WO2021179512A1 - Composé contre le virus de la grippe, son procédé de préparation et son utilisation - Google Patents

Composé contre le virus de la grippe, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2021179512A1
WO2021179512A1 PCT/CN2020/105222 CN2020105222W WO2021179512A1 WO 2021179512 A1 WO2021179512 A1 WO 2021179512A1 CN 2020105222 W CN2020105222 W CN 2020105222W WO 2021179512 A1 WO2021179512 A1 WO 2021179512A1
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compound
solution
influenza virus
ocoo
solvent
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Chinese (zh)
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李学兵
吕迅
陈建忠
王鹏飞
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Institute of Microbiology of CAS
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Institute of Microbiology of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and relates to an anti-influenza virus compound and a preparation method and application thereof.
  • Influenza the full name of influenza, is an acute respiratory infectious disease caused by influenza virus.
  • seasonal influenza and highly pathogenic influenza viruses that have emerged from time to time have always warned of the potential threat of a new round of influenza outbreaks in humans.
  • the prevention and control of influenza is important and urgent.
  • oseltamivir (Tamiflu) and zanamivir (Relexa) represented by influenza virus neuraminidase (NA) inhibitors are still the main methods for preventing and treating influenza.
  • NA neuraminidase
  • Zanamivir trade name Relenza, is a marketed anti-influenza drug developed by Australia Biota. It mainly inhibits the neuraminidase on the surface of the influenza virus to block the newly assembled influenza virus from the host cell. Budding process released into the cell sap. Due to its high hydrophilicity, this drug can only be administered by inhalation in clinical use. Therefore, zanamivir is too water-soluble. After entering the human body, it is quickly metabolized and excreted in the form of urine. It can be made into a nasal spray, which greatly limits its clinical promotion.
  • the purpose of the present invention is to provide a compound which has been proved to have anti-influenza virus activity and its preparation method and application.
  • the zanamivir derivative provided by the present invention has more efficient anti-influenza virus activity, and the water solubility is obviously improved, and it is expected to be made into an oral medicine.
  • n is selected from any natural number in 3-12, and X is selected from OCOO or O;
  • Y is selected from
  • the anti-influenza virus compound is selected from compounds VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI-11, VI-12, VI-13, VI-14, VI-15, or VI-16;
  • a preparation method of an anti-influenza virus compound characterized in that it is prepared from compound V and compound III under reaction conditions d;
  • the compound V is Where m is any natural number from 2-11, and Y 4 is selected from SH, N 3 ,
  • n is any natural number from 3-12
  • X is OCOO or O
  • Y 2 is selected from SH, N 3 ,
  • reaction condition d refers to: dissolving compound V, compound III and cuprous chloride in a mixed solvent, reacting at room temperature overnight, and the solution is concentrated and separated and purified by a Sephadex LH-20 gel chromatography column;
  • the dosage ratio of the mixed solvent of compound V, compound III, cuprous chloride, dichloromethane and methanol is 1mmol:1mmol:0.1-0.5mmol:2-50mL; preferably 1mmol:1mmol:0.1mmol:20mL ;
  • the mixed solvent is selected from: a mixed solvent of dichloromethane and methanol, a mixed solvent of chloroform and methanol, a mixed solvent of chloroform and ethanol, or a mixed solvent of dichloromethane and ethanol; preferably dichloromethane and methanol
  • the mixed solvent the purpose of using the mixed solvent is to make all the compounds can be dissolved in the solvent, forming a uniform system can promote the reaction and increase the yield;
  • reaction condition d refers to: dissolving compound V and compound III in a solvent, reacting overnight at room temperature, and separating and purifying the solution by a Sephadex LH-20 gel chromatography column after concentration;
  • the solvent is selected from absolute ethanol, methanol or water;
  • the volume ratio of dichloromethane and methanol in the mixed solvent of dichloromethane and methanol is 5:1 to 1:5; preferably 1:1.
  • the compound V is prepared from compound IV under reaction condition c;
  • the compound III is prepared from compound I and compound II under reaction condition a;
  • the compound IV is Where m is any natural number from 2-11, and Y 3 is selected from SAc, N 3 ,
  • the compound I is Where R is ClCO or Ts;
  • n is any natural number from 3-12
  • Y 1 is selected from SAc, N 3 ,
  • the reaction condition c refers to dissolving compound IV in a solvent, adding sodium hydroxide aqueous solution dropwise, stirring at room temperature for 1-6 hours, preferably 3 hours, and then neutralizing with Dowex-50 (H+) ion exchange resin to the pH of the solution At 7, the solution is concentrated after filtration, and the concentrated residue is dissolved in a mixed solution of dichloromethane and trifluoroacetic acid, reacted for 1 hour and then concentrated, and the concentrated residue is separated and purified by Sephadex G-15 gel column;
  • the solvent is selected from the group consisting of methanol, ethanol, and water;
  • the dosage ratio of the compound IV, the solvent, the aqueous sodium hydroxide solution, and the mixed solution with a volume ratio of dichloromethane and trifluoroacetic acid of 1/1 is 1mmol:1-100mL:0.5-2M:1-100mL;
  • the effect of dropping sodium hydroxide aqueous solution is to remove the methyl ester group under alkaline conditions
  • Dowex-50(H+) ion exchange resin is used to neutralize and at the same time adsorb Na ions on the resin to remove metal ions in the solution;
  • Concentration is to evaporate the solvent, because the solvent system is not used in subsequent reactions, and the specific operation is to concentrate under reduced pressure on a rotary evaporator;
  • the concentrated residue is dissolved in a mixed solution of dichloromethane and trifluoroacetic acid with a volume ratio of 1/1 to remove Boc and isopropylidene groups;
  • concentration is required for the following "Sephadex G-15 gel column separation and purification".
  • the sample concentration must not be too dilute during the gel column sample loading process, otherwise the separation effect will not be good.
  • the specific operation is to concentrate under reduced pressure on a rotary evaporator;
  • the concentrated residue is separated and purified by Sephadex G-15 gel column.
  • the function of this step is to purify the target compound and separate impurities with a large molecular weight difference from the target compound;
  • the reaction condition a includes: dissolving compound I and compound II in a non-polar solvent, and reacting under reflux at 100-150°C overnight; after the solution is concentrated, the resulting concentrate is passed through a silica gel chromatography column Separate
  • the dosage ratio of the compound I, compound II, and 1,4-dioxane is 1 mol: 1-1.2 mol: 10-200 mL, preferably 1 mol: 1.2 mol: 100 mL;
  • the non-polar solvent is preferably 1,4-dioxane; the temperature condition for the reflux reaction overnight is preferably 125°C;
  • Non-polar solvents can be common non-polar solvents in the field, preferably 1,4-dioxane has the advantage that it can maximize the yield of the final product;
  • the temperature condition of reflux reaction overnight can reach the boiling point of 1,4-dioxane at 100-150°C, and the solvent can boil and reflux, which is the usual saying in chemical reactions;
  • the function of concentration is for the separation and purification needs of the silica gel chromatography column.
  • the sample concentration of the silica gel chromatography column separation and loading process requires that the sample concentration is not too dilute, otherwise the separation effect will not be good.
  • the specific operation is to concentrate under reduced pressure on a rotary evaporator;
  • the reaction condition a includes: dissolving compound I and compound II in pyridine, and stirring and reacting at room temperature overnight; adding methanol to the reaction solution, concentrating and dissolving in a solvent, and then using HCl solution and Wash with NaHCO 3 solution, and concentrate the organic phase to separate the resulting concentrate on a silica gel chromatography column;
  • the solvent is selected from dichloromethane or chloroform;
  • the dosage ratio of the compound I, compound II, pyridine, dichloromethane, HCl solution, and NaHCO 3 solution is 1 mol: 1-2 mol: 10-200 mL: 100-500 mL: 100-500 mL: 100-500 mL, preferably 1 mol: 1.2 mol: 100mL: 100ml: 100ml: 100ml;
  • volume and concentration dosage is only an approximate dosage, and the increase or decrease of dosage does not affect the final result
  • the concentration of the HCl solution in the reaction condition a is 0.5-2M, preferably 1M, and the concentration of the NaHCO 3 solution is 0.5-2M, preferably 1M.
  • the concentration of the sodium methoxide/methanol solution is 1N.
  • the concentration of the sodium methoxide/methanol solution is 1N, which refers to a solution of sodium methoxide dissolved in methanol and the concentration of sodium methoxide in the solution is 1N.
  • the concentration of 1N is recognized as the optimal concentration for the hydrolysis reaction of this method.
  • the dosage form of the medicine is selected from the group consisting of oral agents, nasal drops, injections, and nasal sprays.
  • the general formula of the anti-influenza virus compound provided by the present invention is as follows:
  • the anti-influenza virus compound of the present invention is used to treat various influenza viruses and found that it has good influenza virus inhibitory activity, especially for zanamivir-resistant influenza virus (H3N2, E119V) has more prominent inhibitory activity, and at the same time
  • the anti-influenza virus compound of the present invention obviously improves the water solubility of the original medicine, and the lipid-water distribution coefficient is dozens of times higher than that of the original medicine.
  • Fig. 1 is the body weight change curve and survival rate curve of experimental mice in the "Animal Experiment (Experiment of Protecting Mice by Continuous Administration)" of Experimental Example 2 of the present invention.
  • Reaction condition c Dissolve compound IV (10mmol) in methanol (100mL), add 1M sodium hydroxide aqueous solution (5mL) dropwise, stir at room temperature for 3 hours, and neutralize to solution with Dowex-50(H+) ion exchange resin The pH value is 7, the solution is concentrated after filtration, and the remainder is dissolved in a mixed solution (100mL) with a volume ratio of dichloromethane and trifluoroacetic acid of 1/1. After reacting for 1 hour, it is concentrated, and the remainder is subjected to Sephadex G-15 gel. After column separation and purification, a white solid compound V was obtained. The yield is about 60-72%.
  • NA enzyme activity inhibition experiment the purified NA protein (N1, N5, etc.) was diluted 5 ⁇ , 25 ⁇ , 125 ⁇ , 625 ⁇ , 3125 ⁇ , 15625 ⁇ with 20/150 Tris/NaCl with a pH of 8.0. Then, add 10 ⁇ L of NA solution of different concentrations and 10 ⁇ L of PBS to the black 96-well microtiter plate, incubate in a constant temperature incubator at 37°C for 30 minutes, and add 30 ⁇ L of 167 ⁇ M 4-MUNANA(4-methylumbelliferyl-N -acetylneuraminic acid) fluorescent substrate.
  • the inhibitor (VI) was diluted with PBS in a 10-fold gradient to form a solution with a suitable concentration range, and then 10 ⁇ L of inhibitor solution of different concentration and 10 ⁇ L of NA solution of appropriate concentration were added to the black 96-well plate. In addition, 10 ⁇ L of PBS and 10 ⁇ L of NA solution of appropriate concentration were added to other wells as a positive control, and 20 ⁇ L of PBS was added as a negative control.
  • the 16 anti-influenza virus compounds provided in the above embodiments of the present invention have inhibitory effects on various NA, especially the NA of influenza viruses resistant to zanamivir (H3N2, E119V). Good suppression effect.
  • influenza virus obtained through chicken embryo reproduction was diluted with DMEM into virus solutions of different concentrations according to a 10-fold gradient. Inoculate MDCK cells in a 96-well cell culture plate. After 20h (until the cells grow to the bottom of the culture plate), aspirate the DMEM medium containing the serum double antibody, rinse with sterilized PBS solution for 2 times, and add the pre-diluted solution. 100 ⁇ L of good virus solution. Then the 96-well cell culture plate was placed in a 37°C cell culture incubator containing 5% CO 2 for 48 hours. Repeat 4 times for each virus concentration. Observe the cell status with an inverted microscope, and perform an ELISA test for each well. The results obtained are calculated using the Reed-Muench method to calculate the TCID 50 of the influenza virus.
  • DMEM medium After filtering the 11 mM inhibitor mother liquor with a 0.22 ⁇ m sterile filter, add DMEM medium and dilute it to an inhibitor solution with a suitable concentration range according to a 10-fold gradient.
  • inoculate MDCK cells in a 96-well cell culture plate After 20 hours, when the cells have grown to the bottom of the culture plate, aspirate the DMEM medium containing the serum double antibody, rinse with sterilized PBS solution for 2 times, and add the pre-diluted solution. 100 ⁇ L of a good virus solution of 100 times TCID 50.
  • the 16 zanamivir modifications provided in the above embodiments of the present invention also have a good virus inhibitory effect at the cellular level, and are also resistant to zanamivir-resistant influenza viruses (H3N2, E119V). It has a good inhibitory effect and can be used for the treatment of various influenza virus infections.
  • m, n, X, Y, m and X all have significant effects on the inhibitory effect.
  • the difference in m not only leads to different chain lengths.
  • the cholesterol molecule at one end of the compound molecule can adhere to the surface of the host cell, and the zanamivir at the other end interacts with the NA protein on the surface of the virus, thereby inhibiting the virus from infecting the host. cell. Therefore, the length of the connecting arm between the cholesterol in the compound molecule and zanamivir must be longer than the sum of the lengths of the various protruding substances (such as proteins) contained on the surface of the host cell and the virus.
  • the click connection method compound has few synthetic steps, low difficulty, and high yield.
  • the click ring may cause the drug molecule to be highly toxic and reduce the potential of the drug; the amide bond connection method is more difficult to synthesize, and the yield is lower.
  • the potential toxicity of the molecule is lower, and it may have better drug potential.
  • Animal experiment continuous administration to protect mice experiment: 30 female Balb/c mice were divided into 5 cages, 6 in each cage. After all mice were anesthetized with 5% chloral hydrate injection, 4 cages were inoculated intranasally with 10 4 PFU A/Puerto Rico/8/34 (H1N1) influenza virus 30 ⁇ L, and the other 1 cage was intranasally inoculated with 30 ⁇ L PBS.
  • mice was anesthetized and administrated 15 ⁇ L of VI-5 at a dose of 6mg/kg intragastrically, 1 cage of mice was administered by intragastric 150 ⁇ L of VI-5 at a dose of 60mg/kg, and 1 cage of mice was administered intragastrically 150 ⁇ L of Tamiflu at a dose of 20 mg/kg was administered.
  • One cage of mice was intragastrically administered with 150 ⁇ L of 10% ethanol solution, and the last cage of mice was intragastrically administered with the same volume of 10% ethanol solution for 7 days.
  • the body weight and temperature of the mice were monitored daily for 14 days. When the weight of the mouse drops to 75% of the initial weight, the mouse is deemed dead.
  • the mouse body weight change curve and survival rate curve were drawn by GraphPad Prism (version 5.0) analysis.
  • the compound VI-5 provided in Example 5 of the present invention can protect the infected mice 100% by nasal drops and oral administration in the mouse experiment. Therefore, the compound of the present invention has a developmental potential The potential of oral anti-flu drugs.
  • the compounds VI1-4 and VI6-16 provided by other embodiments 1-4 and 6-16 of the present invention can all obtain the anti-influenza effect similar to VI-5 for oral administration as shown in FIG. 1. In order to save the space of the present invention, I will not repeat them one by one.
  • n-octanol and double distilled water were shaken with a constant temperature (37 ⁇ 1)°C shaker for 24h at room temperature to make them saturated with each other. After standing overnight for layering, the two phases are separated and stored for later use. Accurately weigh an appropriate amount of the compound to be tested in a 10 mL volumetric flask, dissolve it in n-octanol saturated with water, oscillate it ultrasonically for 30 min, and make it constant to obtain a mother liquor with a concentration of 1 mmol/L.
  • the lipid-water partition coefficient (log P) is the main indicator to measure whether a drug can penetrate a biological membrane composed of a lipid bilayer, and it is related to the pharmacokinetic process of drug absorption, distribution, metabolism, and excretion in the human body.
  • Log P The smaller the P value, the stronger the hydrophobicity of the compound, the easier it is to be metabolized in the body, and the higher the clearance rate (such as zanamivir).
  • the larger the log P value the stronger the lipophilicity of the compound.
  • lipid-water partition coefficient of the compounds designed in the present invention is generally significantly higher than that of zanamivir, which can achieve the purpose of improving the water solubility of zanamivir, and is expected to significantly improve the pharmacokinetic properties of the compound. It has a good potential as a medicine.

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  • Health & Medical Sciences (AREA)
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  • Virology (AREA)
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  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Public Health (AREA)
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Abstract

La présente invention concerne " un composé contre le virus de la grippe, son procédé de préparation et son utilisation " relevant du domaine technique de la chimie pharmaceutique. Le composé contre le virus de la grippe a la formule générale structurale suivante : (Formule1), m étant un nombre naturel quelconque choisi parmi 2 à 11, n étant un nombre naturel quelconque choisi parmi 3 à 12, X étant choisi parmi OCOO ou O et Y étant choisi parmi (formule2) ou (formule 3). Le composé contre le virus de la grippe selon la présente invention a une activité d'inhibition significative sur divers virus de la grippe, en particulier sur les virus de la grippe résistants au zanamivir (H3N2, E119V), améliore de manière remarquable la solubilité dans l'eau du médicament d'origine, a un coefficient de séparation lipide/eau des dizaines de fois supérieur à celui du médicament d'origine, et peut obtenir une préparation dans une préparation orale qui est une percée majeure dans les formes posologiques de médicament.
PCT/CN2020/105222 2020-03-12 2020-07-28 Composé contre le virus de la grippe, son procédé de préparation et son utilisation Ceased WO2021179512A1 (fr)

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CN111303235B (zh) * 2020-03-12 2021-08-13 中国科学院微生物研究所 一种抗流感病毒化合物及其制备方法与应用
CN114869896B (zh) * 2022-03-24 2023-10-13 中国科学院微生物研究所 胆固醇在修饰奥司他韦方面的用途及其抗流感病毒化合物与制备方法

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