WO2021182685A1 - Utilisation de l-nucléoside pour le traitement du coronavirus - Google Patents

Utilisation de l-nucléoside pour le traitement du coronavirus Download PDF

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Publication number
WO2021182685A1
WO2021182685A1 PCT/KR2020/010305 KR2020010305W WO2021182685A1 WO 2021182685 A1 WO2021182685 A1 WO 2021182685A1 KR 2020010305 W KR2020010305 W KR 2020010305W WO 2021182685 A1 WO2021182685 A1 WO 2021182685A1
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coronavirus
formula
fluoro
human
hcov
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PCT/KR2020/010305
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English (en)
Korean (ko)
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유희원
엄정윤
전훈
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부광약품 주식회사
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Publication of WO2021182685A1 publication Critical patent/WO2021182685A1/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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 agent for coronavirus, and more particularly, to a use for treating a coronavirus infection by administering a medicament or pharmaceutical composition comprising an L-nucleoside of Formula 1 below:
  • R and R are as defined herein.
  • Coronavirus disease 2019 (COVID-19) is a virus first discovered in Wuhan City, Hubei province, China in 2019, belongs to the family of coronaviruses (Coroviridae) and is a SARS-CoV (severe acute respiratory syndrome coronavirus). ), it is known as a virus similar to the Middle East respiratory syndrome coronavirus (MERS-CoV, Middle East respiratory syndrome coronavirus).
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • MERS-CoV Middle East respiratory syndrome coronavirus
  • COVID-19 coronavirus is a virus that can infect humans and various animals, and is an RNA virus with a gene size of 27 to 32 kb.
  • Coronavirus disease 2019 (COVID-19) has an incubation period of about two weeks and mainly shows respiratory symptoms such as cough with fever, shortness of breath, shortness of breath, and sputum. Gastrointestinal symptoms such as loss of appetite, nausea, vomiting, abdominal pain, and diarrhea may also appear.
  • An object of the present invention is to provide the use of an L-nucleoside compound of Formula 1 or a pharmaceutically acceptable salt, ester or prodrug thereof for use in the treatment of a coronavirus infection:
  • R and R are as defined herein.
  • the present invention provides a medicament for the treatment of coronavirus infection, comprising a therapeutically effective amount of an L-nucleoside compound of Formula 1, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • R is a purine or pyrimidine base
  • R′′ is hydrogen, acyl, alkyl, monophosphate, diphosphate or triphosphate.
  • the present invention provides a therapeutically effective amount of the L-nucleoside compound of Formula 1, or a pharmaceutically acceptable salt, ester or prodrug thereof, and additionally a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for use is provided.
  • the present invention provides a method of treating a coronavirus infection comprising administering to a subject to be treated in a therapeutically effective amount of the L-nucleoside compound of Formula 1, or a pharmaceutically acceptable salt, ester, or prodrug thereof to provide.
  • the present invention provides the use of the L-nucleoside compound of Formula 1, or a pharmaceutically acceptable salt, ester or prodrug thereof for treating a coronavirus infection.
  • the coronavirus infection is human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), severe acute respiratory syndrome coronavirus (SARS-CoV), human coronavirus NL63 ( HCoV-NL63, New Haven Coronavirus), human coronavirus HKU1, Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and coronavirus disease 2019 (COVID-19).
  • alkyl of Formula 1 is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, amyl , t-pentyl, cyclopentyl and C 1 -C 10 alkyl groups including cyclohexyl, but are not limited thereto.
  • acyl of Formula 1 includes, for example, acetyl, propionyl, butyryl, pentanoyl, 3-methylbutyryl, hydrogen succinate, 3-chlorobenzoate, benzoyl, acetyl , pivaloyl, mesylate, propionyl, valeryl, caproic, caprylic, capric, lauric, myristic, palmitic, stearic and oleic.
  • aryl in Formula 1 means phenyl
  • the “base” of Formula 1 may be selected from the group consisting of 5-methyluracil (thymine), 5-iodouracil, cytosine and 5-ethyluracil.
  • the L-nucleoside compound of Formula 1 is 2'-fluoro-5-methyl- ⁇ -L-arabinofuranosyluridine (INN: clevudine) of Formula 2 )am:
  • the L-nucleoside compound of Formula 1 is N1-(2'-deoxy-2'-fluoro- ⁇ -L-arabinofuranosyl)-5-ethyluracil, N1 -(2'-deoxy-2'-fluoro- ⁇ -L-arabinofuranosyl)-5-iodocytosine) and N1-(2'-deoxy-2'-fluoro- ⁇ -L-ara vinofuranosyl)-5-iodouracil.
  • L-nucleoside compounds of Formulas 1 and 2 may use a known compound or a compound that can be easily prepared therefrom.
  • the preparation of L-nucleoside compounds of Formulas 1 and 2 is described in detail in International Publication No. WO 1995/20595 (published on August 3, 1995), which is incorporated herein by reference. do.
  • WO 1995/20595 published on August 3, 1995
  • do the above document is not intended to limit the scope of the invention, as only one exemplary method is presented, and the order of unit operations may be selectively changed as necessary.
  • the L-nucleoside compounds of Formulas 1 and 2 may include a prodrug form that is converted in vivo to exhibit the same effect.
  • the "therapeutically effective amount" for an individual subject means an amount sufficient to achieve the aforementioned pharmacological effect, that is, a therapeutic effect.
  • the amount of the compound will vary with the condition and severity of the subject, the mode of administration, and the age of the subject to be treated, but can be determined by one of ordinary skill in the art based on their own knowledge.
  • the "pharmaceutical composition” may include a pharmaceutically acceptable carrier in addition to the L-nucleoside compounds of Formulas 1 and 2 according to the present invention, and in the present invention, the term “carrier” refers to cells Or it means a compound that facilitates the introduction of the compound into the tissue, and there is no particular limitation thereto.
  • pharmaceutically acceptable refers to a property that does not impair the biological activity and physical properties of a compound.
  • the compounds in the present invention may be formulated into various pharmaceutical dosage forms as desired.
  • the active ingredient specifically the L-nucleoside compound of Formula 1 or 2, or a pharmaceutically acceptable salt, ester or prodrug thereof, is prepared according to the formulation to be prepared. It is admixed with a variety of pharmaceutically acceptable carriers that may be selected.
  • treatment refers to all or part of the elimination of a disease and/or its attendant symptoms.
  • the term “subject” refers to an animal, preferably a mammal (eg, primates), that is the subject of treatment, observation or experimentation.
  • the medicament or pharmaceutical composition according to the present invention can effectively treat coronavirus infection.
  • 1 is a result of measuring the inhibitory effect on COVID-19 replication by plaque reduction assay.
  • 3 is a real-time qRT-PCR evaluation result for measuring the IC 50 of clevudine for COVID-19 replication.
  • SARS-CoV-2 (COVID-19) was used for the virus, Vero was used for the cell line, and the evaluation method was tested by plaque reduction assay, and the concentration of drugs (Lopinavir, Ritonavir, Chloroquine and Clevudine) was used. was set to 12.5 to 3.13 ⁇ M.
  • the concentration of drugs Lipinavir, Ritonavir, Chloroquine and Clevudine was used. was set to 12.5 to 3.13 ⁇ M.
  • the concentration of drugs Lipinavir, Ritonavir, Chloroquine and Clevudine
  • PBS phosphate-buffered saline
  • an agar medium containing the drug was overlaid on the cells and cultured at 37° C. for 3 days. After 3 days of infection, the number of plaques that appeared by staining the infected cells with crystal violet was counted and analyzed in comparison with the control group that was not treated with the drug.
  • SARS-CoV-2 (COVID-19) was used for the virus and Vero cells (2 x 10 4 /well) were used for the cell line, and the evaluation method was real time quantitative reverse transcription PCR, Real time qRT-PCR) (100 ⁇ l) was used, and the concentration of the drug (Clevudine) was 100 ⁇ M to 0.39 ⁇ M (2-fold dilution, 2% FBS, DMEM). After culturing Vero cells in a 96-well plate (2 x 10 4 cells/well), the virus was inoculated with an MOI of 0.1 (2 x 10 3 PFU/100 ⁇ l) and incubated at 37°C for 1 hour. .
  • Infected cells were washed with PBS, and a cell culture medium containing drugs for each concentration was added to the cells. After that, the culture medium was obtained at 24 hours and 48 hours, and the RNA level present in the SARS-CoV-2 virus particles was measured by real-time qRT-PCR and compared with the control group (virus-infected group without drug treatment).
  • SARS-CoV-2 (COVID-19) was used for the virus, and Vero cells (2 x 10 4 /well) were used for the cell line, and the evaluation method was real time qRT-PCR (100 ⁇ l).
  • concentrations of (Lopinavir, Chloroquine and Clevudine) were 0.05 ⁇ M, 0.1 ⁇ M, 0.2 ⁇ M, 0.39 ⁇ M, 0.79 ⁇ M, 1.57 ⁇ M, 3.13 ⁇ M, 6.25 ⁇ M, 12.5 ⁇ M, 25 ⁇ M, 50 ⁇ M and 100 ⁇ M.
  • the virus was inoculated with an MOI of 0.1 (2 x 10 3 PFU/100 ⁇ l) and incubated at 37° C. for 1 hour. Infected cells were washed with PBS, and a cell culture medium containing drugs for each concentration was added to the cells. After that, the culture medium was obtained at 24 hours and 48 hours, and the RNA level present in the SARS-CoV-2 virus particles was measured by real-time qRT-PCR and compared with the control group (virus-infected group without drug treatment).
  • Example 4 Real time qRT-PCR based IC 50 evaluation (human lung epithelial cell)
  • SARS-CoV-2 (COVID-19) was used for the virus, and Calu-3 cells, which are human lung epithelial cells, were used as the cell line.
  • Remdesivir and Clevudine) concentrations were 0.05 ⁇ M, 0.1 ⁇ M, 0.2 ⁇ M, 0.39 ⁇ M, 0.79 ⁇ M, 1.57 ⁇ M, 3.13 ⁇ M, 6.25 ⁇ M, 12.5 ⁇ M, 25 ⁇ M, 50 ⁇ M and 100 ⁇ M.
  • the IC 50 was derived by extracting RNA from the cell culture medium 48 hours after virus infection and measuring real-time RT-PCR.
  • clevudine showed drug-induced cytotoxicity at concentrations exceeding 400 ⁇ M and 200 ⁇ M, respectively, at 24 hours and 48 hours, lower cells than remdesivir and hydroxychloroquine used as controls. showed toxicity.
  • clevudine was able to inhibit the replication of COVID-19 to inhibit infection by COVID-19.
  • human coronavirus 229E HoV-229E
  • human coronavirus OC43 HoV-OC43
  • severe acute respiratory syndrome coronavirus SARS-CoV
  • human coronavirus NL63 HoV-NL63, New Haven coronavirus
  • human coronavirus HKU1 MERS-CoV
  • MERS-CoV Middle East Respiratory Syndrome Coronavirus

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Public Health (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un agent de traitement pour un coronavirus et, plus spécifiquement, une utilisation dans le but de traiter une infection à coronavirus par l'administration d'un médicament ou d'une composition pharmaceutique comprenant un L-nucléoside représenté par la formule chimique 1.
PCT/KR2020/010305 2020-03-10 2020-08-05 Utilisation de l-nucléoside pour le traitement du coronavirus WO2021182685A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20200029446 2020-03-10
KR10-2020-0029446 2020-03-10
KR1020200046764A KR102145197B1 (ko) 2020-03-10 2020-04-17 코로나바이러스를 치료하기 위한 l-뉴클레오사이드의 용도
KR10-2020-0046764 2020-04-17

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Publication number Priority date Publication date Assignee Title
KR102169476B1 (ko) * 2020-05-20 2020-10-23 (주)신테카바이오 제2형 중증급성호흡기증후군 코로나바이러스 감염 질환의 예방 또는 치료용 조성물
KR20220073672A (ko) 2020-11-25 2022-06-03 주식회사 에이치피바이오 코로나바이러스의 rna 의존성 rna 중합효소에 특이적으로 결합하는 rna 앱타머 및 이의 용도
KR20220082125A (ko) 2020-12-09 2022-06-17 주식회사 에이치피바이오 코로나 바이러스에 특이적으로 결합하는 dna 앱타머 및 이의 용도
KR102572694B1 (ko) * 2021-03-16 2023-08-30 한국화학연구원 베네토클락스 및 렘데시비르를 유효성분으로 하는 코로나-19 감염증 예방 또는 치료용 약학 조성물
KR20230073136A (ko) 2021-11-18 2023-05-25 주식회사 노브메타파마 코로나바이러스 감염 질환의 예방 또는 치료용 약제학적 조성물
KR102694547B1 (ko) 2023-03-30 2024-08-12 한국해양과학기술원 푸코잔틴을 포함하는 바이러스 감염증의 예방 또는 치료용 약학적 조성물

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040259934A1 (en) * 2003-05-01 2004-12-23 Olsen David B. Inhibiting Coronaviridae viral replication and treating Coronaviridae viral infection with nucleoside compounds
WO2005020885A2 (fr) * 2003-05-21 2005-03-10 Isis Pharmaceuticals, Inc. Compositions et methodes pour le traitement du syndrome respiratoire aigu severe (sras)
WO2015038596A1 (fr) * 2013-09-11 2015-03-19 Emory University Compositions à base de nucléotide et de nucléoside et utilisations correspondantes
US20150290235A1 (en) * 2012-11-23 2015-10-15 Ab Science Use of small molecule inhibitors/activators in combination with (deoxy)nucleoside or (deoxy)nucleotide analogs for treatment of cancer and hematological malignancies or viral infections
WO2016145142A1 (fr) * 2015-03-10 2016-09-15 Emory University Compositions thérapeutiques renfermant des nucléotides et des nucléosides et utilisations associées

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040259934A1 (en) * 2003-05-01 2004-12-23 Olsen David B. Inhibiting Coronaviridae viral replication and treating Coronaviridae viral infection with nucleoside compounds
WO2005020885A2 (fr) * 2003-05-21 2005-03-10 Isis Pharmaceuticals, Inc. Compositions et methodes pour le traitement du syndrome respiratoire aigu severe (sras)
US20150290235A1 (en) * 2012-11-23 2015-10-15 Ab Science Use of small molecule inhibitors/activators in combination with (deoxy)nucleoside or (deoxy)nucleotide analogs for treatment of cancer and hematological malignancies or viral infections
WO2015038596A1 (fr) * 2013-09-11 2015-03-19 Emory University Compositions à base de nucléotide et de nucléoside et utilisations correspondantes
WO2016145142A1 (fr) * 2015-03-10 2016-09-15 Emory University Compositions thérapeutiques renfermant des nucléotides et des nucléosides et utilisations associées

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