WO2024098856A1 - Dérivés anti-virus de la grippe et leur utilisation - Google Patents

Dérivés anti-virus de la grippe et leur utilisation Download PDF

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WO2024098856A1
WO2024098856A1 PCT/CN2023/111459 CN2023111459W WO2024098856A1 WO 2024098856 A1 WO2024098856 A1 WO 2024098856A1 CN 2023111459 W CN2023111459 W CN 2023111459W WO 2024098856 A1 WO2024098856 A1 WO 2024098856A1
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compound
formula
pharmaceutically acceptable
group
deuterium
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PCT/CN2023/111459
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Chinese (zh)
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张哲峰
李海德
侯雯
姜龙
潘伟
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石家庄迪斯凯威医药科技有限公司
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Publication of WO2024098856A1 publication Critical patent/WO2024098856A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention relates to a compound having anti-influenza virus activity or its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt, and a preparation method and use thereof in anti-influenza virus.
  • Influenza viruses mainly include influenza A virus, influenza B virus, influenza C virus and influenza D virus.
  • the number of influenza cases in my country has generally shown a rapid upward trend. According to data from the Chinese Center for Disease Control and Prevention, it has increased from 306,700 cases in 2016 to 3,538,213 cases in 2019, with 269 deaths in 2019. In the first quarter of 2020, the number of influenza cases in my country was 1,062,393, with 134 deaths. Since the epidemic situation of the Center for Disease Control and Prevention is reported only after it is confirmed, it is limited by the detection methods, and it is estimated that the reported epidemic situation is lower than the actual number of epidemics.
  • neuraminidase inhibitors include adamantane and rimantadine, which target influenza A viruses, but are resistant to currently prevalent influenza virus strains and are not recommended for use in diagnosis and treatment guidelines.
  • the hemagglutinin inhibitor arbidol has not entered the mainstream pharmaceutical market, and its clinical application data in my country is also limited.
  • Neuraminidase inhibitors include oseltamivir, zanamivir, laninamivir, and peramivir, with oseltamivir being the current market-leading drug.
  • neuraminidase inhibitors are currently experiencing drug resistance.
  • the influenza virus genome is very small, and the synthesis of the proteins it needs depends on the host cell's translation system. Therefore, the messenger RNA (mRNA) of the influenza virus needs to have both a 5' cap (CAP) structure and a 3'-poly (A) tail structure that can be recognized by the host cell's translation system.
  • the 5' cap structure is obtained from the host cell's precursor mRNA by the endonuclease activity of the PA subunit in the influenza virus RNA polymerase complex. The 5′ end is “snatched” by cleavage. This method, called “CAP-snatching”—seizing the CAP cap structure of the host mRNA for the virus’ own mRNA transcription—is necessary for the initiation of influenza virus transcription.
  • the RNA polymerase of influenza virus contains a cap-dependent endonuclease. Inhibiting the activity of the cap-dependent endonuclease can inhibit the proliferation of the virus.
  • the enzyme has become a promising target for the development of antiviral drugs.
  • Many companies have turned their attention to cap-dependent endonucleases, and different heterocyclic compounds have been used as cap-dependent endonuclease inhibitors.
  • baloxavir has been reported to have drug resistance.
  • it also exhibits poor physical and chemical properties: such as low solubility and low bioavailability. Therefore, it is still necessary to develop a new generation of cap-dependent endonuclease inhibitors.
  • a class of cyclopropyl-containing compounds has a high-efficiency and broad-spectrum anti-influenza virus effect, and is expected to be developed into an anti-influenza virus drug; further structural optimization has found a molecule with higher activity and better drugability.
  • the compounds of the present invention inhibit the cap-dependent nuclease in influenza virus, inhibit viral replication, target the earlier stage of the viral replication cycle, and thus have a better effect in preventing and treating influenza.
  • the present invention provides a compound having anti-influenza virus effect, a preparation method and use thereof.
  • the present invention provides a compound represented by the following formula (I) or its hydrate, solvate, optical isomer, polymorph, isotope derivative, and pharmaceutically acceptable salt:
  • R a is selected from hydrogen, deuterium, methyl or deuterated methyl
  • R b and R c are each independently selected from hydrogen, deuterium, C1-C3 alkyl, deuterated C1-C3 alkyl, or R b , R c and the carbon atom to which they are attached together form a cyclopropyl group or a deuterated cyclopropyl group;
  • Y 1 , Y 2 , Y 3 and Y 4 are each independently CH or N, and at least one of them is N;
  • X is Se or S
  • R is hydrogen, in,
  • X1 is an O atom or a S atom
  • n1 0, 1 or 2;
  • Each R 1 or R 2 is independently selected from hydrogen, deuterium, methyl or deuterated methyl;
  • R3 is selected from the following groups in which one or more hydrogen atoms are substituted by deuterium or not: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 alkylamino;
  • R4 and R5 are each independently hydroxyl, or one or more hydrogen atoms of the following groups substituted with or not substituted with deuterium: C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 alkylamino, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C6-C10 aryloxy, C7-C12 aralkyloxy; or R4 and R5 together with the attached phosphorus atom form the following wherein R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently hydrogen or a C1-C3 alkyl group, or R 6 and R 7 , R 8 and R 9 , R 11 and R 12 , R 12 and R 13 are each jointly connected to the carbon atom An aromatic ring is formed, and one or more of the hydrogen atoms in the 5-7 membered ring formed by R4 and R5
  • the compound provided by the present invention or its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt is as shown in formula (II-1) and/or formula (II-2):
  • the compound provided by the present invention or its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt is as shown in formula (III-1) and/or formula (III-2):
  • the compound provided by the present invention or its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt is as shown in formula (IV-1) and/or formula (IV-2):
  • the solvate refers to a complex formed by the interaction of a compound with a pharmaceutically acceptable solvent
  • the pharmaceutically acceptable solvent includes ethanol, isopropanol, acetic acid, and ethanolamine.
  • the C1-C8 alkyl group refers to a straight-chain or branched saturated aliphatic hydrocarbon group containing 1 to 8 carbon atoms in the molecule, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, etc.
  • the C1-C8 alkoxy group and C1-C8 alkylthio group refer to a group in which an oxygen atom or a sulfur atom is inserted at any reasonable position in a saturated aliphatic hydrocarbon group containing 1 to 8 carbon atoms in the molecule, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-ethylethoxy, methylthio, ethylthio, propylthio, isopropylthio, isobutylthio and the like.
  • the C1-C8 alkylamino group refers to a saturated aliphatic hydrocarbon group containing 1 to 8 carbon atoms in the molecule with an -NH- or -NH2 group inserted in any reasonable position, including monoalkylamino, dialkylamino and cycloalkylamino, including but not limited to methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino and the like.
  • the C1-C3 alkyl group refers to an alkane containing 1 to 3 carbon atoms in the molecule, including: methyl, ethyl, propyl, isopropyl, and cyclopropyl.
  • the C3-C8 cycloalkoxy group refers to a monocyclic or condensed polycyclic saturated or unsaturated cyclic hydrocarbon group containing 3 to 8 carbon atoms, including but not limited to cyclopropyloxy, cyclopentyloxy, bicyclo[3.1.0]hexyloxy, bicyclo[3.2.0]heptyloxy, etc.
  • the C3-C8 heterocycloalkoxy group refers to a group in which a C3-C8 heterocycloalkyl group is connected to oxygen
  • the C3-C8 heterocycloalkyl group refers to a saturated or unsaturated cyclic group containing 3 to 8 carbon atoms and 1 to 4 heteroatoms in the molecule
  • the C3-C8 heterocycloalkyl group includes but is not limited to aziridine, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, hexahydropyridazinyl, dihydropyridinyl, cyclopentyl sulfide, morpholinyl and the like.
  • the C6-C10 aryloxy group refers to a group consisting of an aromatic ring of 6 to 10 carbon atoms connected to an oxygen atom, including but not limited to phenoxy and naphthoxy.
  • the C7-C12 aralkyloxy group refers to a group consisting of an arylalkyl group consisting of 7 to 12 carbon atoms connected to an oxygen atom, including but not limited to benzyloxy, phenethyloxy, and the like.
  • the group in which one or more hydrogen atoms are substituted by deuterium means that the hydrogen atom at any reasonable position in the group can be substituted by a deuterium atom.
  • the deuterated C1-C8 alkyl group means that any hydrogen atom in the C1-C8 alkyl group can be replaced by deuterium, and the deuterated hydrogen atoms can be one or more, and can be on the same carbon atom or on different carbon atoms.
  • the deuterated C1-C8 alkyl group includes but is not limited to deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated isobutyl, deuterated pentyl, deuterated hexyl, and deuterated heptyl.
  • the C1-C8 alkoxyl group in which one or more hydrogen atoms are replaced by deuterium means that any hydrogen atom in the C1-C8 alkoxyl group can be replaced by deuterium, and the deuterated hydrogen atoms can be one or more, and can be on the same carbon atom or on different carbon atoms.
  • the C1-C8 alkoxyl group in which one or more hydrogen atoms are replaced by deuterium includes but is not limited to deuterated methoxyl, deuterated ethoxyl, deuterated propoxyl, deuterated isopropoxyl, deuterated butoxyl, deuterated isobutoxyl, deuterated pentaneoxyl, deuterated hexaneoxyl, and deuterated heptaneoxyl.
  • Ra is hydrogen; in some embodiments, Ra is deuterium; in some embodiments, Ra is methyl; in some embodiments, Ra is deuterated methyl.
  • R b and R c are both hydrogen; in some embodiments, R b and R c are both deuterium; In some embodiments, R b is hydrogen and R c is deuterium;
  • R b and R c are each independently C1-C3 alkyl; in some specific embodiments, R b and R c are both methyl;
  • R b and R c are each independently a deuterated C1-C3 alkyl group; in some specific embodiments, R b and R c are both deuterated methyl groups;
  • R b is hydrogen, R c is C1-C3 alkyl; in some specific embodiments, R b is hydrogen, R c is methyl;
  • R b is hydrogen, and R c is deuterated C1-C3 alkyl; in some specific embodiments, R b is hydrogen, and R c is deuterated methyl.
  • R b is deuterium, and R c is C1-C3 alkyl; in some specific embodiments, R b is deuterium, and R c is methyl;
  • R b is deuterium, and R c is a deuterated C1-C3 alkyl group; in some specific embodiments, R b is deuterium, and R c is a deuterated methyl group;
  • R b is C1-C3 alkyl, and R c is deuterated C1-C3 alkyl;
  • R b and R c together with the carbon to which they are attached form a cyclopropyl group; in some embodiments, R b and R c together with the carbon to which they are attached form a deuterated cyclopropyl group.
  • Y 1 , Y 2 , Y 3 and Y 4 are each independently CH or N, and at least one of them is N;
  • Y 1 is N, and Y 2 , Y 3 and Y 4 are each independently CH or N; In some specific embodiments, Y 1 is N, and Y 2 , Y 3 and Y 4 are each independently CH;
  • Y2 is N, Y1 , Y3 and Y4 are each independently CH or N; in some specific embodiments, Y3 is N, Y1 , Y2 and Y4 are each independently CH or N; in some specific embodiments, Y4 is N, Y1 , Y2 and Y3 are each independently CH or N.
  • X is Se; in some embodiments, X is S.
  • R is hydrogen; in some embodiments, R is exist In some embodiments, R is
  • n1 is 0; in some embodiments, n1 is 1; in some embodiments, n1 is 2.
  • X 1 is an O atom; in some embodiments, X 1 is a S atom.
  • each R 1 or R 2 is independently hydrogen, deuterium, methyl or deuterated methyl; in some specific embodiments, R 1 or R 2 is methyl; in some specific embodiments, R 1 is methyl and R 2 is hydrogen; in some specific embodiments, R 1 or R 2 is hydrogen; in some specific embodiments, R 1 or R 2 is deuterated methyl, including methyl in which 1 or 2 or 3 hydrogens are replaced by deuterium; in some specific embodiments, R 1 is methyl and R 2 is deuterium; in some specific embodiments, R 1 or R 2 is deuterium; in some specific embodiments, R 1 is hydrogen and R 2 is deuterated methyl.
  • R 3 is selected from the following groups: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio, C1-C18 alkylamino; preferably, R 3 is selected from the following groups: C1-C8 alkyl, C1-C8 alkoxy; more preferably, R 3 is C1-C8 alkoxy;
  • R 3 is selected from the following groups in which one or more hydrogen atoms are replaced by deuterium: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio, C1-C18 alkylamino; preferably, R 3 is selected from the following groups in which one or more hydrogen atoms are replaced by deuterium: C1-C8 alkyl, C1-C8 alkoxy; more preferably, R 3 is C1-C8 alkoxy in which one or more hydrogen atoms are replaced by deuterium.
  • n1 is 1, X1 is an O atom, R1 and R2 are both hydrogen, and R3 is a C1-C8 alkoxy group or a C1-C8 alkyl group; In some specific embodiments, n1 is 1, X1 is an O atom, R1 and R2 are both deuterium, and R3 is a C1-C8 alkoxy group or a C1-C8 alkyl group;
  • n1 is 1, X1 is an O atom, R1 and R2 are both hydrogen, and R3 is a deuterated C1-C8 alkoxy group or a deuterated C1-C8 alkyl group; In some specific embodiments, n1 is 1, X1 is an O atom, R1 and R2 are both deuterium, and R3 is a deuterated C1-C8 alkoxy group or a deuterated C1-C8 alkyl group;
  • n1 is 0, X1 is an O atom, and R3 is a C1-C8 alkoxy group. or a C1-C8 alkyl group;
  • n1 is 1, X1 is an O atom, R1 is hydrogen, R2 is a deuterated methyl group, and R3 is a deuterated C1-C8 alkoxy group or a deuterated C1-C8 alkyl group.
  • R 4 and R 5 are both hydroxyl groups; in some embodiments, R 4 and R 5 are the following groups: C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 alkylamino, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C6-C10 aryloxy, C7-C12 aralkyloxy; in some embodiments, R 4 and R 5 are the following groups in which one or more hydrogen atoms are replaced by deuterium: C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 alkylamino, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C6-C10 aryloxy, C7-C12 aralkyloxy;
  • R4 and R5 together with the attached phosphorus atom form wherein R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently hydrogen or a C1-C3 alkyl group, or R 6 and R 7 , R 8 and R 9 , R 11 and R 12 , R 12 and R 13 each together with the carbon atom to which they are connected form an aromatic ring;
  • R4 and R5 together with the attached phosphorus atom form wherein, one or more of the hydrogen atoms in the 5-7 membered ring formed by R 4 and R 5 together with the phosphorus atom to which they are connected and the substituents on the ring may be substituted with deuterium.
  • n1 is 1, X1 is an O atom, R1 and R2 are both hydrogen, and R4 and R5 are both hydroxyl groups; in some specific embodiments, n1 is 1, X1 is an O atom, R1 and R2 are both deuterium, R 4 and R 5 are hydroxyl groups; in some specific embodiments, n1 is 1, X 1 is an O atom, R 1 is hydrogen, R 2 is a deuterated methyl group, R 4 and R 5 are hydroxyl groups; in some specific embodiments, n1 is 0, X 1 is an O atom, R 4 and R 5 are hydroxyl groups.
  • the pharmaceutically acceptable salt of the compound may be an alkali metal salt, an alkaline earth metal salt, an amine salt, and an amino acid salt; preferably, the pharmaceutically acceptable salt includes: sodium salt, potassium salt, magnesium salt, zinc salt, amine salt, basic amino acid salt, and the like.
  • the pharmaceutically acceptable salts of the compound may be alkali metal salts, alkaline earth metal salts, amine salts and amino acid salts; preferably, the pharmaceutically acceptable salts include: sodium salts, potassium salts, magnesium salts, zinc salts, amine salts, basic amino acid salts and the like.
  • the salt involved in the present invention is obtained by conventional salt-forming method.
  • the pharmaceutically acceptable salt is structurally confirmed by means of nuclear magnetic resonance, mass spectrometry, atomic absorption spectroscopy, elemental analysis, melting point detection, etc.
  • formula (I) contains two chiral centers, and the compounds of the present invention or their intermediates can be obtained by chiral separation to obtain single-configuration compounds.
  • the compounds of the present invention are optical isomers of a single configuration as shown in formula (I).
  • the absolute configuration of optical isomers of a single configuration is determined by electronic circular dichroism spectroscopy.
  • the racemate and the optical isomer of a single configuration are tested for optical rotation according to the optical rotation determination method of the Chinese Pharmacopoeia 2020 Edition-Part IV-0621.
  • the compounds provided by the present invention include but are not limited to the following compounds:
  • the materials N158-1 and N158-3 required for the synthesis of the compounds of the present invention are synthesized completely according to the method in document WO202214834A1; the materials N158-2 and N158-4 are synthesized with reference to the synthesis method of N158-1 and N158-3.
  • Another aspect of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound or its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier includes one or a combination of fillers, binders, diluents, lubricants, preservatives, taste masking agents or cosolvents.
  • the pharmaceutical composition is in the form of tablets, capsules, powders, granules, pills, suspensions, syrups, injections or inhalation preparations.
  • the present invention provides the above-mentioned compound, including its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt, or its pharmaceutical preparation.
  • Composition for use against influenza virus including its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt, or its pharmaceutical preparation.
  • the present invention provides the above-mentioned compound, including the compound, including its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt, or use of its pharmaceutical composition in preparing anti-influenza virus drugs.
  • the present invention provides a method for preventing or treating influenza virus infection, which comprises administering a therapeutically effective amount of the above-mentioned compound, including its hydrates, solvates, optical isomers, polymorphs, isotope derivatives, and pharmaceutically acceptable salts, to an individual in need thereof.
  • the compounds of the present invention have stronger antiviral activity both in vivo and in vitro, and have better safety. They are effective against a variety of influenza virus strains, including avian influenza virus strains, and are also effective against oseltamivir-resistant influenza viruses and other drug-resistant strains;
  • the compounds of the present invention have a stronger ability to enter cells. It is known that this type of structure is a cap-dependent nuclease inhibitor, which needs to enter cells to play a role in the process of viral replication.
  • the compounds of the present invention have a strong ability to enter cells and are more conducive to inhibiting viral replication;
  • the compound of the present invention has good lung tissue distribution in animal experiments, which is more conducive to exerting its anti-influenza virus effect;
  • the compound of the present invention has lower vascular irritation when administered by injection, and studies have also shown that the irritation of the compound by intravenous injection is acceptable, and it is expected to be used for intravenous administration to patients with severe influenza.
  • the lung virus titer was lower and the lesions of the lung tissue were milder; it showed outstanding advantages in weight protection and survival protection, showing the characteristics of rapid recovery after viral infection.
  • Figure 1 shows the body weight change rate of the anti-influenza virus efficacy mouse model.
  • the solvents and reagents used in this example are all common commercial products.
  • the starting materials are all purchased commercial raw materials.
  • Comparative Example compounds M39 and M40 were synthesized by referring to the synthesis method of compounds DSC1581 and DSC1583.
  • Comparative Example compounds M43, M44 and M45 were synthesized by referring to the synthesis method of compound DSC1585.
  • MDCK cells were inoculated in a 96-well culture plate and cultured in a 5% CO 2 , 37°C incubator. During the cell exponential growth phase, cell culture maintenance medium containing samples of different dilutions and positive control drugs was added, with 3 replicate wells for each concentration and a normal cell control well. After adding the sample, the cells were cultured for 72 hours, and the cytotoxicity test of the sample was performed using the CPE method. MDCK cells were also inoculated in a 96-well culture plate and cultured in a 5% CO 2 , 37°C incubator. Cultured in a 37°C incubator. After 24 hours of culture, the cells were infected with influenza virus (A/Hterrorism/359/95 (H3N2)).
  • influenza virus A/Hterrorism/359/95 (H3N2)
  • the virus solution was discarded and cell culture maintenance solution containing samples of different dilutions and positive control drugs was added. Three replicate wells were set for each concentration. Cell control wells and virus control wells were also set up. The cells were cultured in a 5% CO 2 , 37°C incubator.
  • the antiviral test of the test samples was carried out by the CPE method. When the cytopathic effect (CPE) of the virus control group reached 4+, the cytopathic effect (CPE) of each group was observed.
  • the half toxic concentration (TC 50 ) of the sample to cells and the effective concentration (EC 50 ) of the drug that inhibited 50% cytopathic effect were calculated by the Reed-Muench method, as shown in Table 1:
  • the experiment shows that the compounds of the present invention have good anti-influenza virus activity.
  • the antiviral activity of the compounds DSC1581, DSC1582 and DSC1821 to DSC1824 in the present invention is significantly better and safer.
  • the prodrug compounds DSC1583 to DSC15811, DSC1825 to DSC18211 in the present invention also have better antiviral activity and higher safety.
  • Example 14 Vascular irritation test of intravenous administration
  • the experiment used the same rabbit's left and right ears as self-control, with the left ear vein dripping the test drug, and the right ear vein dripping an equal volume of normal saline.
  • the drug concentration was 0.2 mg/mL, the dosage was 5 mL/kg, and the drug administration time was 2.8 min.
  • Sample preparation and use Weigh each compound accurately, dissolve it in physiological saline, and prepare a physiological saline solution with a concentration of 0.2 mg/ml. All samples were prepared one day before the first use, sealed and stored at 2-8°C. Before each use, the solution was restored to room temperature, filtered with a 0.22-micron polyethersulfone microporous filter membrane, and then administered intravenously. Aseptic operation was performed as much as possible during the process.
  • the general condition of the rabbits was observed before, during, after, and 24, 48, and 72 hours after administration, and the injection site was observed with the naked eye and photographed. After the observation period, the rabbits were euthanized, and the ear tissues were collected and HE stained for pathological examination.
  • Pathological sampling Before sampling, the rabbits’ ear hair was carefully removed to avoid damaging the skin. Three parts of the left ear were cut from all animals: the distal end of the ear that was not injected (marked as A1, not mechanically stimulated); 1.5 cm from the injection site (marked as A2, to observe the reaction caused by acupuncture, bleeding and drug stimulation); 3 cm from the injection site (marked as A3, the ear was not physically stimulated but only stimulated by the drug)
  • the blank control group selected the right ear of the animals in group 1 and cut three parts of the ear: the distal end of the ear that was not injected (marked as B1, not mechanically stimulated); 1.5 cm away from the injection site (marked as B2, to observe the reactions caused by acupuncture, bleeding and drug stimulation); 3 cm away from the injection site (marked as B3, the ear was not physically stimulated, but only the reaction caused by direct stimulation of the blood vessels by saline). Cut a 0.5 cm long ear piece from each site.
  • HE staining was used for pathological examination, and the pathological changes of the inspection site were described in detail, and the vascular irritation was analyzed and judged.
  • the main observations were: whether the skin epidermis was swollen, ulcerated, or bleeding; whether the elastic tissue of the endothelial cells and the adventitia of the blood vessels had lesions and vascular ruptures; intravascular thrombi and the area of the cross-sectional area of the lumen; and lesions of the soft tissue around the blood vessels.
  • the main pathological changes were summarized in Table 6:
  • the rabbits in Group 2 did not struggle, the rabbits in Group 1 struggled slightly, and the rabbits in Groups 3, 4, and 5 all struggled significantly; after administration, the rabbits in each group showed varying degrees of local redness and swelling of the blood vessels, but compared with Groups 3, 4, and 5, the symptoms of the rabbits in Groups 1 and 2 were significantly milder, and the scores observed with the naked eye were also lower; the histopathological results showed that no necrosis of the vascular endothelium or extravascular tissue, nor inflammatory cell infiltration, was observed in each group, but it can also be clearly seen that the rabbits in Groups 3, 4, and 5 had more obvious pathological changes, and relatively speaking, the changes in Groups 1 and 2 were milder; during the recovery period, the rabbits in each group showed The vascular irritation symptoms that appeared gradually recovered.
  • the compound of the present invention has a milder vascular irritation when administered by intravenous drip.
  • Example 15 Drug concentration in peripheral blood mononuclear cells (PBMC)
  • 12 cynomolgus monkeys were randomly divided into three groups according to body weight and gender, with 4 monkeys in each group, half male and half female. They were weighed before administration, and the test article DSC1581 was intravenously infused in group 1, the test article M46 was intravenously infused in group 2, and the test article M41 was intravenously infused in group 3.
  • the dosage was 1 mg/kg, the administration volume was 5 ml/kg, and the intravenous infusion time was 20 min.
  • the blood samples were collected before administration (0 h), 1 h, 6 h, 10 h, 12 h, 14 h, 18 h, 24 h, 30 h, 36 h, 48 h and 72 h after the start of administration.
  • Blood was collected from the femoral vein (2 mL whole blood/mouse/time point), anticoagulated with K 2 EDTA, and placed on ice after collection. Blood samples were centrifuged at 20 ⁇ 2 ° C, and PBMCs were isolated within 2 hours after whole blood collection. After the PBMC samples were processed, the test compound was detected by LC-MS/MS method.
  • the AUC 0-t of the DSC1581 group was 36.16 h*ng/1000000 PBMC
  • the AUC 0-t of the M46 group was 30.75 h*ng/1000000 PBMC
  • the AUC 0-t of the M41 group was 27.54 h*ng/1000000PBMC
  • AUC 0- ⁇ of DSC1581 group was 36.84h*ng/1000000PBMC
  • AUC 0- ⁇ of M46 group was 31.79h*ng/1000000PBMC
  • AUC 0- ⁇ of M41 group was 28.13h*ng/1000000PBMC
  • t 1/2 of DSC1581 group was 14.34h
  • t 1/2 of M46 group was 11.68h
  • t 1/2 of M41 group was 12.72h.
  • the exposure of DSC1581 increased by 17.6% and 31.3%, respectively, and the half-life was longer, which indicates that DSC1581 has a stronger ability to enter cells.
  • Example 16 In vivo antiviral test
  • mice Female BALB/c mice aged 6-8 weeks and free of specific pathogens were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd. After 3 days of adaptive feeding, 30 mice were selected and randomly divided into 5 groups: Group A, Group B, Group C, Group D and Group E, 6 mice in each group; the solvent was 0.5% sodium carboxymethylcellulose (CMC-Na) solution, and the positive control drug and the test sample were suspended in 0.5% CMC-Na solution before administration.
  • Group A was the solvent group and was given 0.5% sodium carboxymethylcellulose (CMC-Na) solution;
  • Group B was given a suspension of baloxavir;
  • Group C was given a suspension of DSC1583;
  • Group D was given a suspension of M47;
  • Group E was given a suspension of M42;
  • mice were inoculated with virus (Influenza Virus, A/PR/8/34(H1N1)) by intranasal drops on day 0, with an inoculation dose of 900 p.f.u./mouse. From day 1 to day 7, the mice were treated with the vehicle or the test article for 7 consecutive days, twice a day, by gavage, with a dosing volume of 10 mL/kg. Except for the vehicle group, the dosing dose of all other groups was 5 mg/kg, and the first dosing time was 24 hours after virus inoculation. The animals were continuously observed from day 0 to day 14, and the body weight, health and survival status were recorded. The body weight change rate is shown in Figure 1.
  • the test results showed that the animals in the vehicle group developed infection symptoms after virus inoculation, their weight decreased rapidly and significantly, and eventually all died, with a survival rate of 0%; the control drug baloxavir dipyrone (5 mpk) could alleviate the weight loss of mice caused by virus infection under the set experimental conditions (the maximum decrease was -2.29%), protect mice from death, and the final survival rate was 100%, showing the expected in vivo anti-influenza virus efficacy; the test compound M42 (5 mpk) could alleviate the weight loss of mice caused by virus infection under the set experimental conditions (the maximum decrease was -3.49%), protect mice from death, and the final survival rate was 100%; the test compound M47 (5 mpk) could alleviate the weight loss of mice caused by virus infection under the set experimental conditions.
  • test compounds M42 and M47 showed the expected in vivo anti-influenza virus efficacy.
  • the test compound DSC1583 (5 mpk) could significantly alleviate the weight loss of mice caused by viral infection (the maximum decrease was -0.41%) under the set experimental conditions, protect mice from death, and the final survival rate was 100%, showing the expected in vivo anti-influenza virus efficacy.
  • the weight of animals in the DSC1583 group basically did not decrease, the weight of animals in the baloxavir group and the M42 group recovered on about the 8th day, and the weight of animals in the M47 group recovered on the 11th day.

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Abstract

La présente invention concerne des dérivés antiviraux efficaces et leur utilisation. Lesdits dérivés sont des composés représentés par la formule (I) suivante, ou des hydrates, des solvates, des isomères optiques, des polymorphes, des dérivés d'isotopes et des sels pharmaceutiquement acceptables de ceux-ci. L'invention concerne également un procédé de préparation des dérivés. Les composés fournis par la présente invention peuvent être utilisés pour préparer des médicaments pour prévenir/traiter des virus de la grippe.
PCT/CN2023/111459 2022-11-09 2023-08-07 Dérivés anti-virus de la grippe et leur utilisation WO2024098856A1 (fr)

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CN110637016A (zh) * 2018-01-17 2019-12-31 银杏树药业(苏州)有限公司 吡啶酮衍生物、其组合物及作为抗流感病毒药物的应用
CN112778330A (zh) * 2019-11-05 2021-05-11 上海翰森生物医药科技有限公司 含吡啶酮多环类衍生物抑制剂、其制备方法和应用
CN113226327A (zh) * 2019-07-11 2021-08-06 南京征祥医药有限公司 可用于治疗流感病毒感染的化合物
WO2022148434A1 (fr) * 2021-01-08 2022-07-14 辉诺生物医药科技（杭州）有限公司 Dérivés cycliques de pyridone à éléments multiples et leur utilisation
CN115135646A (zh) * 2019-12-23 2022-09-30 石家庄迪斯凯威医药科技有限公司 取代的多环化合物及其药物组合物和用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103228653A (zh) * 2010-09-24 2013-07-31 盐野义制药株式会社 被取代的多环性氨基甲酰基吡啶酮衍生物的前药
CN110637016A (zh) * 2018-01-17 2019-12-31 银杏树药业(苏州)有限公司 吡啶酮衍生物、其组合物及作为抗流感病毒药物的应用
CN113226327A (zh) * 2019-07-11 2021-08-06 南京征祥医药有限公司 可用于治疗流感病毒感染的化合物
CN112778330A (zh) * 2019-11-05 2021-05-11 上海翰森生物医药科技有限公司 含吡啶酮多环类衍生物抑制剂、其制备方法和应用
CN115135646A (zh) * 2019-12-23 2022-09-30 石家庄迪斯凯威医药科技有限公司 取代的多环化合物及其药物组合物和用途
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