WO2017202207A1 - Composé cyclique de naphtalène substitué, composition pharmaceutique et son application - Google Patents

Composé cyclique de naphtalène substitué, composition pharmaceutique et son application Download PDF

Info

Publication number
WO2017202207A1
WO2017202207A1 PCT/CN2017/083880 CN2017083880W WO2017202207A1 WO 2017202207 A1 WO2017202207 A1 WO 2017202207A1 CN 2017083880 W CN2017083880 W CN 2017083880W WO 2017202207 A1 WO2017202207 A1 WO 2017202207A1
Authority
WO
WIPO (PCT)
Prior art keywords
hepatitis
compound
virus
hydrogen
inhibitor according
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/CN2017/083880
Other languages
English (en)
Chinese (zh)
Inventor
王义汉
赵九洋
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.)
Shenzhen Targetrx Inc
Original Assignee
Shenzhen Targetrx Inc
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 Shenzhen Targetrx Inc filed Critical Shenzhen Targetrx Inc
Priority to CN201780004354.5A priority Critical patent/CN108290844B/zh
Publication of WO2017202207A1 publication Critical patent/WO2017202207A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a hepatitis C virus inhibitor, a pharmaceutical composition and application thereof.
  • HCV Hepatitis C Virus
  • the encapsulated HCV virion contains a positive-stranded RNA genome that encodes all known virus-specific proteins in a single uninterrupted open reading frame.
  • the open reading frame comprises approximately 9500 nucleotides and encodes a single large polyprotein of approximately 3000 amino acids.
  • Polyproteins include core proteins, envelope proteins E1 and E2, membrane-bound protein P7, and non-structural proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B.
  • the therapeutic drugs for HCV were interferon and ribavirin. These two drugs, by modulating the immune system or opening various antiviral genes in the cell, create an environment that is not conducive to viral replication, actually targeting host cells. These drugs have many side effects because they act on every cell in the body. New direct-acting antiviral drugs can directly target viruses, which has great advantages.
  • protease inhibitors, NS5A inhibitors and NS5B polymerase inhibitors are the three major classes of anti-HCV drugs under investigation. There were two HCV drugs approved by the US FDA in 2014, namely Jelly's Harvoni and Abbott's Viekira Pak, all of which are compound preparations.
  • Aibowei's Viekira Pak is mainly composed of ombitasvir, paritaprevir and dasabuvir, and can be used for the treatment of patients with chronic genotype 1 (GT1) hepatitis C virus infection, and also for HCV/HIV-1 co-infection (hepatitis C virus combined with humans).
  • GT1 chronic genotype 1
  • HCV/HIV-1 co-infection hepatitis C virus combined with humans.
  • Immunodeficiency virus type 1 patients and liver transplant patients.
  • Dasabuvir is an indispensable NS5B polymerase inhibitor in this combination.
  • sofosbuvir is currently the first medicine in the world that can completely cure hepatitis C in the short term. It takes the oral route directly to the lesion, and the method has simple side effects and is highly sought after by patients. Sofibuvir is produced by Gilead, USA, and is marketed in the United States in 2013. It has been clinically proven to be effective in treating hepatitis C, type 1, 2, 3, and 4, including liver transplantation, liver cancer, and HCV/HIV-1 co-infection. Clinical Trials. This breakthrough is for patients with hepatitis C worldwide Come the gospel. The US Gilead company has extended the authorization of the new hepatitis C drug Sofibuvir to Egypt last year.
  • Egypt is the country with the highest incidence of hepatitis C in the world. Subsequently agreed to produce sofibru generic drugs in India. Up to now, a total of eight Indian pharmaceutical companies have obtained Gilead's authorization to sell Sophie Buwei to 91 developing countries around the world (China is excluded). Why Sophie Buwei is currently in a blank space in China. On the one hand, there is a large demand, and on the other hand, it is drug-free. In the face of such awkward dilemma, some large hospitals are trying to solve this problem through video remote overseas medical treatment. Some patients who can't wait, have to consider going abroad to see a doctor.
  • the present invention discloses a substituted naphthalene ring compound and a pharmaceutical composition thereof as a hepatitis C virus inhibitor which has better hepatitis C virus protein NS5B inhibitory activity and/or has better pharmacodynamics/ Pharmacokinetic properties.
  • a hepatitis C virus inhibitor such as a naphthalene ring compound compound represented by formula (I), or a polymorphic form thereof, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, an isotope variant, a hydrate or Solvent compound,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 are each independently hydrogen, deuterium, halogen or trifluoromethyl;
  • Additional conditions are R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 And at least one of R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 and R 25 is deuterated or deuterated.
  • the shape and volume of ruthenium in the drug molecule are substantially the same as hydrogen, if in the drug molecule Hydrogen is selectively replaced with hydrazine, and deuterated drugs generally retain their original biological activity and selectivity.
  • the inventors have confirmed through experiments that the binding of carbon-germanium bonds is more stable than the combination of carbon-hydrogen bonds, which can directly affect the absorption, distribution, metabolism and excretion of some drugs, thereby improving the efficacy, safety and tolerability of the drugs.
  • the strontium isotope content of the cerium in the deuterated position is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, and even more preferably greater than 95. %, more preferably greater than 99%.
  • the cesium isotope content of each of the R 5 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 and R 25 is at least 5%, preferably greater than 10 More preferably, more than 15%, more preferably more than 20%, more preferably more than 25%, more preferably more than 30%, more preferably more than 35%, more preferably more than 40%, more preferably more than 45% More preferably greater than 50%, more preferably greater than 55%, more preferably greater than 60%, more preferably greater than 65%, more preferably greater than 70%, more preferably greater than 75%, and even more preferably greater than 80%, More preferably greater than 85%, more preferably greater than 90%, more preferably greater than 95%
  • at least one of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 and R 25 contains at least one of R, more preferably two R ⁇ , preferably three R ⁇ , more preferably four R ⁇ , more preferably five R ⁇ , more preferably six R ⁇ , more preferably seven R ⁇ , more preferably Eight R ⁇ , more preferably nine R ⁇ , more preferably ten R ⁇ , more preferably eleven R ⁇ , more preferably twelve R ⁇ , more preferably thirteen R contains ⁇ , more preferably fourteen R ⁇ , more preferably fifteen R ⁇ , more preferably sixteen R ⁇ , more preferably seventeen R ⁇ , more preferably eighteen R contains
  • R 1 , R 2 and R 3 are each independently hydrazine or hydrogen.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently hydrazine or hydrogen.
  • R 13 and R 14 are each independently hydrazine or hydrogen.
  • R 15 and R 16 are each independently hydrazine or hydrogen.
  • R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are each independently hydrazine or hydrogen.
  • R 23 , R 24 and R 25 are each independently hydrazine or hydrogen.
  • R 1 , R 2 , and R 3 are deuterium.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are ⁇ .
  • R 13 and R 14 are deuterium.
  • R 15 and R 16 are deuterium.
  • R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are ⁇ .
  • R 23 , R 24 , and R 25 are ⁇ .
  • the compound is selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:
  • the compound does not include a non-deuterated compound.
  • the present invention also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the hepatitis C virus inhibitor as described above, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvent thereof
  • a pharmaceutical composition of a compound, stereoisomer, prodrug or isotopic variation comprising a pharmaceutically acceptable carrier and the hepatitis C virus inhibitor as described above, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvent thereof.
  • the pharmaceutical composition further comprises other compounds such as interferon or interference a combination of ribavirin or other HCV inhibitors (eg, HCV polymerase inhibitors or HCV protease inhibitors).
  • HCV inhibitors eg, HCV polymerase inhibitors or HCV protease inhibitors.
  • the present invention also provides a method of preparing a pharmaceutical composition comprising the steps of: administering a pharmaceutically acceptable carrier to a hepatitis C virus inhibitor as described above, or a crystalline form thereof, a pharmaceutically acceptable salt, or a hydrate thereof Or the solvate is mixed to form a pharmaceutical composition.
  • the invention also discloses the use of a hepatitis C virus inhibitor as described above, characterized in that it is used for the preparation of a medicament for the treatment of hepatitis C virus infection.
  • the HCV includes a plurality of genotypes thereof and a plurality of gene subtypes, such as 1a, 1b, 2a, 2b, 3a, 3b, 4a, 5a, 6a.
  • the pharmaceutically acceptable carrier includes a glidant, a sweetener, a diluent, a preservative, a dye/colorant, a flavor enhancer, a surfactant, a wetting agent, a dispersant At least one of a disintegrant, a suspending agent, a stabilizer, an isotonic agent, a solvent or an emulsifier.
  • the pharmaceutical composition is a tablet, a pill, a capsule, a powder, a granule, an ointment, an emulsion, a suspension, a solution, a suppository, an injection, an inhalant, a gel, a microsphere or Aerosol.
  • Typical routes of administration of the pharmaceutical compositions of the invention include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal , intramuscular, subcutaneous, intravenous administration. Oral administration or injection administration is preferred.
  • the pharmaceutical composition of the present invention can be produced by a method known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a pulverization method, an emulsification method, a freeze-drying method, and the like.
  • halogen means F, Cl, Br, and I unless otherwise specified. More preferably, the halogen atom is selected from the group consisting of F, Cl and Br.
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated is used interchangeably with “one or more deuterated”.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • the invention also includes isotopically labeled compounds (also referred to as "isotopic variants"), equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes. In addition, heavier isotopic substitutions such as guanidine, or 2 H, are preferred in certain therapies due to their good metabolic stability, such as increased half-life or reduced dosage in vivo, and therefore may be preferred in certain circumstances. Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid; Amino acids such as amino acid, phenylalanine, aspartic acid, and glutamic acid.
  • salts of the compounds of the invention with bases such as alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), ammonium salts (for example lower alkanolammonium).
  • bases such as alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), ammonium salts (for example lower alkanolammonium).
  • Salts and other pharmaceutically acceptable amine salts such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butyl
  • a base amine salt an ethylenediamine salt, a hydroxyethylamine salt, a dihydroxyethylamine salt, a trihydroxyethylamine salt, and an amine salt formed of morpholine, piperazine, and lysine, respectively.
  • polymorph refers to a different arrangement of chemical drug molecules, generally expressed as the presence of a pharmaceutical material in a solid state.
  • a drug may exist in a plurality of crystalline forms, and different crystal forms of the same drug may have different dissolution and absorption in the body, thereby affecting the dissolution and release of the formulation.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • prodrug refers to a compound that is converted in vivo to an active form having its medical effect by, for example, hydrolysis in blood.
  • a prodrug is any covalently bonded carrier which, when administered to a patient, releases the compound of the invention in vivo.
  • Prodrugs are typically prepared by modifying functional groups that cleave prodrugs in vivo to produce maternal complexes Things.
  • Prodrugs include, for example, a compound of the invention wherein a hydroxy, amino or thiol group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amino or thiol group.
  • prodrugs include, but are not limited to, covalent derivatives of the compounds of the invention formed by the hydroxyl, amino or thiol functional groups thereof with acetic acid, formic acid or benzoic acid.
  • acetic acid formic acid or benzoic acid.
  • an ester such as a methyl ester, an ethyl ester or the like can be used.
  • the ester itself may be active and/or may hydrolyze under conditions in humans.
  • Suitable pharmaceutically acceptable in vivo hydrolysable esters include those which readily decompose in the human body to release the parent acid or its salt.
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of "stereoisomer" forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the beneficial effects of the present invention compared to the prior art are: First, the compound of the present invention has excellent inhibitory effect on the hepatitis C virus protein NS5A. Second, by deuteration this technique changes the metabolism of the compound in the organism, giving the compound better pharmacokinetic parameter characteristics. In this case, the dosage can be changed and a long-acting preparation can be formed to improve the applicability. Third, replacing the hydrogen atom in the compound with hydrazine increases the drug concentration of the compound in the animal due to its strontium isotope effect, thereby improving the drug efficacy. Fourth, replacing the hydrogen atom in the compound with hydrazine can inhibit certain metabolites and improve the safety of the compound.
  • 6-bromo-2-naphthol (2.23 g, 10 mmol) was added to the reaction flask, and dissolved in 40 mL of anhydrous tetrahydrofuran. The temperature was lowered to -78 ° C, n-butyl lithium (10 ml, 25 mmol) was added dropwise under nitrogen atmosphere, and the reaction was carried out for 1 hour. Triisopropyl borate (2.82 g, 15 mmol) was added dropwise, and the reaction was carried out at room temperature for 0.5 hour, and then the reaction was continued to room temperature. After 0.5 hours, after the TLC reaction was completed, the pH was adjusted to be acidic by adding 1 M of dilute hydrochloric acid, and the organic phase was separated. The aqueous phase was extracted twice with diethyl ether. The organic phase was combined, washed with brine, concentrated, and purified by column chromatography. g product, yield 60.2%.
  • Step 7 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-d3-methoxyphenyl)naphthalene Synthesis of 2-yl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Compound 11).
  • the inventors used the HCV Replicon System as an evaluation model. Since its first report in Science in 1999, the HCV replication system has become one of the most important tools for studying HCV RNA replication, pathogenicity and viral persistence, for example, the use of replicons has successfully demonstrated the 5' required for HCV RNA replication. - NCR minimum region, and the HCV replication subsystem has been successfully used as an evaluation model for antiviral drugs. The inventors of the present invention verified according to the methods described in Science, 1999, 285 (5424), 110-3, and J. Virol, 2003, 77(5), 3007-19.
  • Step 1 The compound was diluted 1:3 in 8 series points, double-replicated, and added to a 96-well plate.
  • the DMSO was set to no compound control.
  • the final concentration of DMSO in the cell culture was 0.5%.
  • Step 2 HCV-1a and 1b cells were separately suspended in a culture medium containing 10% FBS, and seeded into a 96-well plate containing the compound at a density of 8,000 cells per well. The cells were cultured for 3 days at 5% CO 2 at 37 °C.
  • Step 3 The cytotoxicity of the compound against GT1b replicon was determined using CellTiter-Fluor (Promega).
  • Step 4 Detection of luciferase assay by Bright-Glo (Promega) for anti-hepatitis C virus activity.
  • Step Five using GraphPad Prism data analysis software, the curve fitting and EC 50 values were calculated and the 50 value CC.
  • HCV GT1a EC 50 (nM) HCV GT1b EC 50 (nM) HCV CC 50 (nM) Dasabuvir 7.61 ⁇ 2.32 >5000 D-1 ⁇ 2.32 ⁇ 2.32 >5000
  • the experimental results show that the compound of the present invention can inhibit multiple genotypes of HCV and exert superior anti-HCV effects by inhibiting the mechanism of HCV NS5B protein.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. Take 25057.5 ⁇ L phosphate The buffer (pH 7.4) was added to a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the metabolic stability of human and rat liver microsomes was evaluated by simultaneously testing the compounds of the present invention and their compounds without deuteration.
  • the half-life and liver intrinsic clearance as indicators of metabolic stability are shown in Table 2.
  • the undeuterated compound Dasabuvir was used as a control sample in Table 2.
  • the compound of the present invention can significantly improve metabolic stability by comparison with the undeuterated compound Dasabuvir, and is thus more suitable as a hepatitis C virus inhibitor.
  • OBJECTIVE To investigate the pharmacokinetic behavior of the compounds of the present invention after administration of Dasabuvir and Compound D-1 to rats.
  • SD rat grade SPF grade
  • Weight range 180 ⁇ 220g (actual weight range is 187 ⁇ 197g)
  • the experimental results show that the present inventors have found that the compound of the present invention has superior activity to Dasabuvir and has excellent pharmacokinetic properties as compared with Dasabuvir, and thus is more suitable as a compound for inhibiting the hepatitis C virus protein NS5B, and is suitable for Preparation of a medicament for treating hepatitis C virus infection.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (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

L'invention concerne un composé cyclique de naphtalène substitué, une composition pharmaceutique et une application associée, le composé cyclique de naphtalène étant le composé de formule (I), ou un polymorphe, un sel pharmaceutiquement acceptable, un promédicament, un stéréoisomère, un variant isotopique, un hydrate ou un solvate de celui-ci. Le composé cyclique de naphtalène peut jouer le rôle d'inhibiteur du virus de l'hépatite C, étant donné son effet inhibiteur de la protéine NS5B du virus de l'hépatite C et ses propriétés pharmacodynamiques/pharmacocinétiques favorables; il est par conséquent approprié pour la préparation d'un médicament destiné au traitement d'une infection par le virus de l'hépatite C.
PCT/CN2017/083880 2016-05-27 2017-05-11 Composé cyclique de naphtalène substitué, composition pharmaceutique et son application Ceased WO2017202207A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201780004354.5A CN108290844B (zh) 2016-05-27 2017-05-11 一种取代的萘环化合物及药物组合物及其应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610362244.3 2016-05-27
CN201610362244 2016-05-27

Publications (1)

Publication Number Publication Date
WO2017202207A1 true WO2017202207A1 (fr) 2017-11-30

Family

ID=60412677

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/083880 Ceased WO2017202207A1 (fr) 2016-05-27 2017-05-11 Composé cyclique de naphtalène substitué, composition pharmaceutique et son application

Country Status (2)

Country Link
CN (1) CN108290844B (fr)
WO (1) WO2017202207A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010048468A1 (fr) * 2008-10-23 2010-04-29 Concert Pharmaceuticals, Inc. Inhibiteurs macrocycliques deutériés de la protéase virale ns3
CN101842360A (zh) * 2007-09-17 2010-09-22 雅培制药有限公司 抗感染嘧啶及其用途
CN104030959A (zh) * 2014-06-24 2014-09-10 苏州东南药业股份有限公司 一种氘代的丙型肝炎病毒抑制剂
WO2014152275A1 (fr) * 2013-03-14 2014-09-25 Concert Pharmaceuticals, Inc. Dérivés modifiés par le deutérium de l'inhibiteur de polymérase ns5b tcm647055
CN104774194A (zh) * 2014-01-09 2015-07-15 正大天晴药业集团股份有限公司 氘代的丙型肝炎病毒抑制剂
WO2015197028A1 (fr) * 2014-06-28 2015-12-30 Sunshine Lake Pharma Co., Ltd. Composés en tant qu'inhibiteurs du virus de l'hépatite c (vhc) et leurs utilisations en médecine
WO2016105547A1 (fr) * 2014-12-24 2016-06-30 Concert Pharmaceuticals, Inc. Dasabuvir deutéré

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2805748A1 (fr) * 2010-07-16 2012-01-19 Shashank Shekhar Procede de preparation de composes antiviraux
US9255074B2 (en) * 2010-07-16 2016-02-09 Abbvie Inc. Process for preparing antiviral compounds

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101842360A (zh) * 2007-09-17 2010-09-22 雅培制药有限公司 抗感染嘧啶及其用途
WO2010048468A1 (fr) * 2008-10-23 2010-04-29 Concert Pharmaceuticals, Inc. Inhibiteurs macrocycliques deutériés de la protéase virale ns3
WO2014152275A1 (fr) * 2013-03-14 2014-09-25 Concert Pharmaceuticals, Inc. Dérivés modifiés par le deutérium de l'inhibiteur de polymérase ns5b tcm647055
CN104774194A (zh) * 2014-01-09 2015-07-15 正大天晴药业集团股份有限公司 氘代的丙型肝炎病毒抑制剂
CN104030959A (zh) * 2014-06-24 2014-09-10 苏州东南药业股份有限公司 一种氘代的丙型肝炎病毒抑制剂
WO2015197028A1 (fr) * 2014-06-28 2015-12-30 Sunshine Lake Pharma Co., Ltd. Composés en tant qu'inhibiteurs du virus de l'hépatite c (vhc) et leurs utilisations en médecine
WO2016105547A1 (fr) * 2014-12-24 2016-06-30 Concert Pharmaceuticals, Inc. Dasabuvir deutéré

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HARBESON, S.L. ET AL.: "Deuterium Medicinal Chemistry: A New Approach to Drug Discovery and Development", MEDCHEM NEWS, 31 May 2014 (2014-05-31), pages 8 - 22, XP055246294 *
WANG, WENFENG ET AL.: "Application of Deuteration in Drug Research", QILU PHARMACEUTICAL AFFAIRS, vol. 29, no. 11, 15 November 2010 (2010-11-15), pages 682 - 684, XP008173943 *

Also Published As

Publication number Publication date
CN108290844B (zh) 2021-04-30
CN108290844A (zh) 2018-07-17

Similar Documents

Publication Publication Date Title
TWI790704B (zh) 含腈之抗病毒化合物類
EP3325477B1 (fr) Nouveaux dérivés d'acide 4-dihydrobenzo[a]quinolizine-3 -carboxylique pour le traitement et la prophylaxie d'une infection par le virus de l'hépatite b
JP6506880B2 (ja) Ｂ型肝炎ウィルス感染症の治療および予防のための新規な四環式４−オキソ−ピリジン−３−カルボン酸誘導体
CN115385983A (zh) 氮杂双环类化合物及其制备方法、药物组合物和用途
KR102894005B1 (ko) 항바이러스 1,3-다이-옥소-인덴 화합물
TW202334123A (zh) 用於預防和治療冠狀病毒感染的化合物及其偶聯物和方法
CN103097370A (zh) 用于治疗丙型肝炎的苯并呋喃衍生物
CN102858777B (zh) 治疗丙型肝炎的吡唑并哒嗪衍生物
WO2023165334A1 (fr) Dérivés de ceto amide et leur utilisation pharmaceutique
WO2017121188A1 (fr) Inhibiteur du virus de l'hépatite c, composition pharmaceutique et application associées
CN118176202B (zh) 一种含氰基取代的多肽类化合物的晶型及其制备方法
CN104884459A (zh) 用于治疗丙型肝炎的大环苯并呋喃和氮杂苯并呋喃化合物
WO2017148290A1 (fr) Composé d'adénine substituée et composition pharmaceutique correspondante
WO2017202207A1 (fr) Composé cyclique de naphtalène substitué, composition pharmaceutique et son application
CN108368123B (zh) 一种取代的咪唑基化合物及其药物组合物
EP3964509B1 (fr) Composé contenant un cycle condensé, son utilisation et composition pharmaceutique le contenant
WO2017121187A1 (fr) Inhibiteur du virus de l'hépatite c, composition pharmaceutique et utilisation associées
WO2017206688A1 (fr) Composés substitués de pyrrolidine, compositions pharmaceutiques et leurs applications
WO2017198102A1 (fr) Composé quinoxaline macrocyclique substitué et composition pharmaceutique et son utilisation
HK40095463A (zh) 含腈的抗病毒化合物
HK40073397B (zh) 含腈的抗病毒化合物
WO2017181947A1 (fr) Carbamate substitué de diamine, composition pharmaceutique et application correspondante
WO2018028541A1 (fr) Composé quinoléine substitué, composition pharmaceutique correspondante et utilisation de celui-ci
HK40073397A (en) Nitrile-containing antiviral compounds
HK40064692A (en) Nitrile-containing antiviral compounds

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: 17802053

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17802053

Country of ref document: EP

Kind code of ref document: A1