WO2021175295A1 - Application d'un composé de myricétine dans la préparation de médicaments pour la prévention et le traitement de la pneumonie à nouveau coronavirus - Google Patents

Application d'un composé de myricétine dans la préparation de médicaments pour la prévention et le traitement de la pneumonie à nouveau coronavirus Download PDF

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WO2021175295A1
WO2021175295A1 PCT/CN2021/079138 CN2021079138W WO2021175295A1 WO 2021175295 A1 WO2021175295 A1 WO 2021175295A1 CN 2021079138 W CN2021079138 W CN 2021079138W WO 2021175295 A1 WO2021175295 A1 WO 2021175295A1
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cov
active ingredient
sars
protease
pharmaceutically acceptable
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PCT/CN2021/079138
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Chinese (zh)
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姚胜
蒋翔锐
许叶春
王震
谢元超
沈敬山
叶阳
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中国科学院上海药物研究所
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the field of medicine, in particular to the application of myricetin compounds in the preparation of drugs for the prevention and treatment of new coronary pneumonia.
  • the new coronavirus (SARS-CoV-2) infection can cause severe pneumonia.
  • the transmission route of SARS-CoV-2 virus is not fully grasped. It is known to be spread through droplets and contact, and there is human-to-human transmission, medical staff infection, a certain risk of community transmission, and the virus may mutate. At present, there is no specific prevention and treatment method for the disease caused by the new coronavirus.
  • the SARS-CoV-2 coronavirus belongs to the genus Coronavirus of the Coronavirus family, and is a single-stranded positive sense RNA virus with an envelope. Similar to other known coronaviruses, SARS-CoV-2 coronavirus also undergoes several processes such as adsorption, penetration, uncoating, biosynthesis, and the assembly and release of progeny viruses to complete the proliferation of progeny viruses.
  • the SARS-CoV-2 coronavirus infection of host cells begins when the spike glycoprotein on the surface of the virus envelope binds to the receptor on the surface of the host cell, and then membrane fusion occurs. The virus enters the host cell and is under the action of cell lysosomes and other organelles.
  • the two major SARS-CoV-2 coronaviruses Essential cysteine proteases: papain-like protease (PL pro ) and 3C-like protease (3C-like protease, 3CL pro ) cleave and process polyprotein precursors at specific sites to produce multiple pairs of viral life A non-structural protein that is very important for the cycle.
  • the viral RNA replicates the nucleic acid material of the progeny virus, and a large number of required structural proteins are translated to complete the assembly and release of the progeny virus.
  • Any link in the life cycle of SARS-CoV-2 coronavirus infected cells or key enzymes can be used as research targets for antiviral drugs, such as the cysteine proteases PL pro and 3CL pro that hydrolyze and cleave polyprotein precursors.
  • RNA polymerase that completes the replication of the genetic material of progeny viruses, etc.
  • 3CL protease (3chymotrypsin-like protease, 3CL pro ), also known as the main protease (M pro ), is the key protease in the process of producing multiple non-structural proteins after the coronavirus RNA is translated into polyproteins pp1a and pp1ab. Replication and infection are essential. Inhibiting the catalytic function of 3CL protease can effectively inhibit the cleavage of viral polyprotein precursors, block viral replication, and inhibit the generation of progeny viruses.
  • 3CL pro is a cysteine protease.
  • 3CL pro is currently recognized as an ideal target for the development of anti-coronavirus drugs.
  • the purpose of the present invention is to provide an active ingredient that can effectively inhibit the Coronavirus 3CL protease and its new use in inhibiting the Coronavirus.
  • the present invention provides the use of the myricetin compound represented by formula I and the composition thereof in anti-coronavirus, especially novel coronavirus (SARS-CoV-2).
  • SARS-CoV-2 novel coronavirus
  • an active ingredient or a preparation containing the active ingredient the active ingredient being a compound of formula I or a pharmaceutically acceptable salt thereof:
  • Each R is independently H, C 1 -C 3 alkyl, or acetyl
  • the active ingredient or the preparation containing the active ingredient is used to prepare (a) inhibitors for inhibiting the 2019 novel coronavirus (SARS-CoV-2) 3CL protease; and/or (b) treatment and/or Drugs to prevent and alleviate related diseases caused by the 2019 novel coronavirus (SARS-CoV-2) infection.
  • SARS-CoV-2 2019 novel coronavirus
  • SARS-CoV-2 2019 novel coronavirus
  • the related disease caused by the 2019 novel coronavirus infection is selected from the following group: respiratory tract infection, pneumonia and its complications, or a combination thereof.
  • the active ingredient is selected from the following group:
  • the active ingredient is selected from the group consisting of myricetin, dihydromyricetin, and 3-O-acetyldihydromyricetin.
  • the drug further includes an additional component selected from the group consisting of: anti-retroviral drugs or immunity-enhancing drugs.
  • the composition or medicine includes: oral preparations and non-oral preparations.
  • the preparation includes: powder, granule, capsule, injection, tincture, oral liquid, tablet, lozenge, or dripping pill.
  • a pharmaceutical composition which contains:
  • the first active ingredient, said first active ingredient is the myricetin compound represented by formula I or a pharmaceutically acceptable salt thereof:
  • Each R is independently H, C 1 -C 3 alkyl, or acetyl
  • said second active ingredient is selected from the following group: (Y1) RNA replicase inhibitors (such as Remdesivir (Remdesivir or GS-5734)); (Y2) Luo Pinavir (Lopinavir); (Y3) Ritonavir (Ritonavir); (Y4) Favipiravir; (Y5) Chloroquine (Chloroquine, Sigma-C6628), hydroxychloroquine, or a pharmaceutically acceptable salt thereof (such as chloroquine phosphate), (Y6) any combination of the above Y1 ⁇ Y5;
  • each R is independently H or an acetyl group
  • R is H
  • the first active ingredient is selected from the following group:
  • the pharmaceutical composition is a pharmaceutical composition for inhibiting the 2019 novel coronavirus (SARS-CoV-2) 3CL protease.
  • the use of the pharmaceutical composition described in the second aspect of the present invention is provided, which is used to prepare (a) an inhibitor for inhibiting the 2019 novel coronavirus (SARS-CoV-2) 3CL protease ; And/or (b) drugs for the treatment and/or prevention and alleviation of related diseases caused by the 2019 novel coronavirus (SARS-CoV-2) infection.
  • SARS-CoV-2 2019 novel coronavirus
  • SARS-CoV-2 2019 novel coronavirus
  • a method for inhibiting the 2019 novel coronavirus (SARS-CoV-2) 3CL protease which includes the steps of combining the first active ingredient or the preparation containing the first active ingredient with the 2019 novel coronavirus Contact with the 3CL protease of the coronavirus (SARS-CoV-2), thereby inhibiting the activity of the 3CL protease;
  • the first active ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof:
  • Each R is independently H, C 1 -C 3 alkyl, or acetyl
  • the first active ingredient is a myricetin compound selected from the following group:
  • the concentration of the compound of formula I or its pharmaceutically acceptable salt contacted with the 3CL protease of the 2019 novel coronavirus (SARS-CoV-2) in the method is 0.5-20 ⁇ M, preferably It is 1-10 ⁇ M.
  • the method is an in vitro method.
  • the method is non-therapeutic and non-diagnostic.
  • Figure 1 shows the inhibition curve of myricetin on SARS-CoV-2 protease.
  • Figure 2 shows the inhibition curve of dihydromyricetin on SARS-CoV-2 protease.
  • Figure 3 shows the inhibition curve of 3-O-acetyldihydromyricetin on SARS-CoV-2 protease.
  • the inventors unexpectedly developed a class of active ingredients for the 3CL protease that can effectively inhibit the 2019 novel coronavirus (SARS-CoV-2) and other coronaviruses.
  • the active ingredient of the present invention (the compound of formula I represented by myricetin, dihydromyricetin, 3-O-acetyldihydromyricetin or a pharmaceutically acceptable salt thereof) can effectively inhibit the 2019 novel coronavirus (SARS-CoV-2) and other coronavirus 3CL protease activity, thereby inhibiting the replication and viability of SARS-CoV-2 coronavirus.
  • the present invention has been completed on this basis.
  • the present invention discloses the use of myricetin, dihydromyricetin, 3-O-acetyldihydromyricetin and their combinations in anti-coronavirus, especially in anti-SARS-CoV-2 virus therapy.
  • Myricetin, dihydromyricetin, 3-O-acetyldihydromyricetin and their compositions have excellent inhibitory effects on the highly conserved 3CL hydrolase, which is essential for the replication of coronaviruses, and has good clinical application prospects.
  • active compound of the present invention As used herein, “active compound of the present invention”, “active ingredient of the present invention”, and “active compound of the present invention for inhibiting 3CL protease” are used interchangeably and refer to myricetin compounds having excellent 3CL protease inhibitory activity, Including compounds represented by formula I, such as myricetin, dihydromyricetin, 3-O-acetyldihydromyricetin or a pharmaceutically acceptable salt thereof, or a combination thereof.
  • the formulation of the present invention refers to a formulation containing the active compound of the present invention.
  • new coronavirus As used herein, the terms “new coronavirus”, “2019-nCov” or “SARS-CoV-2” are used interchangeably.
  • the 2019 new coronavirus is the seventh type of coronavirus that is known to infect humans and causes new coronary pneumonia. (COVID-19) is one of the serious infectious diseases that threaten human health around the world.
  • Coronavirus belongs to the Nidovirales (Nidovirales) Coronaviridae (Coronaviridae), which is an enveloped positive-stranded RNA virus, and its subfamily includes four genera of ⁇ , ⁇ , ⁇ and ⁇ .
  • HCoV-229E and HCoV-NL63 belong to the ⁇ genus coronavirus
  • HCoV-OC43, SARS-CoV, HCoV-HKU1, MERS-CoV and SARS-CoV-2 are all ⁇ genus coronavirus.
  • Virus. SARS-CoV-2 is also known as 2019-nCov.
  • the new coronavirus (SARS-CoV-2) that broke out at the end of 2019 has about 80% similarity with SARS-CoV and 40% similarity with MERS-CoV, and it also belongs to the beta coronavirus.
  • the genome of this type of virus is a single-stranded positive-stranded RNA, which is one of the largest RNA viruses in the genome.
  • the codes include replicase, spike protein, envelope protein, envelope protein, and nucleocapsid protein.
  • the genome is translated into two peptide chains of several thousand amino acids, the precursor polyprotein (Polyprotein), and then the precursor protein is cleaved by proteases to produce non-structural proteins (such as RNA polymerase and unwinding). Enzymes) and structural proteins (such as spike proteins) and accessory proteins.
  • 3CL protease (3 Chymotrypsin-like protease, 3CLpro) is the main protease responsible for cleaving the precursor protein in the coronavirus (so it is also called M pro ), which is indispensable for virus replication.
  • 3CLpro is a cysteine hydrolase, which is highly conserved in various types of coronaviruses. It is also similar to the 3C protease in picornaviruses, but there is no similar protease in the human body. Therefore, it is a broad-spectrum anti-single positive-stranded RNA. Ideal target for viral drugs.
  • an active ingredient that can effectively inhibit the replication of coronaviruses such as the 2019 novel coronavirus (SARS-CoV-2) is provided.
  • the active ingredient is selected from the group consisting of myricetin, dihydromyricetin, 3-O-acetyldihydromyricetin, or a pharmaceutically acceptable salt thereof, or a combination thereof, a crystal thereof, or a solvate thereof.
  • the active ingredient of the present invention can effectively inhibit the 3CL protease of the 2019 novel coronavirus (SARS-CoV-2), thereby inhibiting the replication of the 2019 novel coronavirus (SARS-CoV-2), thereby preventing, treating and/or Relieve SARS-CoV-2 related diseases.
  • SARS-CoV-2 2019 novel coronavirus
  • SARS-CoV-2 2019 novel coronavirus
  • active compound of the present invention and “active compound of the present invention that inhibit 3CL protease” are used interchangeably, and refer to compounds with excellent 3CL protease inhibitory activity, including myricetin, dihydromyricetin, 3- O-acetyldihydromyricetin, or a pharmaceutically acceptable salt, crystal, or solvate thereof.
  • the active ingredient of the present invention includes the active compound of the present invention that inhibits 3CL protease, or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate, or prodrug thereof . It should be understood that the active ingredient of the present invention also includes the crystal form, amorphous compound, and deuterated compound of the active compound of the present invention.
  • the "pharmaceutically acceptable salt” refers to the reaction of the active compound of the present invention with an inorganic acid or an organic acid to form a conventional non-toxic salt.
  • conventional non-toxic salts can be prepared by reacting the active compound of the present invention with inorganic or organic acids.
  • the inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, and phosphoric acid.
  • Acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid , Fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonate Acid, 2-acetoxybenzoic acid, isethionic acid, etc.; or the active compound of the present invention is combined with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic
  • the active ingredient of the present invention is also particularly suitable for combined use with other antiviral drugs.
  • Representative other antiviral drugs include (but are not limited to): reverse transcriptase inhibitors, protease inhibitors, co-receptor antagonists, retroviral integrase inhibitors, virus adsorption inhibitors, specific viral transcription inhibitors Agents, antibodies, or combinations thereof.
  • the active ingredient of the present invention can inhibit the infectious activity of new coronaviruses such as SARS-CoV-2. Therefore, when the active ingredient of the present invention is administered or administered therapeutically, the 3CL protease activity can be inhibited, thereby inhibiting the infection of the 2019 novel coronavirus (SARS-CoV-2) and achieving an antiviral effect.
  • new coronaviruses such as SARS-CoV-2.
  • the present invention also provides the active compound of the present invention that inhibits 3CL protease, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or an extract thereof, or a mixture of one or more of its medicinal materials as an active ingredient Use in the preparation of drugs for the treatment and/or prevention and alleviation of respiratory tract infections, pneumonia and other related diseases caused by the 2019 new coronavirus infection.
  • the pharmaceutical composition provided by the present invention preferably contains the active ingredient in a weight ratio of 0.001-99wt%, and the preferred ratio is that the active compound of the present invention as the active ingredient accounts for 0.1wt% to 90wt% or 1wt% to 50wt% of the total weight,
  • the remaining part is a pharmaceutically acceptable carrier, diluent or solution or salt solution.
  • the carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants and the like in the pharmaceutical field.
  • the compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in suitable solid or liquid carriers or diluents. Neutralization is suitable for sterilization equipment for injection or drip infusion.
  • Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field.
  • the unit measurement of the preparation formula usually contains 0.05-400 mg of the active compound of the present invention.
  • the unit measurement of the preparation formula contains 1 mg-500 mg of the active compound of the present invention.
  • the compounds and pharmaceutical compositions of the present invention can be used clinically on mammals, including humans and animals, and can be administered via oral, nose, skin, lung, or gastrointestinal tract. Most preferred is oral administration.
  • the most preferred daily dose is 0.01-400 mg/kg body weight, taken in one time, or 0.01-200 mg/kg body weight in divided doses. Regardless of the method of administration, the individual's optimal dosage should be determined based on the specific treatment. Usually, start with a small dose and gradually increase the dose until the most suitable dose is found.
  • the drugs or inhibitors of the present invention can be administered in various ways, for example, can be introduced into the body by injection, spraying, nose drops, eye drops, penetration, absorption, physical or chemically mediated methods such as muscle, intradermal, subcutaneous, and intravenous methods. , Mucosal tissue; or mixed or wrapped by other substances into the body.
  • the active compound of the present invention can effectively inhibit SARS-CoV-2 3CL protease, with an IC 50 value of less than 2 ⁇ M, and the optimal IC 50 value of myricetin is about 0.64 ⁇ M
  • the active compound of the present invention has low toxic and side effects and good druggability. This suggests that the myricetin compound of the present invention has a good prospect for medicinal use in the field of anti-new coronary pneumonia.
  • Example 1 Experimental test of myricetin compounds against SARS-CoV-2 M pro protease
  • the inhibitory activity of different compounds on SARS-CoV-2 M pro protease was determined by using fluorescence resonance energy transfer (FRET) technology to determine the 3CL
  • FRET fluorescence resonance energy transfer
  • the enzyme level of the protease inhibitor inhibits the activity.
  • the volume of the entire enzymatic reaction system is 120 ⁇ L, the final concentration of protease is 30 nM, and the final concentration of substrate is 20 ⁇ M.
  • the buffer of the reaction system includes 50mM Tris pH7.3, 1mM EDTA.
  • SARS-CoV-2 2019 novel coronavirus
  • test compounds Add the 3CL protease of 2019 novel coronavirus (SARS-CoV-2) and different concentrations of test compounds to a 96-well plate, incubate at 30°C for 10 minutes, add the substrate and quickly place it in the microplate reader for reading.
  • the excitation light and emission light are 320nm and 405nm, respectively.
  • the test time is 10 minutes, and the fluorescence value is read every 30s to fit the reaction rate and compare with the control group (DMSO) to calculate the inhibition rate and IC50 value.
  • DMSO control group
  • myricetin inhibits the 3CL protease activity of the new coronavirus (SARS-CoV-2) with an IC50 value of 0.64 ⁇ M.
  • Dihydromyricetin inhibits the new coronavirus (SARS -CoV-2) 3CL protease activity IC50 value is 1 ⁇ M
  • 3-O-acetyldihydromyricetin inhibits the new coronavirus (SARS-CoV-2) 3CL protease activity IC50 value 1.72 ⁇ M.
  • myricetin compounds represented by myricetin, dihydromyricetin, and 3-O-acetyldihydromyricetin can effectively inhibit the 3CL protease activity of the new coronavirus (SARS-CoV-2), thereby effectively helping prevent And/or treat diseases caused by the new coronavirus.
  • SARS-CoV-2 new coronavirus
  • myricetin, dihydromyricetin, 3-O-acetyldihydromyricetin or a pharmaceutically acceptable salt thereof have a significant inhibitory effect on 3CLpro of SARS-CoV-2.
  • SARS-CoV-2 anti-2019 new coronavirus

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Abstract

L'invention concerne l'application d'un composé de myricétine dans la préparation de médicaments pour la prévention et le traitement de la pneumonie à nouveau coronavirus. Plus particulièrement, la présente invention concerne l'utilisation d'un composé de myricétine et d'une composition pharmaceutique comme inhibiteur de la protéase 3CL du nouveau coronavirus (SARS-CoV-2) dans la préparation de médicaments pour le traitement et/ou la prévention et le soulagement de maladies apparentées telles que les infections des voies respiratoires et la pneumonie causée par des infections au nouveau coronavirus 2019.
PCT/CN2021/079138 2020-03-06 2021-03-04 Application d'un composé de myricétine dans la préparation de médicaments pour la prévention et le traitement de la pneumonie à nouveau coronavirus WO2021175295A1 (fr)

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CN202010153446.3A CN113350330B (zh) 2020-03-06 2020-03-06 杨梅素类化合物在制备防治新冠肺炎药物中的应用
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