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WO2023030347A1 - Utilisation de médicaments de type purine nucléoside pour la prévention ou le traitement de maladies infectieuses à coronavirus - Google Patents

Utilisation de médicaments de type purine nucléoside pour la prévention ou le traitement de maladies infectieuses à coronavirus Download PDF

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Publication number
WO2023030347A1
WO2023030347A1 PCT/CN2022/116003 CN2022116003W WO2023030347A1 WO 2023030347 A1 WO2023030347 A1 WO 2023030347A1 CN 2022116003 W CN2022116003 W CN 2022116003W WO 2023030347 A1 WO2023030347 A1 WO 2023030347A1
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acid
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常晓宇
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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
    • A61K31/7076—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
    • 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
    • A61K31/708—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 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • 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
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide

Definitions

  • the invention relates to a synthesis process of purine nucleoside drugs and its application in the preparation of drugs for preventing or treating coronaviruses, including novel coronavirus (Covid-19) infectious diseases.
  • Coronavirus is a class of enveloped positive-sense single-stranded RNA viruses that spread widely among humans, other mammals, and birds, and can cause respiratory, intestinal, liver, and nervous system diseases. Seven CoVs are currently known to cause disease in humans, four of which, HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1, circulate in humans and commonly cause common cold symptoms. The other three SARS-CoV, MERS-CoV and new coronavirus (COVID-19) all have serious hazards of fast onset, strong infectivity and high lethality.
  • the present invention provides the purposes of the compound represented by formula (I) or pharmaceutically acceptable salt thereof in the preparation of the medicament for preventing or treating coronavirus infectious disease;
  • X and Y are independently selected from: alkyl or substituted alkyl, halogen, -CN, -N 3 , -OH, -NH 2 , -NHR 3 , -NR 3 (R 3 ), -OR 3 or -SR 3 ;
  • R' and R are each independently selected from: -H, -COR 3 , -COOR 3 , -CONHR 3 or
  • Ar is selected from: aryl or substituted aryl, heteroaryl or substituted heteroaryl;
  • R and R are independently selected from: -H, alkyl or substituted alkyl, alkynyl or substituted alkynyl, alkenyl or substituted alkenyl, or 1-3 haloalkyl;
  • R 1 and R 2 form a 3-6 membered ring saturated aliphatic ring
  • Each R is independently selected from -H, alkyl or substituted alkyl, alkynyl or substituted alkynyl, alkenyl or substituted alkenyl, 1-3 haloalkyl or substituted alkyl, aryl or substituted aryl, or Heteroaryl or substituted heteroaryl;
  • substituents in the "substituted alkyl”, “substituted aryl”, “substituted heteroaryl”, “substituted alkynyl” and “substituted alkenyl” are each independently selected from: alkyl, halogen, -CN, -N 3 , -OH, -NH 2 , -NHR 3 , -NR 3 (R 3 ), -OR 3 , -SR 3 ;
  • halogen atoms in the "halogen” and “haloalkyl” are selected from F, Cl, Br or I;
  • alkyl in the "alkyl” and “haloalkyl” is a C 1-20 straight chain or branched chain alkyl, optionally a C 1-10 straight chain or branched chain alkyl, optionally a C 1-6 Straight chain or branched chain alkyl; alternatives are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, or isopentyl ;
  • the haloalkyl group is 2-chloroethyl, 2-fluoroethyl or trifluoroethyl;
  • alkynyl is C 2 -C 20 alkynyl; optional C 2 -C 10 alkynyl; optional acetylene;
  • alkenyl is C 2 -C 20 alkenyl; optionally C 2 -C 10 alkenyl; optionally vinyl;
  • aryl is a 6-10 membered aryl group; it can be phenyl or naphthyl;
  • heteroaryl is a 5-10 membered heteroaryl group containing at least one heteroatom selected from N, O or S in the ring.
  • X is selected from -H, -NH 2 , -NHR 3 , -NR 3 (R 3 ), -OR 3 or -SR 3 ;
  • Y is -NH 2 ;
  • R' is -H
  • R is -H or
  • R 1 and R 2 are independently selected from: -H or C 1-6 straight or branched chain alkyl
  • Each R 3 is independently C 1-6 straight chain or branched chain alkyl
  • Ar is selected from phenyl or substituted phenyl, naphthyl or substituted naphthyl;
  • the C 1-6 straight chain or branched chain alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-butyl Pentyl, or isopentyl.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II) or a pharmaceutically acceptable salt thereof,
  • X, Y, R' and R are as defined above.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,
  • X is -H, -NH 2 , -NHMe, -N(Me) 2 , -N(Me)(Et), -N(Et) 2 , -OMe, -OEt , -O(iPr), -SMe, -SEt, or -S(iPr);
  • Ar is phenyl or naphthyl.
  • Another aspect of the present invention provides the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is used for the preparation of Drugs for the prevention or treatment of coronavirus infectious diseases.
  • Another aspect of the present invention provides a method for preventing or treating coronavirus infectious diseases, which includes administering a therapeutically or preventively effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need.
  • the pharmaceutically acceptable salts include salts formed by compounds of formula (I) and inorganic acids or organic acids;
  • the inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, hemisulfuric acid, nitric acid, phosphoric acid, or carbonic acid;
  • the organic acids include formic acid, ascorbic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, glucose acid, tartaric acid, glucuronic acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzoic acid, benzenesulfonic acid, p-bromobenzenesulfonic acid, glutamic acid, salicylic acid, or pamoic acid;
  • the pharmaceutically acceptable salt is the hydrochloride salt of the compound of formula (I);
  • the pharmaceutically acceptable salt is the hemisulfate salt of the compound of formula (I).
  • the coronavirus infectious diseases include diseases caused by infecting humans or other animals;
  • the coronavirus includes HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV or COVID-19.
  • the dosage form of the drug is an immediate-release dosage form, a sustained-release dosage form, or a controlled-release dosage form;
  • the dosage form of the drug is tablet, capsule, aqueous or oily suspension, granule, emulsion, syrup, elixir, injection, or powder injection.
  • the present invention also provides a preparation method for the compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising subjecting compound 5 to the dihydroxylation reaction of step e, then to the cyclic sulfoesterification reaction of step f, and then to the step g adopting triethylamine trihydrofluoride to open the ring, and then undergoing the post-hydrolysis cyclization reaction and benzoylation of step h to obtain the step of intermediate compound 9;
  • step e the following reagents and conditions are used: KMnO 4 , NaHCO 3 , acetone;
  • step f the following reagents and conditions are used: SOCl 2 , EtN 3 , NaClO;
  • step g the following reagents and conditions are used: Et 3 N ⁇ 3HF, Et 3 N, HCl;
  • step h the following reagents and conditions are used: BaCl, BzCl, DMAP, Et 3 N, CH 3 CN;
  • the method further includes: using intermediate compound 9 to obtain compound 11 through the reduction reaction of step i and the bromination reaction of step j in sequence, Then compound 11 with response to get Purine nucleosides, which are then obtained through an esterification step
  • step i the following reagents and conditions are used: LiAlH[OC(CH 3 ) 3 ] 3 , THF;
  • step j the following reagents and conditions are used: PPh 3 , CBr 4 , DCM;
  • the method also includes: reacting compound 1 and ethyl acrylate to obtain compound 2 through step a, then brominating step b, hydrolyzing step c, and fluorination reaction step d to obtain compound 5. :
  • step a the following reagents and conditions are used: triethylenediamine (DABCO);
  • step b the following reagents and conditions are used: NBS, DMS, DCM;
  • step c the following reagents and conditions are used: sodium acetate, reflux conditions;
  • step d the following reagents and conditions are used: perfluorobutylsulfonyl fluoride, Et 3 N ⁇ 3HF.
  • Dissolve compound 3 (118 g, 0.40 mol) obtained in the previous step in 1 L of ethanol, add 100 g of anhydrous sodium acetate, and heat to reflux until the reaction of the raw materials is complete. The insoluble matter was filtered off, the temperature of the reaction solution was lowered to 0° C., sodium ethoxide (8.3 g, 0.10 mol) was added, and the temperature was kept until the reaction of the raw materials was complete.
  • the crude compound 10 obtained in the previous step was dissolved in dichloromethane, and PPh 3 (8.0g, 30.7mmol) was added at -20°C. After stirring for 20 minutes, CBr 4 (11.0g, 33.18mmol) was added, and the temperature was raised to 0°C to continue the reaction After 2 hours, after monitoring the completion of the reaction, 30 mL of water was added to quench the reaction, extracted with dichloromethane, and dried over anhydrous sodium sulfate.
  • Potassium tert-butoxide (3.0g, 26.43mmol) was added in batches to a solution of 2-chloro-6-aminopurine (4.5g, 26.43mmol) in 30mL of tert-butanol at room temperature, and after stirring for 1 hour at 30°C, the mixture The solution was poured into the acetonitrile solution of compound 11 (4.0 g, 8.81 mmol) obtained in the previous step, and the temperature was gradually raised to 50 ° C. After 16 hours, TLC monitored that the reaction was complete.
  • CPE cytopathic effect
  • test product III (synthesized in this laboratory), this product is white to light yellow solid. Seal and store in a cool place.
  • Ribavirin injection was purchased from Tianjin Jinyao Group Hubei Tianyao Pharmaceutical Co., Ltd., the batch number is 31712252, the specification is 100mg/ml, diluted to the required concentration when used, and stored in a refrigerator at 4°C.
  • H460 cells were inoculated in a 96-well plate at 1.5 ⁇ 104 cells/well, and after overnight culture, a maintenance solution containing the drug to be tested was added, and the drug to be tested was tested with 8 doses of three-fold dilution samples, and the culture was continued. After 3 days of administration, the toxicity of the drug to the cells under an inverted microscope (CPE method), and the half toxic concentration TC 50 was calculated by the Reed-Muench method, and the calculation formula was as follows:
  • A drug concentration with cumulative inhibitory rate ⁇ 50%
  • B cumulative inhibitory rate > 50% inhibitory rate
  • C cumulative inhibitory rate ⁇ 50% inhibitory rate
  • D log dilution factor
  • the experiment was carried out in the passaged H460 cells.
  • the cells were seeded in 96-well plates at 1.5 ⁇ 104 /well. After overnight culture, 100TCID 50 HCoV-OC43 virus liquid was used to infect the cells in the 96-well plates.
  • the drug to be tested was diluted with culture medium. Measuring at the same time as the infection, the drug to be tested was tested with three times diluted samples of 8 doses, each dose was set with 2 parallel wells, and the results were observed when the virus control group had lesions of 4+, recorded and analyzed by Reed-Muench
  • A drug concentration with cumulative inhibition rate ⁇ 50%
  • B inhibition rate with cumulative inhibition rate>50%
  • C inhibition rate with cumulative inhibition rate ⁇ 50%
  • D log dilution factor
  • the CC 50 of compound III determined by CPE method was >100 ⁇ M, and its IC 50 against HCoV-OC43 was 0.09 ⁇ M; the selection index SI was >1111; the positive control drug RBV half toxic concentration CC 50 was >0.36 ⁇ 0.06 ⁇ M, the IC50 against HCoV-OC43 is 0.015 ⁇ 0.01 ⁇ M, and the selection index SI is >24.
  • the anti-HCoV-OC43 activity of the positive drug RBV was comparable to the results in the literature, indicating that the experimental system was established.
  • Example 3 Test of compound III anti-new coronavirus 2019-nCoV (COVID-19) activity and cytotoxicity in vitro
  • Virus strain 2019-nCoV (COVID-19);
  • Positive control drug remdesivir
  • Reagents DMEM medium (Gibco), fetal bovine serum (Gibco), double antibody, trypsin, MTT (Amresco), etc.;
  • Kit QIAamp viral RNA mini kit (52906, Qiagen), One Step TB Green PrimeScript PLUS RT-PCR Kit (Perfect Real Time) (RR096A TaKaRa)
  • MTT assay The toxicity of compound III to Huh7 cells was detected by MTT assay.
  • the full name of MTT is 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenyltetrazoliumromide, which is a yellow dye.
  • MTT colorimetry is a method to detect cell survival and growth. The detection principle is that succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-purple crystalline formazan (Formazan) and deposit in the cells, while dead cells do not have this function.
  • 10% SDS (dissolved in 0.01mol/L HCl solution) can dissolve formazan in cells, and its light absorption value is measured at a wavelength of 570nm with a multifunctional microplate reader, which can indirectly reflect the number of living cells. Within a certain cell number range, the amount of MTT crystal formation is proportional to the cell number.
  • the survival rate of cells under the concentration of compound III can be calculated, thereby calculating the half-toxic concentration (CC 50 ) of compound III.
  • the antiviral activity was measured on the Huh7 cell model, and each experiment was set up with 3 replicate wells, which were repeated 3 times.
  • the One Step TB Green PrimeScript PLUS RT-PCR Kit (Perfect Real Time) kit was used for qRT-PCR detection, and the primers were RBD-qF1:5’-CAATGGTTTAACAGGCACAGG-3’; RBD-qR1:5’-CTCAAGTGTCTGTGGATCACG-3’.
  • the total volume of the reaction system is 20 ⁇ L: 10 ⁇ L 2X One Step TB Green RT-PCR Buffer 4, 1.2 ⁇ L TaKaRa Ex Taq HS Mix, 0.4 ⁇ L PrimeScript PLUS RTase Mix, 0.8 ⁇ L each of RBD-qF1 and RBD-qR1, 0.4 ⁇ L ROX Reference Dye (50X), 2 ⁇ L viral RNA, 4.4 ⁇ L RNase Free dH2O.
  • the reaction parameters were: reverse transcription at 42°C for 5min, pre-denaturation at 95°C for 10s, 40 cycles of PCR including denaturation at 95°C for 10s, annealing and extension at 60°C for 30s.
  • Test drug EC50 CC 50 Ti Compound III 0.08 ⁇ M >100 ⁇ M >1250 remdesivir 1.50 ⁇ M >45.0 ⁇ M >30.0
  • the concentration required for Compound III to inhibit 50% of the new coronavirus is 0.08 ⁇ M, while Redcivir requires 1.5 ⁇ M.
  • the activity of Compound III in inhibiting the new coronavirus is 18 times that of Redcivir, and the cytotoxicity is less .
  • compound III and its analogues have the effect of preventing or treating coronavirus infectious diseases.

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  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Biochemistry (AREA)
  • Virology (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne l'utilisation d'un composé tel que représenté dans la formule (I) ou d'un sel pharmaceutiquement acceptable de celui-ci dans la préparation de médicaments pour la prévention ou le traitement de maladies infectieuses à coronavirus. Le composé de formule (I) présente une activité significative dans l'inhibition de la réplication de nouveaux coronavirus dans des tests in vitro, et ne présente pas de cytotoxicité significative dans la plage de doses du test.
PCT/CN2022/116003 2021-09-01 2022-08-31 Utilisation de médicaments de type purine nucléoside pour la prévention ou le traitement de maladies infectieuses à coronavirus Ceased WO2023030347A1 (fr)

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CN202111018773.9A CN115721661A (zh) 2021-09-01 2021-09-01 嘌呤核苷类药物预防或治疗冠状病毒感染性疾病的用途
CN202111018773.9 2021-09-01

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Cited By (2)

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US11963967B2 (en) 2020-10-16 2024-04-23 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
US12030904B2 (en) 2020-08-24 2024-07-09 Gilead Sciences, Inc. Phospholipid compounds and uses thereof

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CN103980332A (zh) * 2013-12-09 2014-08-13 南京迈勒克生物技术研究中心 2′-氟-2′-(氟甲基)-2′-脱氧核苷类化合物及其磷酸酯潜药
CN106573011A (zh) * 2014-06-24 2017-04-19 艾丽奥斯生物制药有限公司 取代的核苷、核苷酸和其类似物
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US20040259934A1 (en) * 2003-05-01 2004-12-23 Olsen David B. Inhibiting Coronaviridae viral replication and treating Coronaviridae viral infection with nucleoside compounds
CN103980332A (zh) * 2013-12-09 2014-08-13 南京迈勒克生物技术研究中心 2′-氟-2′-(氟甲基)-2′-脱氧核苷类化合物及其磷酸酯潜药
CN106573011A (zh) * 2014-06-24 2017-04-19 艾丽奥斯生物制药有限公司 取代的核苷、核苷酸和其类似物
US20190085013A1 (en) * 2016-03-07 2019-03-21 Emory University Nucleotide and nucleoside therapeutic compositions and uses related thereto
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12030904B2 (en) 2020-08-24 2024-07-09 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
US12473314B2 (en) 2020-08-24 2025-11-18 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
US11963967B2 (en) 2020-10-16 2024-04-23 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
US12208110B2 (en) 2020-10-16 2025-01-28 Gilead Sciences, Inc. Phospholipid compounds and uses thereof

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