WO2023072292A1 - Composé antiviral efficace et son utilisation - Google Patents

Composé antiviral efficace et son utilisation Download PDF

Info

Publication number
WO2023072292A1
WO2023072292A1 PCT/CN2022/128843 CN2022128843W WO2023072292A1 WO 2023072292 A1 WO2023072292 A1 WO 2023072292A1 CN 2022128843 W CN2022128843 W CN 2022128843W WO 2023072292 A1 WO2023072292 A1 WO 2023072292A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
group
synthesis
Prior art date
Application number
PCT/CN2022/128843
Other languages
English (en)
Chinese (zh)
Inventor
张哲峰
李海德
侯雯
姜龙
潘伟
Original Assignee
南京知和医药科技有限公司
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
Application filed by 南京知和医药科技有限公司 filed Critical 南京知和医药科技有限公司
Publication of WO2023072292A1 publication Critical patent/WO2023072292A1/fr

Links

Images

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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/503—Pyridazines; Hydrogenated pyridazines spiro-condensed
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems
    • 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
    • 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
    • C07F11/00—Compounds containing elements of Groups 6 or 16 of the Periodic Table

Definitions

  • the present invention relates to a compound with anti-influenza virus activity or its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt, its preparation method and use in anti-influenza virus .
  • Influenza viruses mainly include four types of influenza A virus, influenza B virus, influenza C virus and influenza D virus.
  • influenza A virus and influenza B virus are the main human influenza viruses, and influenza A virus is one of them.
  • influenza A virus is one of them.
  • the strongest, the number of people infected is the largest during the flu-prone season, and can induce severe respiratory infections, causing more than 300,000 people to die from influenza every year in the world.
  • tens of millions of people are infected with influenza virus every year, especially among infants and the elderly, the morbidity and mortality are relatively high, and it can cause pneumonia and other diseases.
  • RNA polymerase of influenza virus contains a cap-dependent endonuclease (Cap-dependent endonuclease), and inhibiting the activity of the cap-dependent endonuclease can inhibit the proliferation of the virus.
  • Cap-dependent endonuclease a cap-dependent endonuclease
  • This enzyme has become a promising candidate for the development of antiviral drugs.
  • Targets, different heterocyclic compounds have been used as cap-dependent endonuclease inhibitors.
  • the invention provides a class of compounds with anti-influenza virus effects.
  • Most of the existing drugs play an anti-influenza virus effect by targeting neuraminidase, and the compound of the present invention plays a role in inhibiting virus replication by inhibiting the cap-dependent endonuclease in the influenza virus. Targets the earlier stage of the virus replication cycle, so it has a better effect on preventing and treating influenza. It has shown better anti-influenza virus effects in vitro or in vivo, and is expected to treat resistance to oseltamivir and avian influenza strains (H7N9, H5N1).
  • the compound of the present invention shows better anti-influenza virus effect in the in vivo and in vitro drug efficacy test, and also shows better in vivo exposure in the animal pharmacokinetic test.
  • the lung virus titer of the test animal was lower, and the pathological changes in the lung tissue were milder, indicating that the anti-influenza virus activity of the compound of the present invention was significantly improved;
  • the compounds of the present invention have good lung tissue distribution in animal experiments, and the clearance rate in the lungs is lower and the half-life is longer; (3) although the enantiomers of the compounds of the present invention have Similar antiviral activity, but only the S-configuration has higher antiviral activity in animal experiments, and the R-configuration has basically no.
  • ester compounds of the present invention have significant advantages over other esters in various forms, Show better and higher exposure in vivo, especially compound M19 has the best performance. These characteristics are more conducive to the anti-influenza virus effect of drugs for the treatment of influenza, which is usually transmitted through the respiratory tract, and are expected to have great clinical value and therapeutic advantages.
  • the present invention provides a compound represented by the following formula (I-0) or a hydrate, solvate, optical isomer, polymorph, isotope derivative, or pharmaceutically acceptable salt thereof:
  • n 0, 1, 2, 3, 4;
  • R is fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano
  • R a , R b and R c are each independently selected from hydrogen, deuterium or methyl;
  • X1 is an O atom or an S atom
  • each R 1 , R 2 , R 3 or R 4 is independently selected from hydrogen or methyl
  • R 5 is the following groups substituted or unsubstituted by one or more groups A: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 alkylamino ;
  • Group A is the following groups: halogen, cyano, amino, hydroxyl, carboxyl, nitro, trifluoromethyl, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 carbocyclyl, C2-C8 heterocyclic group, C1-C8 alkylamino group.
  • the compounds provided by the present invention or their hydrates, solvates, optical isomers, polymorphs, isotopic derivatives, and pharmaceutically acceptable salts thereof are shown in formula (I-1):
  • the compounds provided by the present invention or their hydrates, solvates, optical isomers, polymorphs, isotopic derivatives, and pharmaceutically acceptable salts are shown in formula (I-2):
  • the compounds provided by the present invention or their hydrates, solvates, optical isomers, polymorphs, isotopic derivatives, and pharmaceutically acceptable salts are shown in formula (I-3):
  • the compounds provided by the present invention or their hydrates, solvates, optical isomers, polymorphs, isotopic derivatives, and pharmaceutically acceptable salts thereof are shown in formula (I-4):
  • the compounds provided by the present invention or their hydrates, solvates, optical isomers, polymorphs, isotopic derivatives, and pharmaceutically acceptable salts are shown in formula (I-5):
  • the compound provided by the invention or its hydrate, solvate, polymorph, isotopic derivative, pharmaceutically acceptable salt isotopic derivative, pharmaceutically acceptable salt:
  • n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
  • n2 is 0 or 1;
  • X1 is O or S
  • X2 is S or Se
  • each R 1 , R 2 , R 3 or R 4 is independently hydrogen or methyl
  • R 5 is hydrogen or the following groups substituted or unsubstituted by one or more groups A: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio, C1-C18 alkyl Amino group;
  • R 5 is not an alkoxy group of C1-C8;
  • Group A is the following groups: halogen, cyano, amino, hydroxyl, carboxyl, nitro, trifluoromethyl, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 carbocyclyl, C2-C8 heterocyclic group, C1-C8 alkylamino group.
  • the compounds provided by the present invention or their hydrates, solvates, polymorphs, isotopic derivatives, and pharmaceutically acceptable salts are shown in formula (II):
  • the compounds provided by the present invention or their hydrates, solvates, polymorphs, isotopic derivatives, and pharmaceutically acceptable salts are shown in formula (III):
  • the compounds provided by the present invention or their hydrates, solvates, polymorphs, isotopic derivatives, and pharmaceutically acceptable salts are shown in formula (IV):
  • the halogen refers to fluorine, chlorine, bromine, or iodine.
  • the heteroatom refers to N, O or S.
  • the solvate refers to a complex formed by the interaction between the compound and 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 saturated aliphatic hydrocarbon group containing 1 to 8 carbon atoms in the molecule that inserts an oxygen atom at any reasonable position or sulfur atom groups, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-ethylethoxy, methylthio, ethylthio, propoxy Thio, isopropylthio, isobutylthio, etc.
  • the C1-C8 alkylamino group refers to a saturated aliphatic hydrocarbon group containing 1 to 8 carbon atoms in the molecule, and a -NH- or -NH2 group is inserted at any reasonable position.
  • the C3-C8 carbocyclic 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 cyclopropyl , cyclopentyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, cyclopentadienyl, etc.
  • the C2-C8 heterocyclic group refers to a saturated or unsaturated cyclic group containing 2-8 carbon atoms and 1-4 heteroatoms in the molecule. Including but not limited to cycloethoxy, aziridinyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, hexahydropyridazinyl, dihydropyridyl, cyclopentylsulfide, morpholinyl and the like.
  • n is 0; in some embodiments, in formula (I-0), n is 1, 2, 3 or 4; in some specific embodiments, In formula (I-0), n is 1; in some specific embodiments, in formula (I-0), n is 2.
  • R 0 is fluorine, chlorine, bromine or iodine, preferably, R 0 is fluorine or chlorine; in some embodiments, in formula (I-0), R 0 is trifluoromethyl or cyano.
  • R a is hydrogen; in some embodiments, in formula (I-0), R a is deuterium; in some embodiments, formula (I-0) In, R a is a methyl group.
  • Rb and Rc are both hydrogen; in some embodiments, Rb and Rc are both deuterium; in some embodiments, Rb is hydrogen and Rc is deuterium; in some embodiments wherein R b and R c are both methyl; in some embodiments, R b is hydrogen and R c is methyl.
  • Q is hydrogen; In some embodiments, in formula (I-0), Q is In some embodiments, in formula (I-0), Q is In some embodiments, in formula (I-0), Q is In some embodiments, in formula (I-0), Q is hydrogen;
  • n1 and n2 are not 0 at the same time;
  • n1 is 0; in some embodiments, n1 is 1, 2, 3, 4, 5, 6, 7, 8 or 9; in some specific embodiments, n1 is 1; in some In a specific embodiment, n1 is 2;
  • n2 is 0; in some embodiments, n2 is 1.
  • n3 and n4 are not 0 at the same time;
  • n3 is 0; in some embodiments, n3 is 1, 2, 3, 4, 5, 6, 7, 8 or 9; in some specific embodiments, n3 is 1; in some In a specific embodiment, n3 is 2;
  • n4 is 0; in some embodiments, n4 is 1.
  • n5 is 0; in some embodiments, n5 is 1, 2, 3, 4, 5, 6, 7, 8 or 9; in some specific embodiments, n5 is 1; in some In a specific embodiment, n5 is 2.
  • n6 is 0; in some embodiments, n6 is 1.
  • X is an O atom; in some embodiments, X is an S atom.
  • each R 1 or R 2 is independently hydrogen or methyl, which means that the carbons connected by R 1 and R 2 will have n1 or n3 or n5, and when n1 or n3 or n5 When greater than 1, the n1 or n3 or n5 R 1 or R 2 do not affect each other, and can be the same or different.
  • each R 3 or R 4 is independently hydrogen or methyl, that is, the carbon atom connected to R 1 , R 2 , R 3 or R 4 may or may not be substituted by a methyl group. replace.
  • R 5 is the following groups substituted or unsubstituted by one or more groups A: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio, C1 -C18 alkylamino group; preferably, R 5 is the following group substituted or unsubstituted by one or more groups A: C1-C8 alkyl, C1-C8 alkoxy; more preferably, R 5 is a C1-C8 alkoxy group substituted or unsubstituted by one or more groups A.
  • group A is halogen, trifluoromethyl, or cyano; in some embodiments, group A is amino, hydroxyl, carboxyl, nitro; in some embodiments, group A is Group: C1-C8 alkyl group, C1-C8 alkoxy group, C3-C8 carbocyclyl group, C2-C8 heterocyclic group, C1-C8 alkylamino group.
  • the formula (I-0) contains a chiral center (the place marked with * is a chiral carbon atom), and the optical isomers refer to those caused by the different configurations of the carbon atoms shown in * Optical isomers, compounds of the present invention or their intermediates can be separated by chiral separation to obtain single-configuration compounds.
  • the absolute configurations of S-configuration and R-configuration compounds are determined by electron circular dichroism chromatography.
  • the compounds of the invention are racemates; in some embodiments, the compounds of the invention are in the S-configuration.
  • the S-configuration and R-configuration compounds are tested for optical rotation (according to the Chinese Pharmacopoeia 2020 Edition-Sibu-0621 optical rotation measurement method, using methanol as a solvent).
  • the compounds of the present invention are racemates; in some specific embodiments, the compounds of the present invention are levorotatory.
  • the S-configuration compound is a levorotatory isomer.
  • Compounds provided by the invention include but are not limited to the following compounds:
  • the pharmaceutically acceptable salts include their inorganic acid salts and organic acid salts.
  • the pharmaceutically acceptable salts of the compounds include inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, etc., and organic acid salts include trifluoroacetate, formazan Sulfonate, tartrate, p-toluenesulfonate, etc.
  • the second aspect of the present invention provides a preparation route for polycyclic compounds shown in structural formula (I), as shown in the following steps:
  • each group is defined as the group in the structural formula (I), wherein L and L are activating leaving groups, and the groups shown in the formula (II-3) are according to the existing literature Reported method (J.Med.Chem.52, (3), 2009, 771-778; WO2019/136112) synthesis, formula (II-1) and formula (II-2) can generate formula (II) under alkaline conditions -3), then formula (II-3) and formula compound (II-4) can generate formula (I) under basic conditions.
  • Formula SM1 is synthesized by referring to the synthesis method described in patent CN 110300753 A ; formula SM3 and SM5 are synthesized by referring to the synthesis method described in patent CN 113226327 A.
  • the formula SM2 is synthesized in one step from the commercial product SM2-0 and methanesulfonyl chloride, specifically referring to the synthesis method in the patent CN 113226327 A.
  • the third aspect of the present invention is to provide a pharmaceutical preparation containing the above compound or its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt and pharmaceutically acceptable carrier. combination.
  • the pharmaceutically acceptable carrier includes one or a combination of fillers, binders, diluents, lubricants, preservatives, taste-masking agents or co-solvents.
  • the pharmaceutical composition can be used for anti-influenza virus.
  • the dosage forms of the pharmaceutical composition are tablets, capsules, powders, granules, pills, suspensions, syrups, and injections.
  • the compounds described in the present invention including their hydrates, solvates, optical isomers, polymorphs, isotope derivatives, pharmaceutically acceptable salts, or pharmaceutical compositions thereof, are used For anti-influenza virus purposes.
  • the compound of the present invention has stronger antiviral activity in vivo or in vitro. Studies have shown that the S-configuration product has good anti-influenza virus activity in vivo, while the R-configuration product has relatively poor activity.
  • the animal lung virus titer is lower, and the pathological changes of the lung tissue are milder; in the tissue distribution study, the compound of the present invention shows good lung tissue distribution; in the pharmacokinetic study , the ester compound of the present invention shows higher in vivo exposure and shorter peak time than other ester compounds.
  • the present invention provides the above-mentioned compounds, including compounds, including their hydrates, solvates, optical isomers, polymorphs, isotope derivatives, pharmaceutically acceptable salts, or pharmaceutical compositions thereof in the preparation of anti-influenza virus Use in medicine.
  • the present invention provides a method for preventing or treating influenza virus infection, said method comprising administering a therapeutically effective amount of the above-mentioned compound, including its hydrate, solvate, optical isomer, polymorphic form, to an individual in need thereof substances, isotope derivatives, pharmaceutically acceptable salts.
  • Figure 1 is the comparison between the theoretical electron circular dichroism spectrum predicted by quantitative calculation and the experimental ECD spectrum to determine the absolute configuration.
  • Fig. 2 shows the body weight changes of animals in each group in the anti-influenza virus efficacy experiment.
  • Fig. 3 is the change of the survival rate of animals in each group in the anti-influenza virus efficacy experiment.
  • Fig. 4 is the lung virus titer in the anti-influenza virus efficacy experiment.
  • Figure 5 shows the distribution of lung tissue.
  • the solvents and reagents used are common commercial products.
  • the starting materials were all purchased commercial raw materials.
  • Embodiment one the synthesis of M01 and M11
  • compound 1 (100g, 793mmol, 1eq) was dissolved in DMF (1.5L), potassium carbonate (219g, 1.59mol, 2eq) was added, the temperature was cooled to 0°C in an ice-water bath, and benzyl bromide (203g, 1.19mol, 1.5eq), the dropwise addition was completed, and kept at 0°C for 30 minutes, then moved to an oil bath at 80°C for 5 hours.
  • M19 and M19-1 adopt the method widely used in the world to determine the absolute configuration of chiral compounds, quantitatively calculate and predict the theoretical electron circular dichroism (ECD, usually referred to as circular dichroism) spectrum, and compare with the experimental ECD spectrum ( The comparison results are shown in Figure 1), and the experimental ECD signal is consistent with the theoretical calculation results, so that the absolute configuration is finally determined, M19 is the S configuration, and M19-1 is the R configuration.
  • ECD electron circular dichroism
  • Embodiment three the synthesis of PX90-02
  • Embodiment four the synthesis of M10
  • Embodiment five the synthesis of M03 and M14
  • Embodiment six the synthesis of M07 and M08
  • compound M08 was obtained. It was confirmed that M08 was a levorotatory form, and the absolute configuration was S configuration.
  • Embodiment seven the synthesis of M24
  • Embodiment eight the synthesis of compound M26
  • compound N02 was prepared and isolated from compound N01. After the optical rotation test and comparison with the optical rotation of M19, NO2 is levorotatory.
  • N11 was synthesized in one step using N01 as a material, and then compound N12 was obtained by a similar preparation and separation method of M19. After optical rotation test and comparison with M19 optical rotation, N12 is L-isomer, S configuration.
  • MDCK cells were inoculated into 96-well culture plates and cultured at 37°C in 5% CO 2 .
  • the MDCK cells were inoculated into a 96-well culture plate and cultured at 37° C. in 5% CO 2 .
  • Infect influenza virus (A/Hterrorism/359/95(H3N2)) after 24 hours, absorb for 2 hours, discard virus solution, add maintenance solution containing samples of different dilutions and positive control drug, and set 3 replicate wells for each concentration
  • a cell control well and a virus control well were set up, and cultured at 5% CO 2 at 37°C.
  • the antiviral test of the tested samples was carried out by the CPE method, and the cytopathic degree (CPE) of each group was observed when the diseased degree (CPE) of the virus control group reached 4+.
  • the half toxic concentration (TC 50 ) of the sample to the cells and the effective concentration (EC 50 ) of the drug that inhibits 50% of the cytopathic effect of the sample were calculated respectively by the Reed-Muench method, as shown in Table 1:
  • N01, N02, N11, and N12 are compounds disclosed in existing literature, which are used as comparative examples in the present invention.
  • the compound of the present invention has better anti-influenza virus activity.
  • the cell activity of M01 to M08 (all of which are not esterified structures) in the compound of the present invention is significantly better; compared with the comparative example compounds N11, N12 and baloxavir Compared with esters, the compounds of the present invention also have better anti-influenza virus activity; and all compounds do not show obvious cytotoxicity.
  • Embodiment 10 Anti-influenza virus activity in vivo
  • mice Female, 6-8 weeks old. Randomly divided into 6 groups: vehicle group, positive control group, test product group. The mice were inoculated with the virus (A/PR/8/34(H1N1)) by intranasal drops on the 0th day, and the inoculation dose was 1500p.f.u./mouse. From the 1st day to the 7th day, the vehicle or the positive control or the test product were continuously treated for 7 days, twice a day, the administration method was intragastric administration, the administration volume was 10mL/kg, and the first administration time was after the virus inoculation 24 hours. Animals were continuously observed from day 0 to day 14, and body weight, health and survival were recorded.
  • virus A/PR/8/34(H1N1)
  • mice in the vehicle group began to decline significantly from the 3rd day, and then continued to decline until death Or be euthanized
  • the weight of the mice in the baloxavir (5mpk) group began to drop significantly from the 3rd day, and the body weight dropped to the lowest point on the 3rd day, with a maximum drop of 9.59%, and then recovered to the normal level from the 4th day
  • the body weight of mice in group 5 began to decrease significantly from the 3rd day, and the body weight dropped to the lowest point on the 6th day, with a maximum drop of 15.51%, and recovered to the normal level on the 7th day.
  • mice in group 6 began to drop significantly from the 3rd day, and the body weight dropped to the lowest point on the 3rd day, with a maximum drop of 5%, and recovered to the normal level on the 5th day.
  • mice in the vehicle group began to die on the 6th day, and all died on the 9th day, and the final survival rate was 0%; the 3rd group (M19-1 low dose group) mice The mice in the 4th group (M19-1 high-dose group) died from the 7th day, and all died on the 8th day, and the final survival rate was 0%.
  • the survival rate was 0%; neither the baloxavir group nor the M19 high/low dose group died, and the survival rate was 100%.
  • mice in the vehicle group showed symptoms of infection after virus inoculation, and eventually all died, the median survival period was 7.5 days, and the final survival rate was 0%; Weight loss induced by virus infection protected mice from death, showing expected in vivo anti-influenza virus efficacy.
  • the above results meet the inclusion criteria and meet the expectations of the model, which proves that the experimental science is credible, and provides a reference and window for the evaluation of the efficacy of the test compound.
  • the test compound M19-1 which performed better in the cell activity test, failed to relieve the weight loss caused by infection in mice under the set experimental conditions, indicating that it had no anti-influenza virus efficacy in vivo.
  • test compound M19 which performed slightly worse in the cell activity test, was administered 24 hours after virus inoculation, which could alleviate the weight loss of mice caused by virus infection and protect mice from death, indicating that it had good in vivo resistance.
  • Drug efficacy of influenza A virus was administered 24 hours after virus inoculation, which could alleviate the weight loss of mice caused by virus infection and protect mice from death, indicating that it had good in vivo resistance.
  • Embodiment 11 virus titer test and histopathological examination
  • mice Twenty C57BL/6J mice (female, 8 weeks old, 18-20 g) were divided into 4 groups, 5 mice in each group. After intranasal inoculation of semi-lethal dose of A/PR/8/34 (H1N1) virus, test drug was given by intragastric administration twice a day. Lung tissue samples were collected 5 days after infection, the left lung was pathologically examined, and the right lung homogenate was tested for TCID 50 . The virus titer results are shown in Figure 4.
  • Lung virus titer test result shows: compared with vehicle group, the lung tissue virus titer of compound M19 of the present invention, M20 and comparative example compound N12 is lower; Compared with comparative example compound N12, under the same dose, the present invention Compounds M19 and M20 had lower virus titers and showed better anti-influenza virus effects. At the same time, the results of lung histopathological examination also showed that compared with the comparative compound N12, the lung lesions of the mice treated with the compounds M19 and M20 of the present invention were milder.
  • Embodiment 12 Rat oral pharmacokinetic test
  • the analyte (the analyte is M04) is detected by LC-MS/MS.
  • WinNonlin 7.0 Use WinNonlin 7.0 to calculate the main pharmacokinetic parameters according to the non-compartmental model method.
  • the main pharmacokinetic parameters of each group of samples after intragastric administration are shown in Table 2:
  • Table 2 The main pharmacokinetic parameters in rats after equimolar gavage administration of the test product
  • Embodiment 13 Mouse tissue distribution test
  • mice There were 45 DBA/1J mice (6-week-8-week-old, female), and the mice were weighed one day before the administration to calculate the dose. They were randomly divided into 3 groups, 15 rats in each group, and 1 mg/kg of M19, M20 and N12 were administered by oral gavage (N12 was used as a comparative compound in this experiment). Mice were sampled at the following 5 time points: 1 hr, 2 hrs, 4 hrs, 8 hrs and 24 hrs (3 mice per time point). Euthanize mice by CO2 at each time point. Organs (lung, liver, kidney, spleen, and heart) were collected from euthanized mice, the surface was cleaned with normal saline, and the water was blotted dry with filter paper and weighed. Saline was ground and homogenized to obtain the homogenate of each tissue. The homogenate was stored at -80°C. Biological samples were processed and analyzed by LC-MS/MS. The results are shown in Figure 5.

Landscapes

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

Abstract

L'invention concerne un composé tel que représenté dans la formule suivante (I-0) ou un hydrate, un solvate, un isomère optique, un polymorphe, un dérivé isotopique, un sel pharmacologiquement acceptable de celui-ci et un procédé de préparation associé. Le composé peut être utilisé pour préparer un médicament pour prévenir/traiter des infections provoquées par des virus, y compris des virus grippaux.
PCT/CN2022/128843 2021-11-01 2022-11-01 Composé antiviral efficace et son utilisation WO2023072292A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111291506.9 2021-11-01
CN202111291506 2021-11-01

Publications (1)

Publication Number Publication Date
WO2023072292A1 true WO2023072292A1 (fr) 2023-05-04

Family

ID=85047669

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/128843 WO2023072292A1 (fr) 2021-11-01 2022-11-01 Composé antiviral efficace et son utilisation

Country Status (2)

Country Link
CN (2) CN115677698B (fr)
WO (1) WO2023072292A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110300753A (zh) * 2018-01-22 2019-10-01 太景生物科技股份有限公司 帽依赖性核酸内切酶抑制剂
WO2020015669A1 (fr) * 2018-07-17 2020-01-23 南京明德新药研发有限公司 Dérivé tricyclique contre le virus de la grippe
CN111217810A (zh) * 2018-11-23 2020-06-02 维清生物科技(上海)有限公司 一种氮杂环二酮化合物及其制备方法
CN111253391A (zh) * 2018-11-30 2020-06-09 维清生物科技(上海)有限公司 一种含氘氮杂环二酮化合物用于治疗流感
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

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110300753A (zh) * 2018-01-22 2019-10-01 太景生物科技股份有限公司 帽依赖性核酸内切酶抑制剂
WO2020015669A1 (fr) * 2018-07-17 2020-01-23 南京明德新药研发有限公司 Dérivé tricyclique contre le virus de la grippe
CN111217810A (zh) * 2018-11-23 2020-06-02 维清生物科技(上海)有限公司 一种氮杂环二酮化合物及其制备方法
CN111253391A (zh) * 2018-11-30 2020-06-09 维清生物科技(上海)有限公司 一种含氘氮杂环二酮化合物用于治疗流感
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

Also Published As

Publication number Publication date
CN115677698A (zh) 2023-02-03
CN117924284A (zh) 2024-04-26
CN115677698B (zh) 2024-02-02

Similar Documents

Publication Publication Date Title
CN110317211B (zh) 一种取代的多环性吡啶酮化合物及其前药
US20220112177A1 (en) Ketoamide compound and preparation method, pharmaceutical composition, and use thereof
WO2022143473A1 (fr) Composé nucléosidique et son utilisation
CN108250122B (zh) 磺酰胺-芳基酰胺类化合物及其治疗乙型肝炎的药物用途
WO2019011323A1 (fr) Composé thiamidinoamide-arylamide endocyclique et son utilisation dans le traitement de l'hépatite b
KR102254315B1 (ko) 글루타르이미드 유도체, 이의 용도, 이를 기반으로 한 약학 조성물 및 글루타르이미드 유도체를 생산하는 방법
EP3628674A1 (fr) Inhibiteur bicyclique de nucléocapside et son utilisation comme médicament dans le traitement de l'hépatite b
KR102502749B1 (ko) 간 전달 엔테카비어 프로드러그 뉴클레오티드 시클로 포스페이트 화합물 및 응용
WO2018133845A1 (fr) Composé de thiourée et d'urée et utilisation associée
US10913765B2 (en) Liver specific delivery-based gemcitabine prodrug nucleoside cyclic phosphate compound, and application thereof
WO2023072292A1 (fr) Composé antiviral efficace et son utilisation
CN111909174B (zh) 吡啶酮衍生物的晶型及制备方法和应用
CN117003766B (zh) 一种抗流感病毒衍生物及其用途
CN115135646A (zh) 取代的多环化合物及其药物组合物和用途
WO2020151296A1 (fr) Précurseur dinucléotide pour médicament et son procédé de préparation
CN113603689B (zh) 多环吡啶酮化合物及其药物组合物和用途
WO2024098856A1 (fr) Dérivés anti-virus de la grippe et leur utilisation
JP2021506841A (ja) 肝臓送達に基づくシタラビンプロドラッグであるヌクレオシドの環状リン酸エステル化合物および応用
CN115536699B (zh) 一种新型EGFR-TKIs、制备方法、药物组合物及其应用
CN114539204B (zh) 己糖激酶抑制剂及其合成方法和应用
WO2023169119A1 (fr) Forme solide de composé, son procédé de préparation et son utilisation
US11008361B2 (en) Liver-specific delivery-based anti-hepatitis C prodrug nucleoside cyclo-phosphate compound and uses thereof
CN115141206B (zh) 一种ɑ-硫辛酸石蒜碱偶联物及其制备方法和应用
CN116284018A (zh) 一种呋喃并[2,3-b]喹啉衍生物的制备方法及其应用
CN113549046A (zh) 一种双联苄地钱素s衍生物及其制备方法和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22886167

Country of ref document: EP

Kind code of ref document: A1