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WO2022088025A1 - Application de panobinostat dans la préparation d'un médicament pour la prévention et le traitement du coronavirus - Google Patents

Application de panobinostat dans la préparation d'un médicament pour la prévention et le traitement du coronavirus Download PDF

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Publication number
WO2022088025A1
WO2022088025A1 PCT/CN2020/125190 CN2020125190W WO2022088025A1 WO 2022088025 A1 WO2022088025 A1 WO 2022088025A1 CN 2020125190 W CN2020125190 W CN 2020125190W WO 2022088025 A1 WO2022088025 A1 WO 2022088025A1
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Prior art keywords
hydrochloride
coronavirus
panobinostat
cov
sars
Prior art date
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Ceased
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PCT/CN2020/125190
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English (en)
Chinese (zh)
Inventor
袁曙光
李红昌
崔文强
邹荣峰
刘科
陈显翀
李红春
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Shenzhen Institute of Advanced Technology of CAS
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Shenzhen Institute of Advanced Technology of CAS
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Priority to PCT/CN2020/125190 priority Critical patent/WO2022088025A1/fr
Publication of WO2022088025A1 publication Critical patent/WO2022088025A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • 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 invention belongs to the field of medicines, and specifically relates to the application of panobinostat in the preparation of medicines for preventing and treating coronavirus.
  • the new coronavirus pneumonia (Corona Virus Disease 2019) is an infectious disease caused by the infection of the human body by the new coronavirus (SARS-Cov-2). Its symptoms mainly include fever, fatigue, dry cough, dyspnea and renal failure [The Lancet , 2020, 395(10223): 507-513; The Lancet, 2020, 395(10223): 497-506].
  • the coronavirus belongs to the genus Coronavirus in the family Coronaviridae.
  • the virus of the genus Coronavirus is a positive-stranded single-stranded RNA virus with an envelope, with a diameter of about 80-120 nm.
  • RNA viruses Its genetic material is the largest among all RNA viruses, and generally only infects humans, mice, pigs, cats, and dogs. , avian vertebrates.
  • the coronavirus was first isolated from chickens in 1937. The shape of coronavirus particles is irregular, with a diameter of about 60-220 nm.
  • the virus has an envelope structure with three proteins on it: spike glycoprotein (S, Spike Protein), small envelope glycoprotein (E, Envelope Protein) and membrane glycoprotein (M, Membrane Protein), and a few species also have hemagglutination.
  • S spike glycoprotein
  • E small envelope glycoprotein
  • M membrane glycoprotein
  • Glucoprotein HE protein, Haemaglutinin-esterase
  • SARS-Cov-2 virus particles The diameter of SARS-Cov-2 virus particles is between 60 and 140 nm, and there are spikes of 9 to 12 nm outside the envelope, which are shaped like a corolla.
  • Genome sequencing revealed that SARS-Cov-2 is a single-stranded RNA coronavirus. By comparing the gene sequences of other virus samples, it was found that SARS-Cov-2 was similar to SARS-CoV (79.5%) [Nature, 2020] and bat coronavirus (96%) [bioRxiv, 2020, 2020.01.22.914952], and speculated that The virus may have originated from bats [bioRxiv, 2020, 2020.01.24.915157; Nature, 2020].
  • the 2019-nCoV virus belongs to ⁇ CoV and is the seventh member of the HCoV family that is different from SARS-CoV and MERS-CoV [New England Journal of Medicine, 2020], and the remaining six members include HCoV 229E, NL63, OC43, HKU1, SARS -CoV and MERS-CoV.
  • the novel coronavirus pneumonia is caused by a new type of coronavirus. It is the same coronavirus as the well-known SARS-CoV that causes atypical pneumonia, but the type is different. Although its fatality rate is lower than that of SARS-CoV, it is far more infectious. to SARS-CoV.
  • Panobinostat is a histone deacetylase (HDAC) inhibitor that catalyzes the removal of acetyl groups from lysine residues in histones and some non-histone proteins. Inhibition of HDAC activity leads to increased acetylation of histones, resulting in epigenetic changes in chromatin relaxation, leading to transcriptional activation, which in turn induces cell cycle arrest and induces tumor cell apoptosis.
  • HDAC histone deacetylase
  • panobinostat is approved as a drug for the treatment of multiple myeloma, and it is combined with bortezomib and dexamethasone as a third-line drug to treat multiple myeloma after receiving 2 immunosuppressive treatments ( multiplemyeloma, MM) patients.
  • the purpose of the present invention is to provide the application of panobinostat in the preparation of a drug for preventing or treating the novel coronavirus of novel coronavirus pneumonia.
  • the present invention provides panobinostat or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs in the preparation of preventing and/or treating coronary Use in medicines for diseases caused by viruses.
  • panobinostat or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs in the preparation of preventing coronavirus The application of drugs that enter cells.
  • the coronaviruses are novel coronaviruses SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 and MERS-CoV.
  • the disease caused by the coronavirus is pneumonia or its complications caused by any virus of SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 or MERS-CoV.
  • panobinostat is represented by structural formula (1)
  • panobinostat or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs are used as the only active ingredient Application in the preparation of medicaments for preventing and/or treating diseases caused by coronavirus.
  • panobinostat or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs and other antiviral The application of the composition prepared by the medicine as an active ingredient in the preparation of a medicine for preventing and/or treating diseases caused by coronavirus.
  • antiviral drugs are selected from ganciclovir, acyclovir, amantadine, rimantadine, oseltamivir, abacavir, acemannan, acyclovir Sodium, Adefovir, Alovudine, Avesuto, Tricyclodecamine Hydrochloride, Alanodine, Aridone, Ateviridine Mesylate, Afrilidine, Cidofovir, Silicate panthefylline, emtricitabine, cytarabine hydrochloride, delavirdine mesylate, desilovir, didanosine, dioxalisine, eduridine, emivirine, eltra Sitapine, Enviraden, Enviroxime, Heptin, Famciclovir, Chlorphenhydramine Hydrochloride, Noncitabine, Nonauridine, Phosphorate, Foscarnet Sodium, Phos
  • Another aspect of the present invention provides a pharmaceutical composition for treating or preventing diseases caused by coronaviruses of the family Coronaviridae, which comprises panobinostat or its pharmaceutically acceptable salts, isotopes, stereoisomers, stereoisomers Mixtures, tautomers, esters, amides or prodrugs.
  • the pharmaceutical composition further includes pharmaceutically acceptable excipients.
  • the dosage form of the pharmaceutical composition is an oral preparation, a pulmonary inhalation preparation, a mucosal administration preparation, an ophthalmic preparation or an injection.
  • the oral preparation is selected from granules, powders, pills, tablets, capsules or oral liquids.
  • panobinostat as an anti-coronaviridae virus disinfectant.
  • Another aspect of the present invention provides a method for treating diseases caused by coronaviruses, comprising adding a therapeutically effective amount of panobinostat or a pharmaceutically acceptable salt, isotope, stereoisomer, stereoisomer Mixtures of isomers, tautomers, esters or prodrugs are administered to the subject.
  • Another aspect of the present invention provides a method for preventing a subject from being infected with a coronavirus of the family Coronaviridae, comprising adding a therapeutically effective amount of panobinostat or a pharmaceutically acceptable salt, isotope, stereoisomer, Stereoisomer mixture, tautomer, ester or prodrug administration is administered to the subject prior to infection.
  • panobinostat has an inhibitory effect on the novel coronavirus of new coronary pneumonia.
  • Panobinostat is used as an effective drug in the treatment of novel coronavirus infection.
  • Figure 1 shows the production and verification of SARS-2-S pseudotype particles.
  • SARS-2-S protein can be successfully expressed in mammalian cells.
  • SARS-2-S pseudovirion has S protein modification.
  • C The SARS-2-S pseudovirion can successfully infect host cells and integrate the reporter gene.
  • D SARS-2-S pseudovirions enter susceptible cells by recognizing ACE2 receptors.
  • E SARS-2-S pseudovirions were able to infect human 293T cells expressing ACE2-GFP, but not into 293T cells without ACE2 expression.
  • ACE2-GFP green; Flag tag, red, showing the S protein;
  • F SARS-2-S pseudovirion capable of binding to the ACE2 receptor with colocalized signals at different locations within the cell (membrane and cytoplasm).
  • G Time-dependent entry of SARS-2-S pseudovirions into ACE2-GFP/293T cells.
  • Figure 2 shows that panobinostat effectively inhibits pseudovirion infection.
  • Immunofluorescence staining was used to determine the inhibitory effect of the screened clinical drugs on the infection of host cells by SARS-2-S pseudovirus particles. After the pseudovirus particles infect ACE2-GFP expressing 293T cells, the intracellular localization of pseudovirus particles was observed by fixed staining. Blue, DAPI; red, Flag antibody labeled S protein; green, ACE2-GFP signal.
  • treatment refers to reversing, alleviating, inhibiting the progression of, or preventing the diseases or conditions to which the term applies, or one or more symptoms of these diseases or conditions, or the One or more symptoms of a disorder.
  • terapéuticaally effective amount is the amount of Compound 1, or a pharmaceutically acceptable salt thereof, present in the compositions described herein that, when such compositions are administered by the chosen route of administration, at The desired level of drug is provided in the secretions and tissues of the airways and lungs, or alternatively in the bloodstream of the subject to be treated, to produce the desired physiological response or desired biological effect.
  • the precise amount will depend on many factors, such as the specific activity of the composition, the delivery device used, the physical properties of the composition, its intended use, and animal considerations such as the severity of the disease state, etc., and can be determined by one of skill in the art based on The information provided herein makes it easy to determine the exact amount.
  • the active ingredients of the present invention are administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. It will be appreciated that the preferred route may vary depending, for example, on the condition of the recipient.
  • An advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally.
  • the effective dose of the active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active viral infection, delivery method and pharmaceutical formulation, and will be determined by the clinician using routine dose escalation studies.
  • panobinostat or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs and other antiviral The composition of the pharmaceutical preparation is used as an active ingredient in the preparation of a medicine for preventing and/or treating a disease caused by a coronavirus, and for the above-mentioned two or more active ingredients in a unit dosage form combination is administered to a patient simultaneously or sequentially.
  • Combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
  • the cell is any cell, such as eukaryotic or prokaryotic cells, especially refers to a host cell that can be used as a coronavirus, especially a cell containing an ACE2 receptor.
  • the DNA sequence of SARS-2-S protein was modified without changing its amino acid sequence by codon optimization method, which facilitated the abundant expression of SARS-2-S in 293T cells (Fig. 1A).
  • the three-plasmid expression system was transfected in 293T cells, and SARS-2-S was modified on the outer membrane of the pseudovirion to form SARS-2 -S pseudovirion. It can be judged by immunoblotting that this pseudoviral particle removed the original VSV-G envelope glycoprotein and replaced it with SARS-2-S, the envelope glycoprotein of the new coronavirus ( Figure 1B).
  • the pseudovirion carrying the Luciferase reporter gene was used to infect host cells 293T or ACE2/293T cells.
  • the Luciferase cell activity assay showed that the SARS-2-S pseudovirus particles had high infectivity to ACE2/293T cells, and the infection efficiency was about 100 times higher than that of 293T cells ( Figure 1C).
  • pseudovirus particles were also used to infect monkey kidney epithelial Vero-E6 cells with endogenous ACE2 expression, and immunofluorescence staining showed that SARS-2-S pseudovirus particles could well enter Vero-E6 cells; Knockdown of the endogenous ACE2 receptor greatly reduced the infection efficiency of pseudovirions (Fig.
  • SARS-2-S pseudovirus particles were not only localized on the cell membrane, but also could enter cells with ACE2 receptors and transported to the perinuclear cells of cells perinuclear area (Fig. 1F).
  • the entry of SARS-2-S pseudovirions into host cells was also time-dependent, reaching a saturation phase after approximately 2 h (Fig. 1G).
  • Example 1 Using the SARS-2-S pseudovirus particle in vitro infection model (Luciferase reporter system and immunofluorescence staining localization system) constructed in Example 1, the in vitro cell biological verification of panobinostat was carried out. 293T cells were stably inoculated with ACE2-GFP in a 96-well plate, and the cells were pretreated with different concentrations of panobinostat for 2 hours, then SARS-2-S pseudovirus particles were added to infect for 3 hours, and then the supernatant was removed and replaced with fresh complete culture medium.
  • SARS-2-S pseudovirus particle in vitro infection model (Luciferase reporter system and immunofluorescence staining localization system) constructed in Example 1
  • 293T cells were stably inoculated with ACE2-GFP in a 96-well plate, and the cells were pretreated with different concentrations of panobinostat for 2 hours, then SARS-2-S pseudovirus particles were added to infect for 3 hours, and then the supernatant was removed
  • the cells were lysed by the Luciferase Assay System (Promega) and the reaction substrate was added, and the luminescence intensity of luciferase was measured by Glomax 96.
  • the bioluminescence intensity was proportional to the infection efficiency of virus particles.
  • panobinostat had an obvious concentration-dependent effect and could effectively inhibit the infection efficiency of SARS-2-S pseudovirus particles.
  • the EC50 concentration of panobinostat is approximately 2.8 ⁇ 1.0 ⁇ M.

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Abstract

L'invention concerne une application de panobinostat dans la préparation d'un médicament pour la prévention et le traitement d'un coronavirus, et concerne plus particulièrement une application de panobinostat ou d'un sel, d'un isotope, d'un stéréoisomère, d'un mélange de stéréoisomères, d'un tautomère, d'un ester, d'un amide ou d'un promédicament pharmaceutiquement acceptable de celui-ci dans la préparation d'un médicament pour la prévention et/ou le traitement d'une maladie causée par un coronavirus, ledit coronavirus étant le nouveau coronavirus SARS-CoV-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 et MERS-CoV, et une maladie provoquée par un coronavirus étant une pneumonie ou une autre complication due à un virus quelconque parmi le SARS-CoV-2, le SARS-CoV, le HCoV 229E, le NL63, le OC43, le HKU1 ou le MERS-COV, un effet inhibiteur du panobinostat sur le nouveau coronavirus ayant été prouvé pour la première fois.
PCT/CN2020/125190 2020-10-30 2020-10-30 Application de panobinostat dans la préparation d'un médicament pour la prévention et le traitement du coronavirus Ceased WO2022088025A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116115627A (zh) * 2022-10-25 2023-05-16 武汉大学 氯化核苷单磷酸分子2’-Cl-2’-dAMP在制备抗冠状病毒药物中的应用

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116115627A (zh) * 2022-10-25 2023-05-16 武汉大学 氯化核苷单磷酸分子2’-Cl-2’-dAMP在制备抗冠状病毒药物中的应用

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