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WO2014123457A1 - Alkyl [2-(2-{5-[4-(4-{2-[1-(2-méthoxycarbonylamino-acétyl)-pyrrolidin-2-yl]-3n-imidazol-4-yl}-phényl)-buta-1,3-diinyl]-1n-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-éthyl]-carbamate, composition pharmaceutique, médicament et procédé de traiement de maladies virales - Google Patents

Alkyl [2-(2-{5-[4-(4-{2-[1-(2-méthoxycarbonylamino-acétyl)-pyrrolidin-2-yl]-3n-imidazol-4-yl}-phényl)-buta-1,3-diinyl]-1n-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-éthyl]-carbamate, composition pharmaceutique, médicament et procédé de traiement de maladies virales Download PDF

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Publication number
WO2014123457A1
WO2014123457A1 PCT/RU2014/000084 RU2014000084W WO2014123457A1 WO 2014123457 A1 WO2014123457 A1 WO 2014123457A1 RU 2014000084 W RU2014000084 W RU 2014000084W WO 2014123457 A1 WO2014123457 A1 WO 2014123457A1
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Prior art keywords
imidazol
methyl
pyrrolidin
phenyl
buta
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PCT/RU2014/000084
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English (en)
Russian (ru)
Inventor
Александр Васильевич ИВАЩЕНКО
Олег Дмитриевич МИТЬКИН
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"INTELLEKTUAL`NY DIALOG" LLC
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"INTELLEKTUAL`NY DIALOG" LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C07D405/14—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 three or more hetero rings

Definitions

  • This invention relates to new compounds - derivatives of alkyl] 2- (2- ⁇ 5- [4- (4- ⁇ 2- [1- (2-methoxycarbonylamino-acetyl) -pyrrolidin-2-yl] -ZH-imidazole-4 - yl ⁇ -phenyl) -buga-1, 3-Diynyl] - 1 ⁇ -imidazol-2-yl ⁇ -pyrrolidin-1-yl) -2-oxo-e I yl] - carbamate, which exhibits inhibitory activity against NS5A proteins, to a new pharmaceutical composition, an antiviral drug, a method for the prevention and treatment of viral diseases, especially caused by hepatitis C viruses (HCV).
  • HCV hepatitis C viruses
  • Viral infections can cause many diseases, which poses a serious threat to human health and life. Over the past 20 years at least 30 completely new pathogens of infectious diseases have been discovered: AIDS, viral I epatitis, acute and chronic diarrhea, hemorrhagic fevers (Ebola, Venezuelan, Brazilian, Rift Valley) [a) Lednicky JA, Rayner J. O. Uncommon respiratory pathogens. Curr. Opin. Pulm. Med. 2006, 12 (3), 235-239. b) Ilayden FG Respiratory viral threats. Curr. Opin. Infect. Dis. 2006, 19 (2), 169-178].
  • Hepatitis C virus belongs to flaviviruses (genus Flaviviridac). along with other important human pathogens such as yellow fever virus, West Nile virus, Dengue virus and GBV-C hepatitis virus). Flaviviruses have similar genome organization, including the presence of a gene encoding the non-structural NS5A protein. NS5A plays an important role in the replication of the viral RNA genome, being a structural component of the viral replication complex. Since this protein is currently validated in clinical trials as a target for the development of drugs against chronic eiiai n ia C. NS5A seems to be a promising target for other clinically important flaviviruses listed above.
  • Alkyl means an aliphatic hydrocarbon linear or branched group with 1-5 carbon atoms in the chain, preferably with 1-3 carbon atoms (Ci-C alkyl). Branched means that the alkyl chain has one or more substituents, preferably C) -C 3 alkyl, Ci-C 3 alkyloxymethyl, trahydrofuraiyl.
  • Medical substance (medicinal substance, drug substance, drug-substance, active ingredient) means a physiologically active substance of synthetic or other (biotechnological, plant, living, microbial and other) origin, having pharmacological activity and is the active principle of the pharmaceutical composition used for production and manufacture of a medicinal product (product).
  • Medical product - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other formulations intended to restore, correct or alter physiological functions in humans and animals, as well as treatment and prevention of diseases, diagnosis, anesthesia, contraception, cosmetology and other things.
  • the “therapeutic cotail” is a simultaneously administered combination of two or more drugs with a different mechanism of pharmacological action and aimed at different biomiceps involved in the pathogenesis of the disease.
  • “Pharmaceutical composition” means a composition comprising at least one of the claimed compounds and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, omnibus, distributing and perceiving medium ?, delivery vehicles such as coppers, stabilizers, fillers, grinders, moisturizing gels, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, ant tibacterial agents, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage.
  • suspending agents are egoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be provided with a variety of antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid and the like.
  • the composition may also include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged action of the composition can be provided with agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin.
  • Suitable bedding, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate).
  • excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like.
  • grinders and distributors are starch, alginic acid and its salts, silicates.
  • lubricants are magnesium stsarag, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol.
  • the pharmaceutical composition for oral, sublingual, transderm al, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers.
  • Suitable unit dosage forms include oral forms such as table 1 tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
  • R 1 , R 2 , R 3 and R 4 independently of one another are Ci-C 3 alkyl
  • R 5 and R 6 independently of one another, are C 1 -C3 alkyloxymethyl or
  • R 1 , R 2 , R 3 and R 4 independently of one another are C1-C3 alkyl
  • R 5 and R 6 are independently C 1 -C 3 alkyl or C 1 -C 3
  • R 3 and R 5 and R 4 and R 6 together with the carbon atoms to which they are bonded, independently form a tetrahydrofuran cycle
  • Preferred stereoisomers are alkyl [2- (2- ⁇ 5- [4- (4- ⁇ 2- [1 - (2-methoxycarbonylamipo-acetyl) -pyrrolidin-2-yl1-3H-imidazol-4-yl ⁇ -spyl) - buta-1.3-diinyl] - 1 H-imidazol-2-yl ⁇ -pyrrolidin-1-yl) -2-oxo-ethyl] -carbamate naphthalene-1.5-disulfonates are:
  • the salts of naphthalene-1.5-disulfonates of the steroisomers 1.1.1-1.1.10 are prepared by reacting the corresponding bases of formula 1 with naphthalene-1,5-disulfonic acid in methanol, ethanol or isopropanol.
  • the salts obtained according to this invention are characterized by a high amount of salt required for use in pharmacopoeia, and are well stored at low temperatures (from 4.7 ° C to -23 ° C).
  • NS5A protein inhibitors which are compounds of general formula 1 or general formula 1.1, or formulas 1.1.1-1.1.10, possibly in crystalline or polycrystalline form.
  • the subject of this invention is a pharmaceutical composition for treating and preventing diseases caused by hepatitis C virus and GBV-C hepatitis virus, comprising, as an NS5A protein inhibitor, a compound of general formula 1 or general formula 1.1, or formulas 1.1.1 - 1.1.10 in therapeutically effective amount.
  • compositions may include pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients are meant diluents, excipients and / or carriers used in the pharmaceutical field.
  • the pharmaceutical composition along with the compound of general formula 1, or general formula 1.1, or formulas 1.1.1-1.1.10, or its crystalline or polycrystalline form, according to the present invention, may include other active ingredients, provided that they do not cause undesirable effects, for example, allergic reactions.
  • compositions of the present invention can be mixed for the manufacture of various forms, while they can include traditional pharmaceutical carriers; for example, oral forms (such as tablets, gelatine capsules, pills, solutions or suspensions); injection forms (such as injectable solutions or suspensions, or dry powder for injection, which only requires the addition of water for injection before use); local forms (such as ointments or solutions).
  • oral forms such as tablets, gelatine capsules, pills, solutions or suspensions
  • injection forms such as injectable solutions or suspensions, or dry powder for injection, which only requires the addition of water for injection before use
  • local forms such as ointments or solutions).
  • the carriers used in the pharmaceutical compositions of the present invention are carriers that use I CH in the pharmaceutical field to produce common forms, including: in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless agents, flavoring agents; I use 1 antiseptic ageshes in injection forms. solubilizers, stabilizers; in local forms, bases, diluents, lubricants, antiseptic agents are used.
  • a pharmaceutical composition is prepared by mixing at least one compound of general formula 1, or general formula 1.1, or formulas 1.1.1-1.1.10, or its crystalline or polycrystalline form with an inert filling gel and / or solvent.
  • the clinical dosage of a pharmaceutical composition containing, as an active component, a compound of general formula 1, or general formula 1.1, or formulas 1.1.1-1.1.10 in patients can be adjusted depending on or: therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as depending on the patient’s age, gender and stage of illness, while the daily dose in adults is usually 10 ⁇ 500 mg. Therefore, during the preparation of pharmaceutical compositions of the present invention in the form of dosage units, the aforementioned effective dosage must be taken into account, with each dosage unit of the preparation containing 10 ⁇ 500 mg of the compound of general formula 1, or 1.1, or formulas 1.1.1-1.1.10. In accordance with the instructions of a doctor or pharmacist, the data of the drug Mory i is taken several times during certain periods of time (preferably from one to six times).
  • the subject of this invention is a medicament, in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package, for the treatment and prevention of diseases caused by hepatitis C virus and hepatitis GBV-C virus, containing at least one compound as an NS5A protein inhibitor general formula 1, or 1.1, or formulas 1.1 .1 to 1 .1 .10, or a new pharmaceutical composition in a therapeutically effective amount.
  • the subject of this invention is a therapeutic cocktail for the prevention and treatment of diseases caused by hepatitis C virus and hepatitis GBV-C virus, including at least one compound of the general formula 1, or 1.1, or formulas 1.1.1-1.1.10, or a new a pharmaceutical composition, or a new drug in a therapeutically effective amount.
  • Therapeutic cocktails for the prevention and treatment of the above flavavirus diseases may include: Inosia-5- inhibitors dehydrogenase monophosphate, for example, ribavirin (allowed) and ribamidn; Hepatitis C NS3 inhibitors, for example, Telaprevir, Siluprsvir and SCI 1-503034; NS5B RNA polymerase inhibitors, for example, XTL-2125; alpha glucosidase inhibitors, for example, carbohydrate Sslogosivir; as well as agopists TLR-recipe mountains, gspatoprotectors, piclosporins, various proteins (for example, interferons), apt is weak. vaccines etc.
  • Inosia-5- inhibitors dehydrogenase monophosphate for example, ribavirin (allowed) and ribamidn
  • Hepatitis C NS3 inhibitors for example, Telaprevir, Siluprsvir and SCI 1-503034
  • any classes of agents that may be useful when combined with the bis-azoles of the present invention may include, for example, nucleoside and non-nucleoside inhibitors of I 1CV polymerase, protease inhibitors, glycase inhibitors, NS4B inhibitors and medical agents that functionally inhibit the internal ribosome site ⁇ entry (IRES) and other drugs that inhibit the attachment of I ICV cells or virus entry, HCV RNA movement, IICV RNA transcription, replication or HCV co Revan, concentration or attenuated virus.
  • I 1CV polymerase protease inhibitors
  • glycase inhibitors glycase inhibitors
  • NS4B inhibitors NS4B inhibitors
  • HCV HCV protease inhibitors such as telaprevir (VX-950), boceprevir (SCI 1-503034), narlaprevir (SCH-900518), ITMN -191 (R-7227), TMC-435350 (aka TMC-435), M -7009, BI-201335, BI-2061 (ciluprevir), BMS-650032, ACII-1625, ACH-1095 (HCV NS4A inhibits OR concomitant protease factor) VX-500, VX-813, PHX-1766, PHX2054, IDX-136.
  • HCV HCV protease inhibitors such as telaprevir (VX-950), boceprevir (SCI 1-503034), narlaprevir (SCH-900518), ITMN -191 (R-7227), TMC-435350 (aka TMC-435), M -7009, BI-201335, BI-2061 (ciluprevir),
  • nucleoside HCV polymerase inhibitors (replicases) useful in the present invention include, but are not limited to: R7128, PSI-7851, IDX-1 84, IDX-102, R1479, UNX-081 89, PSI-6130, PSI-938 and PSI-879 and various other nucleosides and nucleotide analogs and I ICV inhibitors, including but not limited to 2'-C-methyl modified nucleosides and nucleotides; and 7'-dase, modified nucleosides and nucleotides.
  • Inhibitors of non-nucleoside HCV polymerase (replicase).
  • HCV-796 useful in this invention include, but are not limited to: HCV-796, I ICV-371. VCII-759, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, GL- 59728 and GL-60667.
  • NSA inhibitors of the present invention can be used in combination with cyclophillin and immunophilia antagonists (for example, without limitation, DEBIO compounds, NM-81 1, as well as cyclosporin and its derivatives).
  • cyclophillin and immunophilia antagonists for example, without limitation, DEBIO compounds, NM-81 1, as well as cyclosporin and its derivatives.
  • kinase inhibitors, heat shock protein inhibitors e.g.
  • immunomodulatory agents which may include, without limitation, isherferoys (alpha, beta, omega, gamma, lambda or synthetic) such as Intron ⁇ TM, Roferon-A IM , Canferon-AZOO TM, Advafcron TM, Infergen TM, Humoferon TM, Sumiferon MP IM , Alfaferon 1 M , IFN- ⁇ TM, Feron TM, and the like, pegylated derivatized polyether glycol compounds, such as: PEG interieron-a-2a (Pegasys TM), PEG interferon-2b (PEGIntron TM), pegylated IFN- ⁇ -con 1 and the like; prolonged formulas and derivatives of interferope compounds, such as albumin-fused interferon, Albufcron rM , Loctcron IM .
  • isherferoys alpha, beta, omega, gamma, lambda or synthetic
  • interferons with various types of controlled delivery eg, ITCA-638. omega-interferon delivered by DUROS subcutaneous delivery system
  • compounds that stimulate the synthesis of interferon in cells such as resiquimod and the like
  • interleukins compounds that enhance the development of type 1 helper T cell response, such as SCV-07 and the like
  • TOLL-like receptor agonists such as: CpG-10101 (action), isotorabine, ANA773 and the like; thymosin ⁇ -1, ⁇ -245 and ⁇ -246.
  • any of the methods described above including the administration of an NS5A inhibitor, a type 1 interferon receptor agonist (e.g. IFN- ⁇ ) and a type P interferon receptor agonist (e.g. IFN- ⁇ ) can be enhanced by the administration of an effective amount of TNF-a antagonist.
  • a typical non-limiting TNF-a antagonis1 that is suitable for use in such combination therapy is ENBREL TM and HUMIRA TM.
  • the NS5A inhibitors of the present invention can be used in combination with antiprotozoans, and other antiviruses are considered effective in the treatment of HCV infection such as the nita / oxanide prodrug.
  • Nitazoxanide can be used as an agent in combination with the compounds disclosed in this invention, as well as in combination with other agents useful in the treatment of HCV infection, such as: peginterferon alfa-2a and ribavarin (e.g. Rossignol, JF and Keeffe, EB, Future Microbiol 3: 539-545, 2008).
  • NS5A inhibitors of the present invention can also be used with alternative forms of interferons and pegylated interferons, ribavirin or its analogues (e.g. Tarabavarm, levovirion), microRNA, slightly harmful RNA compounds (e.g. SIRPLEX-140-N and the like), nucleotide or nucleoside analogues, immunoglobulins, hepatoprotectors, anti-inflammatory ages and other NS5A inhibitors.
  • ribavirin or its analogues e.g. Tarabavarm, levovirion
  • microRNA e.g. SIRPLEX-140-N and the like
  • slightly harmful RNA compounds e.g. SIRPLEX-140-N and the like
  • nucleotide or nucleoside analogues e.g. SIRPLEX-140-N and the like
  • immunoglobulins e.g. SIRPLEX-140-N and the like
  • Inhibitors of other targets in the HCV life cycle include NS3 helicase inhibitors; co-factor NS4A inhibitors, antisense oligonucleotide inhibitors such as: ISIS-14803, AVI-4065 and the like; vector-encrypted short hairpin RNA (shRNA); HCV specific ribozymes such as: heptazyme, RPI, 139199 and the like; entry inhibitors such as: HcrsX-C, NscMax-HepC and the like; alpha-glucosidase inhibitors such as: celgosivir, UT-231B and the like; K.RE-02003002 and BIVN 401 and IMPDH inhibitors.
  • Other representative compounds, HCV inhibitors include the inhibitors disclosed in well-known scientific and patent publications.
  • combinations of, for example, ribavirin and iteferon can be introduced as a combination therapy with at least one of the compounds of general formula 1, or general formula 1.1, or formulas 1.1.1-1.1.10.
  • the present invention is not limited to the above classes or compounds, and contemplates known and novel compounds and combinations of biologically active agents. It is understood that the combination therapy of the present invention includes any chemical compatible combinations of the bisazoles of this patent of a state-friendly group with other compounds of the patentable group or other compounds outside the patentable group, and the combination does not exclude the antiviral activity of the compounds of this patentable group or the antiviral activity of the pharmaceutical composition itself .
  • Combination therapy may be sequential, i.e. treatment first with one agent and then with another (for example, when each treatment step involves a different compound of the present invention or when one treatment step includes a compound of the present invention and the other involves one or more biologically active agents) or there may be a treatment with both agents simultaneously .
  • Sequential therapy may include a significant amount of time after the completion of the first therapy and before the second therapy. Treatment with both agents at the same time can be carried out in a single daily dose or in different doses.
  • Combination therapy does not need to be limited to two ages, and three or more agents can be included. Doses for simultaneous and sequential combination therapy will depend on the absorption, distribution, rapid ⁇ her metabolism and excretion of the components of combination therapy, as well as other factors well known to the specialist.
  • the dose size will also vary depending on the severity of the condition that needs to be relieved i b. It should be understood that for each particular subject, the specific dosage regimen and schedule can be adjusted in time in accordance with the needs of the individual and the professional judgment of the person who is treating or observing treatment with the combination therapy method.
  • the subject of this invention is a method for the prevention and treatment of diseases caused by hepatitis C virus and hepatitis GBV-C virus, the introduction of a therapeutically effective amount of at least one compound of general formula 1, or general formula 1.1, or formulas 1.1.1-1.1.10, or a new pharmaceutical composition, or a new drug, or a therapeutic cocktail.
  • Example 1 General method for the preparation of steroisomers of alkyl [2- (2- ⁇ 5- [4- (4- ⁇ 2- [1- (2-methoxycarbonylamino-acetyl yl) -pyrrolidin-2-yl] -ZH-imidazole-4 -yl ⁇ -phenyl) -buta-1,3-diinyl] -1H-imidazol-2-yl ⁇ -pyrrolidin-1-yl) -2-oxoethyl] carbamates of the general formula 1 [1 (1) -1 (3 )].
  • reaction controller Coziness by LCMS method. After completion of the reaction, the solvent is completely distilled off by rotary evaporation! dichlormstan. The extract is washed with 10% sodium carbonate solution, dried over and evaporated on a rotary evaporator. Further purification was carried out using HPLC.
  • Example 2 The General method for producing naphthalene-1, 5-disulfonyl stereoisomers 1.1.1-1.1.10. Dissolve 5 g of the corresponding base of formulas 1.1.1 - 1.1.10 in 150 ml of methanol. The resulting solution was filtered through Cclitc and, with stirring, 1.05 eq of a solution of naphthalene-1, 5-disulfonic acid in methanol was added to it at a rate of 50 ml per 5 g of base.
  • naphthalene-1, 5-disulfonate 1.1.1 -1.1.10 is again transferred to the base. To do this, it is suspended in 100 ml of ethanol, 100 ml of a 10% solution of nafia carbonate are added. After complete dissolution, add 400 ml of dichlorormstan. The organic layer is separated, washed once with water and a saturated solution of sodium chloride, dried over nafia sulfate. evaporated in vacuum at a temperature not exceeding 40 ° C. Next, naphthalene-1, 5-disulfonate 1.1.1-1.1.10 is planted in the above manner.
  • naphthalene disulfonate with a purity of more than 99%, the base is purified by column chromatography. Eluent dioxane: toluene ⁇ 1: 1.5. Combine the middle fractions, evaporate them in vacuum at a temperature not exceeding 40 ° C. Next, naphthalene-1, 5-disulfonate is planted as described above. Yield 60%.
  • nafgalin-1, 5-disulfonaguses are white, crystalline substances with a yellow tint. Their cleanliness and structure confirmed by LC MS and H NMR. According to LC MS, the content of the main substance in analytical samples is> 99%. Salts and bases in the LC MS spectra have the same molecular ions corresponding to the molecular base: 1.1.1: LC MS m / e 711 (M + l) +.
  • Example 3 Determination of the antiviral activity of compounds of the general formulas 1 and 1.1 and formulas 1 .1 .1 - 1.1.10 (inhibitory ability of the protein NS5A).
  • the inhibitory ability of the compounds of formulas 1, 1.1 and formulas 1.1.1-1.1.10 of the NS5A protein was determined in the human hepatoma I Iuh7 cell line containing the subgenomic HCV RNA replicon (genotype l b, clone Con l).
  • a variant of the IFA immunoassay for the viral protein NS5A was used in a 96-well format. Cytotoxicity of the compounds was evaluated in parallel.
  • Huh7 cells were seeded in 96-well plates (7.5x10 3 cells per well in 100 ⁇ l of culture medium), solutions of the test compounds in DMEM (DMEM) IX; Source: Cellgro; Catalog: 10-013-CV ⁇ prepared immediately before use. In total, eleven serial triplicate dilutions were prepared with a concentration of 20 nM to 0.2 pM. 4 hours after plating of cells, serial dilutions of the preparations were added to the cells (100 ⁇ l per well). The final concentration of the tested compounds was or 10 nM to 0.1 pM, and DMSO - 0.5%. If necessary, higher concentrations of test bis-azole were tested. Each dilution of the drug was tested on two identical wells.
  • the cells were incubated for three days at 37 ° C / 5% C0 2 .
  • Cells were fixed by adding 250 ⁇ l / well of acetone / methanol (1: 1). After 1 minute, the cells were washed three times with PBS (Phosphate Buffered Saline). After this, the cells were blocked by adding 150 ⁇ l / well of 10% fetal calf serum in PBS solution for 1 hour at room temperature.
  • PBS Phosphate Buffered Saline
  • the cells were incubated with murine monoclonal antibodies to HCV core antigen, clone C7-50 (Source: Affinity BioRcagcnts; Catalog: MA 1-080) (100 ⁇ l / well, working dilution - 1: 500 in 10% fs1 calf serum in PBS solution) for two hours at 37 ° C. Cells were washed 6 times with PBS / 0.05% Tween 20 solution, after which they were incubated for 1 hour with antibodies.
  • murine monoclonal antibodies to HCV core antigen clone C7-50 (Source: Affinity BioRcagcnts; Catalog: MA 1-080) (100 ⁇ l / well, working dilution - 1: 500 in 10% fs1 calf serum in PBS solution) for two hours at 37 ° C. Cells were washed 6 times with PBS / 0.05% Tween 20 solution, after which they were incubated for 1 hour with antibodies.
  • the reaction was stopped by adding 100 ⁇ l / well of 2N H 2 S0 2 , and the optical density (wavelength 490 im) was measured using a Victor3 V 1420 multichannel spectrophotometer (Perkin Elmer).
  • the IR 5P values (azole concentration that lowers the level of viral RNA replicon by 50%) for each bis-azole tested were calculated using the XL fit 4 program.
  • the cytotoxicity of compounds of the general formula 1, 1.1 and formulas 1.1.1-1.1.10 was studied in experiments on the culture of the human gnatoma cell line Huh7.
  • the number of living cells was determined using the ATPLite kit (Perkin Elmer, Boston, USA) in accordance with the manufacturer's instructions. Cytotoxicity was assessed by plating cells in a black microplate with a clear bottom (96 cells, 10 4 cells per well). Three independent repeats were used for each bis-azole. Test bis-azoles were added after 18 hours, after which the cells were incubated with substances for 96 hours.
  • CC50 concentration of bis-azole, at which 50% of the cells die.
  • TsZo parameter to calculate the inhibition efficiency (% Ing)
  • % Ing [(L " 01 - L ex ) / L sweat - L from )] * 100%, where L ' k - positive control, luminescence in cells with cells without a substance; L neg - negative control, luminescence in cells with a medium without cells; I zx - luminescence in cells with a substance at a certain concentration.CK50 values were then calculated using the XLfit 4 program.
  • test results of new compounds of the general formula I, 1.1 and formulas 1.1.1-1.1.10 indicate their high iicomolar activity.
  • the inhibitory activity with respect to the lb, la, and 2a IICV genes of new compounds is presented in the table and is indicated as: *> 1000 nM, ** from 999 nM to 10 nM, *** from 9.9 nM to 1 nM, and **** ⁇ 1 iM.
  • Example 3 The study of the storage of naphthalene 1.5-disulfonates.
  • the amount of impurities was determined by the internal normalization method; detection was carried out by a UV detector at a wavelength of 220 nm.
  • Example 4 Obtaining a pharmaceutical composition in the form of tablets. 1600 mg of starch, 1600 mg of crushed lactose, 400 mg of pebbles and 1000 mg of compound 1.1.4 are mixed. The resulting bar is crushed into granules and sieved through blue. collecting granules with a size of 14-16 mesh. The resulting granules are tabletted in a suitable tablet form weighing 560 mg each.
  • Example 5 Obtaining a pharmaceutical composition in the form of capsules.
  • Compound 1 (1) is thoroughly mixed with lactose powder in a ratio of 2: 1.
  • the resulting powder mixture is packaged in 300 mg in a suitable size gelatin capsule.
  • the invention can be used in medicine, veterinary medicine, biochemistry.

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  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des inhibiteurs NS5A, une nouvelle composition pharmaceutique, un médicament antiviral, un procédé de prévention et de traitement de maladies virales, notamment de celles provoquées par les virus de l'hépatite virale C(HCV) et de l'hépatite virale GBV-C; on a proposé un alkyl [2-(2-{5-[4-(4-{2-[1-(2-méthoxycarbonylamino-acétyl)-pyrrolidin-2-yl]-3n-imidazol-4-yl}-phényl)-buta-1,3-diinyl]-1n-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-éthyl]-carbamate correspondant à la formule générale 1 et ses naphtalin-1,5-disulphonate mate correspondant à la formule générale 1.1, dans lesquelles : R1, R2, R3 et R4 sont indépendamment C1-C3 alkyle; R5 и R6 sont indépendamment C1-C3 alkyloxyméthyle, ou R3 и R5 и R4 и R6 avec les atomes de carbone auxquels ils sont liés forment indépendamment les uns des autres un cycle tétrahydrofurane, dans lequel : R1, R2, R3 и R4 sont indépendamment C1-C3 alkyle; R5 и R6 sont indépendamment C1-C3 alkyle ou C1-C3 alkyloxyméthyle, ou R3 et R5 и R4 и R6 avec les atomes de carbone auxquels ils sont liés forment indépendamment les uns des autres un cycle tétrahydrofurane.
PCT/RU2014/000084 2013-02-07 2014-02-07 Alkyl [2-(2-{5-[4-(4-{2-[1-(2-méthoxycarbonylamino-acétyl)-pyrrolidin-2-yl]-3n-imidazol-4-yl}-phényl)-buta-1,3-diinyl]-1n-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-éthyl]-carbamate, composition pharmaceutique, médicament et procédé de traiement de maladies virales Ceased WO2014123457A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2013105164 2013-02-07
RU2013105164/04A RU2518369C1 (ru) 2013-02-07 2013-02-07 Алкил [2-(2-{5-[4-(4-{2-[1-(2-метоксикарбониламино-ацетил)-пирролидин-2-ил]-3н-имидазол-4-ил}-фенил)-бута-1,3-диинил]-1н-имидазол-2-ил}-пирролидин-1-ил)-2-оксо-этил]-карбамат, фармацевтическая композиция, лекарственное средство, способ лечения вирусных заболеваний

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WO2014123457A1 true WO2014123457A1 (fr) 2014-08-14

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PCT/RU2014/000084 Ceased WO2014123457A1 (fr) 2013-02-07 2014-02-07 Alkyl [2-(2-{5-[4-(4-{2-[1-(2-méthoxycarbonylamino-acétyl)-pyrrolidin-2-yl]-3n-imidazol-4-yl}-phényl)-buta-1,3-diinyl]-1n-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-éthyl]-carbamate, composition pharmaceutique, médicament et procédé de traiement de maladies virales

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WO (1) WO2014123457A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2723482C1 (ru) * 2019-10-22 2020-06-11 Андрей Александрович Иващенко Пангенотипичный ингибитор белка NS5A вируса гепатита С, фармацевтическая композиция и способы их получения и применения

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010017401A1 (fr) * 2008-08-07 2010-02-11 Bristol-Myers Squibb Company Inhibiteurs du virus de l’hépatite c
WO2010132601A1 (fr) * 2009-05-13 2010-11-18 Gilead Sciences, Inc. Composés antiviraux
RU2452735C1 (ru) * 2010-11-30 2012-06-10 Александр Васильевич Иващенко Замещенные азолы, противовирусный активный компонент, фармацевтическая композиция, способ получения и применения

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010017401A1 (fr) * 2008-08-07 2010-02-11 Bristol-Myers Squibb Company Inhibiteurs du virus de l’hépatite c
WO2010132601A1 (fr) * 2009-05-13 2010-11-18 Gilead Sciences, Inc. Composés antiviraux
RU2452735C1 (ru) * 2010-11-30 2012-06-10 Александр Васильевич Иващенко Замещенные азолы, противовирусный активный компонент, фармацевтическая композиция, способ получения и применения

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