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WO2020125673A1 - Inhibiteur de la réplication du virus de la grippe, intermédiaire correspondant et utilisation associée - Google Patents

Inhibiteur de la réplication du virus de la grippe, intermédiaire correspondant et utilisation associée Download PDF

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Publication number
WO2020125673A1
WO2020125673A1 PCT/CN2019/126277 CN2019126277W WO2020125673A1 WO 2020125673 A1 WO2020125673 A1 WO 2020125673A1 CN 2019126277 W CN2019126277 W CN 2019126277W WO 2020125673 A1 WO2020125673 A1 WO 2020125673A1
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WIPO (PCT)
Prior art keywords
compound
preparation
pyrrolo
amino
influenza
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Ceased
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PCT/CN2019/126277
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English (en)
Chinese (zh)
Inventor
李进
王利莎
王琳
杨民民
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Pharmablock Sciences Nanjing Inc
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Pharmablock Sciences Nanjing Inc
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Priority to CN201980062669.4A priority Critical patent/CN112771048B/zh
Publication of WO2020125673A1 publication Critical patent/WO2020125673A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems

Definitions

  • This application belongs to the field of chemical medicine, and specifically relates to an influenza virus replication inhibitor and its intermediates and uses.
  • Influenza is a respiratory disease caused by the Influenza virus.
  • influenza viruses can be divided into three types: A (A), B (B), and C (C).
  • A A
  • B B
  • C C
  • influenza A is the most common and highly pathogenic. It is prone to large-scale epidemics and seriously threatens human life and health.
  • vaccination and anti-influenza treatment are usually used: vaccination and anti-influenza treatment.
  • Vaccination is an effective measure to prevent influenza.
  • adults can achieve better preventive effects after vaccination, but infants, the elderly, and those with lower immunity are not ideal after vaccination.
  • influenza viruses are constantly mutating, making it difficult for old vaccines to fight new viruses.
  • Chemical drugs are another important means of treating influenza, but so far, the number of anti-influenza chemical drugs on the market is small, and the most used are M2 ion channel inhibitors, neuraminidase (NA) inhibitors and nucleoside antivirus drug.
  • M2 ion channel inhibitors M2 ion channel inhibitors
  • NA neuraminidase
  • influenza RNA polymerase has received widespread attention.
  • RdRp is a heterotrimer composed of three subunits of PA, PB1 and PB2, and plays an important role in the transcription and replication of influenza virus genome.
  • Influenza virus RNA transcription has a special "cap” mechanism.
  • the PB2 subunit is responsible for recognizing and binding the "cap structure" of the host precursor mRNA, and then the PA subunit cleaves the "cap” as a primer to initiate transcription process. Inhibiting "capping" can block the transcription process and achieve the effect of inhibiting the proliferation of influenza virus. Therefore, PB2 is regarded as a promising anti-influenza drug target, which has attracted great attention from pharmaceutical companies and academic research institutions.
  • Pimodivir the world's first drug candidate for influenza virus polymerase complex PB2 subunit inhibitor is Pimodivir. Johnson & Johnson obtained global drug development rights from Vertex Pharmaceuticals in 2014. The drug is currently in Phase III clinical trials. Tests have shown that Pimodivir can significantly reduce the viral load of patients compared to the placebo group. Its structure is as follows:
  • the present application discloses a class of compounds as inhibitors of influenza virus replication and their use in the preparation of drugs for the prevention or treatment of viral infectious diseases. Compared with existing compounds of the same type, the compounds of the present application show better resistance Viral activity.
  • the application provides compounds of formula (I), formula (II) or formula (III):
  • R 1 and R 2 are independently selected from hydrogen, C1-C6 alkyl, cyano, halogen, nitro or amino;
  • X is selected from C or N.
  • R 1 and R 2 are each independently selected from hydrogen, cyano, or halogen.
  • R 1 is selected from hydrogen, cyano, fluorine, or chlorine.
  • R 2 is selected from hydrogen, fluorine, or chlorine.
  • the present application relates to the following compounds and pharmaceutically acceptable salts, esters, solvates, polymorphs, prodrugs, stereoisomers or tautomers, but not limited to these compounds :
  • the present application provides the use of the compound for preparing a medicine for preventing or treating viral infectious diseases.
  • the viral infection is an influenza virus infection.
  • the viral infection is an influenza A virus infection.
  • R 1 is selected from hydrogen, C1-C6 alkyl, cyano, halogen, nitro or amino;
  • R 3 is selected from chlorine, bromine or iodine.
  • R 1 is selected from hydrogen, cyano, fluorine, chlorine, or bromine; R 3 is chlorine.
  • the compound of formula (IV), formula (V), or formula (VI) has the following structure:
  • FIG. 1 Survival diagram of mice treated with H1N1 Puerto Rico/8/34 virus 2 hours before infection;
  • FIG. 1 Survival map of mice treated with H1N1 Puerto Rico/8/34 virus 24 hours after infection.
  • DIPEA N,N-diisopropylethylamine
  • Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;
  • MgSO 4 magnesium sulfate
  • Zn(CN) 2 zinc cyanide
  • DPPF 1,1'-bis(diphenylphosphine)ferrocene
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium
  • K 3 PO 4 potassium phosphate
  • DMSO dimethyl sulfoxide
  • DMAC N,N-dimethylacetamide.
  • 2,4-Dichloropyrrolo[2,1-f][1,2,4]triazine (10.00g, 53.18mmol, 1.0eq.) and THF (100mL) were added to the reaction flask, and the temperature was lowered in an ice water bath.
  • DIPEA 13.75g, 106.4mmol, 2.0eq.
  • (2S, 3S)-3-aminobicyclo[2.2.2]octane-2-carboxylic acid was added to the above reaction system in portions Ethyl ester (12.59g, 63.82mmol, 1.2eq.), stirred at room temperature for 2 hours.
  • Compound 4 was prepared according to a similar method for synthesizing Compound 3 in Example 3, using 6-bromo-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine as a starting material.
  • reaction mixture was concentrated, tetrahydrofuran and methanol were removed, and the residue was diluted with water.
  • Compound 7 was prepared according to the preparation method similar to compound 1 in Example 1, with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)- 1H-Pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester was prepared as the starting material.
  • Compound 10 was prepared according to the preparation method similar to compound 7 in Example 7, with 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine as the starting material.
  • Compound 14 was prepared according to the preparation method similar to compound 1 in Example 1, starting with (1S, 2S, 3S, 4R)-3-aminobicyclo[2.2.2]oct-5-ene-2-carboxylic acid ethyl ester Made from raw materials.
  • Compound 15 was prepared according to the preparation method similar to compound 1 in Example 1, with 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine as the starting material.
  • Compound 16 was prepared similarly to compound 15 in Example 15, with (2S, 3S)-3-((2-chloro-5-fluoropyrrolo[2,1-f][1,2,4] Azin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid ethyl ester as the starting material.
  • the reaction mixture was concentrated to remove tetrahydrofuran and methanol, and the residue was diluted with water.
  • Test article Some compounds 1, 2, and 3 of this application.
  • MDCK cells were cultured in MEM medium containing 10% fetal bovine serum. Virus-infected cells were cultured in MEM medium containing 0.42% bovine serum albumin and 5 ⁇ g/mL trypsin. The day before the virus inoculation, MDCK cells were seeded onto 96-well cell culture plates at a density of 3 ⁇ 10 4 /well. On the next day, 50 PFU of influenza virus (influenza A/CA/07/2009) was added to 100 ⁇ L of MEM medium containing bovine serum albumin to infect MDCK cells, and incubated at 37°C for 1 hour.
  • influenza virus influenza A/CA/07/2009
  • the virus-infected cells were diluted twice with 100 ⁇ L of MEM medium, and incubated in medium containing different concentrations of test compounds (0-10 ⁇ M), and three replicate wells were set for each concentration. Three MDCK cell wells not infected by virus were used as control group. 20 ⁇ L of 0.15 mg/mL resazurin solution was added to each well of cells infected with virus for 72 hours and incubated for 4 hours. Fluorescence quantification experiments were carried out under 560nm excitation/590nm emission conditions. The MDCK cell protection rate is calculated according to the following formula. The EC 50 of the test compound to suppress influenza virus is obtained by transformation of the cell protection rate.
  • Test object some compounds of this application, the structural formula and preparation method are shown in the preparation examples of each compound.
  • MDCK of canine kidney cells was purchased from ATCC, catalog number CCL-34. The cells were cultured using EMEM (Sigma) medium supplemented with 10% fetal bovine serum (Hyclone), 1% double antibody (Hyclone), 1% L-glutamine (Gibco), and 1% non-essential amino acids (Gibco). OptiPRO SFM (Gibco) culture medium supplemented with 1% double antibody, 1% L-glutamine and 1% non-essential amino acids was used as the experimental culture medium. The culture medium for the experiment to which pancreatin (Invitrogen) was added was the culture medium for virus infection.
  • Influenza virus A/PR/8/34 (H1N1) strain was purchased from ATCC, catalog number VR-1469.
  • MDCK cells were seeded into 384-well test plates at a density of 2,000 cells per well and cultured in a 5% CO 2 , 37°C incubator overnight. The next day, compounds (8 concentration points, double wells) and virus were added to 384-well cell culture plates. The final concentrations of DMSO and pancreatin in the culture medium were 0.5% and 2.5 ⁇ g/mL, respectively. The cells were cultured in a 5% CO 2 and 37°C incubator for 5 days until the cytopathy of the compound-free virus control wells reached 80-95%. Cell counting kit 8 kit (Shanghai Li Ji) was used to detect cell viability. The antiviral activity of the compound is represented by the inhibition rate (%) of the compound at different concentrations on the virus-induced cytopathic effect. Calculated as follows:
  • Inhibition rate (%) (test well reading-average virus control value) / (average cell control value-average virus control value) x 100
  • DMSO N,N-dimethyl sulfoxide
  • Solutol HS15 Polyethylene glycol 15 hydroxystearate
  • mice Female BALB/c mice aged 6-8 weeks were selected to be infected with influenza A H1N1A/PuertoRico/8/34 virus by nasal drip.
  • the day of infection was set to the 0th day of the experimental cycle.
  • the oral administration of the test compound was started 2 hours before infection (PI-2) and 24 hours after infection (PI24), and the anti-influenza A virus H1N1 in vivo of the compound was evaluated by observing the survival rate and body weight changes of mice Medicine effect. The administration was continued for 10 days, and the observation period was 20 days. After 20 days, all surviving mice were euthanized.
  • test compound solutions were prepared in physiological saline containing 5% N,N-dimethyl sulfoxide (DMSO) and 10% polyethylene glycol 15 hydroxystearate (Solutol HS15).
  • DMSO N,N-dimethyl sulfoxide
  • Solutol HS15 polyethylene glycol 15 hydroxystearate
  • mice were placed in the anesthesia box, they were anesthetized with oxygen containing 5% v/v isoflurane (2.5 L/min). Under the condition of maintaining anesthesia with oxygen containing 2-2.5% isoflurane, they were slowly instilled into the nasal cavity 50 microliters of LD90 dose of H1N1 Puerto Rico/8/34 virus was used for infection.
  • oral administration was started two hours before infection and 24 hours after infection.
  • the positive control Pimodivir was administered twice daily in two different infection time experiments.
  • the test compound 17 was administered twice a day in the PI-2 experiment and once a day in the PI24 experiment.
  • the administered dose is shown in the results in Figures 1 and 2. Observe the state of mice every day and record body weight and survival rate. When the weight loss of the tested mice exceeded the standards stipulated by the animal welfare organization, the health index reached 6, severe drowsiness, and paralysis and other serious pathological conditions, euthanasia was carried out. At the end of the experiment, all surviving mice were euthanized.
  • mice All the three doses (1, 3, 10 mg/kg, BID) of compound 17 were used in the experiment under the condition of starting medication two hours before infection, and the survival rate of mice reached 100%.
  • the control compound Pimodivir has a survival rate of 0% at low doses (1 mg/kg, BID), and 80% at medium doses (3 mg/kg, BID), only at the highest dose (10 mg/kg, BID) to reach full survival.
  • the survival rate results, after all three doses of the compound 17 group were treated, there was no significant decrease in the body weight of the animals.
  • the control compound Pimodivir the low-dose group began to lose weight from day 4 and began to lose more than 20% of mouse weight on day 8.
  • the survival rate of compound 17 at low dose once-daily administration (1 mg/kg, QD) was 60%, medium-dose and high-dose once-daily administration (3,10 mg/kg, QD), the survival rate of mice reached 100%.
  • the control compound Pimodivir has a survival rate of 40% when administered at a low dose twice daily (1 mg/kg, BID), and 80% at a medium dose (3 mg/kg, BID), only at the highest dose condition (10mg/kg, BID) to achieve complete survival.
  • the currently approved oseltamivir has a survival rate of 80% at 10 mg/kg and a BID dose.
  • Compound 17 showed significantly superior anti-influenza A efficacy compared to the control compound Pimodivir at different administration times. In the case of administration 24 hours after infection, Compound 17 showed a similar drug effect when the total daily dose (3 mg/kg/Day) was much lower than Pimodivir (20 mg/kg/Day).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pulmonology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé qui peut être utilisé comme inhibiteur de la réplication du virus de la grippe, un intermédiaire permettant de préparer le composé, et une utilisation du composé dans la préparation d'un médicament pour la prévention ou le traitement de maladies infectieuses virales, en particulier d'une infection par le virus de la grippe A.
PCT/CN2019/126277 2018-12-19 2019-12-18 Inhibiteur de la réplication du virus de la grippe, intermédiaire correspondant et utilisation associée Ceased WO2020125673A1 (fr)

Priority Applications (1)

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CN201980062669.4A CN112771048B (zh) 2018-12-19 2019-12-18 流感病毒复制抑制剂及其中间体和用途

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CN201811556309 2018-12-19
CN201811556309.3 2018-12-19

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WO2020125673A1 true WO2020125673A1 (fr) 2020-06-25

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022007966A1 (fr) * 2020-07-10 2022-01-13 四川海思科制药有限公司 Inhibiteur de pb2, son procédé de préparation et son utilisation
CN115260105A (zh) * 2021-04-30 2022-11-01 启东东岳药业有限公司 一种芳杂氨基甲酸类化合物及其制备方法和用途
US12459951B2 (en) 2022-04-08 2025-11-04 Shy Therapeutics, Llc Compounds that interact with RAS superfamily proteins for treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017133664A1 (fr) * 2016-02-05 2017-08-10 Savira Pharmaceuticals Gmbh Dérivés bicycliques de pyridine et de pyrimidine et leur utilisation pour traiter ou prévenir la grippe, ou pour atténuer ses symptômes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017133664A1 (fr) * 2016-02-05 2017-08-10 Savira Pharmaceuticals Gmbh Dérivés bicycliques de pyridine et de pyrimidine et leur utilisation pour traiter ou prévenir la grippe, ou pour atténuer ses symptômes

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022007966A1 (fr) * 2020-07-10 2022-01-13 四川海思科制药有限公司 Inhibiteur de pb2, son procédé de préparation et son utilisation
CN115698011A (zh) * 2020-07-10 2023-02-03 四川海思科制药有限公司 Pb2抑制剂及其制备方法和用途
CN115698011B (zh) * 2020-07-10 2023-10-20 四川海思科制药有限公司 Pb2抑制剂及其制备方法和用途
CN115260105A (zh) * 2021-04-30 2022-11-01 启东东岳药业有限公司 一种芳杂氨基甲酸类化合物及其制备方法和用途
CN115260105B (zh) * 2021-04-30 2024-01-16 启东东岳药业有限公司 一种芳杂氨基甲酸类化合物及其制备方法和用途
US12459951B2 (en) 2022-04-08 2025-11-04 Shy Therapeutics, Llc Compounds that interact with RAS superfamily proteins for treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease

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CN112771048A (zh) 2021-05-07

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