WO2023059224A1 - Nouvelle classe de médicaments antiviraux - Google Patents

Nouvelle classe de médicaments antiviraux Download PDF

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Publication number
WO2023059224A1
WO2023059224A1 PCT/RU2022/050228 RU2022050228W WO2023059224A1 WO 2023059224 A1 WO2023059224 A1 WO 2023059224A1 RU 2022050228 W RU2022050228 W RU 2022050228W WO 2023059224 A1 WO2023059224 A1 WO 2023059224A1
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Prior art keywords
derivative
independently selected
pharmaceutically acceptable
isomers
acceptable salts
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PCT/RU2022/050228
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English (en)
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WO2023059224A4 (fr
Inventor
Alexander Vital'evich KURKIN
Denis Nikolaevich KAZYULKIN
Ekaterina Vladimirovna MANASOVA
Evgenii Renol'dovich LUKIANENKO
Grigorii Mihajlovich BELOV
Ildar Rustemovich IUSUPOV
Mikhail Gennad'evich SHURYGIN
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Joint Stock Company "Pharmasyntez"
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Priority claimed from RU2021129450A external-priority patent/RU2021129450A/ru
Application filed by Joint Stock Company "Pharmasyntez" filed Critical Joint Stock Company "Pharmasyntez"
Priority to AU2022359222A priority Critical patent/AU2022359222A1/en
Publication of WO2023059224A1 publication Critical patent/WO2023059224A1/fr
Publication of WO2023059224A4 publication Critical patent/WO2023059224A4/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Definitions

  • the invention relates to new biologically active derivatives of substituted 2,3- dihydrofuran-3-ones, which can be used as antiviral agents with a broad spectrum of antiviral activity.
  • Furanone derivatives have a broad spectrum of biological activity.
  • the use of furanone derivatives as flavoring agents is well known from the prior art.
  • Furanones also possess antiparasitic activity (Li, Honglin; Zhao, Zhenjiang; Huang, Jin; Xu, Yufang; Xu, Minghao; Diao, Yanyan; Zhou, Hongchang; Jin, Huangtao; Gao, Rui; Zhu, Junsheng Preparation of heterocycles as DHODH inhibitors, WO2013075596).
  • furanone derivatives have antibacterial activity (WO 01/85664 A2).
  • the closest structural analogue to the compounds of this invention is nivefuranone, a furanone derivative produced by Aspergillus niveus, which has activity against T-lymphotropic virus (proven on human lymphocyte cultures infected with type 2B T-lymphotropic virus with IC500.78 pg/mL in vitro) (Fujiwara T, Sato A, Kawamura Y, Matsumoto K, Itazaki H. Nivefuranone manufacture with Aspergillus niveus, Japanese Kokai Tokkyo Koho, Patent, 1994).
  • RNA viruses of various types including SARS-CoV-2
  • SARS-CoV-2 The ability of the newly developed compounds to effectively inhibit the replication of RNA viruses of various types, including SARS-CoV-2, points to the potential applicability of 2,3-dihydrofuran-3-one structural class to treat infectious diseases in humans and animals.
  • the objective of the present invention is the design and creation of new compounds effective for the therapy of diseases caused by RNA viruses, in particular but not limited to the therapy of diseases caused by HCoV-OC43, HCoV-HKUl, HCoV-229E, HCoV-NL63, SARS, MERS and SARS-CoV-2 coronaviruses.
  • the technical result of the invention is the development and production of new chemical compounds with high efficacy for the treatment of diseases caused by RNA viruses.
  • the disclosed compounds are promising as therapies of infectious diseases, including but not limited to coronaviruses, in particular SARS-CoV-2 vims, as well as several other species.
  • R 1 represents substituents of the following type where A represents a condensed Ce-aryl or a derivative thereof, 5-6- membered heteroaryl or a derivative thereof containing 1 to 3 heteroatoms independently selected from N, S, and/or O, the asterisk denotes the attachment point of the substituent;
  • X represents N or a substituent of the CR 4 type, where R 4 is independently selected and represents -H, -D, -F, -Cl, -Br, -I, - CN,
  • alkyl or a derivative thereof alkenyl or a derivative thereof, alkynyl or a derivative thereof, Cr,-aryl, 5-6-membered heteroaryl or a derivative thereof containing 1 to 4 heteroatoms, independently selected from
  • R a is independently selected and represents -H, a substituted or unsubstituted Ci-Ce-alkyl, alkenyl or a derivative thereof, -Cs-Cg-cycloalkyl or a derivative thereof, -Ce-aryl or a derivative thereof, a 5-6-membered heteroaryl or a derivative thereof, containing 1 to 4 heteroatoms, independently selected from N, S and/or O, or a 4-9-membered heterocycle or a derivative thereof, containing 1 to 4 heteroatoms, independently selected from N, S and/or O;
  • Y is independently selected and is -H or a substituent of the following type
  • Z is independently selected and represents -H, -Li+, -Na + , -K + , -[N(R f )4] + ;
  • R f is independently selected and represents -H, or -alkyl
  • R 2 and R 3 are independently selected and represent alkyl or a derivative thereof, alkenyl or a derivative thereof, -Ce-Cio-aryl or a derivative thereof, a 5-10- membered heteroaryl or a derivative thereof, containing 1 to 4 heteroatoms, independently selected from N, S and/or O, C 3 -C9-cycloalkyl or a derivative thereof, or a substituted or unsubstituted 4-9-membered heterocycle or a derivative thereof, containing from 1 to 4 heteroatoms, independently selected from N, S and/or O, and also substituents of the following type, the asterisk denotes the attachment point of the substituent
  • the compound of Formula (I) can be a pharmaceutically acceptable salt or optical isomers.
  • substituent R 1 is selected from a group of bicyclic condensed 8-9-membered heteroaryls of the following type
  • R b is independently selected and represents -H, -D, -F, -Cl, -Br, -I, -CH2F,
  • alkyl or its derivative alkenylyl or its derivative, Cs-Cg-cycloalkyl or its derivative, as well as substituents such as - OR C , -SR C , -N(R C ) 2 , -CON(R C ) 2 , -COOR C , -SO 2 R C , -SO 2 N(R C ) 2 ;
  • R c is independently selected and represents -H, a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted -Cs-Cg-cycloalkyl, a substituted or unsubstituted Ce-aryl, a substituted or unsubstituted 5-6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, S and/or O, or a substituted or unsubstituted 4-9-membered heterocycle, containing 1 to 4 heteroatoms, independently selected from N, S and/or O.
  • R d is independently selected and represents alkyl or a derivative thereof, C 3 - Cg-cycloalkyl or a derivative thereof;
  • R e is independently selected and represents -H, -D, -F, -Cl, -Br, -I, -CH2F,
  • alkyl by itself or as part of another substituent, refers to saturated hydrocarbon groups with a straight or branched chain, including hydrocarbon groups having a specified number of carbon atoms (i.e. Ci-6-alkyl means an alkyl containing one to six carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, and isopropyl.
  • heterocycle or “heterocyclic” means in this document nonaromatic mono- or polycyclic systems (saturated or partially unsaturated) having from three to twelve atoms and containing N, O or S heteroatoms.
  • a heterocycle can be attached to the main fragment of the molecule through a nitrogen atom (N- heterocycle) or through a carbon atom. Heterocycles can also be substituted.
  • cycloalkenyl refers herein to a partially unsaturated cycloalkyl containing 5 to 12 carbon atoms with one or two double carbon-carbon bonds.
  • aryl means groups containing an aromatic cycle having five to ten carbon atoms.
  • An example of aryl cyclic group is phenyl.
  • heteroaryl means a stable heterocyclic or polyheterocyclic aromatic fragment having 5-10 atoms in a cycle.
  • a heteroaryl group may be substituted or unsubstituted and may consist of one or more rings. Possible substituents include but are not limited to any of the previously mentioned substituents.
  • heteroaryl cycles are five- and sixmembered monocyclic groups such as thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazolyl, etc., as well as polycyclic heterocyclic groups such as benzo [b] thienyl, isobenzofuranyl, isoindolyl, benzimidazolyl, etc.
  • heteroaryl can be used interchangeably with the terms “heteroaryl cycle” or “heteroaromatic.”
  • An aryl or heteroaryl group (including the heteroaryl portion of heteroaralkyl or heteroaralkoxy fragments, etc.) may contain one or more substituents.
  • suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group include but are not limited to halogen (F, Cl, Br, or I), Ci-3-alkyl, -CN, -OH, -C1.3- alkyl and others.
  • substituted shall mean that one or more hydrogen atoms on any substitutable atom or group referred to as “substituted” is substituted with any of the abovementioned groups, provided that the said atom has normal valency, that the valency of the atom being replaced is not excessive, and that the substitution results in a stable compound.
  • substituted or unsubstituted means that relevant compound or substructure is either unsubstituted or substituted, as defined in the application, with one or more substituents as mentioned or as defined here below.
  • alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, cycloalkenyl, heterocyclic, aryl, and heteroaryl groups can be substituted with one or more substituents:
  • a stable or chemically possible compound is a compound, the stability of which is sufficient for its synthesis and analytical detection.
  • the preferred compounds of the present invention are sufficiently stable and do not decompose at temperatures up to 40 °C in the absence of chemically active conditions, for at least one week.
  • Some compounds of the present invention may exist in tautomeric forms, and this invention includes all such tautomeric forms of such compounds unless otherwise specified.
  • isomers structural or optical isomers (i.e. stereoisomers). Unless otherwise indicated, the structures described herein also imply all their stereoisomers, i.e., the R- and S- isomers for each asymmetric center. In addition, individual stereochemical isomers, as well as enantiomers and diastereomeric mixtures of said compounds also belong to the subject matter of this invention. Therefore, the present invention covers each diastereomer or enantiomer that is largely free of other isomers (>90% and preferably >95% molar purity) as well as mixtures of such isomers.
  • Individual optical isomers can be obtained by racemate resolution according to a standard procedure, for example, obtaining diastereoisomeric salts by treatment with an optically active acid or base, subsequent separation of the mixture of diastereomers by crystallization followed by extraction of the optically active bases from these salts.
  • suitable acids include tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric, and camphorsulfonic acid.
  • Another technique for separating optical isomers involves using a chiral chromatographic column.
  • other method of racemate resolution involves the synthesis of covalent diastereomeric molecules by reacting compounds of this invention with an optically pure acid in activated form or an optically pure isocyanate.
  • the resulting diastereomers can be separated by conventional methods such as chromatography, distillation, crystallization, or sublimation and then hydrolyzed to obtain enantiomerically pure compounds.
  • Optically active compounds of the present invention can be synthesized using optically active starting materials. Such isomers may be in the form of a free acid, free base, ester, or salt.
  • the present invention includes all pharmaceutically acceptable isotopically labeled compounds according to the present invention, in which one or more atoms are substituted with atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number normally found in nature.
  • isotopes suitable for inclusion in compounds according to this invention include hydrogen isotopes, such as 2 H and 3 H, carbon isotopes, such as n C, 13 C and 14 C, chlorine isotopes, such as 36 CI, fluorine isotopes, such as 18 F, iodine isotopes, such as 123 I and 125 I, nitrogen isotopes, such as 13 N and 15 N, oxygen isotopes, such as 15 O, 17 O and 18 O, phosphorus isotopes, such as 32 P, and sulfur isotopes, such as 35 S.
  • hydrogen isotopes such as 2 H and 3 H
  • carbon isotopes such as n C, 13 C and 14 C
  • chlorine isotopes such as 36 CI
  • fluorine isotopes such as 18 F
  • iodine isotopes such as 123 I and 125 I
  • nitrogen isotopes such as 13 N and 15 N
  • Radioactive isotopes such as tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are used for this purpose because of the ease of their introduction and the availability of means of their detection.
  • Substitution with heavier isotopes such as deuterium, i.e., 2 H, may provide certain therapeutic effects due to metabolic stability, such as increased in vivo elimination half-life or reduced dosing rates, and, therefore, may be preferable in some cases.
  • Isotopically labeled compounds according to this invention can be prepared by conventional methods known to those skilled in the art or by methods similar to those described in the accompanying examples of synthesis methods, using appropriate isotopically labeled reagents instead of conventional (unlabeled) ones.
  • solvates according to this invention include solvates where the crystallization solvent can be isotopically substituted, such as D2O, d6-acetone, d6-DMSO.
  • solvate is applicable to an association or complex containing one or more molecules of a solvent and a compound according to this invention.
  • solvents that form solvates include but are not limited to water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate is applicable to a complex where the solvent is water.
  • compositions of the present invention may exist in free form or, if required, in the form of a pharmaceutically acceptable salt or other derivative.
  • pharmaceutically acceptable salt as used herein is applicable to such salts, which, to the best of medical judgment, are suitable for use in contact with human or animal tissues without undue toxicity, irritation, allergic reaction, etc., and have a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in medicine.
  • the salts may be obtained in situ in the process of extraction or purification of the compounds of this invention, or they may be obtained separately by reacting a free acid or base of a compound of this invention with a suitable base or acid, respectively.
  • Examples of pharmaceutically acceptable, non-toxic salts are amino group salts formed by inorganic acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids, such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or obtained by other methods used in the art, such as ion exchange.
  • inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids
  • organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or obtained by other methods used in the art, such as ion exchange.
  • salts include adipinate, alginate, ascorbate, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formiate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanate, hexanate, hydroiodide, 2- hydroxy ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2 -naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pebio
  • Typical salts of alkali and alkaline earth metals contain sodium, lithium, potassium, calcium, magnesium, etc.
  • pharmaceutically acceptable salts may contain, if required, nontoxic ammonium, quaternary ammonium or amine cations obtained using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.
  • Compounds of General Formula (I) can be prepared by reacting a,P-acetylene y-hydroxy nitrile derivatives with carboxylic acid derivatives according to the method described in literature [Synthetic Communications, 45: 2718-2729, 2015],
  • any suitable solvent may be used, preferably aprotonic with a high dielectric constant, preferably selected from triethylamine, acetonitrile, dimethylformamide, etc.
  • Heating is an optional step, because if the heating step is excluded, the synthesis is feasible, sometimes with increasing reaction timeT
  • R 1 represents substituents of the following type where A represents a condensed Ce-aryl or a derivative thereof, 5-6- membered heteroaryl or a derivative thereof containing 1 to 3 heteroatoms independently selected from N, S, and/or O, the asterisk denotes the attachment point of the substituent;
  • X represents N or a substituent of the CR 4 type, where R 4 is independently selected and represents -H, -D, -F, -Cl, -Br, -I, -CN, -CH2F, -CHF2, -CF3, -NO2, alkyl or a derivative thereof, alkenyl or a derivative thereof, alkynyl or a derivative thereof, Cr,-aryl, -5-6-membered heteroaryl or a derivative thereof, containing 1 to 4 heteroatoms, independently selected from N, S and/or O, -Cs-Cg-cycloalkyl or a derivative thereof, or -4-9-membered heterocycle, containing 1 to 4 heteroatoms independently selected from N, S and/or O, as well as substituents such as -CH 2 OR a or -CH2N(R a )2, where
  • R a is independently selected and represents -H, a substituted or unsubstituted -Ci-Ce-alkyl, alkenyl or a derivative thereof, -Cs-Cg-cycloalkyl or a derivative thereof,
  • -Ce-aryl or a derivative thereof a 5-6-membered heteroaryl or a derivative thereof, containing 1 to 4 heteroatoms independently selected from N, S and/or O, or a 4-9- membered heterocycle or a derivative thereof, containing 1 to 4 heteroatoms independently selected from N, S and/or O;
  • Y is independently selected and is -H or a substituent of the following type
  • Z is independently selected and represents -H, -Li+, -Na + , -K + , -[N(R f )4] + ;
  • R f is independently selected and represents -H, or -alkyl;
  • R 2 and R 3 are independently selected and represent alkyl or a derivative thereof, alkenyl or a derivative thereof, -Ce-Cio-aryl or a derivative thereof, a 5-10- membered heteroaryl or a derivative thereof, containing 1 to 4 heteroatoms, independently selected from N, S and/or O, Cs-Cg-cycloalkyl or a derivative thereof, or a substituted or unsubstituted 4-9-membered heterocycle or a derivative thereof, containing from 1 to 4 heteroatoms, independently selected from N, S and/or O, and also substituents of the following type, the asterisk denotes the attachment point of the substituent
  • n is independently selected for Xi, X 2 and X 3 and can take values from 1 to 4; substituents R 2 and R 3 together with the carbon atom, to which they are attached, can form a 8-14-membered spirocycle, where the compound of Formula (I) is a pharmaceutically acceptable salt or optical isomers.
  • substituent R 1 is selected from a group of bicyclic condensed 8-9-membered heteroaryls of the following type
  • R b is independently selected and represents -H, -D, -F, -Cl, -Br, -I, -CH2F, -CHF 2 , -CF 3 , -OCF3, -OCHF2, -CN, -NO2, alkyl or its derivative, alkenylyl or its derivative, C 3 -C9-cycloalkyl or its derivative, as well as substituents such as - OR C , -SR C , -N(R C ) 2 , -CON(R C ) 2 , -COOR C , -SO 2 R C , -SO 2 N(R C ) 2 ;
  • R c is independently selected and represents -H, a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted -C 3 -C9-cycloalkyl, a substituted or unsubstituted Ce-aryl, a substituted or unsubstituted 5-6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, S and/or O, or a substituted or unsubstituted 4-9-membered heterocycle, containing 1 to 4 heteroatoms, independently selected from N, S and/or O.
  • the structure of the obtained compounds was verified by elemental analysis. Elemental analysis for carbon, hydrogen, nitrogen, and sulfur was performed on an elemental analyzer Flash EA 1112 CHNS-O/MAS 200 (Thermo Scientific, USA). Elemental analysis for fluorine, sodium, chlorine, bromine, and phosphorus was performed on an energy dispersive X-ray fluorescence spectrometer EDX-8100 (Shimadzu, Japan).
  • Antiviral activity against MERS, SARS, and SARS-CoV-2 viruses was studied using Vero E6 cell culture.
  • the cells were cultured on DMEM medium supplemented with 10% FBS, antibiotic mixture, and L-glutamine at 37°C in a humid atmosphere containing 5% CO2.
  • SARS-CoV-2 virus strains VIC01/2020 and SPE-RII-3524 V/2020
  • HCoV-229E HCoV-EMC/2012 were used to infect the culture.
  • Virus at a concentration of 1,000 TCID 50 in 100 pl of medium was added to plates with a 1-day monolayer of Vero cells.
  • dilutions of the studied substances were introduced at 100 pl per well in 2 replications.
  • a virus control 100 pl of medium containing virus at a concentration of 1,000 TCID50 + 100 pl of supporting medium
  • a negative cell control 200 pl of medium was added to the wells
  • the study of antiviral activity against HIV-1 virus was performed on human MT-4 cell culture.
  • the following cell culture medium was used: RPMI-1640 containing 0.2% sodium bicarbonate, supplemented with 10% inactivated fetal serum, 2 mM of L-glutamine, and 20 pg/ml of gentamicin.
  • cytotoxicity of the studied substances was examined using the MTT assay. Subsequently, dilutions of the studied substance in the nontoxicity zone were used to determine the antiviral activity against HIV-1.
  • MT-4 cells with the dilutions of the studied substance were incubated for 5 days in a CO2 incubator at 37°C and 5% CO2. After that, 20 pl of MTT reagent solution were added, followed by incubation for 1.5 hours, and then IC50 of the studied substance was determined from the optical density curve.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C., et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
  • Compositions may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, covering agents, glidants, processing aids, colouring agents, sweeteners, fragrances, flavorings, diluents, and other known additives to provide an elegant presentation of a drug (e.g., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (e.g., a medicine).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, covering agents, glidants, processing aids, colouring agents, sweeteners, fragrances, flavorings, diluents, and other known additives to provide an elegant presentation of a drug (e.g., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of
  • compositions were made by combining one or more of the compounds described in Table 1 with suitable excipients.
  • compositions can be found in Remington's Pharmaceutical Sciences, A. Gennaro (ed.), 18th edition, 1990, Mack Publishing Co., Easton, Pennsylvania. The following examples are for illustrative purposes only and should not be construed as limiting this invention.
  • active ingredient refers to one or more of the compounds described in Table 1.
  • Sifted powder of a blend containing 10.0 g of active ingredient, 10.0 g of Crospovidone and 8.0 g of Macrogol 6000 is loaded into a ball mill and micronized for 30 minutes.
  • the active ingredient mixed with Macrogol 6000 and Crospovidone is pelletized in a fluidized bed of 20% lactose and mannitol solution.
  • the resulting pellet powder is dusted with sodium stearyl fumarate (2.0 g) in a cone mixer.
  • the resulting pharmaceutical formulation has the following composition (wt):
  • compositions may include acceptable excipients, both solid and liquid, forming the following compositions, for example:
  • Active ingredient 95-99.99 wt%
  • Active ingredient 0.1-4 wt%
  • Solid finished dosage forms include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may contain from 0.1 to 100% of active ingredient.
  • Liquid finished dosage forms include solutions, suspensions and emulsions.
  • Aerosol preparations may include solutions or powders, which may be in combination with a pharmaceutically acceptable carrier.
  • Pharmaceutical product is preferably kept as a standard unit dose, i.e., in a form, in which it is present in standard unit doses of appropriate size containing appropriate amounts of the active ingredient.
  • Tablets were produced by wet granulation and pressing.
  • the active ingredient was mixed with suitable excipients and carriers by means of wet granulation and pressing.
  • Active ingredient was mixed with suitable excipients and carriers named hereabove by means of pressing.
  • Capsules were produced by dispersing the active ingredient in suitable excipients and filling the mixture into capsules.
  • the active ingredient was mixed with liquid excipients, the mixture was filtered through a sterile microporous filter and sealed tightly in sterile glass ampoules.
  • Example. 5 Suspensions. Active ingredient was mixed with a suitable excipient to form suspensions.
  • Tablets, pills, liquids and solutions, suspensions, emulsions, granules and capsules were administered orally. Injections were administered intravenously in pure form or in a mixture with a common liquid substitute such as glucose, amino acids, etc.; if necessary intramuscular, intradermal, subcutaneous, or intraperitoneal administration of pure form of the drug was used. Suppositories are administered into the rectum.
  • the dosage of the aforementioned pharmaceutical product is chosen depending on intended use, patient's age, sex and other conditions and the severity of the disease, and the amount of the active ingredient is determined individually.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés biologiquement actifs de 2,3-dihydrofuran-3-ones substitués, qui peuvent être utilisés en tant qu'agents antiviraux avec un large spectre d'activité antivirale. Le composé représenté par la formule (I) est décrit : Formule (I). L'invention concerne également une méthode de traitement d'une maladie virale, un procédé de prévention d'une maladie virale, une composition pharmaceutique comprenant le composé selon les revendications 1-5 et un support pharmaceutiquement acceptable, ainsi qu'un procédé d'obtention du composé de formule (I). Le résultat technique de la présente invention est le développement et la production de nouveaux composés chimiques ayant une efficacité élevée pour le traitement de maladies provoquées par des virus à ARN.
PCT/RU2022/050228 2021-10-09 2022-07-21 Nouvelle classe de médicaments antiviraux WO2023059224A1 (fr)

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AU2022359222A AU2022359222A1 (en) 2021-10-09 2022-07-21 A new class of antiviral drugs

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RU2021129450A RU2021129450A (ru) 2021-10-09 Новый класс противовирусных средств

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