WO2022262845A1 - Dérivés d'ester de n4-hydroxycytidine et leur utilisation - Google Patents

Dérivés d'ester de n4-hydroxycytidine et leur utilisation Download PDF

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WO2022262845A1
WO2022262845A1 PCT/CN2022/099403 CN2022099403W WO2022262845A1 WO 2022262845 A1 WO2022262845 A1 WO 2022262845A1 CN 2022099403 W CN2022099403 W CN 2022099403W WO 2022262845 A1 WO2022262845 A1 WO 2022262845A1
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alkyl
virus
tautomer
compound
racemate
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PCT/CN2022/099403
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English (en)
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Zuchun Zhao
Kai Xu
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Suzhou Spring-Sea Bio-Pharmaceuticals Co., Ltd.
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Priority to CN202280040667.7A priority Critical patent/CN117642410A/zh
Publication of WO2022262845A1 publication Critical patent/WO2022262845A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical

Definitions

  • the present disclosure relates to ester derivatives of N 4 -hydroxycytidine (NHC) , to pharmaceutical compositions thereof, and to the use of the ester derivatives of N 4 -hydroxycytidine to treat viral infections.
  • the compounds can be administered orally to provide N 4 -hydroxycytidine.
  • N 4 -hydroxycytidine is a ribonucleoside analog with broad-spectrum antiviral activity against various unrelated RNA viruses including influenza, Ebola, CoV, and Venezuelan equine encephalitis virus (VEEV) and most importantly the human SARS-CoV-2 virus.
  • the oxime form of NHC mimics uridine, matching up with adenosine (left structure below) , while the other tautomer mimics cytidine and matches up with guanosine (right structure below) . Such mismatching might cause virus error catastrophe.
  • N 4 -hydroxycytidine (NHC) Molnupiravire/EIDD2801/MK4486 is currently under clinical trial for treating SARS-CoV-2, the virus that causes COVID-19.
  • the compound is under phase III clinical trial for treating early infected patients by SARS-CoV-2 with planned dose of 800mg twice a day [2] .
  • Both the high dose and BID dosing are required for sustained efficacious concentration of NHC in human body that can induce viral error catastrophe.
  • more and potentially better prodrugs i.e. smaller pills, less frequent dosing and more efficacious
  • NHC N 4 -hydroxycytidine
  • the present disclosure relates to certain ester prodrugs of NHC, combinations, pharmaceutical compositions, use and methods related thereto.
  • the present disclosure provides a compound of formula (I) :
  • Ra is methyl substituted with Ra1, Ra2 and Ra3;
  • Ra1 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered haloheterocycloalkyl, C 1-6 alkyl-O- (CH 2 ) n -, C 1-6 alkyl-O-C 1-6 alkyl-O- (CH 2 ) n -, C 1-6 haloalkyl-O- (CH 2 ) n -, C 3-6 cycloalkyl-O- (CH 2 ) n -, C 3-6 halocycloalkyl-O- (CH 2 ) n -, 3-6 membered heterocycloalkyl-O- (CH 2 ) n -and 3-6 membered haloheterocycloalkyl-O-
  • Ra2 is C 1-6 alkyl or C 1-6 alkyl-O- (CH 2 ) n -;
  • Ra3 is selected from the group consisting of H, C 1-6 alkyl and C 1-6 alkyl-O- (CH 2 ) n -;
  • Ra2 and Ra3 are taken together with the carbon they attached to form C 3-6 cycloalkyl, or 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O; and,
  • n 0 or 1
  • Ra3 is either H or C 1-6 alkyl
  • Ra1 is not any of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl.
  • the present disclosure also provides the compound of the present invention for use as a medicament.
  • the present disclosure also provides the compound of the present invention for use in treating or preventing a RNA viral infection.
  • the present disclosure also provides a pharmaceutical composition, comprising the compound of the present invention and optionally comprising a pharmaceutically acceptable excipient.
  • the present disclosure also provides a kit for treating or preventing a RNA viral infection, comprising a pharmaceutical composition of the present disclosure and an instruction for use.
  • the present disclosure also provides use of the compound of the present invention in the manufacture of a medicament for treating or preventing a RNA viral infection.
  • the present disclosure also provides use of the compound of the present invention for treating or preventing a RNA viral infection.
  • the present disclosure also provides a method of treating or preventing a RNA viral infection in a subject, comprising administering to the subject in need thereof an effective amount of the compound of the present invention.
  • the present disclosure also provides a method for increasing bioavailability of N 4 -hydroxycytidine for treating or preventing a RNA viral infection comprising administering to the subject in need thereof an effective amount of the compound of the present invention.
  • the present disclosure also provides a pharmaceutical combination, comprising the compound of the present invention, and at least one additional therapeutic agent.
  • the present disclosure also provides a process for the preparation of the compound of the present invention, and itermediates for preparing the compound of the present invention.
  • the compound of the present invention may be identified either by their chemical structure and/or chemical name. When the chemical structure and chemical name conflict with each other, the chemical structure is determinative of the identity of the compound.
  • the symbol herein means that the relevant structures are tautomers, which exist in equilibrium and are readily converted from one isomeric form to another.
  • the compound of the present invention may exist in oxime form and the other form. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds, especially the tautomer in oxime form and the tautomer in the other form. Regardless of the tautomer that is shown, and regardless of the nature of the equilibrium between tautomers, the compound of the present invention is understood by those skilled in the art to encompass both oxime form and the other form.
  • Bioavailability refers to the rate and amount of a drug that reaches the systemic circulation of a subject following administration of the drug or prodrug thereof to the subject and can be determined by evaluating, for example, the plasma or blood concentration-versus-time profile for a drug.
  • Parameters useful in characterizing a plasma or blood concentration-versus-time curve include the area under the curve (AUC) , the time to maximum concentration (Tmax ) , and the maximum drug concentration (Cmax ) , where Cmax is the maximum concentration of a drug in the plasma or blood of a subject following administration of a dose of the drug or form of drug to the subject, and Tmax is the time to the maximum concentration (Cmax ) of a drug in the plasma or blood of a subject following administration of a dose of the drug or form of drug to the subject.
  • AUC area under the curve
  • Tmax time to maximum concentration
  • Cmax maximum drug concentration
  • Prodrugs are derivatized forms of drugs that following administration are converted or metabolized to an active form of the parent drug in vivo. Prodrugs are used to modify one or more aspects of the pharmacokinetics of a drug in a manner that enhances the therapeutic efficacy of a parent drug. For example, prodrugs are often used to enhance the oral bioavailability of a drug. To be therapeutically effective, drugs exhibiting poor oral bioavailability may require frequent dosing, large administered doses, or may need to be administered by other than oral routes, such as intravenously. Examples of prodrugs that can be used to improve bioavailability include esters, optionally substituted esters, branched esters, optionally substituted branched esters.
  • Metal intermediate refers to a compound that is formed in vivo by metabolism of a parent compound and that further undergoes reaction in vivo to release an active agent.
  • Compounds of Formula (I) are protected ester prodrugs that are metabolized in vivo to provide the corresponding metabolic intermediates such as N4-hydroxycytidine (NHC) . It is desirable that the reaction products or metabolites thereof not be toxic.
  • Subject refers to a mammal, for example, a human.
  • “Pharmaceutically acceptable” refers to approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound. Such salts include acid addition salts, formed with inorganic acids and one or more protonable functional groups such as hydroxylamine within the parent compound. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • a salt can be formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy
  • “Pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one therapeutic agents and includes both fixed and non-fixed combinations of the therapeutic agents.
  • the term “fixed combination” means that the therapeutic agents, e.g. the compound of the present invention and said at least one additional therapeutic agent, are both administered to a subject simultaneously in the form of a single entity or dosage.
  • the term “non-fixed combination” means that the therapeutic agents, e.g. the compound of the present invention and said at least one additional therapeutic agent, are both administered to a subject as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the agents in the body of the subject.
  • Preventing refers to a reduction in risk of acquiring a disease or disorder, e.g. virus infection, (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease) .
  • preventing or “prevention” refers to reducing symptoms of the disease by taking the compound in a preventative fashion.
  • the application of a therapeutic for preventing or prevention of a disease of disorder is known as prophylaxis.
  • Compounds provided by the present disclosure can provide superior prophylaxis because of antiviral activities.
  • Treating” or “treatment” of a disease or disorder refers to arresting or ameliorating a disease or at least one of the clinical symptoms of a disease or disorder, reducing the risk of acquiring a disease or at least one of the clinical symptoms of a disease, reducing the development of a disease or at least one of the clinical symptoms of the disease or reducing the risk of developing a disease or at least one of the clinical symptoms of a disease.
  • Treating” or “treatment” also refers to inhibiting the disease, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both, and to inhibiting at least one physical parameter or manifestation that may or may not be discernible to the subject. “Treating” or “treatment” also refers to delaying the onset of the disease, e.g. virus infection, or at least one or more symptoms thereof in a subject who may be exposed to or predisposed to a disease or disorder even though that subject does not yet experience or display symptoms of the disease.
  • the term “effective amount” as used herein refers to an amount of the compound of the present invention effective for “treating” or “preventing” , as defined above, virus infection in a subject.
  • the effective amount may cause any changes observable or measurable in a subject as described in the definition of “treating” , “treatment” , “preventing” , or “prevention” above.
  • the “effective amount” may vary depending, for example, on the compound, the disease and/or symptoms of the disease, severity of the disease and/or symptoms of the disease or disorder, the age, weight, and/or health of the subject to be treated, and the judgment of the prescribing physician. An appropriate amount in any given instance may be ascertained by those skilled in the art or capable of determination by routine experimentation.
  • alkyl means a straight or branched chain saturated hydrocarbon moieties such as those containing from 1 to 6 carbon atoms (C 1-6 ) , preferably 1-4 carbon atoms (C 1-4 ) or 1-3 carbon atoms (C 1-3 ) .
  • C 1-6 alkyl refers to the alkyl having 1-6 (1, 2, 3, 4, 5 or 6) carbon atoms.
  • Representative straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl; while branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.
  • cycloalkyl as used herein are referred to herein saturated cyclic hydrocarbon radical having 3-6 ring carbon atoms (C 3-6 ) , such as 5-6 ring carbon atoms (C 5-6 ) .
  • examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • halocycloalkyl herein refers to the cycloalkyl as defined above, in which one or more, for example 1, 2 or 3 hydrogen atoms are replaced with halogen atom.
  • heterocycloalkyl refers to a saturated ring having 3-6 ring atoms (3-6 membered) , 4-6 ring atoms (4-6 membered) or 5-6 ring atoms (5-6 membered) , with one or more of, such as 1, 2 or 3, preferably 1 or 2 of the ring atoms being heteroatoms independently selected from N, O and S, preferably O, and the remaining ring atoms being carbon.
  • heterocycloalkyl examples include, but are not limited to, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, 1, 3-dioxolane moiety and the like.
  • the heterocycloalkyl is tetrahydrofuranyl or tetrahydropyranyl.
  • haloheterocycloalkyl herein refers to the heterocycloalkyl as defined above, in which one or more, for example 1, 2 or 3 hydrogen atoms are replaced with halogen atom.
  • halogen and “halo” refer to fluorine and chlorine.
  • haloalkyl refers to the alkyl as defined herein, in which one or more, for example 1, 2, 3, 4, or 5 hydrogen atoms are replaced with halogen atom.
  • substituted refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are “substituents. ” The molecule can be multiply substituted.
  • Embodiment 1 A compound of Formula (I) :
  • Ra is methyl substituted with Ra1, Ra2 and Ra3;
  • Ra1 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered halo3-6 membered haloheterocycloalkyl, C 1-6 alkyl-O- (CH 2 ) n -, C 1-6 alkyl-O-C 1-6 alkyl-O- (CH 2 ) n -, C 1-6 haloalkyl-O- (CH 2 ) n -, C 3-6 cycloalkyl-O- (CH 2 ) n -, C 3-6 halocycloalkyl-O- (CH 2 ) n -, 3-6 membered 3-6 membered haloheterocycloalkyl-O- (CH 2 ) n -and 3-6
  • Ra2 is C 1-6 alkyl or C 1-6 alkyl-O- (CH 2 ) n -;
  • Ra3 is selected from the group consisting of H, C 1-6 alkyl and C 1-6 alkyl-O- (CH 2 ) n -;
  • Ra2 and Ra3 are taken together with the carbon they attached to form C 3-6 cycloalkyl, or 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O; and,
  • n 0 or 1
  • Ra3 is either H or C 1-6 alkyl
  • Ra1 is not any of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl.
  • Embodiment 2 A compound according to Embodiment 1, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra is methyl substituted with Ra1, Ra2 and Ra3;
  • Ra1 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkyl-O- (CH 2 ) n -, C 1-6 alkyl-O-C 1-6 alkyl-O- (CH 2 ) n -, C 1-6 haloalkyl-O- (CH 2 ) n -, C 3-6 cycloalkyl-O- (CH 2 ) n -and 3-6 membered heterocycloalkyl-O- (CH 2 ) n -,
  • Ra2 is C 1-6 alkyl or C 1-6 alkyl-O- (CH 2 ) n -, and
  • Ra3 is selected from the group consisting of H, C 1-6 alkyl and C 1-6 alkyl-O- (CH 2 ) n -;
  • Ra2 and Ra3 are taken together with the carbon they attached to form C 3-6 cycloalkyl, or 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O;
  • n 0 or 1
  • Ra3 is either H or C 1-6 alkyl
  • Ra1 is not any of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl.
  • Embodiment 3 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, provided that
  • Ra3 is either H or C 1-6 alkyl
  • Ra1 is not any of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl
  • Ra1 is not any of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl.
  • Embodiment 4 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Raa is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-O-C 1-6 alkyl-, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl; preferably C 1-6 alkyl.
  • Embodiment 9 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Raa is selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkyl-O-C 1-4 alkyl-, C 3-5 cycloalkyl and 4-6 membered heterocycloalkyl.
  • Embodiment 10 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Raa is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, 2-methoxyethyl, fluorosubstitued ethyl, flurosubstituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydro-2-furanyl, tetrahydro-3-furanyl or tetrahydro-2H-pyran-4-yl; preferably methyl, ethyl, propyl, isopropyl, oxetanyl and tetrahydro-2H-pyran-4-yl.
  • Raa is selected from the group consisting of methyl,
  • Embodiment 11 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Raa is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and sec-butyl.
  • Embodiment 12 A compound according to any of Embodiments 1-3, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 and Ra3 is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -;
  • Ra2 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -;
  • Ra2 and Ra3 are taken together with the carbon they attached to form C 3-6 cycloalkyl, or 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O;
  • Ra3 is either H or C 1-6 alkyl
  • Ra1 is not H or C 1-6 alkyl.
  • Embodiment 13 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -.
  • Embodiment 14 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra3 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -.
  • Embodiment 15 A compound according to any of Embodiments 1-3, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is C 1-6 alkyl-O-or C 1-6 alkyl-O-CH 2 -
  • Ra2 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -, and
  • Ra3 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -.
  • Embodiment 16 A compound according to any of Embodiments 1-3, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is C 1-6 alkyl-O-
  • Ra2 is C 1-6 alkyl
  • Ra3 is H or C 1-6 alkyl.
  • Embodiment 17 A compound according to any of Embodiments 1-3, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is C 1-6 alkyl-O-CH 2 -
  • each of Ra2 and Ra3 is C 1-6 alkyl.
  • Embodiment 18 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is C 1-6 alkyl-O-or C 1-6 alkyl-O-CH 2 -
  • each of Ra2 and Ra3 is C 1-6 alkyl-O-CH 2 -.
  • Embodiment 19 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is C 1-6 alkyl-O-CH 2 .
  • Ra2 and Ra3 are C 1-6 alkyl, and the other is C 1-6 alkyl-O-CH 2 .
  • Embodiment 20 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is C 1-6 alkyl-O-
  • Ra2 and Ra3 is independently C 1-3 alkyl, preferably Ra2 and Ra3 are the same.
  • Embodiment 21 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is C 1-6 alkyl-O-or C 1-6 alkyl-O-CH 2 -
  • Ra2 and Ra3 are taken together with the carbon they attached to form a C 3-6 cycloalkyl.
  • Embodiment 22 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -;
  • Ra2 and Ra3 are taken together with the carbon they attached to form a 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O;
  • Ra1 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -.
  • Embodiment 25 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Ra1 is C 1-6 alkyl-O-.
  • Embodiment 27 A compound according to any of Embodiments 1-4 and 12, or a tautomer, stereoisomer or racemate thereof or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
  • Embodiment 28 A pharmaceutical composition, comprising the compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.
  • Embodiment 29 Use of the compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a RNA viral infection.
  • Embodiment 30 The use according to Embodiment 29, wherein the RNA virus is coronavirus, e.g., a human coronavirus, SARS coronavirus or MERS coronavirus, alphavirus, e.g., Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, Ross River virus or Barmah Forest virus, filoviridae virus, e.g., ebola virus, orthomyxoviridae virus, e.g., influenza virus, influenza A virus or influenza B virus, paramyxoviridae virus, e.g., respiratory Syncytial Virus (RSV) , flavivirus, e.g., Zika virus or Powassan virus; preferably, a SARS-CoV-2/COVID-19 virus, an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-
  • Embodiment 31 A method of treating or preventing a RNA viral infection in a subject, comprising administering to the subject in need thereof an effective amount of the compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof.
  • Embodiment 32 The method according to Embodiment 31, wherein the RNA virus is coronavirus, e.g., a human coronavirus, SARS coronavirus or MERS coronavirus, alphavirus, e.g., Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus or Ross River virus, filoviridae virus, e.g., ebola virus, orthomyxoviridae virus, e.g., influenza virus, influenza A virus or influenza B virus, paramyxoviridae virus, e.g., respiratory Syncytial Virus (RSV) , flavivirus, e.g., Zika virus; preferably, a SARS-CoV-2/COVID-19 virus, an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-2/COVID-19 virus, a gamm
  • Embodiment 33 The compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • Embodiment 34 The compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, for use in treating or preventing a RNA viral infection.
  • Embodiment 35 The compound for use according to Embodiment 34, wherein the RNA virus is coronavirus, e.g., a human coronavirus, SARS coronavirus or MERS coronavirus, alphavirus, e.g., Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus or Ross River virus, filoviridae virus, e.g., ebola virus, orthomyxoviridae virus, e.g., influenza virus, influenza A virus or influenza B virus, paramyxoviridae virus, e.g., respiratory Syncytial Virus (RSV) , flavivirus, e.g., Zika virus; preferably, a SARS-CoV-2/COVID-19 virus, an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-2/COVID-19 virus, a
  • Embodiment 36 A method for increasing bioavailability of N 4 -hydroxycytidine for treating or preventing a RNA viral infection comprising administering to the subject in need thereof an effective amount of the compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof.
  • Embodiment 37 A pharmaceutical combination, comprising the compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.
  • Embodiment 38 The pharmaceutical combination according to Embodiment 37, wherein additional therapeutic agent is selected from the group consisting of:
  • the RNA virus is coronavirus, e.g., a human coronavirus, SARS coronavirus or MERS coronavirus, alphavirus, e.g., Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus or Ross River virus, filoviridae virus, e.g., ebola virus, orthomyxoviridae virus, e.g., influenza virus, influenza A virus (including subtype H1N1, H3N2, H7N9, or H5N1) , influenza B virus or influenza C, paramyxoviridae virus, e.g., respiratory Syncytial Virus (RSV) , flavivirus, e.g., Zika virus, rotavirus, e.g., rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E;
  • alphavirus
  • the RNA virus is a human coronavirus, SARS coronavirus, MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, Ross River virus, orthomyxoviridae virus, paramyxoviridae virus, RSV virus, influenza A virus, influenza B virus, filoviridae virus, or Ebola virus.
  • the RNA virus is a human coronavirus, a SARS-CoV-2/COVID-19 virus, an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-2/COVID-19 virus, a gamma variant SARS-CoV-2/COVID-19 virus, a delta variant SARS-CoV-2/COVID-19 virus, or any other variant SARS-CoV-2/COVID-19 virus.
  • the subject is at risk of, exhibiting symptoms of, or diagnosed with SARS-CoV-2/COVID-19 virus, influenza A virus including subtype H1N1, H3N2, H7N9, or H5N1, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, human coronavirus, SARS coronavirus, MERS coronavirus, human adenovirus types (HAdV-1 to 55) , human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV) , BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV) , Dengue virus, Zika virus, chik
  • influenza A virus
  • the subject is diagnosed with SARS-CoV-2/COVID-19 virus including an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-2/COVID-19 virus, a gamma variant SARS-CoV-2/COVID-19 virus, a delta variant SARS-CoV-2/COVID-19 virus, or any variant SARS-CoV-2/COVID-19 virus that could be treated by formula (I) compound or pharmaceuticals contain formula (1) compound.
  • influenza A virus including subtypes H1N1, H3N2, H7N9, H5N1 (low path) , and H5N1 (high path) influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus, MERS-CoV, human adenovirus types (HAdV-1 to 55) , human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV) , BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV) , yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, parainflu
  • the subject is diagnosed with gastroenteritis, acute respiratory disease, severe acute respiratory syndrome, post-viral fatigue syndrome, viral hemorrhagic fevers, acquired immunodeficiency syndrome or hepatitis.
  • the compounds of the present invention can be formulated into a pharmaceutical composition.
  • the pharmaceutical composition includes: (a) an effective amount of the compound of the present invention; (b) a pharmaceutically acceptable excipient (for example, one or more pharmaceutically acceptable carriers) ; and optionally (c) at least one additional therapeutic agent.
  • a pharmaceutically acceptable excipient refers to an excipient that is compatible with the active ingredient (s) in the composition (in some embodiments, can stabilize the active ingredient) and is not harmful to the subject being treated.
  • Suitable pharmaceutically acceptable excipients are disclosed in standard reference books in the art (e.g., Remington's Pharmaceutical Sciences, Remington: The Science and Practice of Pharmacy.
  • ) including one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., the compounds of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament) .
  • buffers including one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., the compounds of the present invention or pharmaceutical composition thereof) or
  • the compound of the invention can be administered in various known manners, such as orally, parenterally, by inhalation, or through the lungs, i.e., pulmonary administration, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic route, or as an implant or stent.
  • parenterally as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion.
  • Oral or parenteral administration is preferred, especially oral administration.
  • the compound of the invention may be administered in any convenient formulation, e.g., tablets, powders, capsules, pills, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, aqueous buffer, such as a saline or phosphate buffer etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and an addtional active agent.
  • the dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and most preferably 0.1 to 15 mg/kg of body weight.
  • the compound described herein can be administered adjunctively with at least one additional therapeutic agent.
  • the additional therapeutic agents include but are not limited to analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics, anti-narcoleptics, and antiviral agents.
  • the antiviral agent is a non-CNS targeting antiviral compound.
  • “Adjunctive administration” means the compound can be administered in the same dosage form or in separate dosage forms with one or more other active agents.
  • the additional therapeutic agent (s) can be formulated for immediate release, controlled release, or combinations thereof.
  • antiviral agent such as abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, balapiravir, BCX4430, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, GS-5734, ibacitabine, imunovir, idoxuridine, imiqui
  • antiviral agent such as abacavir, acyclovir, acyclovir,
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with any of the compounds disclosed in WO2012119559 for the treatment of SARS-CoV-2/COVID-19 infection.
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with any of the compounds disclosed in WO2012119559 for the prevention of SARS-CoV-2/COVID-19 infection.
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with proxalutamide for the treatment of SARS-CoV-2/COVID-19 infection.
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with proxalutamide for the prevention of SARS-CoV-2/COVID-19 infection.
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with compound-X for the treatment of SARS-CoV-2/COVID-19 infection.
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with compound-X for the prevention of SARS-CoV-2/COVID-19 infection.
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with PF-07321332 for the treatment of SARS-CoV-2/COVID-19 infection.
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with PF-07321332 for the prevention of SARS-CoV-2/COVID-19 infection.
  • the present disclosure also provides a pharmaceutical combination, comprising the compound of the present invention and at least one additional therapeutic agent.
  • additional therapeutic agent include, but are not limited to, those agents mentioned above, preferably proxalutamide, Compound-X and PF-07321332.
  • reaction vessel was cooled to room temperature, and pH was adjusted with 4M HCl in dioxane (200 mL, 99%) to the point at which pH just changes from >12 to 7, indicating neutralization of excess sodium methoxide without protonating the sodium salt of the carboxylate.
  • the reaction mixture was filtered to remove salts, and the salt cake was washed twice with 5 mL of methanol.
  • the organic layer were dried with sodium sulfate and concentrated to afford compound (I-3) as a liquid (73g, 95%) which was of sufficient purity to be used without purification.
  • 1 H NMR (CD 3 OD) ⁇ 3.67 (q, 1H) , 3.33 (s, 3H) , and 1.33 ppm (d, 3H) .
  • 2-Ethoxyisobutyric acid was prepared according to reference (Ragan, John A.; Ide, Nathan D.; Cai, Weiling; Cawley, James J.; Colon-Cruz, Roberto; Kumar, Rajesh; Peng, Zhihui; Vanderplas, Brian C. [Organic process research and development, 2010, vol. 14, #6, p.
  • 2-Ethyl-2-bromo-butyric acid (I-61) is commercially available or can be prepared according to the procedure described by Doran; Shonle in Journal of Organic Chemistry, 1938, vol. 3, p. 195.
  • 1-Methyl-2, 2-Dimethoxy-isobutyric acid (I-142) was prepared from commercially available 2, 2-bis (hydroxymethyl) propanoic acid according to Reference Example 14 of EP1437352.
  • 1 ⁇ (hydroxymethyl) cyclopropane ⁇ 1 ⁇ carboxylic acid methyl ester (I-223) was prepared according to the procedure described in Reference example 22-1 of US9546155. The hydroxy group was then alkylated with Methyl iodide using the similar process described by Shen, Peng-Xiang; et al., in Journal of the American Chemical Society, 2018, vol. 140, #21, p. 6545 -6549. The ester is then hydrolyzed to afford 1 ⁇ (methoxymethyl) cyclopropane ⁇ 1 ⁇ carboxylic acid (I-225) .
  • 1-Hydroxy-2, 2-Diethoxy-isobutyric acids ethyl ester (I-249) was prepared according to the procedure described by Bernardon, C. et al. In Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1968, vol. 266, p. 1502 -1505. The hydroxy group was then alkylated with Methyl iodide followed by ester hydrolysis using the similar process described in Reference example K-19 in US10040791 to afford 1-Methoxy-2, 2-Diethoxy-isobutyric acid (I-251) .
  • methyl 2-methoxylacetate (I-289) was alkylated with dibromoethane in the same manner as those described in Example 26 3A of US10464914 to afforded the 1-methoxycyclopropanecarboxylic acid methyl ester which was then hydrolyzed under basic condition to afford the corresponding acid (I-291) .
  • the acid (I-291) was then trnasformed to the corresponding anhydride (I-292) according to the process of Preparation 2 to afford it as an oil.
  • N4-hydroxycytidine (NHC) or 1- (3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -4- (hydroxyamino) pyrimidin-2-one.
  • the following examplary compounds were prepared similarly as described Example 2 by using anhydrides (I-268) , (I-271) , (I-274) , (I-143) , (I-149) , (I-152) , (I-155) , (I-188) , (I-191) , (I-194) , (I-197) , (I-252) , (I-255) , (I-258) , (I-261) , (I-160) , (I-163) , (I-166) , (I-169) , (I-200) , (I-203) , (I-206) , (I-209) , (I-278) , (I-281) , (I-174) , (I-177) , (I-212) , (I-215) , (I-285) , (I-288) , (I-182) , (I-185) , (I-218) and (I-221) .
  • Molnupiravir is prepared according to the process of example 10 of US2020276219 using 2’, 3’-O-isopropylidene-uridine (I-318) and isobutyric anhydride to afford it as a white solid.
  • 1H NMR 400 MHz, D 2 O
  • Plasma Incubations Plasma incubations were conducted in duplicate in 96-well plate at 37°C.
  • Plasma was prewarmed in a total volume of 198 ⁇ L for 5 min at 37°C, then added 2 ⁇ L of 100 ⁇ M test compound into an incubation well containing plasma, pipette-mixed to achieve a homogenous suspension and immediately transferred 20 ⁇ L incubate as a 0 min sample to wells in a "Quenching" plate followed by adding 200 ⁇ L of acetonitrile with metolazone as internal standard (IS) and pipette-mixing.
  • IS internal standard
  • Microsome Incubations Incubation mixtures were prepared in a total volume of 200 ⁇ L with final component concentrations as follows: 0.1M PBS (pH 7.4) , NADPH (2 mM) and liver microsomes (0.2 mg/mL) as well as test compound (1 ⁇ M) or Molnupiravir (1 ⁇ M) as a positive control, wherein the NADPH was added after a 5-min preincubation of all other components at 37°C.
  • Example 22 Mouse PK Study: NHC, Example compounds and molnupiravir
  • Solution A PEG 400/Tween 80 (90%/10%)
  • the Example compounds, NHC and molnupiravir were suspended in the vehicle at 0.4mol/10mL respectively.
  • the mice were dosed at 0.4 mol/kg, 10 mL/kg via oral gavage.
  • the animals were restrained manually, and approx. 150 ⁇ L of blood/time point was collected into pre-cooled EDTA-K2 tubes via retro-orbital injection.
  • Blood samples were centrifuged at 4°C (4000 g, 5 min) to obtain plasma within 15 min after sample collection. Plasma samples were stored at approximately -80°C until analysis.
  • the plasma samples were analyzed using LC-MS/MS. The results of the test are shown in FIG. 1 and in the following Table, wherein the PK parameters were estimated by non-compartmental model using Winnonlin software.
  • Example 24 Treatment with NHC, Example compounds in a Ferret /Mice Model of Influenza Infection
  • Example 25 Treatment with NHC, Example compounds in a Ferret/mice Model of SARS-CoV-2 Infection

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Abstract

La présente invention concerne des dérivés d'ester de N4-hydroxycytidine (NHC), des compositions pharmaceutiques de ceux-ci, et un procédé d'utilisation de N4-hydroxycytidine pour traiter des infections virales.
PCT/CN2022/099403 2021-06-18 2022-06-17 Dérivés d'ester de n4-hydroxycytidine et leur utilisation WO2022262845A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012119559A1 (fr) * 2011-03-10 2012-09-13 Suzhou Kintor Pharmaceuticals,Inc. Antagonistes des récepteurs d'androgènes et leurs utilisations
CN107427529A (zh) * 2014-12-26 2017-12-01 埃莫里大学 N4‑羟基胞苷和衍生物及与其相关的抗病毒用途
CN111372592A (zh) * 2017-12-07 2020-07-03 埃默里大学 N4-羟基胞苷及衍生物和与其相关的抗病毒用途
CN111548384A (zh) * 2020-03-29 2020-08-18 常州安蒂卫生物科技有限公司 用于抗新型冠状病毒治疗的被取代的n4-羟基胞苷衍生物及其前药
CN112074506A (zh) * 2018-03-07 2020-12-11 埃默里大学 含4′-卤素的核苷酸和核苷治疗组合物以及其相关用途
CN112552288A (zh) * 2021-02-19 2021-03-26 南京桦冠生物技术有限公司 一种4-肟-5`-（2-甲基丙酰基）尿苷的制备方法
WO2021159044A1 (fr) * 2020-02-07 2021-08-12 Emory University N4-hydroxycytidine et ses dérivés et utilisations antivirales associées

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012119559A1 (fr) * 2011-03-10 2012-09-13 Suzhou Kintor Pharmaceuticals,Inc. Antagonistes des récepteurs d'androgènes et leurs utilisations
CN107427529A (zh) * 2014-12-26 2017-12-01 埃莫里大学 N4‑羟基胞苷和衍生物及与其相关的抗病毒用途
CN111372592A (zh) * 2017-12-07 2020-07-03 埃默里大学 N4-羟基胞苷及衍生物和与其相关的抗病毒用途
CN112074506A (zh) * 2018-03-07 2020-12-11 埃默里大学 含4′-卤素的核苷酸和核苷治疗组合物以及其相关用途
WO2021159044A1 (fr) * 2020-02-07 2021-08-12 Emory University N4-hydroxycytidine et ses dérivés et utilisations antivirales associées
CN111548384A (zh) * 2020-03-29 2020-08-18 常州安蒂卫生物科技有限公司 用于抗新型冠状病毒治疗的被取代的n4-羟基胞苷衍生物及其前药
CN112552288A (zh) * 2021-02-19 2021-03-26 南京桦冠生物技术有限公司 一种4-肟-5`-（2-甲基丙酰基）尿苷的制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CADEGIANI FLÁVIO ADSUARA, MCCOY JOHN, WAMBIER CARLOS GUSTAVO, GOREN ANDY: "5-Alpha-Reductase Inhibitors Reduce Remission Time of COVID-19: Results From a Randomized Double Blind Placebo Controlled Interventional Trial in 130 SARS-CoV-2 Positive Men", MEDRXIV, 18 November 2020 (2020-11-18), XP055950355, Retrieved from the Internet <URL:https://www.medrxiv.org/content/10.1101/2020.11.16.20232512v1.full.pdf> [retrieved on 20220810], DOI: 10.1101/2020.11.16.20232512 *
HALFORD BETHANY: "Pfizer unveils its oral SARS-CoV-2 inhibitor", ACS MEETING NEWS, ACS, vol. 99, no. 13, 12 April 2021 (2021-04-12), pages 1 - 2, XP055976884 *

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