前药和/或权利要求9或10所述的药物组合物。
  18. 一种预防和/或治疗病毒感染宿主细胞引起的疾病的方法，其特征在于，所述病毒为表面具有棘蛋白的病毒，所述方法包括向患有或疑似患有所述病毒感染宿主细胞引起的疾病的患者施用权利要求9或10所述的药物组合物，
    任选地，所述疾病包括新冠肺炎、甲型流感、乙型流感；
    任选地，所述病毒包括冠状病毒和流感病毒；
    任选地，所述冠状病毒包括SARS、MERS、SARS-CoV-2。
  19. 一种降低维生素K水平的方法，其特征在于，所述方法包括向有降低维生素K水平需求的患者施用权利要求9或10所述的药物组合物。
  20. 一种预防和/或治疗肺部血管栓塞疾病的方法，其特征在于，所述方法包括向患有或疑似患有所述肺部血管栓塞疾病的患者施用权利要求9或10所述的药物组合物。
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