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WO2024123207A1 - 5'-о-(3-phénylpropionyl)-n4-hydroxycytidine et utilisation - Google Patents

5'-о-(3-phénylpropionyl)-n4-hydroxycytidine et utilisation Download PDF

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Publication number
WO2024123207A1
WO2024123207A1 PCT/RU2023/000255 RU2023000255W WO2024123207A1 WO 2024123207 A1 WO2024123207 A1 WO 2024123207A1 RU 2023000255 W RU2023000255 W RU 2023000255W WO 2024123207 A1 WO2024123207 A1 WO 2024123207A1
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WO
WIPO (PCT)
Prior art keywords
hydroxycytidine
compound
virus
cov
sars
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/RU2023/000255
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English (en)
Russian (ru)
Inventor
Наталья Сергеевна ШАСТИНА
Андрей Эдуардович СИНЯВИН
Сергей Игоревич ЛУЙКСААР
Сергей Анатольевич ЗОЛОТОВ
Анна Борисовна ШЕРЕМЕТ
Тимофей Андреевич РЕМИЗОВ
Игорь Андреевич ИВАНОВ
Анастасия Андреевна ЗАХАРОВА
Александр Александрович ТЕРЕХОВ
Дарья Владимировна ВАСИНА
Леонид Иванович РУССУ
Елизавета Сергеевна ДАРНОТУК
Анна Михайловна ИНШАКОВА
Наталия Евгеньевна БОНДАРЕВА
Анна Владимировна СОЛОВЬЕВА
Елизавета Александровна ТОКАРСКАЯ
Надежда Леонидовна ЛУБЕНЕЦ
Надежда Анатольевна КУЗНЕЦОВА
Елена Владимировна ШИДЛОВСКАЯ
Евгений Валерьевич УСАЧЕВ
Артем Петрович ТКАЧУК
Наталья Михайловна Тухватулина
Денис Юрьевич ЛОГУНОВ
Наиля Ахатовна ЗИГАНГИРОВА
Владимир Алексеевич ГУЩИН
Александр Леонидович ГИНЦБУРГ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NF Gamaleya Institute of Epidemiology and Microbiology
Original Assignee
NF Gamaleya Institute of Epidemiology and Microbiology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from RU2022132163A external-priority patent/RU2791523C1/ru
Application filed by NF Gamaleya Institute of Epidemiology and Microbiology filed Critical NF Gamaleya Institute of Epidemiology and Microbiology
Publication of WO2024123207A1 publication Critical patent/WO2024123207A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • A61K31/70—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical

Definitions

  • the group of inventions relates to chemistry, pharmaceuticals and medicine, namely to a new chemical compound derived from M4-hydroxycytidine, which can be used to inhibit the replication of RNA and DNA-containing viruses (coronavirus, Arbovirus and Orthopoxvirus).
  • Viruses carried by arthropods such as mosquitoes, ticks and flies, mainly belong to the families Flaviviridae, Togaviridae and Bunyaviridae, and are transmitted by them to humans or other vertebrates [10.1007/3-211-29981-5 4]. These viruses are transmitted to vertebrates through saliva when an infected arthropod vector feeds on blood. There are more than 250 species of arboviruses, and at least 80 of them cause human diseases, including hemorrhagic fever, encephalitis, arthritis and meningitis [10.1099/0022-1317-82-8-1867]. Diseases caused by arboviruses account for the majority of vector-borne diseases, and 80% of the world's population lives in areas where one is endemic
  • Poxviruses are widespread in almost all countries of the world.
  • M4-hydroxycytidine derivatives are known to be used for the treatment or prevention of viral infections, in particular, eastern, western and Venezuelan equine encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola fever, influenza, seasonal and pandemic coronaviruses (MERS). and SARS), respiratory syncytial virus (RSV) and Zika virus [WO2019113462, W02016106050, US20190022116].
  • EEE eastern, western and Venezuelan equine encephalitis
  • CHIK Chikungunya fever
  • Ebola fever influenza
  • seasonal and pandemic coronaviruses MERS
  • SARS respiratory syncytial virus
  • Zika virus WO2019113462, W02016106050, US20190022116.
  • N4-hydroxycytidine derivatives activity against new variants of SARS-CoV-2, as well as for other viruses, remains unknown.
  • the technical result of the claimed invention is the production of an ester derivative of H4-hydroxycytidine with a carboxylic acid, which has high activity against the SARS-CoV-2 coronavirus, arboviruses and exhibits an antiviral effect against Orthopoxviruses.
  • fig. 1 shows the preparation of M4-trityloxy-2',3'-O-isopropylidenecytidine (3).
  • FIG. 2 shows the preparation of 5'-O-(3-phenylpropionyl)-M4-hydroxycytidine(5).
  • FIG. 3 shows dose-dependent curves and 1C5o( ⁇ M) values of CPE inhibition of various variants of SARS-CoV-2 using the test compound.
  • FIG. 4 shows dose-dependent curves and ICso(pM) values of CPE inhibition of various Arbovirus variants using the test compound.
  • Figure 5 shows the dose-dependent curves and 1C5o( ⁇ M) values of inhibition of CPE of the smallpox vaccine strain (Lister)BHpyca using the test compound.
  • FIG. 6 presents data on the effectiveness of the resulting compound SN 9 against SARS-CoV-2 infection in vivo.
  • the dynamics of changes in the weight of animals before and after infection (A), changes in viral load (B) and virus titer (C) in lung tissues in the control group of animals and animals receiving the studied drugs are shown.
  • the vicinal 2' and 3' hydroxyl groups of P-P-4-hydroxycytidine (NHC)npn were blocked using acetonide protection.
  • the optimal reaction conditions were the use of para-toluenesulfonic acid (p-TSA) as a catalyst and the reaction in acetone at room temperature for 2 hours.
  • trityl (Tg) protecting group was chosen, the choice being due to the ease of introducing the protection, as well as its acid lability, which makes it possible to deblock all protective groups under acidic conditions.
  • the reaction was carried out in methylene chloride by the action of trityl chloride (Tr-Cl) in the presence of 4-dimethylaminopyridine (DMAP) as a catalyst, as well as triethylamine.
  • DMAP 4-dimethylaminopyridine
  • H4-dimethoxytrityloxy-2',3'-O-isopropylidenecytidine was reacted with phenylpropionic acid in the presence of 1,3-dicyclohexylcarbodiimide in methylene chloride, stirring was carried out at room temperature for 2 hours.
  • the intermediate product was purified on silica gel and subjected to acid hydrolysis by the action of an 80% aqueous solution of formic acid, stirred at room temperature for 20 hours.
  • the compound was isolated by flash chromatography on silica gel in the system chloroform:methanol (5% methanol).
  • the compound was obtained in 4 stages.
  • the synthesis scheme is presented in Fig. 1 and Fig. 2.
  • the intermediate product 2',3'-O-isopropylidene-K4-hydroxycytidine (2) was prepared (Fig. 1).
  • 3.7 g (19.69 mmol) of para-toluenesulfonic acid was added to 1.7 g (6.56 mmol) of N-hydroxycytidine (1) in dry acetone (240 ml), the resulting mixture was stirred at room temperature for 2 hours.
  • the reaction was neutralized by adding triethylamine, solvents distilled off, the residue was purified by flash chromatography on silica gel in the system chloroform:methanol (5% methanol).
  • the intermediate product M4-trityloxy-2',3'-O-isopropylidenecytidine (3) was obtained (Fig. 2).
  • 1.1 ml (8.06 mmol) of triethylamine and 7 mg (0.054 mmol) 4-dimethylaminopyridine the mixture was stirred for 15 minutes.
  • a solution of 1.5 g (5.37 mmol) of trityl chloride in dichloromethane (50 ml) was added dropwise to the reaction flask and stirred at room temperature overnight.
  • intermediate product (4) was exposed to an 80% aqueous solution of formic acid (5 ml), stirred at room temperature for 20 hours, evaporated and purified by flash chromatography on silica gel in a solvent mixture of chloroform:methanol (5% methanol).
  • Example 2 Study of antiviral effect against SARS-CoV-2 variants.
  • the purpose of this experiment is to evaluate the ability of the resulting compound (5'-O-(3-phenylpropionyl)-N4-hydroxycytidine) to inhibit the replication of various variants of the SARS-CoV-2 virus.
  • Cells were cultured in DMEM growth medium (Gibco, USA) supplemented with 5% fetal bovine serum (FBS; HyClone, USA), lx antibiotic-antimycotic (CapricomScientificGmbH) and 1x GlutaMAX (Gibco, USA).
  • FBS HyClone
  • lx antibiotic-antimycotic CapricomScientificGmbH
  • 1x GlutaMAX Gibco, USA.
  • Vero E6 cells (2x10 4 cells/well) were seeded in 96-well plates in complete growth medium DMEM the day before the experiment. Then, various dilutions of the test compound were added to the cell monolayer and incubated for 1 hour at 37°C and 5% CO 2 .
  • TCID50 is a tissue cytopathogenic dose that causes the death of 50% of the cells of the monolayer.
  • TCID50 is a tissue cytopathogenic dose that causes the death of 50% of the cells of the monolayer.
  • the following variants of the SARS-CoV-2 virus were used: “Wuhan” V.1.1 (PMVL-4), “Omicron” VA.4.6 (PMVL-55), “Omicron” VA.5 (PMVL-52) and “ Omicron” VA.5.2 (PMVL-54).
  • CPE virus-induced cytological effect
  • the purpose of this experiment is to evaluate the ability of the resulting compound (5'-O-(3-phenylpropionyl)-N4-hydroxycytidine) to inhibit the replication of various viruses from the Arbovirus group.
  • Vero E6 cell line ATCC CRL-1586.
  • Cells were cultured in DMEM growth medium (Gibco, USA) supplemented with 5% fetal bovine serum (FBS; HyClone, USA), 1x antibiotic-antimycotic (CapricomScientificGmbH) and 1x GlutaMAX (Gibco, USA).
  • FBS fetal bovine serum
  • CapricomScientificGmbH 1x antibiotic-antimycotic
  • GlutaMAX GlutaMAX
  • Example 4 Study of the antiviral effect against the smallpox virus.
  • the purpose of this experiment is to evaluate the ability of the resulting compound (5'-O-(3-phenylpropionyl)-N4-hydroxycytidine) to inhibit the replication of the smallpox virus.
  • Vego E6 cell line ATCC CRL-1586.
  • Cells were cultured in DMEM growth medium (Gibco, USA) supplemented with 5% fetal bovine serum (FBS; HyClone, USA), lx antibiotic-antimycotic (CapricomScientificGmbH) and 1x GlutaMAX (Gibco, USA).
  • FBS fetal bovine serum
  • CapricomScientificGmbH lx antibiotic-antimycotic
  • 1x GlutaMAX GlutaMAX
  • a vaccine strain of the smallpox virus (Lister; Microgen, Russia) and VegoEb cells were used.
  • the cells were infected with the smallpox virus at 100 TCID50.
  • Inhibition of the virus-induced cytopathic effect by the compound was determined using the MTT test 72 hours after infection. The results of the experiment are presented in Fig. 5.
  • Example 5 Study of the effectiveness of the resulting compound against the SARS-CoV-2 virus in animals.
  • the resulting compound can be introduced into the body of mammals by any route. Preliminary studies have shown that the optimal route of administration is the oral route. The maximum dose of the drug was determined as 350 mg/kg.
  • mice Female Syrian hamsters were used in the experiment. The animals were divided into two groups of 5 animals, which were administered:
  • intranasal infection of animals was carried out at 10 5 TCID5oSARS-CoV-2PMVL-4. Over the course of 4 days, the animals were administered the study drugs twice a day. day. After euthanasia of the animals on the fifth day of the experiment, they are autopsied and the lungs are collected. Hamster lungs were homogenized, followed by separation of the supernatant by low-speed centrifugation. The virus titer was determined in a monolayer of Vero E6 cells grown in 48-well plates. The virus titer for each lung homogenate sample was determined after 72 hours and expressed as PFU/mg lung.
  • the reverse transcription reaction was performed using a set of reagents for the quantitative determination of RNA of the coronavirus SARS-CoV-2 “SARS-CoV-2 FRT” using a panel characterized by the number of copies of the amplified fragment of SARS-CoV-2 (N.F. Gamaleya Research Center for Epidemiology and Microbiology). .
  • the results were expressed as numbers converted to log 10 SARS-CoV-2 viral load per mg of lung tissue.
  • the technical result of the invention is confirmed by the fact that the claimed compound - 5 O - (3 - phenyl propionyl)-N4-hydroxycytidine - differs from the known prototypes of H4-hydroxycytidine derivatives and exhibits a higher antiviral effect against the smallpox virus, various variants of SARS-CoV-2 and Arboviruses.
  • this compound exhibits therapeutic activity against SARS-CoV-2 infection in vivo, and can be used for the treatment/prevention of COVID-19.
  • the resulting compound (5'-O-(3-phenylpropionyl)-H4-hydroxycytidine) can be used in healthcare as a new drug for the treatment of various viral infections.
  • the developed and studied compound has a specific antiviral and multitarget effect.
  • Multi-targeting consists of an antiviral effect against various viral infections represented by coronaviruses SARS-CoV-2, Arboviruses and Orthopoxviruses.

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

Abstract

Ce groupe d'inventions se rapporte au domaine de la chimie, de la pharmacie et de la médecine, et concerne un nouveau composé chimique consistant en un dérivé de N4-hydroxycytidine qui peut être utilisé afin d'inhiber une réplication de virus contenant de l'ARN et de l'ADN (coronavirus, arbovirus et orthopoxvirus). Cette invention permet d'obtenir un nouveau composé chimique possédant une grande activité contre le coronavirus SARS-CoV-2, les arbovirus et présentant un effet antiviral contre les orthopoxvirus.
PCT/RU2023/000255 2022-12-08 2023-08-22 5'-о-(3-phénylpropionyl)-n4-hydroxycytidine et utilisation Ceased WO2024123207A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2022132163 2022-12-08
RU2022132163A RU2791523C1 (ru) 2022-12-08 5'-О-(3-фенилпропионил)-N4-гидроксицитидин и его применение

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WO2024123207A1 true WO2024123207A1 (fr) 2024-06-13

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016106050A1 (fr) * 2014-12-26 2016-06-30 Emory University N4-hydroxycytidine, ses dérivés et utilisations anti-virales
RU2015119999A (ru) * 2012-10-29 2016-12-20 Кокристал Фарма, Инк. Пиримидиновые нуклеозиды и их монофосфатные пролекарства для лечения вырусных инфекций и рака
WO2021137913A2 (fr) * 2019-10-08 2021-07-08 Emory University Compositions thérapeutiques à base de nucléosides et de nucléotides contenant du 4-halogène et utilisations associées
WO2021159044A1 (fr) * 2020-02-07 2021-08-12 Emory University N4-hydroxycytidine et ses dérivés et utilisations antivirales associées
CN113321694A (zh) * 2021-06-22 2021-08-31 药康众拓(江苏)医药科技有限公司 N4-羟基胞苷衍生物及其制备方法和用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2015119999A (ru) * 2012-10-29 2016-12-20 Кокристал Фарма, Инк. Пиримидиновые нуклеозиды и их монофосфатные пролекарства для лечения вырусных инфекций и рака
WO2016106050A1 (fr) * 2014-12-26 2016-06-30 Emory University N4-hydroxycytidine, ses dérivés et utilisations anti-virales
WO2021137913A2 (fr) * 2019-10-08 2021-07-08 Emory University Compositions thérapeutiques à base de nucléosides et de nucléotides contenant du 4-halogène et utilisations associées
WO2021159044A1 (fr) * 2020-02-07 2021-08-12 Emory University N4-hydroxycytidine et ses dérivés et utilisations antivirales associées
CN113321694A (zh) * 2021-06-22 2021-08-31 药康众拓(江苏)医药科技有限公司 N4-羟基胞苷衍生物及其制备方法和用途

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