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WO2017118355A1 - Dérivé nucléotidique de l'inhibiteur ns5b deutéré du vhc et son utilisation - Google Patents

Dérivé nucléotidique de l'inhibiteur ns5b deutéré du vhc et son utilisation Download PDF

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Publication number
WO2017118355A1
WO2017118355A1 PCT/CN2016/113815 CN2016113815W WO2017118355A1 WO 2017118355 A1 WO2017118355 A1 WO 2017118355A1 CN 2016113815 W CN2016113815 W CN 2016113815W WO 2017118355 A1 WO2017118355 A1 WO 2017118355A1
Authority
WO
WIPO (PCT)
Prior art keywords
mixture
compound
hepatitis
virus
inhibitors
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/CN2016/113815
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English (en)
Chinese (zh)
Inventor
王喆
曾志宏
江荣珍
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Longwood Biopharmaceuticals Ltd
Original Assignee
Longwood Biopharmaceuticals 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 Longwood Biopharmaceuticals Ltd filed Critical Longwood Biopharmaceuticals Ltd
Priority to CN201680077803.4A priority Critical patent/CN108473525A/zh
Publication of WO2017118355A1 publication Critical patent/WO2017118355A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the field of medicine, and particularly relates to a novel class of deuterated nucleoside (amino) phosphate compounds, compositions containing the same, and preparation of the compounds and medicaments thereof for HCV (Hepatitis C Virus) infectious diseases the use of.
  • HCV Hepatitis C Virus
  • Hepatitis C virus infection causes chronic liver diseases such as cirrhosis and liver cancer. Hepatitis C virus infection is one of the major infectious diseases. According to the World Health Organization, there are 170 million hepatitis C victims worldwide, and there are nearly 39 million hepatitis C infected people in China. Studies to date have shown that hepatitis C virus (HCV) is the leading cause of most non-A, non-B hepatitis. Hepatitis C virus is a flavivirus (F1aviviridae) positive single-stranded RNA virus. The standard protocol for the treatment of HCV was previously a combination of interferon or PEG interferon A and ribavirin. However, the side effects of interferon are obvious, and the side effects of interferon and ribavirin are combined to cause hemolysis, anemia and fatigue.
  • HCV hepatitis C virus
  • BMS BMS-986094 is a guanosine nucleotide phosphate prodrug for clinical treatment of hepatitis C.
  • the patient terminated his clinical trial after death due to heart failure.
  • Idenix's IDX19368 also stopped clinical trials. Therefore, there is still a need for effective compounds for the treatment and/or prevention of HCV infection.
  • R 1 H or D
  • R 2 H or D
  • R 3 H or D
  • R 4 H or D
  • R 5 CH 3 or CD 3
  • R 6 H or D
  • X -O Or -NH.
  • the compound is selected from the group consisting of:
  • the position of the ⁇ (D) generation in the compounds of the present application has at least 50% D, such as at least 90% D, 50-90% D.
  • the position of the ⁇ (D) generation in the compounds of the present application has at least 95% D.
  • the present application also provides an isomer mixture of the compounds described herein, wherein the two isomers of the mixture each comprise 50%, the mixture being as claimed in claim 5.
  • the application provides a compound of formula I, including the specific compounds listed, for use in the treatment or prevention of HCV infection.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient a compound or a mixture of isomers of the present application, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present application further comprises one or more additional active ingredients.
  • the one or more additional active ingredients in the pharmaceutical composition of the present application are selected from the group consisting of (1) an immunomodulatory agent; (2) a hepatitis C virus protease (NS3) inhibitor; Hepatitis C virus NS4b inhibitor; (4) Hepatitis C virus NS5a inhibitor; (5) Hepatitis C virus polymerase (NS5b) inhibitor; (5) No Nucleosides and nucleoside derivatives belonging to (2)-(5); (6) Hepatitis B virus (HBV) inhibitors; (7) Human immunodeficiency virus (HIV) inhibitors; (8) Cancer drugs; 9) an anti-inflammatory drug; or (10) other compounds not belonging to the above (1) to (9).
  • the one or more additional active ingredients are selected from the group consisting of HCV NS3 protease inhibitors, HCV NS5A inhibitors, HCV NS5B polymerase inhibitors, interferons or interferon derivatives, ribavirin.
  • HCV NS3 protease inhibitors HCV NS5A inhibitors
  • HCV NS5B polymerase inhibitors interferons or interferon derivatives
  • ribavirin are selected from the group consisting of HCV NS3 protease inhibitors, HCV NS5A inhibitors, HCV NS5B polymerase inhibitors, interferons or interferon derivatives, ribavirin.
  • compositions of the present application include, but are not limited to, oral dosage forms and parenteral administration dosage forms.
  • the pharmaceutical composition may be an oral tablet, capsule, pill, powder, sustained release formulation, solution and suspension, sterile solution, suspension or emulsion for parenteral injection.
  • the pharmaceutical composition is in a unit dosage form suitable for single administration of precise dosages.
  • the amount of the compound ranges from about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day. In other embodiments, the amount of the compound ranges from about 0.5 mg/kg body weight/day to about 50 mg/kg body weight/day. In some embodiments, the amount of the compound is from about 0.001 g/day to about 7 g/day.
  • the amount of the compound is from about 0.002 g/day to about 6 g/day. In other embodiments, the amount of the compound is from about 0.005 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.01 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound is from about 0.1 g/day to about 1 g/day. In other embodiments, a dose level below the lower limit of the above range may already be sufficient.
  • the compound is administered in a single dose, once a day. In other embodiments, the compound is administered in multiple doses more than once a day. In some embodiments, the compound is administered twice daily. In other embodiments, the compound is administered three times a day. In other embodiments, the compound is administered four times a day. In other embodiments, the compound is administered more than four times a day. In some embodiments, the individual to which the pharmaceutical composition is administered is a mammal. In other embodiments, the mammal is a human. In other embodiments, if the pharmaceutical composition comprises a plurality of active ingredients, the active ingredients may be combined in a single dosage form, and they may also be in separate dosage forms without mixing with one another.
  • the application provides the use of a compound or mixture of the present application in the manufacture of a medicament for the treatment or prevention of HCV infection.
  • the application provides the use of a compound or mixture of the present application in combination with one or more other active ingredients described herein for the manufacture of a medicament for the treatment or prevention of HCV infection.
  • the present application provides a method of treating or preventing an HCV infection, the method comprising administering an effective amount of a compound or mixture or pharmaceutical composition of the present application to a subject in need thereof.
  • the above method of treating or preventing an HCV infection comprises administering an effective amount of a compound or mixture of the present application in combination with one or more other active ingredients described herein to a subject in need thereof Tester.
  • the HCV infections described herein include chronic hepatitis C.
  • the terms "subject,” “patient,” or “individual” refer to an individual, including a mammal, and a non-mammal, having a disease, disorder, condition, or the like.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domesticated Animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs.
  • non-human mammals include, but are not limited to, birds and fish.
  • the mammal is a human.
  • treatment includes alleviating, alleviating or ameliorating the symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing a potential metabolic cause of the symptoms, inhibiting the disease or condition, such as preventing the progression of the disease or condition, Ameliorating a disease or condition, ameliorating the disease or condition, alleviating the symptoms caused by the disease or condition, or terminating the symptoms of the disease or condition, and further, the term includes the purpose of prevention.
  • the term also includes obtaining a therapeutic effect and/or a preventive effect.
  • the therapeutic effect refers to curing or ameliorating the underlying disease to be treated.
  • the healing or amelioration of one or more physiological symptoms associated with a underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, an improvement in the patient's condition is observed.
  • the composition can be administered to a patient at risk of developing a particular disease, or even if a diagnosis of the disease has not been made, the composition is administered to a patient who develops one or more physiological symptoms of the disease.
  • an "effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
  • an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration.
  • parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical and rectal administration topical and rectal administration.
  • the techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those discussed in Pa.
  • the compounds and compositions discussed herein are administered orally.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.
  • composition refers to a biologically active compound, optionally in admixture with at least one pharmaceutically acceptable chemical component, including but not limited to a carrier.
  • carrier refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of a compound into a cell or tissue.
  • pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness of the free acid and free base of the specified compound, and which has no adverse effects biologically or otherwise.
  • the compounds of the present application also include pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt refers to a form in which a base group in a parent compound is converted into a salt.
  • stereoisomer refers to an isomer produced by the different arrangement of atoms in a molecule in space.
  • the compounds of formula I contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. All stereostructures and mixtures of Formula I, including racemic mixtures, are part of the current application.
  • the mixture of diastereomers can be separated into individual diastereomers, based on their different physicochemical properties, using well-known means, for example, resolution of the enantiomers can be carried out with appropriate optically active substances (eg chirality)
  • the alcohol or Mosher ⁇ s molyl chloride reaction is converted to a diastereomer which is separated and converted (e.g., hydrolyzed) to the corresponding single isomer.
  • Some of the compounds of Formula 1 may be atropisomers (e.g., substituted aryl groups) are also part of this application.
  • Enantiomers can also be separated using a chiral column.
  • the compounds of formula I may exist in different tautomeric forms, and such forms are embraced within the scope of the present application. For example, compounds in the form of keto-enol and imine-enamine.
  • the method for synthesizing the compounds in the present application includes, but is not limited to, the following reaction formulas and reaction steps:
  • EtOAc EtOAc
  • EtOAc eluted eluted (20ml)
  • the mixture was extracted, the aqueous phase and solid were combined, ethyl acetate was added, and 4N HCl aqueous solution was added dropwise with stirring to adjust pH ⁇ 2, and the organic phase was separated, and concentrated to give 1.19 g of a red foamy solid.
  • the compound 1f (93 mg, 0.261 mmol) was dissolved in 1.0 ml of THF, and a solution of t-BuMgCl (1M, 0.784 ml) in THF was added dropwise at 0 to 5 ° C, and the reaction was carried out at 0 to 5 ° C for 30 min, and a large amount of solid precipitated, 0 to THF was added compound 11 (183mg, 0.418mmol) at the 5 °C (1.0 ml) solution, all the solid clear solution, warmed to room temperature stirred overnight, TLC tracking completion of the reaction was added saturated aqueous NH 4 Cl, EA, the organic phase was washed with The mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated and then purified by column chromatography.
  • the eluent was n-heptane / ethyl
  • the compound 2c (130 mg, 0.47 mmol) was dissolved in 1.5 ml of THF, and a solution of t-BuMgCl (1 M) in THF (1.41 ml) was added dropwise at 0 to 5 ° C, and the reaction was carried out at 0 to 5 ° C for 30 min, and a large amount of solid precipitated.
  • the compound 3d (150 mg, 0.39 mmol) was dissolved in 1.5 ml of THF, and a solution of t-BuMgCl (1 M) in THF (1.2 ml) was added dropwise at 0 to 5 ° C, and the reaction was carried out at 0 to 5 ° C for 30 min, and a large amount of solid precipitated.
  • the compound 4e (150 mg, 0.39 mmol) was dissolved in 1.5 ml of THF, and a solution of t-BuMgCl (1 M) in THF (1.2 ml) was added dropwise at 0 to 5 ° C, and the reaction was carried out at 0 to 5 ° C for 30 min, and a large amount of solid precipitated.
  • Stable hepatitis C virus replicon GT1a and GT1b cell lines were transfected into Huh-7 cells by in vitro transcription of hepatitis C virus subgenomic GT1a (H77) and GT1b (Con1) replicon plasmid DNA into cells and selected by G418. And established.
  • the GT1a and GT1b stable cell lines were constructed by WuXi PharmaTech (Wuxi AppTech Huh7-GT1a (H77) and Huh7-GT1b (con1)).
  • Reagents or consumables DMEM medium, fetal bovine serum, streptomycin, MEM non-essential amino acids, glutamine, G418, 0.05% trypsin, DMSO, 96-well black cell culture plate, CellTiter-flour, Bright-Glo.
  • the compound was dissolved in DMSO to a 10 mmol/L concentrated stock solution and stored in a nitrogen cabinet. Gradient dilution of the compound: The compound was added to a 96-well plate with Echo, and each compound was subjected to a 1:3 serial dilution of 8 concentration points, double duplicate wells, and added to columns 3-10 of the 96-well plate. In column 11, only DMSO was added as an ineffective control well. The final volume of DMSO in each well was 607.5 nanoliters. See the layout below.
  • HCV GT1a or GT1b cells were digested from T150 cell culture flasks, and the cell density was adjusted to 65,843 cells/ml with cell culture medium, and then the cell suspension was added to a 96-well plate to which the compound had been added. The well was added to 121.5 microliters. The final density of cells in 96-well plates was 8,000 cells/well, and the final concentration of DMSO in each well was 0.5%. No cells were added to the 100% effective control wells in column 2. A 96-well plate containing cells and compounds was placed in 5% CO 2 and cultured at 37 ° C for 3 days.
  • CellTiter-Flour was used to detect the cell viability of each well in a 96-well plate: 40 ⁇ l of CellTitter-flour was added to each well, and then cultured at 37 ° C, 5% CO 2 for 1 hour, and then read with EnVision. The fluorescence signal (excitation light 405 nm, emission light 515 nm) was detected. The anti-hepatitis C virus activity of the compounds was examined by Bright-Glo: the supernatant of the 96-well plate in which the activity of the cells was detected was removed, and then 100 ⁇ l of the prepared 1X Bright-Glo reagent was added to each well, and the chemiluminescence signal was detected within 5 minutes.
  • ZPE Mean value of DMSO ineffective control well signal
  • HPE 100% effective control well (cell-free control well) signal mean
  • RFU Relative Fluorescence Unit
  • the representative compound represented by the formula (I) of the present application exhibits an EC50 (50% inhibition rate for the HCV GT1a and GT1b subgene replicon inhibition test, and the sofosbuvir raw material drug is a reference compound) As shown in the table below.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente demande concerne un dérivé nucléotidique d'un inhibiteur NS5B deutéré du VHC (virus de l'hépatite C), ou un sel pharmaceutiquement acceptable, un stéréoisomère, un tautomère dudit inhibiteur, et son utilisation dans la préparation de médicaments destinés à traiter ou à prévenir les infections par le VHC. L'inhibiteur est représenté par la formule générale (I).
PCT/CN2016/113815 2016-01-04 2016-12-30 Dérivé nucléotidique de l'inhibiteur ns5b deutéré du vhc et son utilisation Ceased WO2017118355A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201680077803.4A CN108473525A (zh) 2016-01-04 2016-12-30 氘代HCV NS5b抑制剂核苷酸衍生物及其用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610003455 2016-01-04
CN201610003455.8 2016-01-04

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Publication Number Publication Date
WO2017118355A1 true WO2017118355A1 (fr) 2017-07-13

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Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108473525A (zh) * 2016-01-04 2018-08-31 上海长森药业有限公司 氘代HCV NS5b抑制剂核苷酸衍生物及其用途
CN111918870B (zh) * 2018-05-18 2022-07-08 正大天晴药业集团股份有限公司 氘代的低聚核苷酸及前体药物

Citations (3)

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WO2014169280A2 (fr) * 2013-04-12 2014-10-16 Achillion Pharmaceuticals, Inc. Promédicaments de nucléoside deutérisé utilisés pour traiter l'hépatite c
CN104672288A (zh) * 2014-11-07 2015-06-03 王彩琴 一种氘代索菲布韦及其用途
WO2015116248A1 (fr) * 2013-02-01 2015-08-06 Enanta Pharmaceuticals, Inc. Dérivés nucléosidiques ou nucléotidiques de 5, 6-d2 uridine

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SG11201407674TA (en) * 2012-05-22 2014-12-30 Idenix Pharmaceuticals Inc D-amino acid compounds for liver disease
US20160346198A1 (en) * 2014-02-05 2016-12-01 Merck Sharp & Dohme Corp. Novel disintegration systems for pharmaceutical dosage forms
US20170066795A1 (en) * 2014-03-05 2017-03-09 Idenix Pharmaceuticals Llc Solid prodrug forms of 2'-chloro-2'-methyl uridine for hcv
CN106543253B (zh) * 2015-11-24 2019-04-02 杨学聪 抗病毒核苷氨基磷酸酯及其药物组合和用途
CN108473525A (zh) * 2016-01-04 2018-08-31 上海长森药业有限公司 氘代HCV NS5b抑制剂核苷酸衍生物及其用途

Patent Citations (3)

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WO2015116248A1 (fr) * 2013-02-01 2015-08-06 Enanta Pharmaceuticals, Inc. Dérivés nucléosidiques ou nucléotidiques de 5, 6-d2 uridine
WO2014169280A2 (fr) * 2013-04-12 2014-10-16 Achillion Pharmaceuticals, Inc. Promédicaments de nucléoside deutérisé utilisés pour traiter l'hépatite c
CN104672288A (zh) * 2014-11-07 2015-06-03 王彩琴 一种氘代索菲布韦及其用途

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CN106699828B (zh) 2019-05-21
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