WO2023085979A1 - Nouveaux dérivés de favipiravine - Google Patents

Nouveaux dérivés de favipiravine Download PDF

Info

Publication number
WO2023085979A1
WO2023085979A1 PCT/RU2022/050352 RU2022050352W WO2023085979A1 WO 2023085979 A1 WO2023085979 A1 WO 2023085979A1 RU 2022050352 W RU2022050352 W RU 2022050352W WO 2023085979 A1 WO2023085979 A1 WO 2023085979A1
Authority
WO
WIPO (PCT)
Prior art keywords
favipiravir
drug
virus
pharmaceutical composition
paragraphs
Prior art date
Application number
PCT/RU2022/050352
Other languages
English (en)
Russian (ru)
Inventor
Петр Александрович Белый
Эдуард Юрьевич Лопатухин
Владимир Львович КОРОЛЕВ
Кира Яковлевна ЗАСЛАВСКАЯ
Original Assignee
Общество С Ограниченной Ответственностью "Промомед Рус"
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from RU2021132756A external-priority patent/RU2021132756A/ru
Application filed by Общество С Ограниченной Ответственностью "Промомед Рус" filed Critical Общество С Ограниченной Ответственностью "Промомед Рус"
Publication of WO2023085979A1 publication Critical patent/WO2023085979A1/fr

Links

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
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the invention relates to the field of chemical-pharmaceutical industry and medicine, and represents new derivatives of favipiravir, namely, new salts of favipiravir with amino acids, as well as a pharmaceutical composition and a drug containing new salts of favipiravir.
  • viruses are viruses whose genome is encoded by a single strand of RNA and which use the viral RNA-dependent RNA polymerase for their replication.
  • viruses are influenza virus, coronavirus, picornavirus, arenavirus, flavivirus, bunyavirus, filovirus, phlebovirus, hantavirus, enterovirus, togavirus, calicivirus, respiratory syncytial virus, parainfluenza virus, rhinovirus, metapneumovirus, rotavirus, or noravirus.
  • Nucleoside analogues directly target blocking the activity of RNA-dependent RNA polymerase and block the synthesis of the viral RNA chain for a wide range of RNA viruses, including the human coronavirus family.
  • favipiravir 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
  • a guanine analogue approved in clinical practice for the treatment of influenza effectively blocks the RNA-dependent RNA polymerase of influenza viruses (various types), Ebola virus, yellow fever, chikungunya, noroviruses, enteroviruses, etc.
  • De Clercq E. New nucleoside analogues for the treatment of hemorrhagic fever virus infections. Chem. Asian J. 14, 3962-3968, 2019].
  • favipiravir The universal mechanism of action of favipiravir, which specifically acts on the fundamental enzyme of the viral replication apparatus, suggests a wide spectrum of antiviral activity of this substance, which has been demonstrated in many studies listed below. Antiviral activity of favipiravir.
  • the disease is caused by influenza virus strains of varying virulence.
  • the highly pathogenic avian influenza A(H5N1) virus caused the first outbreak in Hong Kong in 1997. and continues to cause local outbreaks of this type of influenza every year.
  • Avian influenza A(H7N9) epidemic in China in 2013 and the influenza A(H1N1) pandemic in 2009 resulted in 17,700 deaths, and influenza is still one of the major public health problems worldwide, not only in terms of incidence but also in the critical health complications it causes [Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection.- 2010,- N. Engl. J. Med.].
  • Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is effective against a wide range of influenza virus strains, including A(H1N1), A(H5N1) and A(H7N9), due to the fact that viral RNA -dependent RNA polymerase (PsRp) misidentifies the favipirovir-RTF metabolite as a purine nucleotide.
  • PsRp viral RNA -dependent RNA polymerase
  • Favipiravir has completed phase III trials in Japan and Phase II trials in the United States for the treatment of influenza.
  • favipiravir inhibits the replication of arenaviruses, phleboviruses (Rift-Valle fever, phlebotomic fever and Punta Toro fever), hantaviruses (Maporal, Dobrava and Prospect Hill); flaviviruses (yellow fever and West Nile fever); enteroviruses (full and rhinoviruses); respiratory syncytium paramyxovirus and norovirus [Yousuke Furuta, Brian B. Gowen, KazumiTakahashi, Kimiyasu Shiraki, Donald F. Smee, Dale L. Barnard. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Research, 2013, Volume 100, Issue 2].
  • favipiravir showed high antiviral activity against all strains of the influenza virus, A, B and C.
  • the effective concentration (hereinafter EC50) ranged from 0.014 to 0.55cg/ml [Furuta Y, Takahashi K., Fukuda Y, Kuno M., Kamiyama T., Kozaki K., Nomura N., Egawa H., Minami S., Watanabe Y, Narita H., Shiraki K. In vitro and in vivo activities of anti-influenza virus compound T-705.-2002,- Antimicrob Agents Chemother; 46(4), p. 977-981].
  • Favipiravir is known to be active against 53 strains of the influenza virus, including seasonal strains A(H1N1), A(H3N2), and strains of influenza type B; A(HlNl)pdmO9 pandemic virus, highly pathogenic avian influenza A(H5N1) isolated from humans, strains A(H1N1) and A(H1N2) isolated from pigs, and A(H2N2), A(H4N2), A(H7N2) .
  • mice In vivo, in mouse models of viral infection with lethal doses of strains H3N2 (A/Victoria/3/75), H3N2 (A/Osaka/5/70) or H5N1 (A/Duck/MN/1525/81), favipiravir was administered one hour after infection . Survival of mice at doses of 30 mg/kg/day 2 or 4 times a day was significant, while all infected control mice died.
  • favipiravir When administered at 60 to 300 mg/kg/day, favipiravir has been shown to be effective in reducing the viral load in the lungs of H1N1-infected mice (A/ Califomia/04/09), as well as delayed use up to 96 hours post-infection [Takahashi K ., Furuta Y, Fukuda Y, Kuno M., Kamiyama T, Kozaki K., Nomura N., Egawa H., Minami S., Shiraki K. In vitro and in vivo activities of T-705 and oseltamivir against influenza virus. antivirus. Chem.
  • Arenaviruses cause fatal human diseases [Moraz M.L., Kunz S. Pathogenesis of arenavirus hemorrhagic fevers. - 2011. - Expert Rev. Anti infection. Then-9(1), p. 49-59], for which there are no antiviral drugs, except for ribavirin, which has a pronounced toxic effect.
  • favipiravir showed greater selectivity than ribavirin.
  • the EC50 values for the drug were 0.79-0.94 cg/ml for Yunin, Pichinde and Takaribe viruses.
  • the viral load during the use of favipiravir significantly decreased by the third day.
  • favipiravir prevented death, reduced the number of viral titers in the blood and tissues, at dosages of 60 mg/kg/day, twice prevented liver damage when used for 7 days, starting from 4 hours post-infection [Gowen V.V., Wong M.N., Jung K.N., Sanders A.V., Mendenhall M., Bailey K.W., Furuta Y, Sidwell R.W. In vitro and in vivo activities of T-705 against arenavirus and bunyavirus infections. Antimicrob. Agents Chemother.- 2007,- 51(9), p. 3168-3176].
  • Viral load also decreased significantly at the start of treatment from days 4, 5 and 6 post-infection.
  • the survival of animals significantly increased [Gowen V.V., Smee D.F., Wong M.N., Hall J.O., Jung K.H., Bailey K.W., Stevens J.R., Furuta Y, Morrey J.D.
  • Treatment of stage disease in a model of arenaviral hemorrhagic fever: T-705 efficacy and reduced toxicity suggests an alternative to ribavirin. - 2008, - PLoS One 3, e3725].
  • favipiravir demonstrated its effectiveness even after the onset of acute symptoms of the disease [Mendenhall M., Russell A., Smee DF, Hall J. O., Skirpstunas R., Furuta Y, Gowen BB Effective oral favipiravir (T-705 ) therapy initiated after the onset of clinical disease in a model of arenavirus hemorrhagic fever.- 2011,- PLoS Negl. Trop. Dis. 5, el342].
  • favpiravir When using favpiravir at a dose of 300 mg/kg/day, it showed significant effects on survival: 100% of the animals participating in the experiment survived, at a dose of 150 mg/kg/day, the indicators decreased to 50 and 25%, the animals maintained body weight, their temperature dropped to normal and all indicators were generally better than those for ribavirin at a dosage of 50 mg/kg/day.
  • Mean infectious dose viremia per ml of eluate decreased to an average of 2.1, 1.3, and 1.6 logIO SS50/ml in the high and medium dose favipiravir and ribavirin groups, respectively.
  • favipiravir The efficacy of oral administration of favipiravir has also been shown in models infected with the lethal Lassa virus in guinea pigs and mice [Safronetz D., et al. The broad-spectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset.- 2015,- Sci. Rep. 5, 14775]. The therapeutic effect was observed on the 2nd day after infection. Subcutaneous administration of favipiravir at doses of 300 mg/kg/day once a day reduced temperature, prevented weight loss, and increased animal survival. The effects of favipiravir were many times greater than those of ribavirin at a dose of 50 mg/kg/day.
  • Viruses of the Bunyaviride family including La Croce virus (LACV), Rift Valley fever virus (RVFV), Crimean-Congo hemorrhagic fever virus (CCHFV), acute fever with thrombocytopenia syndrome virus (SFTSV), and hantavirus, cause severe hemorrhagic fevers with concomitant pulmonary and renal complications.
  • LACV La Croce virus
  • RVV Rift Valley fever virus
  • CCHFV Crimean-Congo hemorrhagic fever virus
  • SFTSV thrombocytopenia syndrome virus
  • hantavirus cause severe hemorrhagic fevers with concomitant pulmonary and renal complications.
  • EC50 values in Plaque Forming Units (PFU) studies in cell culture started in the range of 0.9-30 ng/mL of the drug for Lassa, Punta Toro, Reef Valle, Acute Fever (SFTSV), Phlebotomy Fever, and Dobrava, Maporal, and Prospect Hill Hantaviruses [Tani H., et al. Efficacy of T-705 (Favipiravir) in the treatment of infections with lethal severe fever with thrombocytopenia syndrome virus. - 2016. - m Sphere 1].
  • Thrombocytopenic fever virus emerged several years ago as a seasonal disease in China, Korea and Japan [Yu X., Liang M., et al. Fever with thrombocytopenia associated with a novel bunyavirus in China. - 2011. - N. Engl. J. Med, 364, pp. 523-1532].
  • Favipiravir inhibited SFTSV replication in cell culture with EC values of 0.71-1.3 cg/mL.
  • IFNAR-/- interferon-a receptor knockout
  • Favipiravir blocks the replication of viruses of the flaviviride family, including yellow fever virus (YFV) and West Nile virus (WNV) [Julander JG, et al. Activity of T-705 in a hamster model of yellow fever virus infection in comparison with a chemically related compound T-1106. - 2009. - Antimicrob. Agents Chemother, 53(1), p. - 202-209; Morrey JD, et al. Efficacy of orally administered T-705 pyrazine analog on lethal West Nile virus infection in rodents. - 2008. - Antiviral Res., 80(3), p. 377-379], however, at higher concentrations than needed to block influenza virus activity.
  • the EC90 of favipiravir against YFV is 51.8 cg/ml in in vitro studies to determine the release of active viral particles on Vero cell culture.
  • YFV-infected hamsters were treated orally with favipiravir at doses ranging from 200 to 400 mg/kg/day for 8 days starting treatment 4 hours prior to infection.
  • This therapy significantly reduced the mortality rate of animals at the beginning of treatment [Julander J.G., et al. Activity of T-705 in a hamster model of yellow fever virus infection in comparison with a chemically related compound T-1106. - 2009. - Antimicrob. Agents Chemother, 53(1), p. 202-209].
  • Favipiravir exhibits antiviral activity against Western equine encephalitis virus (WEEV) in Vero cell culture, reaching an EC90 at 49 cg/mL [Julander J.G., et al. Effect of T-705 treatment on western equine encephalitis in a mouse model. Antiviral Res, 82(3), p. 169-171].
  • WEEV Western equine encephalitis virus
  • Favipiravir showed antiviral activity against Chikungunya virus (CHIKV) in Vero cell culture, reaching an EC50 at 0.3-9.4 cg/mL.
  • CHIKV-infected mice oral administration of favipiravir improved survival rates at double doses from 300 mg/kg/day starting 24 hours before or 4 hours before after infection [Delang L., et al. Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral. - 2014, - J. Antimicrob. Chemother, 69(10), p. 2770-2784].
  • Favipiravir also blocked poliovirus replication in Vero cell culture and rhinovirus in HeLa cell culture at 3K50s of 4.8 and 23 cg/ml, and with a selectivity index of 29 and >43, respectively [Furuta Y, et al. In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob. 2002. - Agents Chemother, 46(4), p. 977-981]. Favipiravir inhibited Enterovirus replication at an EC50 of 23 cg/mL [Wang Y, et al. In vitro assessment of combinations of enterovirus inhibitors against enterovirus 71,- 2016,- Antimicrob. Agents Chemother, 60(9), p. 5357-5367].
  • Favipiravir is active against murine noravirus with EC50 values of 39 cg/mL in viral plaque scoring studies in the RAW 264.7 mouse macrophage cell line.
  • Real-time PNR revealed blocking of RNA synthesis using favipiravir with EC50 from 19 cg/ml [Rocha-Pereira J., et al. Favipiravir (T-705) inhibits in vitro norovirus replication. - 2012. - Biochem. Biophys. Res. Commun, 424(4), p. 777-780].
  • favipiravir-RTF inhibits the RNA polymerase activity of human Noraviruses [Jin Z., et al. Biochemical evaluation of the inhibition properties of Favipiravir and 2'-C-methyl-cytidine triphosphates against human and mouse norovirus RNA polymerases. - 2015 Antimicrob. Agents Chem other],
  • Favipiravir showed antiviral activity against the Zaire Ebola virus (Mayinga 1976 strain) in a Vero E6 cell culture with an EC50 of 10.5 cg/ml.
  • oral administration of favipiravir avoided death and reduced viral titers in the blood when administered twice from 300 mg/kg/day for 8 days from day 6 post-infection, while in the placebo group all mice died [Oestereich L., et al. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model.- 2014,- Antiviral Res, 105, p. 17-21].
  • Favipiravir significantly reduced morbidity and mortality in RABV-infected mice when given orally at doses of 300 mg/kg/day twice for 7 days starting at 1 hour post-infection. Coronavirus.
  • favipiravir According to the Global Substances Report, favipiravir has now entered clinical trials against COVID-19 disease based on its proven mechanism of action against viral RsRp. In a clinical study by the National Center for Clinical Research on Infectious Diseases in Shenzhen, favipiravir was administered to 340 patients (age groups and comorbidities not specified) in two doses (2 doses) of 1600 mg on the first day and two doses of 600 mg for the next 13 days in addition to an inhalation aerosol of interferon-alpha (5 million units * 2 / day).
  • This dosage resulted in more rapid disappearance of the virus to undetectable values in the blood) than in the group of patients taking the combination of anti-HIV proteases - lopinavir / ritonavir, with a median clearance of viral particles of 4 days, versus 11, respectively, and was assessed by control CT chest section.
  • the use of favipiravir reduces the number of detectable viral particles in the blood, which means that it effectively inhibits viral replication, delays the development of an aggressive course of COVID-19 or even prevents it.
  • Favipiravir relying on a wide spectrum and proven mechanism of its action, can also alleviate the course of viral diseases, if taken on time, and also significantly reduce the viral load in the course of diseases with complications.
  • favipiravir Despite the high efficacy of favipiravir against viral diseases, there are a number of difficulties associated with the physicochemical, technological and pharmacological characteristics of drugs based on favipiravir in free form, in particular, the solubility of favipiravir in free form in water is extremely low, which complicates the production of new dosage forms.
  • the free-form favipiravir substance remains stable and shows acceptable performance, including hygroscopicity and flowability, for only about three years.
  • Favipiravir derivatives with various substances of a basic nature are known from the prior art, namely, favipiravir compounds with meglumine (CN103209967, Toyama Chemical Co LTD) and favipiravir sodium salt (TW201934539, Fujifilm Toyama Chemical Co LTD).
  • the objective of the present invention is to create new antiviral compounds, namely favipiravir derivatives, the substances and dosage forms of which have an improved safety profile, as well as improved physicochemical, technological and pharmacological properties.
  • the problem is solved by creating new derivatives of favipiravir, in particular salts of favipiravir with amino acids, namely, compounds of formula I:
  • composition means a composition comprising an amino acid salt of favipiravir in an effective amount
  • a pharmaceutical composition in the context of the present invention may additionally contain one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, such as, but not limited to specified, fillers, solubilizers, solvents, co-solvents, antioxidants, buffering agents, cryoprotectants, diluents, preservatives, stabilizers, humectants, emulsifiers, lubricants, lubricants, suspending agents, thickeners, sweeteners, fragrances, fragrances, antibacterial agents, fungicides, slow release regulators delivery, isotonic agents, pH adjusting agents, the choice and ratio of which depends on the nature, purpose and dosage of the drug.
  • pharmaceutically acceptable and pharmacologically compatible excipients such as, but not limited to specified, fillers, solubilizers, solvents, co-solvents, antioxidants, buffering agents
  • Non-limiting (illustrative) examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, as well as mixtures of these substances.
  • Protection of the pharmaceutical composition from the action of microorganisms can be provided using a variety of antibacterial and antifungal agents, such as, but not limited to, sorbic acid, parabens (methylparaben, propylparaben, ethylparaben, butylparaben, isobutylparaben, isopropylparaben, benzylparaben, heptylparaben and mixtures thereof) , chlorobutanol and similar compounds.
  • parabens methylparaben, propylparaben, ethylparaben, butylparaben, isobutylparaben, isopropylparaben, benzylparaben, heptylparaben and mixtures thereof
  • the pharmaceutical composition may include, but is not limited to, sugars, sodium chloride, sodium bicarbonate, etc.
  • Prolonged action of the pharmaceutical composition can be provided, but not limited to, using agents that slow down the absorption of the active agent (for example, hydrophilic and hydrophobic polymeric release inhibitors).
  • Non-limiting (illustrative) examples of suitable fillers are lactose, various types of starch, microcrystalline cellulose, calcium carbonate and phosphate, and others.
  • solvents and diluents water, suitable for parenteral forms, organic esters, ethanol, polyalcohols, and mixtures thereof can be used, but are not limited to.
  • examples of lubricants can be magnesium or calcium stearate, talc, sodium lauryl sulfate, sodium stearyl fumarate, etc. Silicon dioxide, talc, kaolin, bentonites, etc. can be used as lubricants.
  • organic and inorganic acids or alkalis can be used to adjust the pH, such as, but not limited to, hydrochloric acid, malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, sorbic acids, sodium hydroxide, etc.
  • dispersing agents and spreading agents are, but not limited to, starch, alginic acid and its salts, silicates.
  • the pharmaceutical composition can be administered to animals and humans orally, parenterally (intradermally, subcutaneously, intramuscularly, intravenously, intraarterially, in the cavity), sublingually, topically, including, but not limited to, ophthalmic, nasal administration, etc., rectally in a standard form of administration , as a mixture with traditional pharmaceutical carriers.
  • Suitable unit forms of administration include (without limitation) oral forms: tablets, capsules, pellets, granules, powders, solutions, oral and nasal spray solutions, syrups, suspensions, etc., oral: solutions, suspensions, emulsions, concentrates for preparation of injection and infusion dosage forms, aerosols and powders for inhalation administration, powders and lyophilizates for the preparation of injection and infusion dosage forms; rectal: suppositories, capsules, etc.; as well as eye drops.
  • excipient in the context of the present invention characterizes substances of inorganic or organic origin used in the manufacturing process, the manufacture of drugs to give them the necessary physical and chemical properties.
  • “Pharmaceutical salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention.
  • pharmaceutically acceptable in the context of the present invention means that the substance or composition to which the term is applied must be chemically and/or toxicologically compatible with other formulation ingredients and are safe for the person being treated with the substance or composition.
  • amino acids in the context of the present invention means organic substances, the molecules of which simultaneously contain carboxyl and amine groups, which can exist in the form of isomers and mixtures thereof.
  • substance in the context of the present invention means a synthesis product, which is any substance or mixture of substances of synthetic or other (biological, biochemical, mineral, plant, animal, microbial and other) origin, intended for the production of pharmaceutical compositions and medicines, which in during the production of a medicinal product (drug) becomes the active ingredient of this medicinal product and determines its effectiveness.
  • substances are intended to exhibit pharmacological activity or other direct effect in the diagnosis, treatment, relief of symptoms, or prevention of disease and relief of symptoms, or to affect the structure or function of the body.
  • drug in the context of the present invention characterizes substances or combinations thereof that come into contact with the human or animal body, penetrate into the organs, tissues of the human or animal body, used for the prevention, treatment of diseases, obtained by synthetic methods. Medicines are medicines.
  • the drug can be presented in the form of various ready-made forms intended for introduction into the animal or human body in various ways, for example, but not limited to, orally, sublingually, topically, rectally, parenterally.
  • terapéuticaally effective amount in the context of the present invention means the amount of a substance (as well as a combination of substances) which, when administered to a subject for the treatment or prevention of a disease, or at least one of the clinical symptoms of the disease, or disorder, is sufficient to effect such treatment (prophylaxis ) to a disease, disorder, or symptom.
  • the "therapeutically effective amount” may vary depending on the form of the substance (e.g., polymorph, salt, solvate, hydrate, etc.), disease, the disorder and/or symptoms of the disease or disorder, the severity of the disorder, disorder and/or symptoms of the disease or disorder, and the age and/or weight of the subject in need of such treatment (prophylaxis).
  • free form of a substance in the context of the present invention means the form of a substance in which the molecules of the substance do not interact with other molecules and/or particles, in particular cations or anions, ligands or complexing agents through ionic or van der Waals interactions, while atoms in a given molecule are linked only by covalent bonds.
  • bound form of a substance in the context of the present invention means the form of a substance in which the molecules of a given substance interact with other molecules and/or particles, in particular cations or anions, ligands or complexing agents through ionic or van der Waals interactions.
  • Examples of related compounds are organic and inorganic salts and complexes.
  • derivatives of organic compounds in the context of the present invention means a compound obtained from a compound of a similar structure (structural analogue) through a chemical reaction, if one or more atoms are replaced by other atoms (or a group of atoms), including functional groups; or there is an addition to the original molecule of acid or base residues, solvent molecules or other small molecules through chemical bonds or intermolecular interactions; or splitting off atoms or groups of atoms to form multiple bonds.
  • physical properties of medicinal substances characterizes the density, shape, size and nature of the surface of the particles, the specific surface of the particles, the forces of adhesion (adhesion on the surface) and cohesion (adhesion of particles inside the body), surface activity, melting point of medicinal substances and etc.
  • chemical properties of medicinal substances in the context of the present invention characterizes the solubility, stability, reactivity of medicinal substances, etc.
  • technological properties of medicinal substances in the context of the present invention characterizes bulk density, degree of compaction, flowability, moisture content, fractional composition, dispersion, porosity, compressibility of medicinal substances, etc.
  • favipiravir with amino acids, in particular, favipiravir lysinate, favipiravir ornithinate and favipiravir histidinate.
  • amino acids of the present invention are amino acids in the L or D configuration.
  • the amino acid of the present invention is favipiravir L-lysinate.
  • the amino acid of the present invention is favipiravir L-ornithinate.
  • the amino acid of the present invention is favipiravir L-histidinate.
  • the amino acid of the present invention is favipiravir D-lysinate.
  • the amino acid of the present invention is favipiravir D-ornithinate.
  • the amino acid of the present invention is favipiravir D-histidinate.
  • the novel compounds of the present invention may be administered in the form of prodrugs.
  • the prodrug may include a covalently linked carrier that releases the active parent drug upon administration to a mammalian subject.
  • Prodrugs can be prepared by modifying the functional groups present on the compounds such that the modifications are cleaved, either during routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include, for example, compounds in which a hydroxyl group is bonded to any group that, when administered to a subject, is cleaved to form a free hydroxyl group.
  • Examples of prodrugs include, without limitation, acetate, formate and benzoate derivatives of alcohol functional groups in the compounds.
  • Typical prodrugs form the active metabolite by converting the prodrug with hydrolytic enzymes, hydrolyzing amides, lactams, peptides, carboxylic acid esters, epoxides, or cleaving inorganic acid esters.
  • dioxane dimethyl sulfoxide, ethylene glycol, tetrahydrofuran, alcohols (for example, but not limited to methanol, ethanol, isopropanol), dimethylacetamide, dimethylformamide, etc., as well as their mixtures in various proportions.
  • a pharmaceutical composition for the treatment and/or prevention of viral diseases containing a compound in a therapeutically effective amount, which is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate.
  • a pharmaceutical composition for the treatment and/or prevention of viral diseases containing in a therapeutically effective amount a compound representing favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate, and at least one pharmaceutically acceptable excipient.
  • One embodiment of the invention is a pharmaceutical composition in which the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 100 to 4000 mg.
  • the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 100 to 3700 mg.
  • the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from PO to 3300 mg.
  • the amount of the compound which is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 120 to 3000 mg. More preferably, the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 130 to 2700 mg.
  • the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 140 to 2400 mg.
  • the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 150 to 2100 mg.
  • the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 160 to 1800 mg.
  • the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 170 to 1500 mg.
  • the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 180 to 1200 mg.
  • the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is 190 to 900 mg.
  • the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is 200 to 600 mg.
  • One embodiment of the invention is a pharmaceutical composition wherein the pharmaceutically acceptable excipients are selected from the group including, but not limited to, excipients, stabilizers, solubilizers, solvents, humectants, lubricants, lubricants, thickeners, sweeteners, fragrances, fragrances, fungicides, sustained release regulators, co-solvents, diluents, fillers, emulsifiers, preservatives, antioxidants, buffering agents, cryoprotectants, pH adjusting agents, isotonicity or corrective agents.
  • the solvent of the present invention is, but is not limited to, saline, injection water, pyrogen-free water, distilled water, Ringer's solution, Hartman's solution, or glucose solution.
  • One of the embodiments of the invention is a pharmaceutical composition for the treatment and/or prevention of viral diseases, where the virus is an RNA-containing virus.
  • One of the embodiments of the invention is a pharmaceutical composition for the treatment and/or prevention of viral diseases, where the virus is a virus whose genome is encoded by a single-stranded sense (+)-strand, as well as an antisense (-)-strand of RNA and which uses a viral RNA-dependent -RNA polymerase for its replication.
  • the virus of the present invention is an influenza virus, coronavirus, picornavirus, arenavirus, flavivirus, bunyavirus, filovirus, phlebovirus, hantavirus, enterovirus, togavirus, calicivirus, respiratory syncytial virus, parainfluenza virus, rhinoviruses, metapneumoviruses, rotavirus, or noravirus.
  • the virus of the present invention is a highly virulent or low virulent virus.
  • the virus of the present invention is SARS-CoV, SARS-CoV-2, MERS-CoV or Influenza A, B, C.
  • influenza virus of the present invention is, but not limited to, influenza A virus, including strains A (H1N1), A (H1N1) pdm09, A (H1N2), A (H3N2), A (H2N2), A (H4N2) , A (H7N2), swine influenza type A, avian influenza type A, including highly pathogenic strains (including H5N1 and H7N9).
  • influenza A virus including strains A (H1N1), A (H1N1) pdm09, A (H1N2), A (H3N2), A (H2N2), A (H4N2) , A (H7N2), swine influenza type A, avian influenza type A, including highly pathogenic strains (including H5N1 and H7N9).
  • the problem is solved, and the claimed technical result is achieved by obtaining a drug for the treatment and/or prevention of viral diseases, containing a pharmaceutical composition of the present invention.
  • the problem is solved, and the claimed technical result is achieved by obtaining a drug for the treatment and/or prevention of viral diseases, containing a pharmaceutical composition of the present invention and at least one pharmaceutically acceptable excipient.
  • the problem is solved, and the claimed technical result is achieved by obtaining a drug for the treatment and/or prevention of viral diseases, containing the pharmaceutical composition of the present invention in a therapeutically effective amount.
  • One embodiment of the invention is a drug that is a solid drug.
  • the solid drug of the present invention is, but not limited to, a tablet, capsule, pellet, sachet, dragee, powder, or lyophilisate.
  • Lyophilization is a process of removing a solvent from a frozen material by sublimation (sublimation) of solvent crystals under vacuum, i.e. converting it to vapor, bypassing the liquid phase.
  • the drug in the form of a lyophilizate fully retains its pharmacological activity.
  • the removal of the solvent during freeze-drying is carried out mainly by sublimation.
  • Sublimation is the removal of a solvent from a frozen object without the formation of a liquid phase, it is carried out under vacuum or much less often in an inert gas.
  • the freezing step is one of the determining steps for obtaining a quality drug in the form of a lyophilisate.
  • auxiliary excipients used in freeze-dried medicinal preparations of the present invention include: solvents, solubilizers (EDTA, a-cyclodextrin, etc.), fillers (mannitol, glycine, glucose, sucrose, lactose, milk, etc.), preservatives (benzyl alcohol, ethyl and methyl parahydroxybenzoate, etc.), pH regulators (buffer solutions, sodium hydroxide, hydrochloric acid), stabilizers, cryoprotectants (dextran, gelatin, hydroxyethyl starch, etc.).
  • solvents solvents
  • solubilizers EDTA, a-cyclodextrin, etc.
  • fillers mannitol, glycine, glucose, sucrose, lactose, milk, etc.
  • preservatives benzyl alcohol, ethyl and methyl parahydroxybenzoate, etc.
  • pH regulators buffer solutions, sodium hydroxide, hydrochloric acid
  • One embodiment of the invention is a drug that is an oral drug. More preferably, the oral drug of the present invention is, but not limited to, a tablet, capsule, pellet, dragee, powder, suspension, syrup, or solution.
  • One embodiment of the invention is a drug that is a liquid drug.
  • the liquid drug of the present invention is, but not limited to, a solution, a concentrate, a syrup, a suspension.
  • the liquid drug of the present invention is a parenteral drug.
  • Parenteral drug administration is a way of introducing drugs into the body, in which they bypass the gastrointestinal tract, in contrast to the oral route of drug administration.
  • Parenteral medicinal products are sterile preparations intended for administration by injection, infusion, inhalation or implantation into the human or animal body. These include solutions, emulsions, suspensions, aerosols, powders and tablets for the preparation of solutions and implantation, powders for inhalation, lyophilized preparations for the preparation of dosage forms administered parenterally (subcutaneously, intramuscularly, intravenously, intraarterially, into various cavities).
  • Parenteral routes of administration include administration into tissues (intradermally, subcutaneously, intramuscularly, intraosseously), into vessels (intravenously, intraarterially, into lymphatic vessels), into cavities (into the pleural, abdominal, cardiac and articular cavities), into the subarachnoid space, as well as inhalation , intranasal and subconjunctival administration.
  • the parenteral drug is an infusion solution.
  • the parenteral drug is an injectable solution.
  • One of the embodiments of the invention is a drug, which is an inhalation drug.
  • the inhalation drug of the present invention is, but not limited to, an aerosol, powder, or pulverized powder.
  • a drug which is a drug for topical administration.
  • Local administration of drugs refers to the application of a medicinal product to mucous membranes (including ophthalmic, nasal, rectal, vaginal application, application to the gums, oral mucosa, etc.), as well as the introduction into the external auditory canal.
  • the topical drug of the present invention is an ophthalmic, nasal, and rectal drug.
  • One embodiment of the invention is a drug that is a rectal drug.
  • the rectal drug of the present invention is, but not limited to, suppositories or capsules.
  • One embodiment of the invention is a medicament wherein the pharmaceutically acceptable excipients are selected from the group including, but not limited to, excipients, stabilizers, solubilizers, solvents, humectants, lubricants, lubricants, thickeners, sweeteners, perfumes, fragrances, fungicides, sustained release regulators, co-solvents, diluents, fillers, emulsifiers, preservatives, antioxidants, buffering agents, cryoprotectants, pH adjusting agents, isotonicity or corrective agents.
  • the pharmaceutically acceptable excipients are selected from the group including, but not limited to, excipients, stabilizers, solubilizers, solvents, humectants, lubricants, lubricants, thickeners, sweeteners, perfumes, fragrances, fungicides, sustained release regulators, co-solvents, diluents, fillers, emulsifiers, preservatives,
  • the solvent of the present invention is, but is not limited to, saline, injection water, pyrogen-free water, distilled water, Ringer's solution, or glucose solution.
  • new compounds of the present invention which are favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate, to obtain a pharmaceutical composition for the treatment and/or prevention of viral diseases.
  • the problem is solved, and the claimed technical result is achieved through the use of the pharmaceutical composition of the present invention for obtaining a medicinal product for the treatment and/or prevention of viral diseases.
  • new compounds of the present invention which are favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate, for the treatment and/or prevention of viral infections.
  • the viral infection of the present invention is SARS-CoV, SARS-CoV-2, MERS-CoV or Influenza A, B C.
  • the problem is solved, and the claimed technical result is achieved by a method for the treatment and / or prevention of viral diseases, including the introduction to a patient in need of such treatment, a new compound of the present invention, which is favipiravir lysinate, favipiravir ornithinat or favipiravir histidinate, in a therapeutically effective amount .
  • the problem is solved, and the claimed technical result is achieved by a method for the treatment and/or prevention of viral diseases, including the introduction of a pharmaceutical composition of the present invention in a therapeutically effective amount to a patient in need of such treatment.
  • the problem is solved, and the claimed technical result is achieved by a method for the treatment and / or prevention of viral diseases, including the introduction of a patient in need of such treatment, the drug of the present invention, in a therapeutically effective amount.
  • Example 1 Obtaining new compounds of the present invention.
  • General procedure for obtaining new compounds of the present invention namely, compounds of general formula I:
  • the reaction vessel was filled with distilled water and thermostated at a temperature of 40-45°C. Then, with stirring, the calculated amount of amino acid was gradually added to the water. The temperature of the reaction medium was raised to 60-70°C and the calculated amount of a mixture of favipiravir with dimethylformamide was added to the solution, provided that the total volume of this mixture a did not exceed 5-15% of the volume of the amino acid solution. The addition of favipiravir occurred in stages, namely four servings in a mass ratio of 4:2:1:0.5.
  • the reaction vessel was kept in an ultrasonic bath for 5-10 minutes, after which the fourth portion of the mixture was added. Then the temperature of the reaction medium was raised to 75-80°C. The solution was kept under stirring and constant temperature, then the solvent was removed from the reaction mass by evaporation under reduced pressure. The temperature during evaporation did not exceed 50°C. As a result, a fine powder of favipiravir salt with the indicated amino acids was obtained.
  • favipiravir lysinate was confirmed as a result of the analysis of the experiments performed by 13 C NMR spectroscopy of lysine, favipiravir and favipiravir lysinate.
  • the formation of a lysine salt was confirmed by downfield shifts of the C(4) and C(5) signals of favipiravir from 122.8 to 125.1 ppm, from 160.2 to 165.9 ppm. respectively, and high-field shifts of favipiravir signals at C(2) and C(1) from 136.2 ppm. by 135.2 ppm, from 152.9 to 150.1 ppm, respectively.
  • a shift of all signals in the 13 C NMR spectrum of lysine to the upfield was also found.
  • the error in measuring chemical shifts is 0.1 ppm, and the spin-spin interaction constants are 0.3 Hz.
  • CioHisFNsC Elemental analysis of CioHisFNsC: calculated C 41.52%, H 5.58%, F 6.57%, N 24.21%, O 22.12%; found C 41.40%, H 5.64%, F 6.71%, N 24.39%, O 21.97%.
  • NMR 33 C 5 (ppm): 38.1, 50.3, 50.1, 53.8, 138.4, 140.6, 143.1, 158.9, 161.3, 164.5 , 168.5, 171.8.
  • the measurement error of chemical shifts is 0.1 ppm, the spin-spin interaction constants are 0.3 Hz.
  • CiiHisFNeC calculated C 42.31%, H 4.20%, F 6.08%, N 26.91%, O 20.49%; found C 42.04%, H 4.51%, F 5.90%, N 26.58%, O 20.75%.
  • NMR 33 C 5 (ppm): 26.1, 32.8, 50.1, 53.8, 74.2, 135.9, 142.7, 146.6, 163.0, 165.3 , 179.1.
  • CieHieFNsOT calculated C 45.83%, H 5.94%, F 6.59%, N 19.44%, O 22.20%; found C 45.91%, H 5.86%, F 6.64%, N 19.50%, O 22.16%.
  • Example 2 Obtaining dosage forms of new derivatives of favipiravir.
  • a solution for injection of new favipiravir derivatives according to the present invention water for injection was first placed under sterile conditions in a container for preparing solutions. Next, the calculated amount of favipiravir salt according to the present invention was added to the container and stirred until complete dissolution of the active agent at a temperature of 50-70°C to obtain a transparent pharmaceutical composition in the form of a solution. Further, if necessary, the pH value was adjusted, filtered through a membrane filter, and the filtrate was placed in sterile containers and tightly sealed.
  • a 10% humectant solution was initially prepared.
  • the low-substituted hyprolose, the favipiravir salt of the present invention, and half of the microcrystalline cellulose were sequentially loaded into the mixer granulator.
  • the resulting mixture was stirred with a stirrer for 5 minutes, followed by the addition of a humidifier.
  • the mixing process was continued until complete introduction of the humidifier.
  • the resulting pharmaceutical composition was granulated, followed by drying of the granules in a fluidized bed unit. Next, the granules were calibrated through a sieve with a mesh size of 1 mm.
  • the obtained granulate was mixed with the remaining half of microcrystalline cellulose, crospovidone and colloidal silicon dioxide in a gravimetric mixer.
  • the resulting pharmaceutical composition was powdered with stearic acid, followed by tableting on a rotary tablet press.
  • favipiravir derivatives namely favipiravir salts with amino acids selected from the group: lysine, hydroxylysine, ornithine, leucine or histidine
  • an experiment was conducted on laboratory animals.
  • blood biochemical parameters were studied, such as the levels of alanine and aspartate aminotransferases, alkaline phosphatase and bilirubin, the increase of which in most cases is associated with liver damage.
  • mice were divided into four groups of ten individuals each. Animals were divided into groups using body weight as a criterion, so that the individual weight of the animals did not differ by more than 10% from the average weight of the animals.
  • group 2 favipiravir ornithinat
  • 6th group favipiravir argininate preparation, obtained in accordance with the method described in the source CN111214446 (closest analogue).
  • Dosing of the drug to animals was carried out according to the following scheme: daily individuals from groups 1, 2, 3, 4, 5 and 6 were orally administered 1500 mg of the drug in terms of free favipiravir (dosage is per person) by gavage for 10 days.
  • Serum separated by centrifugation of whole blood collected at the time of decapitation of animals was subjected to biochemical research. It determined the level of enzymes aspartic (AsAT) and alanine (AlAT) aminotransferases, alkaline phosphatase (AP) and bilirubin. The results obtained are presented in table 1.
  • new salts of favipiravir with amino acids namely, favipiravir lysinate, favipiravir ornithinate and favipiravir histidinate
  • favipiravir salts namely favipiravir hydroxylysinate and favipiravir leucinate
  • favipiravir arginate known in the prior art in terms of safety. use.
  • Example 4 Study of the therapeutic effect of new derivatives of favipiravir against the influenza virus.
  • Modeling of viral infection in mice was performed by intranasal administration of units of highly pathogenic H1N1 avian influenza virus. The experiment was carried out on 40 mature mice. The animals were kept under standard vivarium conditions and received sterile rodent food and sterile water.
  • the animals were divided into four groups of 10 individuals.
  • group 1 favipiravir lysinate preparation
  • group 2 favipiravir ornithinat
  • microcrystalline cellulose placebo
  • Treatment was started 24 hours after infection.
  • the drugs were administered orally as a suspension through a tube at a dosage of 400 mg 4 times a day for 5 days (dosages are given in terms of free favipiravir in terms of a person).
  • the fourth group received microcrystalline cellulose in suspension via gavage 4 times a day.
  • new derivatives of favipiravir in the form of pharmaceutically acceptable salts of favipiravir with amino acids namely, favipiravir lysinate, favipiravir ornithinate and favipiravir histidinate, exhibit highly effective antiviral activity.

Abstract

L'invention se rapporte au domaine de l'industrie chimio-pharmaceutique et de la médecine, et concerne de nouveaux dérivés de favipiravine, notamment de nouveaux sels de favipiravine avec des acides aminés, ainsi qu'un lysinate de favipiravine, un ornithinate de favipiravine et un histidinate de favipiravine, ainsi qu'une composition pharmaceutique et un agent médicamenteux contenant de nouveaux sels de favipiravine. L'invention permet de réduire les risques d'augmentation du niveau de transaminases hépatiques pendant une thérapie, associée à une affection toxique du foie.
PCT/RU2022/050352 2021-11-10 2022-11-08 Nouveaux dérivés de favipiravine WO2023085979A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2021132756A RU2021132756A (ru) 2021-11-10 Новые производные фавипиравира
RU2021132756 2021-11-10

Publications (1)

Publication Number Publication Date
WO2023085979A1 true WO2023085979A1 (fr) 2023-05-19

Family

ID=86336554

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/RU2022/050352 WO2023085979A1 (fr) 2021-11-10 2022-11-08 Nouveaux dérivés de favipiravine

Country Status (1)

Country Link
WO (1) WO2023085979A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111214446A (zh) * 2020-03-07 2020-06-02 瑞阳制药有限公司 一种供注射用法匹拉韦l-精氨酸盐冻干制剂
RU2740660C1 (ru) * 2020-05-20 2021-01-19 Общество С Ограниченной Ответственностью "Промомед Рус" Противовирусная композиция

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111214446A (zh) * 2020-03-07 2020-06-02 瑞阳制药有限公司 一种供注射用法匹拉韦l-精氨酸盐冻干制剂
RU2740660C1 (ru) * 2020-05-20 2021-01-19 Общество С Ограниченной Ответственностью "Промомед Рус" Противовирусная композиция

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHUESHOV V.I. ET AL.: "Promyshlennaia tekhnologiia lekarstv (pages 306, 310, 311, 330-334, 379, 393-398, 416-420, 445,448, 495, 496, 504, 510, 608-612, 621, 639", TOM 2. KHARKOV, IZDATELSTVO NFAU, MTK-KNIGA, 2002, pages 306 - ?, XP09546606 *
EVAN A THACKABERRY: "Non-clinical toxicological considerations for pharmaceutical salt selection", EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, ASHLEY PRODUCTIONS LONDON, GB, vol. 8, no. 11, 1 November 2012 (2012-11-01), GB , pages 1419 - 1433, XP055497267, ISSN: 1742-5255, DOI: 10.1517/17425255.2012.717614 *
KAIZER A. A. ET AL.: "Biokhimichesky sostav, pishchevaia i lekarstvennaia tsennost lishainika (Cetraria island ica), proizrastaiushchego na Taimyre", AGRARNYE PROBLEMY GORNOGO ALTAIA I SOPREDELNYKH REGIONOV, GORNO-ALTAISK, 30 June 2020 (2020-06-30), XP009546618 *
MOROZOV S. V. ET AL., GEPATOPROTEKTORY V KLINICHESKOI PRAKTIKE: RATSIONALNYE ASPEKTY ISPOLZOVANIIA: POSOBIE DLIA VRACHEI, 2011, Moscow, XP09546620 *
SEVERIANOVA L. A. ET AL.: "Sovremennye predstavleniia o deistvii aminokisloty L- lizina na nervnuiu i immunnuiu reguliatornye sistemy", KURSKY NAUCHNO-PRAKTICHESKY VESTNIK ''CHELOVEK I EGO ZDOROVE, 2007, pages 67 - 79, XP009546616 *
TILBORG ANAËLLE; NORBERG BERNADETTE; WOUTERS JOHAN : "Pharmaceutical salts and cocrystals involving amino acids: A brief structural overview of the state-of-art", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 74, 18 January 2014 (2014-01-18), AMSTERDAM, NL , pages 411 - 426, XP028623271, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2013.11.045 *

Similar Documents

Publication Publication Date Title
KR20200131784A (ko) 제2형 중증급성호흡기증후군 코로나바이러스 감염 질환의 예방 또는 치료용 조성물
CN104840467A (zh) 五环三萜类肠道病毒ev71抑制剂、其药物组合物及医药用途
JP2009522257A (ja) ウイルス感染症治療用薬剤
JP2022019937A (ja) ヒト又は動物の慢性若しくは急性のウイルス感染症及び／又は敗血症の予防若しくは治療のための組成物
RU2740660C1 (ru) Противовирусная композиция
WO2013031831A1 (fr) Procédé pour améliorer la thérapie pour des maladies auto-immunes telles que la polyarthrite rhumatoïde
WO2023085979A1 (fr) Nouveaux dérivés de favipiravine
RU2783282C1 (ru) Противовирусная фармацевтическая композиция, содержащая фавипиравир и аминокислоту, лекарственное средство, ее содержащее, а также их применение для лечения и/или профилактики вирусных инфекций
JP6910043B2 (ja) ヘマグルチニン結合ペプチド、および、これを含むインフルエンザウイルス感染症の予防・治療薬
RU2789612C1 (ru) Противовирусная фармацевтическая композиция, содержащая фавипиравир и гидрат аминокислоты и/или ее фармацевтически приемлемой соли
RU2814927C1 (ru) Противовирусная фармацевтическая композиция, содержащая фавипиравир и аминокислоту, лекарственное средство, ее содержащее, а также их применение для лечения и/или профилактики вирусных инфекций
RU2740657C1 (ru) Противовирусная композиция
CN111329859B (zh) 叶绿素铜钠盐在制备用于抗肠道病毒的药物中的应用
WO2023033683A1 (fr) Composition pharmaceutique antivirale contenant du favipiravir et un acide aminé
CA3175528A1 (fr) Inhibition virale
CA2754281A1 (fr) Combinaison antivirale de zinc et de trimethoprime
RU2270708C1 (ru) Натриевая соль сополимера карбоксиметилцеллюлозы и госсипола, фармацевтическая композиция и способ профилактики или лечения вирусных заболеваний
RU2751108C1 (ru) Противовирусная композиция
AU2016364380B2 (en) Formulations for intravenous injection of danirixin
JPS6333332A (ja) エイズ・ウイルス増殖抑制剤
US11197912B2 (en) Prevention and treatment of viral infection and viral infection-induced organ failure
WO2019031981A1 (fr) Inhibiteur d'entrée du virus de l'hépatite et composition pharmaceutique pour traiter l'hépatite
RU2626003C2 (ru) Амид 1,2,4-триазол-3-илтиогликолевой кислоты, обладающий противовирусной активностью, или его фармацевтически приемлемые соли, фармацевтические композиции и их применение для лечения и профилактики гриппа
RU2770518C2 (ru) Жидкая лекарственная форма для лечения и профилактики гриппа и орви
EP3906934A1 (fr) Application de dalargine pour la prévention d'infections virales des voies respiratoires et la prévention du développement de complications lors d'infections virales des voies respiratoires

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: 22893362

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202392752

Country of ref document: EA