WO2021164677A1 - Inhibiteur capable de résister à la fusion du virus respiratoire syncytial - Google Patents

Inhibiteur capable de résister à la fusion du virus respiratoire syncytial Download PDF

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Publication number
WO2021164677A1
WO2021164677A1 PCT/CN2021/076437 CN2021076437W WO2021164677A1 WO 2021164677 A1 WO2021164677 A1 WO 2021164677A1 CN 2021076437 W CN2021076437 W CN 2021076437W WO 2021164677 A1 WO2021164677 A1 WO 2021164677A1
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Prior art keywords
lys
cholesterol
glu
compound
rsv
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PCT/CN2021/076437
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English (en)
Chinese (zh)
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周述靓
王鹏
邓岚
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成都奥达生物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to an anti-syncytial virus membrane fusion inhibitor and its use.
  • RSV Human Respiratory Syncytial Virus
  • WHO World Health Organization
  • the invention provides a new anti-syncytial virus membrane fusion inhibitor and its use.
  • the present invention first provides a compound represented by structure I, a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex formed by the compound, and a drug based on the compound Precursor, or any mixture of the above forms.
  • AA1 is Ile, or Leu
  • AA3 is Gln, or Glu
  • AA10 is Gln or Glu
  • AA14 is Phe, or Lys
  • AA17 is Lys, or Glu
  • AA21 is Leu, or Lys
  • AA24 is Asn, or Glu
  • AA28 is Gly or Lys
  • AA29 is Lys, or Dap, or Orn, or Dab, or Dah;
  • AA30 means Cys, or does not exist
  • AA31 is NH 2 or OH.
  • R1 in structure I is H, or cholesterol succinate monoester, or 2-cholesterol acetic acid, or 2-cholesterol propionic acid, or 2-cholesterol butanoic acid, or 2-cholesterol isobutyrate, or It is 2-cholesterol valeric acid, or 2-cholesterol isovaleric acid, or 2-cholesterol hexanoic acid, HO 2 C(CH 2 ) n1 CO-( ⁇ Glu) n2 -(PEG n3 (CH2) n4 CO) n5- , Or CH 3 (CH 2 ) n1 CO-( ⁇ Glu) n2 -, or absent;
  • n1 is an integer from 10 to 20;
  • n2 is an integer from 1 to 5;
  • n3 is an integer from 1 to 30;
  • n4 is an integer from 1 to 5;
  • n5 is an integer from 1 to 5.
  • R2 in structure I is cholesterol acetate, or cholesterol propionate, or cholesterol butyrate, or cholesterol isobutyrate, or cholesterol valerate, or cholesterol isovalerate, or hexyl Cholesterol ester, or non-existent.
  • the present invention also provides a pharmaceutical composition comprising the compound according to the present invention, and the pharmaceutical composition provided with the compound of the present invention is used for preparing a medicine for the treatment of diseases.
  • the pharmaceutical composition is used in the preparation of a medicine for treating syncytial virus pneumonia.
  • any chemical structure within the scope described herein, whether part or the entire structure contains the above-mentioned similar structure includes all possible enantiomers and diastereomers of the compound, including A simple stereoisomer (such as a simple geometric isomer, a simple enantiomer or a simple diastereomer) and any mixture of these isomers.
  • the compounds of structural formula I include, but are not limited to, optical isomers, racemates and/or other mixtures of these compounds.
  • a single enantiomer or diastereomer, such as an optical isomer can be obtained by asymmetric synthesis or racemate resolution.
  • the resolution of racemates can be achieved by different methods, such as conventional recrystallization with reagents that assist resolution, or chromatographic methods.
  • the compounds of structural formula I also contain cis and/or trans isomers with double bonds.
  • the compounds of the present invention include, but are not limited to, the compounds represented by structural formula I and all of their pharmaceutically usable different forms.
  • the pharmaceutically usable different forms of these compounds include various pharmaceutically acceptable salts, solvates, complexes, chelates, non-covalent complexes, prodrugs based on the above-mentioned substances and the above-mentioned forms. Any mixture.
  • the above-mentioned prodrug includes the ester or amide derivative of the compound represented by structural formula I contained in the compound.
  • the compound shown in structure I provided by the present invention has stable properties, is a new type of anti-syncytial virus membrane fusion inhibitor, and can be used for the treatment of syncytial virus pneumonia.
  • Figure 1 shows the inhibitory activity on RSV-EGFP infected target cells
  • Figure 2 shows the inhibitory activity on RSV-Luc
  • FIG. 3 shows the effect on the weight change of RSV-infected mice
  • Figure 4 shows the in vivo imaging detection of RSV-infected mice
  • Figure 5 shows the statistical analysis of the fluorescence signal of the nasal cavity of RSV-infected mice
  • Figure 6 shows the statistical analysis of fluorescence signals in the lungs of RSV-infected mice
  • Figure 7 shows the quantitative analysis of RSV virus levels in the lungs of RSV-infected mice by RT-qPCR
  • Figure 8 shows the quantitative analysis of RSV replication ability in mouse lung tissue by enzyme-linked immunospot method.
  • the invention discloses an anti-syncytial virus membrane fusion inhibitor and its use. Those skilled in the art can learn from the content of this article and appropriately improve the relevant parameters to achieve it. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention.
  • the method of the present invention has been described through preferred embodiments, and the relevant personnel can obviously modify or appropriately change and combine the compounds and preparation methods described herein without departing from the content, spirit and scope of the present invention to achieve and Apply the technology of the present invention.
  • the preparation method includes: preparing the peptide resin by solid-phase peptide synthesis, then acid hydrolyzing the peptide resin to obtain the crude product, and finally the crude product is purified to obtain the pure product; wherein the step of preparing the peptide resin by the solid-phase peptide synthesis method is to solidify the peptide resin on the carrier resin.
  • the phase coupling synthesis method sequentially connects the corresponding protected amino acids or fragments in the following sequences to prepare peptide resins:
  • the amount of the Fmoc-protected amino acid or protected amino acid fragment is 1.2-6 times the total moles of the resin charged; preferably 2.5-3.5 times.
  • the substitution value of the carrier resin is 0.2-1.0 mmol/g resin, and the preferred substitution value is 0.3-0.5 mmol/g resin.
  • the solid-phase coupling synthesis method is: the protected amino acid-resin obtained in the previous step reaction removes the Fmoc protective group and then couples with the next protected amino acid.
  • the deprotection time for Fmoc protection is 10-60 minutes, preferably 15-25 minutes.
  • the coupling reaction time is 60-300 minutes, preferably 100-140 minutes.
  • the coupling reaction requires the addition of a condensation reagent, which is selected from DIC (N,N-diisopropylcarbodiimide), N,N-dicyclohexylcarbodiimide, and benzotriazole hexafluorophosphate -1-yl-oxytripyrrolidinyl phosphorus, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate , Benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate or O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoro
  • a condensation reagent which is selected from DIC (N,N-diisopropylcarbodiimide), N,N-dicyclohexylcarbodiimide, and benzotriazole hexaflu
  • the coupling reaction needs to add an activating reagent, and the activating reagent is selected from 1-hydroxybenzotriazole or N-hydroxy-7-azabenzotriazole, preferably 1-hydroxybenzotriazole.
  • the amount of the activating reagent is 1.2-6 times the total moles of amino groups in the amino resin, preferably 2.5-3.5 times.
  • the reagent for removing Fmoc protection is a PIP/DMF (piperidine/N,N-dimethylformamide) mixed solution, and the mixed solution contains 10-30% piperidine (V ).
  • the amount of the de-Fmoc protection reagent is 5-15 mL per gram of amino resin, preferably 8-12 mL per gram of amino resin.
  • the peptide resin undergoes acid hydrolysis to simultaneously remove the resin and side chain protecting groups to obtain a crude product:
  • the acid hydrolyzing agent used in the acid hydrolysis of the peptide resin is a mixed solvent of trifluoroacetic acid (TFA), 1,2-ethanedithiol (EDT) and water, and the volume ratio of the mixed solvent is: TFA It is 80-95%, EDT is 1-10%, and the balance is water.
  • the volume ratio of the mixed solvent is as follows: TFA is 89% to 91%, EDT is 4% to 6%, and the balance is water. Optimally, the volume ratio of the mixed solvent is: TFA is 90%, EDT is 5%, and the balance is water.
  • the dosage of the acid hydrolyzing agent is 4-15 mL of acid hydrolyzing agent per gram of peptide resin; preferably, 7-10 mL of acid hydrolyzing agent is required per gram of peptide resin.
  • the cleavage time using an acid hydrolyzing agent is 1 to 6 hours at room temperature, preferably 3 to 4 hours.
  • the crude product is purified by high performance liquid chromatography and freeze-dried to obtain the pure product.
  • the specific method is as follows:
  • Purification was carried out by high performance liquid chromatography.
  • the chromatographic packing used for purification was 10 ⁇ m reversed-phase C18, the mobile phase system was 0.1% TFA/water solution-0.1% TFA/acetonitrile solution, and the flow rate of 77mm*250mm chromatographic column was 90mL/min.
  • Gradient system elution, cyclic injection purification take the crude solution and load it on the chromatographic column, start the mobile phase elution, collect the main peak and evaporate the acetonitrile to obtain the purified intermediate concentrate;
  • High performance liquid chromatography was used for salt exchange, the mobile phase system was 1% acetic acid/water-acetonitrile, the chromatographic packing used for purification was 10 ⁇ m reversed-phase C18, the flow rate of 77mm*250mm column was 90mL/min (according to different specifications Chromatographic column, adjust the corresponding flow rate); Adopt gradient elution, cyclic loading method, load the sample on the chromatographic column, start the mobile phase elution, collect the spectrum, observe the change of absorbance, collect the main peak of salt change and use the analytical liquid to detect For purity, combine the salt-changing main peak solutions, concentrate under reduced pressure to obtain pure aqueous acetic acid solution, and obtain pure product after freeze-drying.
  • Rink Amide BHHA resin as the carrier resin, through de-Fmoc protection and coupling reactions, sequentially coupled with the protected amino acids shown in the table below to prepare peptide resins.
  • the protected amino acids corresponding to the protected amino acids used in this example are as follows:
  • the activated first protected amino acid solution is added to the Fmoc-free resin, the coupling reaction is 60-300 minutes, and the resin is filtered and washed to obtain a resin containing 1 protected amino acid.
  • the purified intermediate concentrate was filtered with a 0.45 ⁇ m filter membrane for use, and the salt was replaced by high performance liquid chromatography.
  • the mobile phase system was 1% acetic acid/water solution-acetonitrile, and the purification chromatographic packing was 10 ⁇ m reversed-phase C18, 30mm*250mm
  • the flow rate of the chromatographic column is 20mL/min (the corresponding flow rate can be adjusted according to the different specifications of the chromatographic column); the gradient elution is adopted, and the cyclic loading method is adopted. For the change of absorbance, collect the main peak of salt exchange and check the purity with the analytical liquid phase.
  • the preparation method is the same as in Example 1.
  • the protected amino acids used are as follows:
  • the pure product was 6.5 g, the purity was 96.9%, and the total yield was 16.4%.
  • the molecular weight is 3971.6 (100% M+H).
  • the peptide resin is prepared by coupling with the protected amino acids shown in the following table in sequence.
  • the protected amino acids corresponding to the protected amino acids used in this example are as follows:
  • the activated first protected amino acid solution is added to the Fmoc-free resin, the coupling reaction is 60-300 minutes, and the resin is filtered and washed to obtain a resin containing 1 protected amino acid.
  • the preparation method is the same as in Example 5.
  • the protected amino acids used are as follows:
  • the preparation method is the same as in Example 5.
  • the protected amino acids used are as follows:
  • the pure product was 6.6 g, the purity was 97.2%, and the total yield was 15.9%.
  • the molecular weight is 4157.8 (100% M+H).
  • HEp-2 cells at a seeding density of 2 ⁇ 10 4 cells/well. After culturing for 24 hours, the peptides were serially diluted by 3 times and mixed with 3000PFU of RSV-EGFP respectively. After incubating for 5 minutes at 37°C under 5% CO2, the above mixture was added to a 96-well plate containing HEp-2 cells. Continue to incubate at 37°C for 48 hours. Uninfected HEp-2 cells were used as cell negative controls, and virus-infected wells without drug treatment were used as positive controls.
  • a multifunctional microplate reader was used to detect the fluorescence intensity at an excitation wavelength of 479nm and an emission wavelength of 517nm, and GraphPad was used to calculate the relative inhibition rate of virus infection and IC50 value.
  • the experimental results are shown in the following table and Figure 1.
  • the antiviral activity of the new RSV fusion inhibitor was further evaluated using RSV virus (RSV-luc) based on the luciferase reporter gene marker.
  • the peptide drugs were diluted in a 3-fold gradient in a 96-well plate, with 3 replicate wells for each peptide, 9 dilution gradients, and a final volume of 50 ⁇ L/well. Then, 50 ⁇ L (100TCID 50 )RSV was added to the 96-well plate containing the peptide drugs. -luc virus solution, incubate at room temperature for 1h. Prepare a Hep-2 cell suspension with a concentration of 10 ⁇ 10 4 /mL with DMEM medium, mix well and add to the above 96-well plate, 100 ⁇ L/well.
  • the antiviral activity was determined using a mouse animal model.
  • mice 8-week-old SFP female BALB/c mice (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were used for pharmaceutical evaluation.
  • the experiment set up PBS treatment control group, RSV infection control group, SV29 treatment group and SV29-Chol treatment Group. Each group of 4-6. Under anesthesia with avertin (250mg/Kg), 50 ⁇ l of a polypeptide PBS solution with a concentration of 50 ⁇ M was first administered by nasal drops, 15 minutes later, RSV-Luc virus (5 x 10 4 PFU) infection was administered via the nasal route. The changes in the weight of the mice were tested every day.
  • Lumina II Small Animal Live Imaging System (Lumina II Small Animal Live Imaging System) was used to detect the virus infection, and the mouse live imaging was performed 10 minutes after the injection of 50 ⁇ l of fluorescein substrate D-Luciferin (7.5 mg/ml; PBS). Five days after infection, the mice were euthanized, the lung tissues were weighed, milled, and total RNA was extracted to quantitatively detect RSV infection in lung tissues using RT-qPCR method.
  • the PCR primers used are designed and synthesized in reference 4.
  • Enzyme-linked immunospot method to detect the amount of virus in mouse lung tissue HEp-2 cells were inoculated in a 96-well plate, 2 ⁇ 104 cells/well; mouse lung tissue was weighed and ground (0.1g lung tissue/0.1ml PBS(0.1 %BSA)), centrifuge at 10,000 ⁇ g at 4°C for 5min to separate the supernatant; serially dilute and add to the above 96-well plate, 3 replicates/dilution, negative control well cells only add maintenance solution, and incubate at 37°C for 1h Then discard the culture medium, add 1% methylcellulose, 100 ⁇ l/well; continue to culture at 37°C for 3 days, fix and block, add goat anti-human RSV polyclonal antibody (1:500 dilution), HRP-labeled rabbit anti-goat antibody ( 1: 5 000 dilution), TMB color development, count the number of virus spots under an inverted microscope.
  • mice Compared with the PBS-treated control mice, the body weight of the mice began to decrease 1 day after RSV infection, and the most decreased 2 days after infection. SV29 and SV29-Chol were administered intranasally according to the above method, and the results did not significantly affect the body weight of the mice. The result is shown in Figure 3.
  • the results of the detection using the small animal in vivo imaging system showed that there was no fluorescence signal in the PBS treatment group, and the RSV infected persons could see obvious fluorescence signals on day 1-5, which were distributed in the nasal cavity and the mouse. Lungs.
  • RSV was significantly reduced in the nasal cavity from the untreated RSV control group 1 to 4 days after treatment, especially during the peak period of virus replication on the second day.
  • the results showed that the RSV signal in the SV29 treatment group decreased, but the decrease in the SV29-Chol treatment group was not significant.

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Abstract

L'invention concerne un inhibiteur capable de résister à la fusion du virus respiratoire syncytial (VRS) et tombant dans le domaine de la synthèse pharmaceutique. L'inhibiteur capable de résister à la fusion du virus respiratoire syncytial fourni par la présente invention peut être utilisé pour traiter des maladies, telles que la pneumonie à virus respiratoire syncytial.
PCT/CN2021/076437 2020-02-21 2021-02-10 Inhibiteur capable de résister à la fusion du virus respiratoire syncytial WO2021164677A1 (fr)

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CN202010108065.3A CN111303245B (zh) 2020-02-21 2020-02-21 一种抗合胞病毒膜融合抑制剂
CN202010108065.3 2020-02-21

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CN111303245B (zh) * 2020-02-21 2023-06-27 成都奥达生物科技有限公司 一种抗合胞病毒膜融合抑制剂
CN112625094B (zh) * 2021-01-19 2023-09-26 成都奥达生物科技有限公司 一种广谱冠状病毒膜融合抑制剂及其药物用途

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