[go: up one dir, main page]

WO2016095814A1 - Composés cycliques pontés comme inhibiteurs du virus de l'hépatite c et préparation les comprenant - Google Patents

Composés cycliques pontés comme inhibiteurs du virus de l'hépatite c et préparation les comprenant Download PDF

Info

Publication number
WO2016095814A1
WO2016095814A1 PCT/CN2015/097489 CN2015097489W WO2016095814A1 WO 2016095814 A1 WO2016095814 A1 WO 2016095814A1 CN 2015097489 W CN2015097489 W CN 2015097489W WO 2016095814 A1 WO2016095814 A1 WO 2016095814A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
hcv
acid salt
inorganic acid
salt
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2015/097489
Other languages
English (en)
Inventor
Yingjun Zhang
Hongming XIE
Bailin HU
Zhiqiang Liu
Jiancun Zhang
Qinghong Fang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sunshine Lake Pharma Co Ltd
Original Assignee
Sunshine Lake Pharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sunshine Lake Pharma Co Ltd filed Critical Sunshine Lake Pharma Co Ltd
Publication of WO2016095814A1 publication Critical patent/WO2016095814A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • 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

Definitions

  • the present disclosure relates to the field of medicine, and more particularly to compounds for treating Hepatitis C virus (HCV) infection, compositions comprising the compounds, uses of the compounds or the compositions thereof, and using methods thereof.
  • HCV Hepatitis C virus
  • the invention relates to use of the compounds and the pharmaceutical compositions as NS5A protein inhibitors.
  • HCV is a major human pathogen, infecting an estimated 170 million persons worldwide—roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma. Chronic HCV infection is thus a major worldwide cause of liver-related premature mortality.
  • HCV therapy employs a combination of alpha-interferon and ribavirin, leading to sustained efficacy in 40%of patients.
  • Recent clinical results demonstrate that pegylated alpha-interferon is superior to unmodified alpha-interferon as monotherapy.
  • a substantial fraction of patients do not have a sustained reduction in viral load.
  • Many patients do not durably respond to treatment due to side effects of the treatment.
  • new and effective methods of treating HCV infection are urgently needed.
  • HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5’ untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame (ORF) .
  • ORF open reading frame
  • Considerable heterogeneity is found within nucleotide and encoded amino acid sequence throughout the HCV genome. At least seven major genotypes have been characterized, and more than 50 subtypes have been described.
  • RNA is translated into a polyprotein that is cleaved into ten individual proteins.
  • structural proteins followed by E1 and E2.
  • non-structural proteins namely, NS2, NS3, NS4A, NS4B, NS5A and NS5B, which play a function role in the HCV lifecycle (see, for example, Lindenbach et al., Nature, 2005, 436, 933-938) .
  • HCV NS5A protein is described, for example, in Tan et al., Virology, 2001, 284, 1-12; and in Park et al., J. Biol. Chem., 2003, 278, 30711-30718.
  • the above structure is a mixture of diastereoisomers.
  • the properties of a drug in a mixture form are uncertain to some extent, such as the physical property and the chemical property, they are different between diastereoisomers, so the radio of which cannot be control exactly usually in the preparing process, and the biological properties of which are difficult to reproduce, that is to say the quality of the diastereoisomers drug cannot be control easily in the preparing process.
  • any one single configuration of the diastereoisomers as a research object is better than the diastereoisomers mixture, the properties of which has repeatability; repeatability is a very important basis for drug research and development, any studies on properties such as pharmacodynamic properties and pharmacokinetic properties are based on repeatability.
  • the diastereoisomers were isolated, and the synthesis and pharmacokinetic properties of acid addition salts of the single isomer were studied, the acid addition salts have good water solubility and pharmacokinetics properties.
  • the present invention provides both single isomers of the bridge compound and pharmaceutically acceptable salts; their properties can be control easily in the preparing process and which have good repeatability, one of the most important conditions is satisfied as a drug research object; and also provides a composition of the single isomer or a pharmaceutically acceptable salt thereof, and a method of preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder.
  • the compound of the invention or the pharmaceutical composition thereof has a good inhibitory effect for HCV infection, especially for HCV NS5A protein.
  • a compound having structure (I) or (Ia) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof:
  • the pharmaceutically acceptable salt is an inorganic acid salt.
  • the inorganic acid salt is a haloid acid salt, halogen series containing oxygen inorganic acid salt, carbon series containing oxygen inorganic acid salt, nitrogen series containing oxygen inorganic acid salt, boron series containing oxygen inorganic acid salt, silicon series containing oxygen inorganic acid salt, phosphorus series containing oxygen inorganic acid salt or sulphur series inorganic acid salt.
  • the inorganic acid salt is hydrochloride, hydrosulfate, nitrate or dihydrogen phosphate.
  • the inorganic acid salt is hydrochloride, sulfate, hydrosulfate, nitrate, hydrobromide, hydriodate, carbonate, hydrocarbonate, sulfite, perchlorate, persulfate, hemisulfate, bisulfate, phosphate, hydrogen phosphate, dihydrogen phosphate or metaphosphate.
  • the pharmaceutically acceptable salt is an organic acid salt.
  • the organic acid salt is a carboxylate, sulfonate, sulfinate or carbothioate.
  • the organic acid salt is mesilate, citrate, benzene sulfonate, tosilate, tartrate, fumarate, maleate, 2-naphthalene sulfonate or oxalate.
  • the organic acid salt is formate, acetate, benzoate, malonate, succinate, mesilate, ethanesulfonate, citrate, benzene sulfonate, tosilate, malate, tartrate, fumarate, glycolate, hydroxyethyl sulphonate, maleate, lactate, lactobionate, pamoate, salicylate, galactarate, gluceptate, mandelate, gluconate, 1, 2-ethanedisulfonate, 2-naphthalene sulfonate, oxalate, trifluoroacetate, adipate, alginate, ascorbate, aspartate, benzene sulfonate, butyrate, camphorate, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethyl sulfonate, glycerophosphate,
  • the pharmaceutically acceptable salt is a monosalt.
  • the pharmaceutically acceptable salt is a disalt.
  • provided herein is an intermediate for preparing the compound of Formula (I) having Formula (III) or (V) , or a salt thereof; or provided herein is an intermediate for preparing the compound of Formula (Ia) having Formula (IIIa) or (Va) , or a salt thereof;
  • Pg is an amino protecting group selected from Boc, Cbz, Ac, Tfa, Bn, PMB, Dmb, Sem, Tos, Fmoc, Alloc, Teoc and Trt.
  • a pharmaceutical composition comprising the compound of structure (I) or (Ia) , or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • the pharmaceutical composition further comprises an anti-HCV agent, wherein the anti-HCV agent is different from the compound.
  • the anti-HCV agent is interferon ⁇ -2b, pegylated interferon ⁇ , interferon ⁇ -2a, pegylated interferon ⁇ -2a, consensus interferon- ⁇ , interferon ⁇ , ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiquimod, an inosine5’ -monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, hepatitis C immune globulin, a HCV neutralizing polyclonal antibody, boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, paritaprevir, danoprevir, sovaprevir, grazoprevir,
  • the anti-HCV agent is used for inhibiting the HCV replication process and/or a function of a HCV viral protein; wherein the HCV replication process comprises HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly and HCV egress; and wherein the HCV viral protein is a metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES) and inosine-5’ -monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • the HCV replication process comprises HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly and HCV egress
  • the HCV viral protein is a metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES) and inosine-5’
  • provided herein is use of the compound or the pharmaceutical composition thereof of the invention in the manufacture of a medicament for preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient.
  • provided herein is the compound or the pharmaceutical composition thereof of the invention for use in preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient.
  • provided herein is a method of preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient comprising administering to the patient a therapeutically effective amount of the compound or the pharmaceutical composition of the invention.
  • grammatical articles “a” , “an” and “the” are intended to include “at least one” or “one or more” unless otherwise indicated herein or clearly contradicted by the context.
  • the articles are used herein to refer to one or more than one (i.e. at least one) of the grammatical objects of the article.
  • a component means one or more components, and thus, possibly, more than one component is contemplated and may be employed or used in an implementation of the described embodiments.
  • subject refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female) , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate.
  • the subject is a human.
  • patient refers to a human (including adults and children) or other animal. In one embodiment, “patient” refers to a human.
  • Stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomer, diastereomers, conformer (rotamer) , geometric (cis/trans) isomer, atropisomer, etc.
  • Chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.
  • optically active compounds Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center (s) .
  • the prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • a specific stereoisomer may be referred to as an enantiomer, and a mixture of such stereoisomers is called an enantiomeric mixture.
  • a 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon or the like) of the compound (s) disclosed herein can be present in racemic or enantiomerically enriched, for example the (R) -, (S) -or (R, S) -configuration.
  • each asymmetric atom has at least 50 %enantiomeric excess, at least 60 %enantiomeric excess, at least 70 %enantiomeric excess, at least 80 %enantiomeric excess, at least 90 %enantiomeric excess, at least 95 %enantiomeric excess, or at least 99 %enantiomeric excess in the (R) -or (S) -configuration.
  • the compounds can be present in the form of one of the possible stereoisomers or as mixtures thereof, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
  • Optically active (R) -and (S) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis-or trans-configuration.
  • Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization.
  • racemates of final products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof.
  • Racemic products can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • Preferred enantiomers can also be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) ; Principles of Asymmetric Synthesis (2 nd Ed.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g. in solution) , a chemical equilibrium of tautomers can be reached.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4 (lH) -one tautomers. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.
  • Annular tautomerism is a type of prototropic tautomerism wherein a proton can occupy two or more positions of a heterocyclic system; both of the tautomers coexist and convert to each other rapidly.
  • 1H-and 3H-imidazole 1H, 2H-and 4H-1, 2, 4-triazole; 1H-and 2H-isobenzazole.
  • the pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1977, 66: 1-19, which is incorporated herein by reference.
  • Some non-limiting examples of the pharmaceutically salt include salts of an amino group formed with inorganic acids, such as haloid acid salt, halogen series containing oxygen inorganic acid salt, carbon series containing oxygen inorganic acid salt, nitrogen series containing oxygen inorganic acid salt, boron series containing oxygen inorganic acid salt, silicon series containing oxygen inorganic acid salt, phosphorus series containing oxygen inorganic acid salt or sulphur series inorganic acid salt, specificly such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as carboxylic acid, sulfonic acid, sulfinic acid, carbothioic acid, specificly such as acetic acid, oxalic acid, maleic acid, tart
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, sodium malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionat
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil soluble or dispersible products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 sulfonate or aryl sulfonate.
  • pharmaceutical composition refers to a mixture of one or more salts of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof and other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to facilitate administration of the compound on living organisms
  • the term “treat” , “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
  • “treat” , “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat” , “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
  • “treat” , “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Haloid acid salt refers to a salt derived from a reaction of haloid acid and a base.
  • haloid acid salt refers to a salt derived from a reaction of haloid acid and a base.
  • haloid acid salt for example, hydrofluoride, hydrochloride, hydrobromide, hydriodate and the like.
  • Halogen series containing oxygen inorganic acid salt refers to a salt derived from a reaction of halogen series containing oxygen inorganic acid and a base.
  • halogen series containing oxygen inorganic acid and a base For example, pypocholoride, chlorate, perchlorate, hypobromite, bromated, hypoiodite, iodate, periodate and the like.
  • Carbon series containing oxygen inorganic acid salt refers to a salt derived from a reaction of carbon series containing oxygen inorganic acid and a base. For example, carbonate, bicarbonate and the like.
  • Nonrogen series containing oxygen inorganic acid salt refers to a salt derived from a reaction of nitrogen series containing oxygen inorganic acid and a base. For example, nitrite, subnitrate, nitrate and the like.
  • “Boron series containing oxygen inorganic acid salt” refers to a salt derived from a reaction of bonron series containing oxygen inorganic acid and a base. For example, metaborate, ortho-borate, perborate and the like.
  • Silicon series containing oxygen inorganic acid salt refers to a salt derived from a reaction of silicon series containing oxygen inorganic acid and a base. For example, metasilicate, silicate and the like.
  • Phosphorus series containing oxygen inorganic acid salt refers to a salt derived from a reaction of phosphorus series containing oxygen inorganic acid and a base.
  • phosphorus series containing oxygen inorganic acid salt refers to a salt derived from a reaction of phosphorus series containing oxygen inorganic acid and a base.
  • “Sulphur series inorganic acid salt” refers to a salt derived from a reaction of sulphur inorganic acid and a base. For example, hydrogensulfat, sulfite, hydrosulphite, sulfate, hydrosulfate, peroxy (mono) sulfate, thiosulfite, thiosulfate, dithionate, pyrosulfate, peroxydisulfate and the like.
  • “Monosalt” as presented herein means a salt wherein 1 eq of the corresponding free base of the compound of the invention is combined with 0.7 to 1.3 eq, preferably 0.9 to 1.1 eq, more preferably 1 eq of the acid as mentioned above.
  • “Disalt” as presented herein means a salt wherein 1 eq of the corresponding free base of the compound of the invention is combined with 1.7 to 2.3 eq, preferably 1.9 to 2.1 eq, more preferably 2 eq of the acid as mentioned above.
  • any formula given herein is also intended to represent isotopically unenriched forms as well as isotopically enriched forms of the compounds.
  • Isotopically enriched compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H (deuterium, D) , 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I, respectively.
  • the compounds of the invention include isotopically enriched compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 14 C and 18 F, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • isotopically enriched compounds are useful in metabolic studies (with 14 C) , reaction kinetic studies (with, for example 2 H or 3 H) , detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18F-enriched compound may be particularly desirable for PET or SPECT studies.
  • Isotopically-enriched compounds of Formula (I) or (Ia) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium
  • such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5%deuterium incorporation at each designated deuterium atom) , at least 4000 (60%deuterium incorporation) , at least 4500 (67.5%deuterium incorporation) , at least 5000 (75%deuterium incorporation) , at least 5500 (82.5%deuterium incorporation) , at least 6000 (90%deuterium incorporation) , at least 6333.3 (95%deuterium incorporation) , at least 6466.7 (97%deuterium incorporation) , at least 6600 (99%deuterium incorporation) , or at least 6633.3 (99.5%deuterium incorporation) .
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, acetone-d 6 , DMSO-d
  • inhibiting HCV viral protein should be broadly understood, which comprises inhibiting the expression level of HCV viral protein, inhibiting activity level of HCV viral protein, viral assembly and egress level.
  • the expression level of HCV protein includes but not limited to translation level of the viral protein, posttranslational modification level of the viral protein, replication level of genetic material in offsprings and so on.
  • the pharmaceutical composition disclosed herein comprises any one of the compounds.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • the pharmaceutical composition can be used for treating HCV infection or a HCV disorder, especially, it is great for inhibiting HCV NS5A protein.
  • some non-limiting examples of materials which can serve as pharmaceutically acceptable carriers include ion exchanger; aluminum; alumina; aluminum stearate; lecithin; serum protein such as human serum albumin; buffer substance such as phosphate; glycine; sorbic acid; potassium sorbate; partial glyceride mixture of saturated vegetable fatty acid; water; electrolyte such as protamine sulfate, disodium hydrogen phosphate and potassium hydrogen phosphate; salt such as sodium chloride and zinc salt; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylate; waxe; polyethylene-polyoxypropylene-block polymer; wool fat; sugar such as lactose, glucose and sucrose; starch such as corn starch and potato starch; cellulose and its derivative such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such
  • the pharmaceutical composition disclosed herein further comprises an anti-HCV agent, wherein the anti-HCV agent is different from the compound.
  • the anti-HCV agent may be any other known anti-HCV agent except the compound described herein, such as interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, an interfering RNA, an anti-sense RNA, imiquimod, an inosine-5’ -monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, hepatitis C immune globulin ( ) , boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, paritaprevir (ABT-450) , danoprevir, sovaprevir, grazopre
  • the interferon is interferon ⁇ -2b, pegylated interferon ⁇ , interferon ⁇ -2a, pegylated interferon ⁇ -2a, consensus interferon- ⁇ , interferon ⁇ or a combination thereof.
  • the anti-HCV agent inhibits HCV replication process, a function of HCV viral protein or a combination thereof.
  • the HCV replication process disclosed herein comprises of HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly and HCV egress.
  • the HCV viral protein disclosed herein is or comprises a metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES) or inosine-5’ -monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • a metalloproteinase non-structural protein NS2, NS3, NS4A, NS4B, NS5A or NS5B
  • IVS internal ribosome entry site
  • IMPDH inosine-5’ -monophosphate dehydrogenase
  • therapeutically effective amounts of a compound of the invention, as well as pharmaceutically acceptable salts thereof may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical compositions, which include therapeutically effective amounts of compounds of the invention or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • therapeutically effective amount refers to the total amount of each active component that is sufficient to show a meaningful patient benefit (e.g., a reduction in viral load) .
  • a meaningful patient benefit e.g., a reduction in viral load
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously.
  • the compounds of the invention and pharmaceutically acceptable salts thereof, are as described above.
  • the carrier (s) , diluents (s) , or excipient (s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to recipient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of the invention, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • pharmaceutically acceptable refers to those compounds, materials, composition, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Dosage levels of between about 0.01 and about 250 milligram per kilogram ( “mg/kg” ) body weight per day, preferably between about 0.05 and about 100 mg/kg body weight per day of the compounds of the present disclosure are typical in a monotherapy for the prevention and treatment of HCV mediated disease. Typically, the pharmaceutical compositions of this disclosure will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
  • mg/kg milligram per kilogram
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, gender, weight, and condition of the patient.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Treatment may be initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the compound is most desirably administered at a concentration level that will generally afford antivirally effective results without causing any harmful or deleterious side effects.
  • compositions of this disclosure comprise a combination of a compound of the present disclosure and one or more additional therapeutic or prophylactic agent
  • both the compound and the additional agent are usually present at dosage levels of between about 10 to 150%, and more preferably between about 10 and 80%of the dosage normally administered in a monotherapy regimen.
  • Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual) , rectal, nasal, topical (including buccal, sublingual, or transdermal) , vaginal, or parenteral (including subcutaneous, intracutaneous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous, or intradermal injections or infusions) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier (s) or excipient (s) . Oral administration of administration by injection is preferred.
  • compositions adapted for oral administration may be presented as discrete units such as capsules of tablets; powders or granules; solution or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present.
  • Capsules are maded by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or ⁇ -lactose, natural paraguttas such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, etc.
  • Lubricants used in these dosage forms include sodium oleate, sodium chloride, etc.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, etc.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitable comminuted, with a diluents or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or and absorption agent such as betonite, kaolin, or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt and/or
  • absorption agent such as betonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, or solution of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage, or solution of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present disclosure can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac,
  • Oral fluids such as solution, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, etc can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating of embedding particulate material in polymers, wax, or the like.
  • the compounds of formula (I) or (Ia) , and pharmaceutically acceptable salts thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • liposomes can be formed from a variety of phopholipids, such as cholesterol, stearylamine, or phophatidylcholines.
  • the compounds of formula (I) or (Ia) and pharmaceutically acceptable salts thereof may also be delivered by the use of monoclonal antibodies as individual carrier to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, poly ( ⁇ -caprolactone) , polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, poly ( ⁇ -caprolactone) , polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmacol. Res., 1986, 3 (6) , 318.
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patch.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for nasal administration wherein the carrier is a solid include a course powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers, or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the HCV replication process comprises of HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly and HCV egress.
  • the HCV viral protein is non-structural protein or an internal ribosome entry site (IRES) or inosine-5’ -monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • IRS internal ribosome entry site
  • IMPDH inosine-5’ -monophosphate dehydrogenase
  • any one of the compounds or the pharmaceutical compositions disclosed herein can be used for treating HCV infection or a HCV disorder, especially it is effective as inhibitor of the non-structural 5A (NS5A) protein of HCV.
  • a method which comprises administering the compound or the pharmaceutical composition disclosed herein, further comprising administering to the patient additional anti-HCV agents (combination therapy) , wherein the anti-HCV agent is an interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, an interfering RNA, an anti-sense RNA, imiquimod, an inosine-5’ -monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, hepatitis C immune globulin ( ), boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, paritaprevir (ABT-450) , danoprevir, sovaprevir, grazoprevir (MK-5172) , ve
  • interferon is interferon ⁇ -2b, pegylated interferon ⁇ , interferon ⁇ -2a, pegylated interferon ⁇ -2a, consensus interferon- ⁇ , interferon ⁇ or a combination thereof.
  • the treatment method that includes administering a compound or composition disclosed herein can further include administering to the patient an additional anti-HCV agent, wherein the additional anti-HCV drug is administered together with a compound or composition disclosed herein as a single dosage form or separately from the compound or composition as part of a multiple dosage form.
  • the additional anti-HCV agent may be administered at the same time as a compound disclosed herein or at a different time. In the latter case, administration may be staggered by, for example, 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.
  • an “effective amount” or “effective dose” of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of the aforementioned disorders.
  • the compounds and compositions, according to the method disclosed herein, may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder or disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, etc.
  • a compound or composition can also be administered with one or more other therapeutic agents, as discussed above.
  • the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for Formula (I) or (Ia) , above, except where further noted.
  • the following non-limiting schemes and examples are presented to further exemplify the invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by refluxing the solvent with sodium.
  • Anhydrous dichloromethane and chloroform were obtained by refluxing the solvent with calcium hydride.
  • Ethyl acetate, petroleum ether, hexane, N, N-dimethylacetamide and N, N-dimethylformamide were treated with anhydrous sodium sulfate prior to use.
  • reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
  • MS data were also determined on an Agilent 6320 series LC-MS spectrometer equipped with G1312A binary pumps, a G1316A TCC (Temperature Control of Column, maintained at 30 °C) , a G1329A autosampler and a G1315B DAD detector were used in the analysis.
  • An ESI source was used on the LC-MS spectrometer.
  • MS data were also determined on an Agilent 6120 series LC-MS spectrometer equipped with G1311A Quaternary pump, a G1316A TCC (Temperature Control of Column, maintained at 30 °C) , a G1329A autosampler and a G1315D DAD detector were used in the analysis.
  • An ESI source was used on the LC-MS spectrometer.
  • a silica-based coated with polysaccharide derivatives normal phase chiral chromatographic column was used in preparative HPLC in the invention; specifically, the column is AD-H (10*250 mm, 5 ⁇ m) or AD-H (20*250 mm, 5 ⁇ m) .
  • the mobile phase is a mixture of two or more of methanol, ethanol, isopropanol, acetonitrile, n-hexane, n-pentane, isohexane, n-heptane, diethylamine, triethylamine, trifluoroacetic acid or glacial acetic acid; more specifically, the volume ratio of n-hexane, n-pentane, isohexane or n-heptane in the mobile phase mixture is from 50%to 100%, the volume ratio of methanol, ethanol, isopropanol or acetonitrile in the mobile mixture phase is from 0%to 50%, the sum total of volume ratio of every component is 100%; more specifically, the volume ratio of n-hexane in the mobile phase mixture is from 80%to 100%, the volume ratio of ethanol in the mobile phase mixture is from 0%to 20%, the sum total of volume ratio of every component is 100%; the determine wavelength is from 280 nm
  • Ion chromatography was used in the present invention to detect the inorganic anions described herein.
  • the inorganic anion was detected on an ion chromatograph (850 Professional Ic Metrohm) , and AS23 anion exchange column (250 ⁇ 4.0 mm, Dionex) was used in the detection.
  • the column temperature was at 30 °C
  • the eluent was consisted of 4.5 mM Na 2 CO 3 and 0.8 mM NaHCO 3
  • the flow rate of eluent was 1.0 mL/min
  • the injection volume was 100 ⁇ L
  • the equipment was ran for 20 to 25 min, and the results were measured by an suppressed conductivity detector.
  • the data of a single crystal was collected on a single-crystal diffractometer (Agilent Technologies Gemini A Ultra) , using Cu K ⁇ radiation, the X-ray tube voltage was about 40 kv, the X-ray tube current was about 40 mA, a total of 12498 reflections was collected by ⁇ scans.
  • Figure 1 is the single crystal stereochemical structure projection of compound 0-1
  • Figure 2 is the cell accumulation projection of compound 0-1.
  • Step 1) preparation of compound 0-1 and compound 0-1a
  • Step 2) preparation of compound 1-2 and compound 1-2a
  • Compound 1-2 (0.03 g, yield: 30%) was prepared by using compound 0-1 and compound 0-2 and referring to the method described in CN 201310337556 and WO 2014019344;
  • Compound 1-2a (0.2 g, yield: 81%) was prepared by using the same method as above.
  • Compound 1-3a (170 mg, 92%) was prepared by using compound 1-2a and according the preparing method of compound 1-3.
  • the sample ground to a fine powder was weighed and placed in a certain amount of solvent at 25°C ⁇ 2°C; The mixture was shook strongly for 30 sec every 5 min; The mixture was observed in 30 min, which was deemed to be dissolved completely if the solute particles cannot be seen.
  • AUC area under curve
  • Cl clearance
  • C max the maximum concentration
  • MRT INF mean residence time
  • T 1/2 half life
  • T max time of maximum concentration
  • V ss steady-state volume of distribution
  • F bioavailability.
  • a solution having a concentration of 1 mg/mL was prepared by adding the compound of the present invention into a solvent of 5%DMSO + 5%Solutol + 90%Saline; the male SD rats were administered by intravenous injection (iv) at a dose of 2 mg/kg and by gavage (po) at a dose of 5 mg/kg respectively with the above solution after 12 hours of fasting.
  • Plasma samples were collected after administering at different time points; the plasma samples were treated by using liquid-liquid extraction method.
  • the drug concentrations were measured by using LC-MS/MS and the pharmacokinetic parameters were calculated by Winnonlin software. The results were shown in table 2:
  • N/A Not avaliable
  • Grouped male Beagle dogs were administered with capsules of compound 1 or salts thereof respectively by oral at a dose of 5 mg/kg.
  • Blood samples were collected at 8 or 9 time points within 24 hours, and the standard curve were established based on the concentrations of the samples in a suitable range; AB SCIEX API4000 was used to detect the concentration of the test compound in plasma samples in an MRM mode, and quantitative analysis was performed.
  • Pharmacokinetic parameters were calculated according to drug concentration-time curve using noncompartmental method by WinNonLin 6.3 software. The results were shown in table 3:
  • the compound of the present invention can inhibit HCV through inhibiting other than NS5A.
  • the compound of the present invention can inhibit HCV replicons; in other embodiment, the compound of the present invention can inhibit NS5A.
  • the compound of the present invention can inhibit various genotypes of HCV.

Landscapes

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

Abstract

La présente invention concerne un composé de structure (I) ou (Ia), ou un stéréoisomère, un tautomère, un N-oxyde, un hydrate, un solvate, un métabolite, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci. L'invention concerne également des compositions pharmaceutiques contenant le composé de structure (I) ou (Ia) et l'utilisation des composés ou des compositions pharmaceutiques les comprenant dans le traitement d'une infection à VHC.
PCT/CN2015/097489 2014-12-16 2015-12-15 Composés cycliques pontés comme inhibiteurs du virus de l'hépatite c et préparation les comprenant Ceased WO2016095814A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410783855 2014-12-16
CN201410783855.6 2014-12-16

Publications (1)

Publication Number Publication Date
WO2016095814A1 true WO2016095814A1 (fr) 2016-06-23

Family

ID=56125940

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/097489 Ceased WO2016095814A1 (fr) 2014-12-16 2015-12-15 Composés cycliques pontés comme inhibiteurs du virus de l'hépatite c et préparation les comprenant

Country Status (3)

Country Link
CN (1) CN105693700B (fr)
TW (1) TWI675029B (fr)
WO (1) WO2016095814A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110905454A (zh) * 2019-11-29 2020-03-24 南通仁隆科研仪器有限公司 一种水合物储层井间电学动态监控模拟实验装置

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112019019724A2 (pt) * 2017-03-22 2020-04-14 Chia Tai Tianqing Pharmaceutical Group Co Ltd composto contendo silício para resistência à infecção pelo vírus da hepatite c
CN109270178B (zh) * 2018-09-10 2021-06-29 重庆华邦制药有限公司 一种高效液相色谱法分离测定度他雄胺软胶囊中度他雄胺及有关物质的方法
CN112843013A (zh) * 2019-11-28 2021-05-28 宜昌东阳光长江药业股份有限公司 治疗丙型肝炎的组合物及其制备方法
CN112843053B (zh) * 2019-11-28 2023-12-08 宜昌东阳光长江药业股份有限公司 Ns5a抑制剂组合物
CN114805306A (zh) * 2021-01-19 2022-07-29 宜昌东阳光长江药业股份有限公司 依米他韦生产工艺

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103570693A (zh) * 2012-08-03 2014-02-12 广东东阳光药业有限公司 作为丙型肝炎抑制剂的桥环化合物及其在药物中的应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX363732B (es) * 2009-05-13 2019-04-01 Gilead Pharmasset Llc Star Compuestos antivirales.
US20120195857A1 (en) * 2010-08-12 2012-08-02 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103570693A (zh) * 2012-08-03 2014-02-12 广东东阳光药业有限公司 作为丙型肝炎抑制剂的桥环化合物及其在药物中的应用

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110905454A (zh) * 2019-11-29 2020-03-24 南通仁隆科研仪器有限公司 一种水合物储层井间电学动态监控模拟实验装置
CN110905454B (zh) * 2019-11-29 2022-01-04 南通仁隆科研仪器有限公司 一种水合物储层井间电学动态监控模拟实验装置

Also Published As

Publication number Publication date
TW201623290A (zh) 2016-07-01
CN105693700B (zh) 2019-01-04
TWI675029B (zh) 2019-10-21
CN105693700A (zh) 2016-06-22

Similar Documents

Publication Publication Date Title
CN108299532B (zh) 一种抗病毒核苷类似物前药及其组合物、用途
CN106065009B (zh) 作为丙型肝炎抑制剂的化合物及其在药物中的应用
WO2016095814A1 (fr) Composés cycliques pontés comme inhibiteurs du virus de l'hépatite c et préparation les comprenant
CN104803989B (zh) 作为丙型肝炎抑制剂的桥环化合物及其在药物中的应用
EP2598498B1 (fr) Dérivés hétéro-bicycliques en tant qu'inhibiteurs du vhc
EP2575475A1 (fr) Inhibiteurs de ns5a de vhc
EP2797911B1 (fr) Dérivés hétérobicycliques en tant qu'inhibiteurs de vhc
CN105884779B (zh) 作为丙型肝炎抑制剂的化合物及其在药物中的应用
WO2016141890A1 (fr) Composés en tant qu'inhibiteurs du virus de l'hépatite c et utilisations pharmaceutiques associées
CN103880823B (zh) 作为丙型肝炎抑制剂的螺环化合物及其在药物中的应用
AU2012360910B8 (en) Quinazolinone derivatives as HCV inhibitors
CN105384792B (zh) 作为丙型肝炎抑制剂的化合物及其在药物中的应用
EP3471737A1 (fr) Composés nucléosides cycliques à substitution phosphate et leurs procédés d'utilisation pour le traitement de maladies virales
WO2018028634A1 (fr) Sels utilisés comme inhibiteurs du virus de l'hépatite c
CN105085493A (zh) 作为丙型肝炎抑制剂的螺环化合物及其在药物中的应用
CN107722109B (zh) 作为丙型肝炎病毒抑制剂的晶型
CN110117287B (zh) 作为丙型肝炎病毒抑制剂的盐
HK1245775B (zh) 作为丙型肝炎病毒抑制剂的盐

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: 15869321

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 08.11.2017)

122 Ep: pct application non-entry in european phase

Ref document number: 15869321

Country of ref document: EP

Kind code of ref document: A1