WO2021215517A1 - 新型コロナウイルス感染症（ｃｏｖｉｄ－１９）の治療及び／又は予防剤 - Google Patents

新型コロナウイルス感染症（ｃｏｖｉｄ－１９）の治療及び／又は予防剤 Download PDF

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WO2021215517A1
WO2021215517A1 PCT/JP2021/016372 JP2021016372W WO2021215517A1 WO 2021215517 A1 WO2021215517 A1 WO 2021215517A1 JP 2021016372 W JP2021016372 W JP 2021016372W WO 2021215517 A1 WO2021215517 A1 WO 2021215517A1
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covid
therapeutic
inhibitor
ala
coronavirus infection
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French (fr)
Japanese (ja)
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潔 北
公一 森田
二朗 安田
康晃 櫻井
聡史 河田
田中　徹
基康 富岡
清考 藤根
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Nagasaki University NUC
Neopharma Japan Co Ltd
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Nagasaki University NUC
Neopharma Japan Co Ltd
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Priority to US17/920,703 priority Critical patent/US20230190690A1/en
Priority to EP21792108.9A priority patent/EP4140479A4/en
Priority to JP2022517104A priority patent/JPWO2021215517A1/ja
Priority to CN202180029760.3A priority patent/CN115768415A/zh
Publication of WO2021215517A1 publication Critical patent/WO2021215517A1/ja
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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention relates to a therapeutic and / or prophylactic agent for a new coronavirus infection (COVID-19), and more particularly to a new coronavirus infection containing 5-aminolevulinic acid (5-ALA) or a derivative thereof or a salt thereof.
  • COVID-19 treatment and / or preventive agent and treatment and / or prevention of new coronavirus infection (COVID-19) using the same.
  • the new coronavirus infection (COVID-19) is a new type of pneumonia caused by the new coronavirus (SARS-CoV-2), which was reported in December 2019.
  • the new coronavirus (SARS-CoV-2) is a newly identified virus that has similarities to SARS-CoV that causes severe acute respiratory syndrome (SARS).
  • the new coronavirus infection (COVID-19) has a wide range of symptoms such as pneumonia, fever, cough, shortness of breath, dyspnea, chills, chills, muscle pain, headache, sore throat, taste disorder, or olfactory disorder. It is known to cause symptoms.
  • the number of patients with coronavirus infection (COVID-19) is increasing rapidly around the world, with more than 150,000 reported deaths.
  • Non-Patent Document 1 Non-Patent Document 1
  • Non-Patent Documents 3 and 4 the development of more effective therapeutic agents is eagerly desired.
  • 5-ALA is a common precursor of heme compounds produced in intracellular mitochondria, and 5-ALA, which is ultimately converted from protoporphyrin (PPIX) to heme, is a specific inflammatory disease. It is known that it has an anti-inflammatory effect on. In addition, it is known that PPIX accumulates in some cancer cells due to inhibition of conversion from PPIX to heme, and studies are being conducted to visualize cancer cells using the accumulated PPIX (non-patent documents). 2). However, 5-ALA and its derivatives can suppress infection, proliferation and / or viral protein expression of the new coronavirus (SARS-CoV-2) and treat or prevent the new coronavirus infection (COVID-19). Also, it was not known that the combined use of PPIX excretion inhibitor enhances the therapeutic or preventive effect.
  • SARS-CoV-2 new coronavirus
  • Non-Patent Document 1 Cell Research, 2020, Vol. 30, pp. 269-271 Scientific Reports, 2019, Vol. 9, pp. no. 8666, doi: https: // doi. org / 10.1038 / s41598-019-44981-y Review in Medical History. 2021 Mar 16. doi: 10.1002 / rmv. 2231 "Correspondence to new coronavirus infection (mutant strain)" Ministry of Health, Labor and Welfare (URL: https://www.mhlw.go.jp/content/10900000/000766545.pdf, access date: April 20, 2021)
  • An object of the present invention is to provide a therapeutic and / or preventive agent for a new type of coronavirus infection (COVID-19). More specifically, it is to provide a therapeutic and / or preventive agent for a new type of coronavirus infection (COVID-19) containing 5-ALA or a derivative thereof or a salt thereof. Another aspect is to provide a method for treating and / or preventing a new type of coronavirus infection (COVID-19) using 5-ALA or a derivative thereof or a salt thereof.
  • the subject of the present invention is a method for treating and / or preventing a new type of coronavirus infection (COVID-19) by using 5-ALA or a derivative thereof or a salt thereof in combination with a PPIX excretion inhibitor, and the treatment thereof. And / or to provide a drug for use for prophylaxis.
  • the present invention uses 5-ALA or a derivative thereof or a salt thereof, preferably in combination with a PPIX excretion inhibitor, to infect, proliferate and proliferate the new coronavirus (SARS-CoV-2). / Or a method for suppressing the expression of a viral nucleic acid or protein, and a medicament for use in the method are provided.
  • the present inventors have, quite surprisingly, the new coronavirus (SARS-CoV-) in which 5-ALA is the causative virus of the new coronavirus infection (COVID-19). 2) It was found that it suppresses infection, proliferation and / or viral protein expression, treats or prevents COVID-19, and further finds that it has a synergistically excellent effect when used in combination with a PPIX excretion inhibitor.
  • SARS-CoV- the new coronavirus in which 5-ALA is the causative virus of the new coronavirus infection (COVID-19).
  • 5-ALA is a common precursor of heme compounds produced in intracellular mitochondria. It has been known that 5-ALA has an anti-inflammatory effect on specific inflammatory diseases, but 5-ALA and its derivatives are infected with the new coronavirus (SARS-CoV-2), propagated and / or It was not known that it could suppress viral protein expression and treat or prevent Severe Acute Respiratory Syndrome (COVID-19).
  • SARS-CoV-2 new coronavirus
  • COVID-19 Severe Acute Respiratory Syndrome
  • the present invention newly provides a medicament containing 5-ALA and a derivative thereof and its use for treating or preventing a new type of coronavirus infection (COVID-19).
  • the present inventors have achieved extremely excellent new coronavirus infection (COVID-19) by using a combination of 5-ALA and a metal-containing compound such as sodium ferrous citrate (SFC). It has also been found that a therapeutic or preventive effect can be obtained.
  • COVID-19 new coronavirus infection
  • SFC sodium ferrous citrate
  • the present invention provides the following.
  • a therapeutic and / or prophylactic agent for a new type of coronavirus infection (COVID-19) containing the compound indicated by or a salt thereof.
  • a therapeutic and / or preventive agent for a new type of coronavirus infection (COVID-19) according to item 1 or 2, which comprises one or more metal-containing compounds.
  • the metal-containing compound is a compound containing iron, magnesium, zinc, nickel, vanadium, copper, chromium, molybdenum or cobalt. / Or a preventive agent.
  • the metal-containing compound is a compound containing iron, magnesium or zinc.
  • R 1 represents a hydrogen atom or an acyl group
  • R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group.
  • the therapeutic and / or prophylactic agent for the new coronavirus infection (COVID-19) of the present invention strongly suppresses viral cell infection or proliferation, expression or aggregation of viral capsid proteins, and / or release of viral particles. By doing so, it suppresses the increase of infected cells and exerts an excellent therapeutic and / or preventive effect on new coronavirus infection (COVID-19).
  • the method and the medicament used for the treatment and / or prevention have the effect of providing the treatment and / or prevention of new coronavirus infection (COVID-19).
  • FIG. 1 is a graph showing the effects of 5-ALA and FTC on SARS-CoV-2 infection in VeroE6 cells.
  • FIG. 2 is a graph showing the effects of 5-ALA and FTC on SARS-CoV-2 infection in VeroE6 cells.
  • FIG. 3 is a graph showing the effects of 5-ALA or 5-ALA and SFC on SARS-CoV-2 infection in Caco-2 cells.
  • FIG. 4 is a graph showing the effects of 5-ALA or 5-ALA and SFC on SARS-CoV-2 infection in Caco-2 cells.
  • FIG. 5 is a graph showing the concentration-dependent infection inhibitory effect and cytotoxic effect of 5-ALA, 5-ALA and SFC, and SFC alone application on SARS-CoV-2 infection in VeroE6 cells.
  • FIG. 6 is a graph showing the concentration-dependent infection inhibitory effect and cytotoxic effect of 5-ALA, 5-ALA and SFC, and SFC alone application on SARS-CoV-2 infection in Caco-2 cells.
  • mutant strain with mutation of N501Y includes a mutant strain confirmed in the United Kingdom (VOC-2012 / 01), a mutant strain confirmed in South Africa (501Y.V2), and a mutant strain confirmed in Brazil (VOC).
  • 501Y.V3 and mutants confirmed in the Philippines are mentioned
  • mutant with E484K mutation includes mutants confirmed in South Africa (501Y.V2) and mutants confirmed in Brazil. Examples include, but are not limited to, mutant strains identified in (501Y.V3) and the Philippines.
  • the active ingredient of the therapeutic and / or preventive agent for the new coronavirus infection (COVID-19) of the present invention, and the protein expression inhibitor of the new coronavirus (SARS-CoV-2) is represented by the formula (I). It can be exemplified as the indicated compound or a salt thereof (hereinafter, these may be collectively referred to as “ALA”).
  • 5-ALA which is also called ⁇ -aminolevulinic acid
  • R 1 and R 2 of the formula (I) are both hydrogen atoms, and is one of the amino acids.
  • R 1 of the formula (I) is a hydrogen atom or an acyl group
  • R 2 of the formula (I) is a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl.
  • Compounds other than the underlying 5-ALA can be mentioned.
  • acyl group in the formula (I) examples include linear or branched alkanoyl groups having 1 to 8 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl and benzylcarbonyl groups. , Benzoyl, 1-naphthoyl, 2-naphthoyl group and other aroyl groups having 7 to 14 carbon atoms can be mentioned.
  • the alkyl group in the formula (I) may be a linear or branched group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl groups.
  • Alkyl groups having 1 to 8 carbon atoms can be mentioned.
  • cycloalkyl group in the formula (I) a saturated or partially unsaturated bond such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, 1-cyclohexenyl group may be present.
  • Cycloalkyl groups having 3 to 8 carbon atoms can be mentioned.
  • Examples of the aryl group in the formula (I) include an aryl group having 6 to 14 carbon atoms such as a phenyl, naphthyl, anthryl, and phenanthryl group.
  • the aryl moiety can be exemplified in the same manner as the above aryl group, and the alkyl moiety can be exemplified in the same manner as the above alkyl group.
  • Trityl, naphthylmethyl, naphthylethyl group and other aralkyl groups having 7 to 15 carbon atoms can be mentioned.
  • a compound in which R 1 is a formyl, acetyl, propionyl, butyryl group or the like, or a compound in which R 2 is a methyl, ethyl, propyl, butyl, pentyl group or the like is preferable, and the above R Compounds in which the combination of 1 and R 2 is a combination of formyl and methyl, acetyl and methyl, propionyl and methyl, butyryl and methyl, formyl and ethyl, acetyl and ethyl, propionyl and ethyl, and butyryl and ethyl can be preferably mentioned. can.
  • the 5-ALAs may act as an active ingredient in the state of 5-ALA of the formula (I) or a derivative thereof in vivo, and various salts, esters, etc. for increasing solubility may be used depending on the form of administration. Alternatively, it may be administered as a prodrug (precursor) that is decomposed by an enzyme in the living body.
  • the salt of 5-ALA and its derivative include a pharmacologically acceptable acid addition salt, metal salt, ammonium salt, organic amine addition salt and the like.
  • Examples of the acid addition salt include hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate and other inorganic acid salts, formate, acetate, propionate and toluenesulfonic acid. Salt, succinate, oxalate, lactate, tartrate, glycolate, methanesulfonate, butyrate, valerate, citrate, fumarate, maleate, malate, etc.
  • Organic acid addition salts can be exemplified.
  • Examples of the metal salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, and metal salts such as aluminum and zinc.
  • ammonium salt examples include alkylammonium salts such as ammonium salt and tetramethylammonium salt.
  • organic amine salt examples include each salt such as triethylamine salt, piperidine salt, morpholine salt, and toluidine salt. These salts can also be used as a solution at the time of use.
  • 5-ALA and various esters such as 5-ALA methyl ester, 5-ALA ethyl ester, 5-ALA propyl ester, 5-ALA butyl ester and 5-ALA pentyl ester.
  • these hydrochlorides, phosphates, sulfates, and ALA hydrochlorides, 5-ALA phosphates can be particularly preferably exemplified.
  • the above ALAs can be produced by any known method of chemical synthesis, production by microorganisms, and production by enzymes.
  • the above ALAs may form a hydrate or a solvate, and either one may be used alone or two or more thereof may be used in combination as appropriate.
  • the therapeutic and / or preventive agent for the novel coronavirus infection (COVID-19) of the present invention and the new coronavirus (SARS-CoV-2) protein expression inhibitor are further metal-containing compounds as long as they do not cause excess disease.
  • the metal portion of the metal-containing compound include iron, magnesium, zinc, nickel, vanadium, cobalt, copper, chromium and molybdenum, with iron, magnesium and zinc being preferred, among others. Iron can be preferably exemplified.
  • the new coronavirus (SARS-CoV-2) infection, proliferation and / or viral protein expression inhibitory effect, and an excellent new corona A therapeutic and / or preventive effect on viral infection (COVID-19) can be obtained.
  • the iron compound may be an organic salt or an inorganic salt
  • examples of the inorganic salt include ferric chloride, iron sesquioxide, iron sulfate, and ferrous pyrophosphate
  • examples of the organic salt are carboxylates.
  • magnesium compound examples include magnesium citrate, magnesium benzoate, magnesium acetate, magnesium oxide, magnesium chloride, magnesium hydroxide, magnesium carbonate, magnesium sulfate, magnesium silicate, magnesium nitrate, diethylenetriamine pentamagnesium diammonate, and ethylenediamine tetraacetate.
  • magnesium disodium and magnesium protoporphyrin examples include magnesium disodium and magnesium protoporphyrin.
  • Examples of the zinc compound include zinc chloride, zinc oxide, zinc nitrate, zinc carbonate, zinc sulfate, diethylenetriamine diammonium pentaacetate, disodium ethylenediamine tetraacetate, zinc protoporphyrin, and zinc-containing yeast.
  • the metal-containing compound one type or two or more types can be used, respectively, and the dose of the metal-containing compound may be 0 to 100 times the molar ratio of 5-ALA, which is 0. It is preferably 0.01 to 10 times, more preferably 0.1 to 8 times.
  • the therapeutic and / or prophylactic agent for the new coronavirus infection (COVID-19) of the present invention can be used in combination with other antiviral agents and other disease therapeutic agents as long as it does not cause excess disease.
  • the dose of these other agents and the ratio to the dose of 5-ALA can be appropriately adjusted by those skilled in the art.
  • the ALAs of the present invention are preferably used in combination with a PPIX emission inhibitor.
  • a PPIX excretion inhibitor a transporter inhibitor or an exocytosis inhibitor can be used, and these include, for example, a multidrug-resistant transporter inhibitor such as an ABCG2 inhibitor, a dynamine inhibitor, a chelating agent, and vitamin D.
  • Activators can be used.
  • the specific PPIX emission inhibitor used in the present invention is not particularly limited. Examples include ABCG2 inhibitors, chelators, and vitamin D activators. Chelating agents can be used to increase the accumulation of PpIX in cells, for example, WO2014 / 2023833, Photochem Photobiol. 2010, Vol. 86, no. 2, pp. 471-475. In addition, vitamin D activators can be used to increase the amount of PpIX accumulated in cells, for example, Cancer Res, 2011, Vol, 71, no. 18, pp. 6040-6050.
  • ABCG2 inhibitors that can be optionally used in the present invention include, for example, Int J Biochem Mol Biol, 2012, Vol. 3, no. 1, pp. Compounds described in Table 3 and Table 4 of 1-27, Chin J Cancer, 2012, Vol. 31, no. 2, The compound described in Table 2 on p75-99, topoisomerase II inhibitor (Mitoxantrone, Bisantrine, Etopocide, Becatecarin, NB-506, J-107088, etc.); .
  • Sorafenib, Tandutinib, CI1033 Pan-HER TKI), CP-724,714 (HER2 TKI), Systemex (fms-like tyrosine kinase 3 inhibitor), etc.); Tomudex (antifolates), Trimetrexatte, piritrexim, metoprine, pyrimethamine (lipophilic antifolates), 5-fluorouracil (pyrimidine analog), CdAMP (nucleotide), such as cladribine (nucleoside)); such cyclin-dependent kinase inhibitor (Flavopiridol); CDK and aurora Kinases inhibitor (JNJ-7706621, etc.); non-steroidal anti-androgen (Bicalutamide, etc.); PEITC (Phenethyl isothinocynate, etc.); indazole-baseTyrosine (Tubisite) and glucuronide conjugates of xenobiotics
  • the PPIX excretion inhibitor one type or two or more types can be used, respectively, and the dose of the PPIX excretion inhibitor can be appropriately selected according to the desired therapeutic effect, for example, administration of 5-ALA.
  • a dose of 0 to 10000 times, preferably 0.0 to 1000 times, more preferably 1 to 300 times, still more preferably 10 to 100 times the molar ratio can be used.
  • ALAs, PPIX emission inhibitors, metal-containing compounds or other agents are all of these. It can be administered as a composition containing, or as a composition containing each of them alone or only a part thereof. In one embodiment, when a composition containing ALAs and other drugs alone or only a part thereof is used, these may be administered at the same time or separately.
  • the ALAs and other agents can be administered in combination so that they can exert an additive or synergistic effect.
  • the administration intervals are 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1
  • the time can be set to, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, etc., but is not limited thereto.
  • the route of administration of the new coronavirus infection (COVID-19) of the present invention and / or the preventive agent is not particularly limited, but is oral administration, inhalation administration, injection, intravenous administration by infusion, transdermal administration, suppository, etc.
  • parenteral administration such as administration by forced enteral nutrition using a nasogastric tube, a nasogastric tube, a gastric fistula tube, or an intestinal fistula tube can be used.
  • the dosage form of the therapeutic and / or preventive agent for the new coronavirus infection (COVID-19) of the present invention can be appropriately determined according to the above-mentioned administration route, but is an injection, a drip, a tablet, or a capsule. , Fine granules, powders, liquids, liquids dissolved in syrups, poultices, suppositories and the like.
  • Pharmacologically acceptable carriers, excipients, diluents, additives, as needed, to prepare therapeutic and / or prophylactic agents for the novel coronavirus infection (COVID-19) of the present invention Disintegrants, binders, coatings, lubricants, gliding agents, lubricants, flavoring agents, sweeteners, solubilizers, solvents, gelling agents, nutritional agents, etc. can be added. Ingredients can be selected according to the purpose.
  • the dose, frequency, and duration of the new coronavirus infection (COVID-19) of the present invention and / or the preventive agent are the types of animals for which the new coronavirus infection (COVID-19) is to be treated or prevented.
  • the dose of ALA is 0.01-200 mg / kg body weight / day, preferably 0.5- in terms of 5-ALA weight. 100 mg / kg body weight / day, more preferably 1-50 mg / kg body weight / day, even more preferably 5-30 mg / kg body weight / day, with continued low doses, especially when used as a prophylactic agent. It is desirable to take it.
  • 0.1-30 mg / kg body weight / day when administered as a prophylactic supplement, 0.1-30 mg / kg body weight / day, preferably 0.3 to 10 mg / kg body weight / day, more preferably 1.0 to 5 mg / kg body weight / day, etc. It can be administered at a dose.
  • the frequency of administration may be exemplified by administration once to a plurality of times a day or continuous administration by infusion or the like.
  • the duration of administration as a therapeutic or prophylactic agent can be determined by a method known by a specialist in the art such as a doctor.
  • the treatment and / or preventive agent for the new coronavirus infection (COVID-19) of the present invention causes the infection of the new coronavirus (SARS-CoV-2) and / or the onset of the new coronavirus infection (COVID-19). It can be applied to the treatment and prevention of various symptoms that occur as. Such symptoms may include, but are not limited to, pneumonia, fever, cough, shortness of breath, dyspnea, chills, chills tremors, muscle pain, headache, sore throat, dysgeusia, or olfactory dysfunction. ..
  • the therapeutic and / or preventive agent for the new coronavirus infection (COVID-19) of the present invention is administered to humans, monkeys, dogs, cats, minks, cows, pigs and their related animals, other mammals, birds and the like. can do.
  • VeroE6 derived from African green monkey kidney was obtained from Dr. Takada of Hokkaido University.
  • Caco-2 cells derived from human colon cancer were obtained from Dr. Iida of Osaka University.
  • VeroE6 cells from African green monkey kidneys were cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% Fetal Bovine Serum (FBS) and 1% penicillin / streptomycin solution. Caco-2 cells were also cultured in the same manner.
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS Fetal Bovine Serum
  • Caco-2 cells were also cultured in the same manner.
  • 5-Aminolevulinic acid (5-ALA) hydrochloride is prepared in 100 mM solution with pure water, sodium ferrous citrate (SFC) is prepared in 25 mM solution with pure water and 1N HCl, fumitremorgin C (FTC). was prepared to 5 mM with DMSO and diluted with DMEM for each experiment.
  • SFC sodium ferrous citrate
  • FTC fumitremorgin C
  • Virus SARS-CoV-2 used in this experiment was isolated from infected individuals in Japan (A JPN / NGS / IA-1 / 2020, GISAID accession no. EPI-ISL-481251).
  • British strain QK002 hCoV-19 / Japan / QK002 / 2020, GISAID ID: EPI_ISL_768526
  • British strain QHN001 hCoV-19 / Japan /
  • the virus was subcultured using VeroE6 cells, cultured for 3 to 4 days, then the culture supernatant was collected, centrifuged at 2000 xg for 15 minutes, and the supernatant was stored at -80 ° C and thawed for each experiment. Used later. All infection experiments using this virus were carried out in the BSL3 laboratory owned by Nagasaki University.
  • Drug efficacy evaluation test (a) Test using VeroE6 cells VeroE6 cells VeroE6 cells were seeded on a 96-well plate at a density of 0.5x10 ⁇ 4 cells / well, and after the cells adhered to the bottom of the plate, each drug was added to the medium.
  • the test agents include 5-ALA (1000uM), 5-ALA (1000uM) + FTC (10uM), 5-ALA (1000uM) + SFC (250uM), 5-ALA (1000uM) + SFC (250uM) + FTC (10uM), FTC. (10uM) was used. After the drug was added, the cells were cultured at 37 ° C. for 48 hours or 72 hours. It was then infected with SARS-CoV-2 in the BSL3 laboratory.
  • infected cells Forty-eight hours after the start of infection, infected cells were immersed in 4% paraformaldehyde (PFA) overnight to fix the cells and inactivate the virus. Further, the cells were permeabilized with 0.2% Triton X-100, blocked with 10% goat serum, treated with primary antibody with rabbit anti-SARS-CoV antibody, and subjected to Alexa Fluor 488 goat antibody-rabbit. The cells were treated with a secondary antibody and stained with Hoechst 33342. Then, an image of the infected cells was taken using a Cytation 5-cell imaging plate reader (BioTek).
  • the images were analyzed using CellProfiler image analysis software (Broad Institute, MIT), the number of infected cells and the total number of cells were calculated, and graphs were created and statistically processed using GraphPad Prism (MDF).
  • MDF GraphPad Prism

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PCT/JP2021/016372 2020-04-22 2021-04-22 新型コロナウイルス感染症（ｃｏｖｉｄ－１９）の治療及び／又は予防剤 Ceased WO2021215517A1 (ja)

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WO2024210119A1 (ja) * 2023-04-03 2024-10-10 国立大学法人 長崎大学 化学感覚障害の予防又は治療用組成物

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000510123A (ja) * 1996-05-08 2000-08-08 ニューヨーク・ブラッド・センター・インコーポレイテッド ウイルス感染の治療方法
WO2004069233A1 (ja) 2003-02-04 2004-08-19 Kabushiki Kaisha Yakult Honsha 乳癌耐性蛋白阻害剤
WO2004069243A1 (ja) 2003-02-04 2004-08-19 Kabushiki Kaisha Yakult Honsha 乳癌耐性蛋白（ｂｃｒｐ）阻害剤
WO2006106778A1 (ja) 2005-03-30 2006-10-12 Kabushiki Kaisha Yakult Honsha Ｂｃｒｐ／ａｂｃｇ２阻害剤
WO2009072267A1 (ja) 2007-12-03 2009-06-11 Kabushiki Kaisha Yakult Honsha Ａｂｃｇ２阻害剤
WO2014013664A1 (ja) * 2012-07-19 2014-01-23 Ｓｂｉファーマ株式会社 インフルエンザウイルス感染症の予防・治療剤
WO2014202383A1 (en) 2013-06-18 2014-12-24 Nestec S.A. Filter unit for a capsule
WO2020218577A1 (ja) * 2019-04-26 2020-10-29 ネオファーマジャパン株式会社 フラビウイルス感染症治療剤

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HK1246682A1 (en) * 2015-04-10 2018-09-14 Sbi Pharmaceuticals Co., Ltd. Prophylactic/therapeutic agent for virus infections which comprises ala compound
US10987329B1 (en) 2020-04-22 2021-04-27 Nadimpally Satyavarahala Raju Combination therapy for coronavirus infections including the novel corona virus (COVID-19)
US11883376B2 (en) 2020-04-22 2024-01-30 Nadimpally Satyavarahala Raju Viral infection treatment with 5-aminolevulinic acid

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000510123A (ja) * 1996-05-08 2000-08-08 ニューヨーク・ブラッド・センター・インコーポレイテッド ウイルス感染の治療方法
WO2004069233A1 (ja) 2003-02-04 2004-08-19 Kabushiki Kaisha Yakult Honsha 乳癌耐性蛋白阻害剤
WO2004069243A1 (ja) 2003-02-04 2004-08-19 Kabushiki Kaisha Yakult Honsha 乳癌耐性蛋白（ｂｃｒｐ）阻害剤
WO2006106778A1 (ja) 2005-03-30 2006-10-12 Kabushiki Kaisha Yakult Honsha Ｂｃｒｐ／ａｂｃｇ２阻害剤
WO2009072267A1 (ja) 2007-12-03 2009-06-11 Kabushiki Kaisha Yakult Honsha Ａｂｃｇ２阻害剤
WO2014013664A1 (ja) * 2012-07-19 2014-01-23 Ｓｂｉファーマ株式会社 インフルエンザウイルス感染症の予防・治療剤
WO2014202383A1 (en) 2013-06-18 2014-12-24 Nestec S.A. Filter unit for a capsule
WO2020218577A1 (ja) * 2019-04-26 2020-10-29 ネオファーマジャパン株式会社 フラビウイルス感染症治療剤

Non-Patent Citations (24)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "History of Changes for Study: NCT04542850", CLINICALTRIALS.GOV ARCHIVE, 6 September 2020 (2020-09-06), XP055867952, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/history/NCT04542850?V_1=View#StudyPageTop> [retrieved on 20211201] *
BIOCHEM. BIOPHYS. REP., vol. 11, 2017, pages 105 - 111
CANCER RES, vol. 71, no. 18, 2011, pages 6040 - 6050
CELL RESEARCH, vol. 30, 2020, pages 269 - 271
CHIN J CANCER, vol. 31, no. 2, 2012, pages 75 - 99
GU CHENJIAN, WU YANG, GUO HUIMIN, ZHU YUANFEI, XU WEI, WANG YUYAN, ZHOU YU, SUN ZHIPING, CAI XIA, LI YUTANG, LIU JING, HUANG ZHONG: "Protoporphyrin IX and verteporfin potently inhibit SARS-CoV-2 infection in vitro and in a mouse model expressing human ACE2", SCIENCE BULLETIN, ZHONGGUO KEXUE ZAZHISHE, CN, vol. 66, no. 9, 1 May 2021 (2021-05-01), CN , pages 925 - 936, XP055867921, ISSN: 2095-9273, DOI: 10.1016/j.scib.2020.12.005 *
INT J BIOCHEM MOL BIOL, vol. 3, no. 1, 2012, pages 1 - 27
INT. J. CANCER, vol. 108, 2004, pages 146 - 151
ITO, HIDENORI ET AL.: "Oral administration of 5-aminolevulinic acid induces heme oxygenase-1 expression in peripheral blood mononuclear cells of healthy human subjects in combination with ferrous iron", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 833, 2018, pages 25 - 33, XP055759241, DOI: 10.1016/j.ejphar.2018.05.009 *
JIMMY SUSANTO, YU-HSING LIN, YUN-NAN CHEN, CHIA-RUI SHEN, YU-TING YAN, SHENG-TA TSAI, CHUNG-HSUAN CHEN, CHIA-NING SHEN: "Porphyrin Homeostasis Maintained by ABCG2 Regulates Self-Renewal of Embryonic Stem Cells", PLOS ONE, vol. 3, no. 12, pages e4023, XP055320025, DOI: 10.1371/journal.pone.0004023 *
MOL. CANCER THER., vol. 1, 2002, pages 417 - 425
MOL. CANCER THER., vol. 2, 2003, pages 105 - 112
PHOTOCHEM PHOTOBIOL, vol. 86, no. 2, 2010, pages 471 - 475
REVIEW IN MEDICAL VIROLOGY, 16 March 2021 (2021-03-16)
ROSSI, MAXIME ET AL.: "Heme oxygenase-1 (HO-1) cytoprotective pathway: A potential treatment strategy against coronavirus disease 2019 (COVID-19)- induced cytokine storm syndrome", MEDICAL HYPOTHESES, vol. 144, no. 110242, 3 September 2020 (2020-09-03), pages 1 - 4, XP086361066, DOI: 10.1016/j.mehy.2020.110242 *
SAKURAI YASUTERU, NGWE TUN MYA MYAT, KUROSAKI YOHEI, SAKURA TAKAYA, INAOKA DANIEL KEN, FUJINE KIYOTAKA, KITA KIYOSHI, MORITA KOUIC: "5-amino levulinic acid inhibits SARS-CoV-2 infection in vitro", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ELSEVIER, AMSTERDAM NL, vol. 545, 1 March 2021 (2021-03-01), Amsterdam NL , pages 203 - 207, XP055867915, ISSN: 0006-291X, DOI: 10.1016/j.bbrc.2021.01.091 *
SCIENTIFIC REPORTS, vol. 9, no. 8666, 2019
See also references of EP4140479A4
SINGH, DEVENDRA ET AL.: "Heme oxygenase-1 modulation: A potential therapeutic target for COVID-19 and associated complications", FREE RADICAL BIOLOGY AND MEDICINE, vol. 161, 19 October 2020 (2020-10-19), pages 263 - 271, XP086389131, DOI: 10.1016/j.freeradbiomed.2020.10.016 *
TAKANO TOMOMI, SATOH KUMI, DOKI TOMOYOSHI: "Possible Antiviral Activity of 5-Aminolevulinic Acid in Feline Infectious Peritonitis Virus (Feline Coronavirus) Infection", FRONTIERS IN VETERINARY SCIENCE, vol. 8, XP055867919, DOI: 10.3389/fvets.2021.647189 *
THE MINISTRY OF HEALTH, LABOUR AND WELFARE, RESPONSE TO CORONAVIRUS DISEASE 2019 (VARIANTS, 20 April 2021 (2021-04-20), Retrieved from the Internet <URL:https://www.mhlw.go.jp/content/10900000/000766545.pdf>
WU, FAN ET AL.: "A new coronavirus associated with human respiratory disease", CHINA, NATURE, vol. 579, 3 February 2020 (2020-02-03), pages 265 - 269, XP037525882, DOI: 10.1038/s41586-020-2008-3 *
YANG, XUE ET AL.: "Aminolevulinic Acid-Based Tumor Detection and Therapy: Molecular Mechanisms and Strategies for Enhancement", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 16, 2015, pages 25865 - 25880, XP055759593, DOI: 10.3390/ijms161025865 *
ZHAO, MINGYI ET AL.: "5 -Aminolevulinic acid combined with sodium ferrous citrate ameliorates H202-induced cardiomyocyte hypertrophy via activation of the MAPK/Nrf2/HO-1 pathwa y", AM J PHYSIOL CELL PHYSIOL, vol. 308, 2015, pages C665 - C672, XP055759245, DOI: 10.1152/ajpcell.00369.2014 *

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EP4316479A4 (en) * 2021-03-26 2025-03-05 Tokyo Institute of Technology Pharmaceutical composition for suppressing tmprss2 expression

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