WO2019022357A1 - Composition pharmaceutique pour prévenir ou traiter le syndrome respiratoire du moyen-orient - Google Patents

Composition pharmaceutique pour prévenir ou traiter le syndrome respiratoire du moyen-orient Download PDF

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WO2019022357A1
WO2019022357A1 PCT/KR2018/005761 KR2018005761W WO2019022357A1 WO 2019022357 A1 WO2019022357 A1 WO 2019022357A1 KR 2018005761 W KR2018005761 W KR 2018005761W WO 2019022357 A1 WO2019022357 A1 WO 2019022357A1
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mers
respiratory syndrome
cov
formula
present
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PCT/KR2018/005761
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English (en)
Korean (ko)
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김성한
김지연
김인기
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울산대학교 산학협력단
재단법인 아산사회복지재단
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Publication of WO2019022357A1 publication Critical patent/WO2019022357A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/10—Washing or bathing preparations
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health

Definitions

  • the present invention relates to a pharmaceutical composition for prevention or treatment of the Middle Respiratory Syndrome (MERS) and to an agent for preventing respiratory syndrome coronavirus (MERS-CoV) adsorption.
  • MERS Middle Respiratory Syndrome
  • MERS-CoV respiratory syndrome coronavirus
  • Virus means a toxic substance in Latin and refers to a group of infectious pathogenic particles that pass through bacterial filter paper (0.22 ⁇ m). Viruses can be classified as bacteriophages, plant viruses, and animal viruses according to the type of host cells. DNA viruses and RNA viruses can be classified according to the type of nucleic acid. Recently, various virus diseases such as H1N1, AI, and foot-and-mouth disease have caused a great social problem, and the concern about effective measures for viral diseases has raised a great interest in society.
  • Coronavirus is divided into four genus, alpha, beta, gamma and delta. Mors coronavirus belongs to the beta coronavirus. In the early days of its discovery, it was treated as a similar virus of the same Beta coronavirus, or just a new coronavirus, but on May 23, 2013, the International Commission on Taxonomy adopted the official name of corn virus But it has an independent official name different from the SARS virus.
  • MERS Middle East Respiratory Syndrome
  • MERS Middle East Respiratory Syndrome
  • Patent Document 1 Korean Patent Laid-Open Publication No. 10-2004-0091722
  • the present invention has been made in view of the above problems, and it is an object of the present invention to provide a novel pharmaceutical composition for the prevention or treatment of the Middle Respiratory Tract Syndrome (MERS).
  • MERS Middle Respiratory Tract Syndrome
  • Another object of the present invention is to provide a medicament for preventing respiratory syndrome coronavirus (MERS-CoV) adsorption.
  • MERS-CoV respiratory syndrome coronavirus
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising 1 or 2 compounds selected from the group consisting of compounds represented by the following formulas (1) and (2), a pharmaceutically acceptable salt thereof or a prodrug thereof as an active ingredient
  • MERS Middle East Respiratory Syndrome
  • the present invention also provides a method of preventing, ameliorating or treating the medicinal respiratory syndrome (MERS) comprising administering the pharmaceutical composition to a subject in need thereof.
  • MERS medicinal respiratory syndrome
  • the present invention also relates to a medicament for the treatment or prevention of mids respiratory syndrome (MERS) comprising 1 or 2 compounds selected from the group consisting of compounds represented by the following formulas (1) and (2), a pharmaceutically acceptable salt thereof or a prodrug thereof as an active ingredient ).
  • MERS mids respiratory syndrome
  • the health functional food is characterized by containing 0.001 to 15% by weight of the compound based on the total weight.
  • the present invention also relates to the use of a compound of the formula (I) or (II) or a pharmaceutically acceptable salt or prodrug thereof as an active ingredient in the manufacture of a medicament for the treatment of respiratory syndrome coronavirus (MERS-CoV). ≪ / RTI >
  • the present invention also relates to the use of a compound of the formula (I) or (II) or a pharmaceutically acceptable salt or prodrug thereof as an active ingredient in the manufacture of a medicament for the treatment of respiratory syndrome coronavirus (MERS-CoV) adsorption inhibitor.
  • MERS-CoV respiratory syndrome coronavirus
  • the present invention also relates to a method of treating or preventing a respiratory syndrome coronavirus (hereinafter referred to as " respiratory syndrome coronavirus ") comprising the step of coating the above-mentioned medium-respiratory syndrome coronavirus (MERS- MERS-CoV) adsorption prevention method.
  • a respiratory syndrome coronavirus hereinafter referred to as " respiratory syndrome coronavirus "
  • MERS- MERS-CoV medium-respiratory syndrome coronavirus
  • the present invention also provides a coating agent, a detergent (an automobile cleaner, a mouthwash or a hand cleaner), a spray (snow spray, a nose spray or an oral spray) containing the above adsorption inhibitor.
  • the compound of formula (I) or (II), a pharmaceutically acceptable salt thereof or a prodrug thereof selected from the group consisting of compounds represented by formula (I) and formula (II) according to the present invention binds to the Spike protein of the respiratory syndrome coronavirus Thereby inhibiting activation and preventing adsorption to the cell surface, thereby effectively preventing, ameliorating, or treating the respiratory syndrome in the Middle East.
  • composition containing the compound of the present invention as an active ingredient can be usefully used as a pharmaceutical or health food composition that can treat or prevent the respiratory syndrome of the Middle East.
  • the present invention analyzes the adsorption inhibitory activity against MERS-PV pseudovirus (MERS-PV pseudovirus) prepared to express the S protein of the respiratory syndrome coronavirus of the Middle East, respiratory syndrome coronavirus, and measures cell survival rate , While the toxicity was low and the preventive effect was remarkable.
  • MERS-PV pseudovirus MERS-PV pseudovirus
  • FIG. 1 is a process diagram showing a screening process according to the present invention in steps.
  • FIG. 2 shows the result of neutralization antibody analysis (Neutralization) of MERS-PV by plasma of MERS-CoV patients.
  • Neutralization neutralization antibody analysis
  • FIG. 4 is a graph showing the MERS-PV adsorption blocking effect of a compound represented by the formula 1 (b) (E-64-C) and dihydrotanshinone (a)
  • time-point-assay the final selected compounds were treated with MERS-PV-adhered host cells (pre-attachment assay, post-attachment, circle dots), treated with MERS-PV simultaneously with host cells, do.
  • the compound is mixed with MERS-PV and cultured for 2 hours and then treated with host cells (pre-attachment, horizontal stripes).
  • the relative infection rate (%) was significantly higher than before or during adherence.
  • the experiment was carried out in total of three iterations, and the data were expressed as mean and standard deviation.
  • An aspect of the present invention relates to a medicament for the treatment or prevention of a respiratory syndrome (hereinafter referred to as " respiratory syndrome ") comprising 1 or 2 compounds selected from the group consisting of compounds represented by Chemical Formulas 1 and 2, a pharmaceutically acceptable salt thereof or a prodrug thereof, Coronavirus (MERS-CoV). ≪ / RTI >
  • Another aspect of the invention relates to a method for the prevention, amelioration or treatment of the Middle Respiratory Tract Syndrome (MERS) comprising the step of administering the pharmaceutical composition to a subject in need thereof.
  • MERS Middle Respiratory Tract Syndrome
  • MERS-CoV was considered to bind to dipeptidyl peptidase 4 (DPP4) in host cells using an S protein called spike protein (hereinafter referred to as S protein), and MERS (MERS-PV) expressing the S protein present on the surface of CoV was designed and prepared, and the infectivity was evaluated by adding it to Huh7.5 with a large amount of DPP4 receptor. As a result, it was confirmed that Huh7.5 cells were effectively infected with MERS-PV and neutralized by human plasma diagnosed with MERS-CoV.
  • DPP4 dipeptidyl peptidase 4
  • a first plasmid vector (pVRC5601 12-09 luciferase) encoding Env-deficient HIV-1 and expressing luciferase
  • a second plasmid vector (pVRC4766 MERS S TM Korea 002) with MERS-CoV S protein and an envelope (MERS-PV) co-transfected with a third plasmid vector (pVRC5602 polymerase) and then treating the candidate compound with the MERS-PV to measure the luciferase activity.
  • pVRC5602 polymerase a third plasmid vector
  • the compound of the formula 1 or 2 according to the present invention also has a substituent .
  • the effect of inhibiting the activity of the coronavirus S protein of the Middle East Respiratory Syndrome may be decreased and the preventive or therapeutic effect on the respiratory syndrome of the Middle East may be reduced.
  • the compounds of formula (1) or (2) selected by the above-mentioned methods inhibit MERS-PV infection by 50% or more, VSV-PV (vesicular stomatitis virus-pseudovirus) (Cell survival rate of 90% or more) was not observed.
  • VSV-PV vesicular stomatitis virus-pseudovirus
  • the compound represented by the above formula (1) or (2) inhibits MERS-CoV infection by blocking the process of MERS-CoV adsorbed on the cell surface and entering into the cell through pre-cell adhesion and post-cell adsorption assay Respectively.
  • the pharmaceutical composition according to the present invention comprising the compound represented by the above formula (1) or (2) does not inhibit the RNA replication process of MERS-CoV in the host cell, but inhibits the cell adsorption of MERS-CoV in advance And that the compound of the present invention can be used as a preventive and therapeutic agent for a disease caused by the above-mentioned MERS-CoV.
  • the present invention by using a spike protein of a pseudovirus-mediated respiratory syndrome coronavirus (MERS-CoV) in a luciferase reporter backbone, 502 kinds of compounds can be detected through an assay capable of measuring a high-
  • the compounds represented by Formulas 1 and 2 of the present invention were finally selected as nontoxic compounds having no cytotoxicity while having an excellent prophylactic or therapeutic effect even at a low concentration (1 ⁇ ⁇ / ml).
  • the Middle Respiratory Syndrome may be a disease caused by the Middle East Respiratory Syndrome Coronavirus (MERS-CoV).
  • &quot refers to a salt of a compound that does not cause serious irritation to the organism to which it is administered and does not impair the biological activity and properties of the compound.
  • the pharmacological or pharmacological salt may be an acid which forms a non-toxic acid addition salt containing a pharmaceutically or pharmacologically acceptable anion, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, Organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and salicinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p -Sulfonic acid such as toluenesulfonic acid and the like.
  • an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid
  • Organic carboxylic acids such as tartaric acid, formic acid,
  • carboxylic acid salts include metal salts or alkaline earth metal salts formed with lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, etc., dicyclohexylamine , Organic salts such as N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline and triethylamine, and the like.
  • the compounds of formula (I) or (II) according to the invention may also be converted into their salts by conventional methods.
  • prodrug refers to pharmacologically or pharmacologically acceptable derivatives, such as esters, amides and phosphate derivatives, wherein the in vivo biological conversion product of the derivative is represented by formula 1 or 2 ≪ / RTI > Prodrugs are often used because they are easier to administer than parent drugs. For example, they may obtain viability by oral administration, whereas the parent drug or parent food may not. Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th ed, McGraw-Hill, Int. Ed., 1992, “Biotransformation of Drugs", p 13-15) describes conventional prodrugs and is incorporated herein by reference.
  • Prodrugs may also have enhanced solubility in pharmaceutical or food compositions than parent drug or parent food.
  • a prodrug is an ester that facilitates the passage of a cell membrane that is hydrolyzed to a carboxylic acid that is active by metabolism in cells whose water solubility is beneficial, &Quot;).
  • Another example of a prodrug may be a short peptide (polyamino acid) that is bound to an acid group that is converted by metabolism so that the peptide reveals the active site.
  • composition of the present invention 0.0001 to 50% by weight of any one of the compounds represented by Formulas (1) and (2), a pharmaceutically acceptable salt thereof or a prodrug thereof may be contained have.
  • the composition may be formulated with or combined with a medicament having a preventive or therapeutic effect on the above-mentioned Middle Respiratory Syndrome (MERS).
  • MERS Middle Respiratory Syndrome
  • compositions of the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of pharmaceutical compositions.
  • Carrier is defined as a compound that facilitates the addition of a compound into a cell or tissue.
  • DMSO dimethylsulfoxide
  • DMSO dimethylsulfoxide
  • a " diluent" is defined as a compound that not only stabilizes the biologically active form of the compound of interest, but also dilutes it in the water in which the compound is dissolved. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, since it mimics the salt state of the human solution.
  • buffer salts can control the pH of the solution at low concentrations, buffer diluents rarely modify the biological activity of the compounds.
  • subject " or " patient” means any single subject in need of treatment, including human, cow, dog, guinea pig, rabbit, chicken, insect and the like.
  • any subject who participates in a clinical study test that does not show any disease clinical findings, or who participates in epidemiological studies or used as a control group is included.
  • the pharmaceutical composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method .
  • Examples of carriers, excipients and diluents that can be contained in the composition containing the compound represented by Formula 1 or Formula 2 of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, But are not limited to, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, Magnesium stearate and mineral oil.
  • a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used.
  • Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose or lactose , Gelatin, and the like.
  • excipients such as starch, calcium carbonate, sucrose or lactose , Gelatin, and the like.
  • lubricants such as magnesium stearate and talc are also used.
  • the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups.
  • various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included .
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like.
  • the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
  • a pharmaceutical or therapeutic " effective amount" is an appropriate amount that affects a beneficial or desired clinical or biochemical outcome.
  • An effective amount may be administered one or more times.
  • an effective amount is an amount sufficient to temporarily alleviate, ameliorate, stabilize, reverse, slow down or slow the progression of a disease state. If the recipient animal is capable of enduring the administration of the composition, or the administration of the composition to the animal is suitable, the composition will be " pharmaceutically or physiologically acceptable ". If the amount administered is physiologically significant, it can be said that the formulation is administered in a " therapeutically effective amount ".
  • the formulation is physiologically relevant if the presence of the formulation results in a physiologically detectable change in the recipient.
  • treating refers to reversing, alleviating, inhibiting, or preventing the disease or condition to which the term applies, or one or more symptoms of the disease or disorder .
  • " treatment &quot refers to an act of treating when " treating " is defined as above.
  • the dosage of the pharmaceutical composition of the present invention may vary depending on the age, sex, and body weight of the patient, but may be 0.0001 to 100 mg / kg, preferably 0.001 to 10 mg / kg, once to several times per day.
  • the dosage may also be increased or decreased depending on the route of administration, degree of disease, sex, weight, age, and the like. Accordingly, the dosage is not limited in any way to the scope of the present invention.
  • the pharmaceutical composition may be administered to mammals such as rats, mice, livestock, humans, and the like in a variety of routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine dural or intracerebral injection.
  • compositions of the present invention may also be used in the form of their pharmaceutically acceptable salts and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable set.
  • Another aspect of the present invention is a medicament for the treatment or prevention of a respiratory syndrome or a respiratory syndrome comprising 1 or 2 compounds selected from the group consisting of the compounds represented by formulas (1) and (2), a pharmaceutically acceptable salt thereof or a prodrug thereof, To a functional food for preventing or ameliorating diseases caused by coronavirus (MERS-CoV).
  • MERS-CoV coronavirus
  • the term "functional food" means a food having improved functionality of a general food by adding a compound represented by the following formula (1) or (2) of the present invention to a general food.
  • a compound represented by the formula (1) or (2) of the present invention is added to a general food, the physical properties and physiological function of the general food will be improved.
  • the present invention can provide such an improved function Of foods are collectively referred to as 'functional foods'.
  • the compounds of formula (I) or (II) of the present invention can produce functional foods for the prevention and improvement of the Middle Respiratory Tract Syndrome (MERS).
  • functional foods and the like can be produced using the same.
  • the compound represented by the general formula (1) or the general formula (2) of the present invention or a pharmaceutically acceptable salt thereof or a prodrug thereof may be used as a main component, an additive and an adjuvant in the production of various functional foods and health functional foods.
  • Examples of foods to which this can be added include various foods, powders, granules, tablets, capsules, syrups, drinks, gums, tea, vitamin complexes, and health functional foods.
  • the compound of formula (I) or formula (II) of the present invention may be added to foods or beverages for the purpose of prevention of the Middle Respiratory Tract Syndrome (MERS).
  • MERS Middle Respiratory Tract Syndrome
  • the amount of the compound in the food or beverage is generally from 0.001 to 15% by weight of the total food weight of the health food composition of the present invention, and 0.02 to 30 g, Can be added in a proportion of 0.3 to 10 g.
  • the health beverage composition of the present invention is not limited to liquid ingredients other than the above-mentioned compounds (formula (1) or (2)) as essential ingredients in the indicated ratios, and may contain various flavors or natural carbohydrates, .
  • natural carbohydrates include monosaccharides such as disaccharides such as glucose and fructose such as maltose, sucrose and the like and polysaccharides such as dextrin, cyclodextrin and the like Sugar, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • Natural flavors can be advantageously used as flavors other than those described above
  • the ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.
  • composition of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates (cheese, chocolate etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like.
  • a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates (cheese, chocolate etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like.
  • compositions of the present invention may contain flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
  • the compound represented by the formula (1) or (2) of the present invention is a natural compound, it has little toxicity and side effects and can be safely used for prolonged use for preventive purposes.
  • Another aspect of the present invention is the use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt or prodrug thereof as an active ingredient, Coronavirus (MERS-CoV). ≪ / RTI >
  • the anti-viral agent inhibits the interaction of DPP4 with the S protein of the coronavirus of the respiratory syndrome of the middle respiratory syndrome, thereby preventing the virus from entering or entering the cell by interfering with adsorption and adhesion with cells.
  • the antiviral agent inhibits cysteine protease cathepsin, which is a key factor that activates the S protein of the middle respiratory syndrome coronavirus for adsorption to a target cell, inhibits the S protein activity of the middle respiratory syndrome coronavirus, Block the attachment.
  • the adsorption inhibitor of the present invention inhibits the binding and fusion step between the MERS-CoV and the target cell to block adsorption of the MERS-CoV virus to the target cell (MERS-CoV), which is injected prior to exposure to the Middle Respiratory Syncytial Virus coronavirus (MERS-CoV), as well as the effect of preventing entry of the infected cells And also has an effect of inhibiting the progression of symptoms.
  • MERS-CoV Middle Respiratory Syncytial Virus coronavirus
  • Another aspect of the present invention relates to a medicament for the treatment or prevention of diseases caused by a compound of the formula (I) or a pharmaceutically acceptable salt or prodrug thereof, Syndrome coronavirus (MERS-CoV) adsorption inhibitor.
  • MERS-CoV Syndrome coronavirus
  • Another aspect of the present invention is a method of treating or preventing a respiratory syndrome comprising administering to a subject a coating agent or spraying the subject with a medicament for preventing or treating respiratory syndrome coronavirus (MERS-CoV) Coronavirus (MERS-CoV).
  • MERS-CoV respiratory syndrome coronavirus
  • MERS-CoV respiratory syndrome coronavirus
  • Adsorption inhibitor &quot is an antiviral composition of the middle respiratory syndrome coronavirus targeting the step of interaction between DPP4 of the target cell and the S protein of the middle respiratory syndrome coronavirus that occurs before the viral infection into the target cell.
  • it is a compound designed to inhibit cellular uptake or adherence of coronavirus of the Middle East Respiratory Syndrome and inhibit intracellular entry
  • the anti-adherence agent containing it as an active ingredient includes the terms anti-adhesion agent, anti-entry agent, inflow inhibitor, , All antiadhesive agents work by intercepting the ability of the coronavirus to infect target cells and subsequently infect target cells.
  • the present anti-adsorption agent may be a compound represented by the general formula (1) or (2), and the compound represented by the general formula (1) or (2) may be any one of the compounds represented by the general formulas A pharmaceutically acceptable salt or prodrug thereof.
  • the antiadhesive agent according to the present invention inhibits the interaction of DPP4 with the S protein of the coronavirus of the respiratory syndrome of the Middle East and interferes with the adsorption to the cells.
  • the compound is an inhibitor of cysteine protease cathepsin, which is a major factor that activates S protein of the middle respiratory syndrome coronavirus for adsorption to a target cell. It inhibits the S protein activity of the respiratory syndrome coronavirus of the Middle East, Thereby blocking adsorption.
  • the adsorption inhibitor of the present invention inhibits the binding and fusion step between the MERS-CoV and the target cell to block adsorption of the MERS-CoV virus to the target cell , And further prevents entry into the cell.
  • the anti-adsorption agent may be used as a coating agent, and the coating agent may further include a binder component that can be cured under an environment of 10 to 120 ° C.
  • a binder component either an inorganic binder or an organic binder may be selected and used, but the present invention is not limited thereto.
  • the binder may be any one selected from the group consisting of a silica binder, a zirconia binder, an alumina binder, a titania binder, and combinations thereof.
  • the content of the binder is preferably 0.1 to 10% by weight in the adsorption inhibitor, the coating agent is dispersed stably in the content of the binder, the coating agent is applied to the coating agent, and the coating agent is cured, Uniformity can be achieved, and excellent coating adhesion can be obtained.
  • the coating of the present invention may be applied to a coating to produce an article having anti-viral properties against the respiratory syndrome coronavirus of the Middle East Respiratory Syndrome, said article being deposited on at least a portion of the outermost side (e.g., It has a film formed with the coating agent of the present invention and includes articles such as building construction materials, sanitary articles and antifouling articles.
  • the above adsorption inhibitor can be used as various fragrances or detergent compositions having an antiviral effect against the MERS-CoV virus of Middle East Respiratory Syndrome (MERS-CoV).
  • MERS-CoV Middle East Respiratory Syndrome
  • it can be applied to any formulations such as liquid, cream, paste, .
  • the application can also be applied to various fields.
  • a detergent composition such as an automobile detergent, a hand detergent, an oral detergent, a whole body detergent, a kitchen dish cleaner, a residential environment detergent, or the like, or a perfume composition such as volatilization or spraying.
  • the various fragrances and cleaning agents of the present invention can be prepared by uniformly mixing an adsorption inhibitor containing a compound represented by the following formula (1) or (2) in a usual base composition of various fragrances or cleaning agents in a mixer, A cream or a paste, and the compositions of other formulations can be produced in solid or spray form according to generally known methods.
  • the adsorption inhibitor may be used in a variety of products including human and animal foodstuffs, pharmaceutical products, veterinary products, cosmetics, mask or filter products, personal hygiene products and household articles.
  • composition of the present invention can be used as an external preparation for skin, and can be preferably used as an external preparation for skin in the form of an ointment, a lotion, a spray, a patch, a cream, a powder, a suspension, a gel or a gel.
  • the anti-adherence agent of the present invention can be used as a foodstuff, and is preferably used as a foodstuff such as margarine, fat continuous or water continuous or bicontinuous spread, fat reduced spread, chocolate, bread, It can be used as confectionery, gum, ice cream, ice cream coating, ice cream, dressing, mayonnaise, cheese, cream substitute, dried soup, drink, cereal bar, sauce, snack bar, dairy product,
  • the anti-adsorption agent of the present invention can be used as a personal hygiene product and is preferably used as a soap, a cosmetic, a wet tissue, a tissue, a shampoo, a skin cream, a face cream, a toothpaste, a mouthwash, a lipstick, , Ball touch, mascara, eye shadow, sunscreen lotion, hair care product, air freshner gel or cleaning gel.
  • the compound of formula (I) or (II) of the present invention is a cytotoxic compound, there is no problem such as toxicity and side effects.
  • the anti-adsorption agent of the present invention can be used as a drug, and can be used in the form of, for example, liquid toothpaste, mouthwash, oral spray, eye spray, nasal spray, oral ointment, oral varnish and the like.
  • 293TN and Huh7.5 cells were obtained from the laboratory of Professor Shin, Hee - cheol of the graduate School of Medicine, KAIST. Cells were cultured in DMEM medium (Gibco, Grand Island, NY, USA) containing 10% fetal bovine serum (Gibco) and 1% streptomycin / penicillin (Gibco) It was cultured in the% CO 2 conditions.
  • Experimental data of the present invention are expressed as mean ⁇ standard deviation (SD), and data analysis and graph plotting are performed with Graphpad Prism 5. Pre-attachment data and post-attachment data are compared using a pair of student's t-tests. Significant values of p ⁇ 0.05 are denoted by *, and very significant values of p ⁇ 0.01 are denoted by **.
  • Huh7.5 cells were plated in 96-well plates (2 ⁇ 10 4 / well) together with polybrene (8 ⁇ g / ml) (Sigma-Aldrich co. Was used.
  • TCID 50 was calculated using the Reed-Muench equation (Reed LJ, Muench H. A simple method of estimating fifty percent endpoints. The Am J Hyg 1938; 27: 493-7).
  • MERS-CoV S protein expressed by MERS-PV was measured by neutralizing assay using plasma of patients recovered and diagnosed with MERS-CoV.
  • Patient plasma was prepared by mixing serial dilutions (1:10 to 1: 5120), mixing with MERS-PV, incubating for 2 hours, adding to Huh7.5 cells with polybrene (8 ug / ml) , And cultured for 2 hours. After 2 hours, fresh medium was added to the cells, and after further incubation for 70 hours, RLU was measured by the method described above. This is to confirm whether MERS-PV can be used as a substitute for MERS-CoV. Plasma of patients diagnosed with MERS-CoV expression of S protein (spike protein) from MERS-PV is used.
  • FIG. 2 is a graph showing the results of neutralization antibody analysis (neutralization) of MERS-PV by plasma of a MERS-CoV patient, and the data are expressed as mean and standard deviation.
  • the plasma dilution ratio is 1: 1280 or more.
  • the dilution ratio of the plasma is preferably 1: 1000 to 1: 5500.
  • neutralization activity was not detected in the control medium containing no plasma. It is confirmed that MERS-PV can replace MERS-CoV.
  • &quot MERS-PV " expressing the S protein (spike protein) of MERS-CoV and the luciferase reporter gene of the digested product for a large amount of screening process capable of detecting an active ingredient against mers ).
  • Plasmids required for vector production were obtained from Dr Barney S. Graham of the National Institutes of Health in Bethesda, Maryland. (PVRC5601 12-09 luciferase) encoding Env-deficient HIV-1, a second plasmid vector (pVRC4766 MERS S TM Korea 002) with MERS-CoV S protein and an envelope packaging third plasmid vector (pVRC5602 polymerase).
  • 293TN cells were inoculated into a T175 tissue culture flask and incubated overnight to obtain a single layer of 293 TN cells.
  • 17.5 ⁇ g of the first plasmid (pVRC5601), 17.5 ⁇ g of the second plasmid (pVRC5602) and 1 ⁇ g of the third plasmid (pVRC4766) were simultaneously transfected using a jetprime transfection solution (Polyplus transfection, Illkirch, France) Lt; / RTI > for 48 hours.
  • the supernatant was recovered by centrifugation, and then filtered using a 0.45 ⁇ m filter (Millipore, Darmstadt, Germany). Then, using Wellprot virus concentrating reagent (Welgene, Gyeongsan, Gyeongsangbuk-do, Republic of Korea) 10 fold concentrated.
  • BALD-pseudovirus lacking S protein of MERS-CoV prepared by transfection with only the first plasmid (pVRC5601) and the second plasmid (pVRC5602) was used.
  • the positive control group also expresses the G protein of the bovine stomatitis virus prepared by co-transfection with a plasmid (pCMV VSV-G), a first plasmid (pVRC5601) and a second plasmid (pVRC5602) (Hereinafter also referred to as " VSV-PV ") was used.
  • pCMV VSV-G plasmid
  • pVRC5601 first plasmid
  • pVRC5602 second plasmid
  • MERS-PV a pseudovirus that expresses the S protein produced through the above-described procedures
  • MERS-PV a pseudovirus that expresses the S protein produced through the above-described procedures
  • the host cell was treated with 2 ⁇ 10 4 / the infection rate of the MERS-PV (50 ⁇ l) was 1209 ⁇ 35 RLU
  • the infection rate of VSV-PV (positive control) was 12884 ⁇ 442 RLU
  • BALD-PV negative control
  • Huh7.5 cells are inoculated into 96-well plates (1 ⁇ 10 4 / well) and cultured at 37 ° C for 18 hours to prepare Huh7.5 cells.
  • 60 ⁇ l of each of 502 test compound solutions (1 ⁇ g / ml concentration) and 60 ⁇ l of MERS-PV having 2000 TCID 50 / ml were mixed in separate 96-well plates and cultured at 37 ° C. for 2 hours, .
  • 100 ⁇ l of each of the above mixed solutions and 100 ⁇ l of polybrene (8 ⁇ g / ml) are added to the previously prepared Huh7.5 cells and cultured at 37 ° C for 2 hours.
  • Fresh DMEM10 100 [mu] l was added and infected cells were incubated for 70 hours.
  • the positive control group was mixed with the same amount of assay medium and MERS-PV
  • the negative control group was the same amount of assay medium mixed with BALD-PV.
  • the relative infection rate (%) of MERS-PV of the culture solution cultured through the above-mentioned procedure is measured, and only the compounds satisfying the appropriate level among these results are firstly selected. At this time, the relative infectivity (%) is calculated by the following equation (1).
  • Relative infectivity (%) (RLU of test compound - RLU of negative control) / (RLU of positive control) x 100
  • the ten compounds selected through the above-mentioned Experimental Example 1 were repeatedly carried out in the same procedure, and the relative infection rate (%) of 9 compounds with MERS-PV and luciferase assay, VSV-PV relative infection rate (%) And cell viability (%) are measured, and a compound satisfying an appropriate level among these results is secondarily selected.
  • the relative infectivity (%) is calculated through Equation (1).
  • Cell viability is analyzed with a CellTiterGlo kit (Promega) according to the manufacturer's instructions and measured with a luminometer.
  • this additional screening process is referred to as a secondary screening process.
  • the compounds of Formulas 1 and 2 are administered at various concentrations (0.25, 0.5, 1, 2 and 4 / / ml), and in parallel with the compound of Formulas 1, 2 and 3 without addition of pseudovirus (%) ≪ / RTI > The experiment is repeated three times.
  • Huh7.5 cells are seeded in 96-well plates (2x10 4 / well) and cultured at 37 ° C for 18 hours. Add 50 ⁇ l of the selected compound solution (1 ⁇ g / ml) and 50 ⁇ l of MERS-PV with 2000 TCID50 / ml and continue culturing at 37 ° C for 2 hours. Then, fresh DMEM10 medium (100 ⁇ ⁇ ) is added and cultured at 37 ⁇ ⁇ for 70 hours. In this experiment, the positive control group was mixed with the same amount of assay medium and VSV-PV, and the negative control group was the same amount of assay medium mixed with BALD-PV. Cell viability is analyzed with a CellTiterGlo kit (Promega) according to the manufacturer's instructions and measured with a luminometer.
  • a CellTiterGlo kit Promega
  • the compound represented by formula 2 inhibited the infectivity of MERS-PV by 50% or more, inhibited the infectivity of VSV-PV by less than 20% at a concentration of 1 ⁇ g / ml or more, (%) At a concentration of less than 90% (Fig. 3a).
  • the compound represented by the formula (1) inhibited the infectivity of MERS-PV by 50% or more at a concentration of 1 ⁇ g / ml or more and suppressed the infectivity of VSV-PV by less than 10% at a concentration of less than 4 ⁇ g / (%) (FIG. 3B).
  • MERS-PV is added to pre-cultured Huh7.5 cells. After 2 hours, the final selected compounds (1 / / ml) represented by formulas 1 and 2 are added.
  • FIG. 4 is a graph showing the MERS-PV adsorption blocking effect of a compound represented by the formula 1 (b) (E-64-C) and dihydrotanshinone (a)
  • a dihydrotanshinone
  • the final selected compounds were treated with MERS-PV-adhered host cells (pre-attachment assay, post-attachment, circle dots), treated with MERS-PV simultaneously with host cells, (Simultaneous cell adhesion assay; during-attachment).
  • the compound is mixed with MERS-PV and cultured for 2 hours and then treated with host cells (pre-attachment, horizontal stripes).
  • the relative infection rate (%) was significantly higher than before (adherent cell adhesion assay) or adherent (simultaneous cell adhesion ability).
  • the experiment was carried out in total of three iterations, and the data were expressed as mean and standard deviation.
  • the relative infection rate (%) of MERS-PV treated with each compound was different before and after attachment. Specifically, the relative infection rate (%) was 80% in the analysis of posterior cell adhesiveness, the relative infection rate (%) was 50% in the pre-cell adhesion ability analysis and the relative infection rate (%) was less than 50% .

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Abstract

La présente invention concerne une composition pharmaceutique destinée à prévenir ou à traiter le syndrome respiratoire du Moyen-Orient (MERS) et un agent de prévention de l'adsorption du coronavirus du syndrome respiratoire du Moyen-Orient (MERS-CoV), et peut empêcher ou traiter efficacement le syndrome respiratoire du Moyen-Orient en inhibant une infection par le coronavirus du syndrome respiratoire du Moyen-Orient par l'intermédiaire d'un mécanisme d'adsorption intracellulaire.
PCT/KR2018/005761 2017-07-28 2018-05-21 Composition pharmaceutique pour prévenir ou traiter le syndrome respiratoire du moyen-orient WO2019022357A1 (fr)

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WO2023272571A1 (fr) * 2021-06-30 2023-01-05 中国人民解放军军事科学院军事医学研究院 Utilisation médicale d'un dérivé de 2,3-époxysuccinyle

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Publication number Priority date Publication date Assignee Title
WO2023272571A1 (fr) * 2021-06-30 2023-01-05 中国人民解放军军事科学院军事医学研究院 Utilisation médicale d'un dérivé de 2,3-époxysuccinyle

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