WO2022116981A1 - 一种聚阴离子纤维二糖苷类化合物的应用 - Google Patents

一种聚阴离子纤维二糖苷类化合物的应用 Download PDF

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WO2022116981A1
WO2022116981A1 PCT/CN2021/134613 CN2021134613W WO2022116981A1 WO 2022116981 A1 WO2022116981 A1 WO 2022116981A1 CN 2021134613 W CN2021134613 W CN 2021134613W WO 2022116981 A1 WO2022116981 A1 WO 2022116981A1
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acute respiratory
respiratory distress
distress syndrome
caused
application
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PCT/CN2021/134613
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English (en)
French (fr)
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王勇
李宁
章津
徐航
罗军杰
郑宇铎
帕里什克里斯托弗
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远大医药（中国）有限公司
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Priority to CN202180080201.5A priority Critical patent/CN116829157A/zh
Publication of WO2022116981A1 publication Critical patent/WO2022116981A1/zh

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to the application of a polyanionic cellobioside compound.
  • coronavirus pneumonia (Corona Virus Disease 2019) is a new acute respiratory infectious disease caused by SARS-CoV-2 (also known as 2019-nCoV). Infection, with more than 4 million deaths, has now become a major global public health event, with a significant impact on the world.
  • 2019 new coronavirus-infected pneumonia can be divided into light, ordinary, severe and critical types according to the severity of the disease.
  • the mild clinical symptoms are mild, only manifested as low-grade fever, mild fatigue, etc., without pneumonia.
  • the common type has symptoms such as fever and respiratory tract (cough, sore throat, nasal congestion, shortness of breath, fatigue, etc.), and pneumonia can be seen on imaging. Severe cases show dyspnea, shortness of breath, hypoxemia, lethargy, and convulsions; severe cases can rapidly progress to acute respiratory distress syndrome, sepsis, septic shock, multiple organ failure, and even death.
  • the technical problem to be solved by the present invention is that the existing medicines for the treatment of acute respiratory distress syndrome and novel coronavirus pneumonia have a single structure. Therefore, the present invention provides the application of a polyanionic cellobioside compound. Such compounds are not only safe, but can also significantly improve the related diseases or conditions caused by 2019-nCoV infection, and can also achieve therapeutic effects on acute respiratory distress syndrome caused by other causes.
  • the first aspect of the present invention provides a compound of formula II (1-O-methyl 2,2',3,3',4',6,6'-hepta-O-sulfonyl- ⁇ -cellobioside hepta Sodium salt) in the preparation of medicines for the treatment of related diseases or conditions caused by 2019-nCoV infection;
  • the "2019-nCoV” mentioned in the present invention refers to the 2019 new coronavirus named by the World Health Organization, also known as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).
  • the 2019-nCoV described in the present invention includes various strains, such as all strains included in NCBI or GISAID (Global Initiative for Shared Influenza Data), especially important variants with strong transmissibility, pathogenicity or immune escape. strains, such as WHO-designated Alpha, Beta, Gamma, Delta, Eta, Iota, Kappa, Lambda or Omicron variants, and subsequently designated important variants.
  • the related diseases or conditions caused by 2019-nCoV infection described in the present invention include but are not limited to: pneumonia, organ damage, respiratory distress, hypoxemia, thrombosis and embolism, microcirculation disorders, acute respiratory distress syndrome, acute respiratory distress syndrome One or more of failure, sepsis, septic shock, multiple organ failure, fever, respiratory symptoms (cough, sore throat, nasal congestion, shortness of breath, fatigue, etc.), dyspnea, lethargy and convulsions; Preferably, wherein the pneumonia is COVID-19, more preferably severe or critical COVID-19.
  • the acute respiratory distress syndrome may be lipopolysaccharide-induced acute respiratory distress syndrome.
  • COVID-19 refers to pneumonia caused by 2019-nCoV infection.
  • Organ damage includes, but is not limited to, one or more of lung damage, kidney damage, myocardial damage, and liver damage.
  • the lung damage may include: lung capillary endothelial cell damage and/or alveolar epithelial cell damage.
  • the pathological basis of acute respiratory distress syndrome is diffuse alveolar damage, which is characterized by extensive damage to capillary endothelial cells in lung tissue caused by inflammation, resulting in increased capillary exudation; and damage to alveolar epithelial cells, leading to lung ventilation.
  • Increased permeability, filling of alveoli and interstitium with protein-rich pulmonary edema fluid, hyaline membrane formation, and infiltration of inflammatory cells results in a severe imbalance of ventilation/blood ratio.
  • the clinical manifestations of acute respiratory distress syndrome are respiratory distress and refractory hypoxemia, and the lung imaging manifestations are heterogeneous exudative lesions. It is generally believed that the early stage of the disease is acute lung injury, moderate or severe called acute respiratory distress syndrome.
  • Sepsis generally refers to the body's overactive systemic inflammatory response to infection (such as 2019-nCoV), resulting in life-threatening multiple organ dysfunction, which can further develop into septic shock and multiple organ failure;
  • Organ failure includes, but is not limited to: pulmonary failure, renal failure and liver failure.
  • the second aspect of the present invention also provides the application of a pharmaceutical composition in the preparation of medicine
  • the pharmaceutical composition comprises the compound of formula II (1-O-methyl 2,2',3,3',4',6,6'-hepta-O-sulfonyl- ⁇ -cellobioside hepta-sodium salt ) and pharmaceutically acceptable excipients;
  • the drug is a drug for treating related diseases or conditions caused by 2019-nCoV infection.
  • 2019-nCoV infection diseases or conditions caused by the 2019-nCoV infection are as described above, such as severe or critical COVID-19, or acute respiratory distress syndrome caused by lipopolysaccharide.
  • compositions can be formulated for administration in solid or liquid form, including but not limited to: injection (eg, subcutaneous, intramuscular, intravenous or epidural), mucosal, transdermal or topical administration , nasal or oral inhalation administration and ocular administration.
  • pharmaceutically acceptable adjuvants include but are not limited to: diluents, fillers, disintegrants, wetting agents, lubricants, pH adjusters, buffers, colorants, flavoring agents, preservatives or other conventional additives.
  • the pharmaceutical composition may be an injectable pharmaceutical composition.
  • the pharmaceutical composition for injection can be prepared in the form of a powder or a concentrated solution (a person in the art understands that the powder and the concentrated solution are generally sterile), and the powder or the concentrated solution can be dissolved or dissolved during use. Disperse in a pharmaceutically acceptable carrier for clinical use.
  • the pharmaceutically acceptable carrier can be a solvent or dispersion medium including, but not limited to, water, Ringer's solution, isotonic saline, phosphate buffered saline, ethanol or polyol and the like.
  • the pH of the concentrated solution is about 7.0-8.0, further 7.4-7.6, and further 7.5
  • the pH can be adjusted by adding a buffer
  • the buffer can be selected from phosphates buffer, citrate buffer and acetate buffer.
  • the concentration of the compound of formula II in the concentrated solution may be 50-500 mg/mL, further 60-100 mg/mL, preferably 65-85 mg/mL, more preferably At 68-80 mg/ml (eg, 70 mg/ml), it can be administered by intravenous infusion after dilution according to a clinical protocol, which can be diluted with the following reagents: water, Ringer's solution, isotonic saline, and the like.
  • the infusion rate of the concentrated solution can be 15-120 mg/hr, preferably 20-90 mg/hr, for example: 25 mg/hr, 30 mg, when the concentrated solution is used clinically (ie, the solution after the concentrated solution is diluted).
  • the infusion time can be 1-120hr, for example: 2hr, 4hr, 6hr, 8hr, 10hr, 12hr, 24hr, 36hr, 48hr, 60hr, 72hr, 84hr, 96hr, 108hr, etc.
  • the numerical value includes the median of all point values.
  • the pharmaceutical composition may be administered directly to the airway of a subject in the form of an aerosol or by nebulization.
  • solutions or suspensions of the pharmaceutically acceptable compositions of the present invention may be packaged in pressurized aerosols together with suitable propellants, for example hydrocarbon propellants such as propane, butane or isobutane, and conventional adjuvants in the container.
  • suitable propellants for example hydrocarbon propellants such as propane, butane or isobutane, and conventional adjuvants in the container.
  • Such compositions may also be administered in non-pressurized form, eg, in a nebulizer or nebulizer.
  • the third aspect of the present invention also provides a compound of formula II (1-O-methyl 2,2',3,3',4',6,6'-hepta-O-sulfonyl- ⁇ -cellobioside
  • hepta sodium salt in the preparation of the medicine for the treatment of acute respiratory distress syndrome or acute respiratory failure
  • the acute respiratory distress syndrome may be acute respiratory distress syndrome caused by infection or acute respiratory distress syndrome caused by lipopolysaccharide, or acute respiratory distress syndrome caused by 2019-nCoV infection.
  • the fourth aspect of the present invention also provides a method for treating the above-mentioned related diseases or conditions caused by 2019-nCoV infection, which comprises administering to a patient a therapeutically effective amount of the compound of formula II (1-O-methyl 2,2' ,3,3',4',6,6'-hepta-O-sulfonyl- ⁇ -cellobioside hepta-sodium salt);
  • the related diseases or conditions caused by the 2019-nCoV infection are such as COVID-19, and another example is severe or critical COVID-19.
  • the related diseases or conditions caused by the 2019-nCoV infection are such as acute respiratory distress syndrome or acute respiratory failure, and for example, acute respiratory distress syndrome caused by lipopolysaccharide.
  • the infusion rate can be 15-120 mg/hr, preferably 20-90 mg/hr, for example: 25 mg/hr, 30 mg/hr, 35 mg/hr, 40 mg/hr, 45 mg/hr hr, 50mg/hr, 55mg/hr, 58.3mg/hr, 60mg/hr, 65mg/hr, 70mg/hr, 75mg/hr, 80mg/hr, 87.5mg/hr, or 90mg/hr; infusion time can be 1 -120hr, for example: 2hr, 4hr, 6hr, 8hr, 10hr, 12hr, 24hr, 36hr, 48hr, 60hr, 72hr, 84hr, 96hr, 108hr, etc.
  • the numerical value includes the median of all point values.
  • a fifth aspect of the present invention also provides a method for treating acute respiratory distress syndrome or acute respiratory failure, comprising administering to a patient a therapeutically effective amount of the compound of formula II (1-O-methyl 2,2',3,3' ,4',6,6'-hepta-O-sulfonyl- ⁇ -cellobioside hepta-sodium salt);
  • the acute respiratory distress syndrome may be acute respiratory distress syndrome caused by infection or acute respiratory distress syndrome caused by lipopolysaccharide, or acute respiratory distress syndrome caused by 2019-nCoV infection.
  • ARDS Acute Respiratory Distress Syndrome
  • acute respiratory distress syndrome There are many causes of acute respiratory distress syndrome, which can be divided into pulmonary causes: bacterial or viral pneumonia (including coronavirus pneumonia), gastric contents aspiration, pulmonary contusion, toxic inhalation, drowning, etc., and extrapulmonary causes : sepsis, pancreatitis, severe trauma, massive blood transfusion and burns, etc., but their common pathological basis is diffuse alveolar injury, and the clinical manifestations are mainly characterized by progressive respiratory distress and refractory hypoxemia.
  • Pathological studies of acute respiratory distress syndrome have long found that there are a large number of proteins and a variety of inflammatory cells in the edema fluid accumulated in the alveoli and pulmonary interstitium, among which neutrophils are the main ones.
  • the acute respiratory distress syndrome is acute respiratory distress syndrome caused by infection or non-infection;
  • the infection includes but is not limited to viral, bacterial, fungal, mycoplasma or chlamydia infection.
  • the bacteria include, but are not limited to, Streptococcus pneumoniae, Staphylococcus or Klebsiella pneumoniae.
  • viruses include, but are not limited to, influenza, parainfluenza, or coronaviruses (eg, 2019-nCoV).
  • Said fungi include but are not limited to Aspergillus actinomycetes.
  • the present invention further provides a method for treating acute respiratory distress syndrome, comprising administering to a patient a therapeutically effective amount of the polyanionic cellobioside compound represented by formula II.
  • the infusion rate can be 15-120 mg/hr, preferably 20-90 mg/hr, for example: 25 mg/hr, 30 mg/hr, 35 mg/hr, 40 mg/hr, 45 mg/hr hr, 50mg/hr, 55mg/hr, 58.3mg/hr, 60mg/hr, 65mg/hr, 70mg/hr, 75mg/hr, 80mg/hr, 87.5mg/hr, or 90mg/hr; infusion time can be 1 -120hr, for example: 2hr, 4hr, 6hr, 8hr, 10hr, 12hr, 24hr, 36hr, 48hr, 60hr
  • C 1-6 alkyl means a straight or branched chain alkyl group having the specified number of carbon atoms (eg one, two, three, four, five or six carbon atoms), eg methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, 2-methylbutyl, 1-methylbutyl , 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methyl Pentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl butyl, 2,3-dimethylbut
  • therapeutically effective amount refers to an amount of a compound administered to a patient sufficient to be effective in treating a disease.
  • the therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted as appropriate by those skilled in the art.
  • treating refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that causes the disease; (3) slowing the disease development of one or more biological manifestations.
  • patient refers to any animal, preferably a mammal, most preferably a human, who has been or is about to undergo treatment. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive improvement effect of the present invention is that the compound of formula II of the present invention is not only safe, but also can significantly improve the related diseases or symptoms caused by 2019-nCoV infection, and can also achieve therapeutic effects on acute respiratory distress syndrome caused by other reasons.
  • Figure 1 shows the effect of the compound of formula II on the degree of inflammatory lesions in the lung tissue of acute respiratory distress syndrome model rats.
  • Age at the start of modeling 6 to 8 weeks old.
  • Animal grouping 56 qualified male animals were randomly divided into normal control group, model control group, low-dose group, medium-dose group, and high-dose group according to the body weight measured before grouping. Dosage group; 8 in normal control group, and 12 in other groups.
  • Test batches This test was carried out in two batches. The first batch is the first half of the animals in each group, and the second batch is the last half of the animals in each group. The model construction, administration, and index detection of each batch of animals are consistent.
  • D0 animals in each group were extracted with modeling reagents (lipopolysaccharide, LPS) according to their body weight, and lipopolysaccharide (0.8 mg/kg, 400 ⁇ L/kg) was administered by intraperitoneal injection.
  • LPS lipopolysaccharide
  • D1 16h ( ⁇ 30min) after intraperitoneal injection, isoflurane inhalation anesthesia, and lipopolysaccharide (5mg/kg, 1000 ⁇ L/kg) was administered to animals in each group by intratracheal aerosolization.
  • LPS lipopolysaccharide
  • Intra-airway aerosolized lipopolysaccharide the animal is anesthetized by isoflurane inhalation, and then fixed on a rat immobilizer placed at 45°, using a small animal anesthesia laryngoscope, pressing the base of the animal's tongue, exposing the glottis, and extracting the The pulmonary micro-liquid nebulizer needle (blunt) for the quantitative lipopolysaccharide (LPS) solution is gently inserted into the trachea, then the plunger is quickly pushed to nebulize the LPS solution into the lung, and the needle is quickly withdrawn and removed from the holder.
  • LPS Intra-airway aerosolized lipopolysaccharide
  • the volume of lipopolysaccharide administered is kept to one decimal place. When the volume of lipopolysaccharide is between the two graduated volume lines, it is drawn according to the upper graduation value.
  • test article After the animal model was constructed, the test article and the reference substance were administered according to the following table. See the table below for details:
  • the test substance is the compound of formula II (1-O-methyl 2,2',3,3',4',6,6'-hepta-O-sulfonyl- ⁇ -cellobioside hepta-sodium salt),
  • the compound of formula II is configured as a 70 mg/mL stock solution (the solvent is a phosphate buffer at pH 7.5), and before administration, the 70 mg/mL stock solution is diluted into 1 mg/mL, 5 mg/mL, 20mg/mL of the test solution.
  • the normal control group and the model control group were given sodium chloride injection by intravenous injection.
  • Administration route Group 1 to Group 5: tail vein injection.
  • Dosing frequency and time Group 1 to Group 5: D1, D2: 9:00-10:30 am, 13:00-14:30, 16:00-17:30; D3 (2 administrations): morning 8:30 ⁇ 10:00, 11:00 ⁇ 12:30.
  • Rats were anesthetized by intraperitoneal injection of chloral hydrate (350 mg/kg, 100 mg/mL), the abdominal midline was incised longitudinally, the abdominal aorta was separated, and about 0.5 mL of arterial blood was collected using an arterial blood collection device, which was rubbed in the palm of the hand. Activate the syringe and turn it upside down for 5 seconds each. None return the blood collection device for blood mixing.
  • Detection method After the arterial blood is collected, gently insert the needle into the blood injection port of the test card, slowly push the blood in, and fill the sample filling tube. The blood will automatically enter the test tube, insert the test card into the blood gas analyzer, and wait for the test result.
  • Detection indicators PO2 (mmHg), PCO2 (mmHg), pH, sO2%.
  • Sample collection After the animals were euthanized, the skin and tissues of the neck and chest were cut to expose the trachea, bronchi and lungs, and the right lung bronchus was isolated and ligated. Pass suture under the trachea, and make a 1/2 incision between the tracheal cartilage rings at an appropriate position under the thyroid cartilage. Slowly insert the tracheal cannula into the airway along the incision to the left bronchus. The cannula and the trachea were fastened at the appropriate part of the incision in the centripetal direction.
  • BALF treatment keep 2 mL of the collected lavage fluid for each animal (the excess part is treated as medical waste), and centrifuge for 10 min at 4°C and about 2000 rpm. The supernatant was divided into 2 tubes, all of which were stored below -70°C for later use (send to the client after the test or processed in other ways). The pellet was resuspended in 1 mL of PBS buffer for total and differential counting of leukocytes.
  • Detection of histone concentration in lavage fluid At the end of the test, the supernatant of lung lavage fluid was tested for histone concentration in lung lavage fluid according to the steps required by the kit.
  • White blood cell classification detection The resuspended lung lavage fluid is used for white blood cell count and classification using an automatic blood cell analyzer.
  • the blood, tissue fluid and other foreign bodies on the surface of the right lung middle lobe tissue were wiped clean with paper towels and weighed. Then the right lung middle lobe tissue was placed in an oven at 60°C for 72 hours and weighed again to calculate the wet/dry weight ratio.
  • Data collection Data is collected by means of system generation and manual recording.
  • Modeling conditions Pathological changes such as alveolar cavity, blood vessels, alveolar wall inflammatory cell infiltration/alveolar wall septum thickening, and intra-alveolar hemorrhage (with or without hemoglobin crystals) in the model control group were observed under the microscope; the pulmonary perfusion of the model control group was During washing, WBC, Neut and histone increased from 0.32 ⁇ 0.22, 0.04 ⁇ 0.02, 0.039 ⁇ 0.012 in normal control group to 9.41 ⁇ 2.01, 5.17 ⁇ 1.90, 0.835 ⁇ 0.380, respectively; lung wet-dry ratio was increased from 1.17 ⁇ 0.09 in normal control group increased to 2.26 ⁇ 0.51; PO2 and sO2% decreased from 103.3 ⁇ 5.9 and 98.4 ⁇ 0.5 in the normal control group to 77.5 ⁇ 11.4 and 95.3 ⁇ 2.5, respectively; and the above indicators were all statistically different.
  • the model of acute respiratory distress syndrome was successfully constructed by intraperitoneal injection combined with intra-airway aerosol administration of the modeling rea
  • Detection of lung lavage fluid the total number of leukocytes and the average value of classification indexes in the lung lavage fluid of the low-dose, medium-dose and high-dose groups of the test product were reduced to (2.88 ⁇ 2.01) compared with the mean value of WBC index in the model control group (9.41 ⁇ 2.01). 1.50), (0.91 ⁇ 0.45) and (0.59 ⁇ 0.49); compared with the mean value of Neut index in the model control group (5.17 ⁇ 1.90), they were reduced to (1.45 ⁇ 1.13), (0.50 ⁇ 0.43) and (0.30 ⁇ 0.26) respectively; The mean values of Lymph and Mono indexes were also significantly lower; and they were all statistically different.
  • Table 2 The data are detailed in the attached table: Table 2.
  • Blood gas analysis and detection The mean values of corresponding blood gas analysis indexes of the animals in the low, medium and high dose groups of the test product were increased to (88.4 ⁇ 8.6), (90.3 ⁇ 6.4) compared with the mean value of PO2 index in the model control group (77.5 ⁇ 11.4). ) and (92.3 ⁇ 9.2), which were increased to (97.2 ⁇ 1.1), (97.4 ⁇ 0.8) and (97.3 ⁇ 1.2) respectively compared with the mean value of sO2% in the model control group (95.3 ⁇ 2.5). There were no statistical differences in PCO2 and pH. For details, please refer to the attached table: Table 3.
  • Histone detection Compared with the mean value of histone index of the animals in the low, medium and high dose groups of the test product, compared with the mean value of histone index in the lung lavage fluid of the model control group (0.835 ⁇ 0.380), they were reduced to (0.686 ⁇ 0.452), ( 0.415 ⁇ 0.445) and (0.449 ⁇ 0.606), and there was a statistical difference between the medium and high dose groups of the test product; compared with the mean value of arterial plasma histones in the model control group (0.164 ⁇ 0.093), they were reduced to (0.126 ⁇ 0.039) respectively ), (0.117 ⁇ 0.062) and (0.091 ⁇ 0.035), and the high-dose group of the test product had a statistical difference; compared with the mean value of venous plasma histone indexes in the model control group (0.074 ⁇ 0.019), they were reduced to (0.073 ⁇ 0.046) ), (0.057 ⁇ 0.008) and (0.049 ⁇ 0.009), and there were statistical differences between the medium and high dose groups of the test product.
  • the data are detailed
  • Lung wet-dry ratio detection Compared with the model control group (2.26 ⁇ 0.51), the mean values of the lung wet-dry ratio of the animals in the low, medium and high dose groups of the test product were decreased to (1.97 ⁇ 0.33) and (1.85 ⁇ 0.20) respectively. and (1.61 ⁇ 0.43), and there were statistical differences between the medium and high dose groups of the test article.
  • Table 5 For details, please refer to the attached table: Table 5.
  • Pathological detection During this experiment, lung inflammation was observed in all model animals, and the main manifestations of inflammation were: inflammatory cells dominated by neutrophils (alveolar cavity, blood vessels, alveolar wall), thickening of alveolar wall septum, and intra-alveolar hemorrhage. (with or without hemoglobin crystals). The degree of inflammation in the animals in the administration group was significantly lower than that in the model control group, indicating that the test article reduced the degree of inflammation, and there was a dose relationship between the animals in each administration group. The data are shown in the accompanying drawings: Figure 1 (1. No pathological changes were found in the lung histopathological examination of the normal control group animals, so they were not shown in the figure; 2.
  • the number of lung lobes for pathological examination in each group the number of animals in each group ( 12) ⁇ number of lung lobes in each animal (3 lobes: right upper lobe, right lower lobe and accessory lobe), 36 lobes in each group).
  • This study is a randomized, open-label, multicenter clinical study to evaluate the safety and efficacy of a continuous infusion formulation of the compound of formula II in patients with severe COVID-19 pneumonia.
  • Subjects will be randomized 2:2:1 into three cohorts to receive a continuous infusion of a compound of formula II at 58.3 mg/hour or 87.5 mg/hour for 3 days (72 hours), or the appropriate standard Nursing (placebo is 0.9% Sodium Chloride Injection). All subjects in the formula II compound treatment group will also receive standard of care as background therapy.
  • the compound of formula II is formulated into a sterile concentrated solution (70 mg/mL, the solvent is phosphate buffered saline at pH 7.5), packed in a 10 mL glass bottle equipped with a rubber stopper and a sealed cap, and stored under refrigeration at 2°C-8°C. Before use, it is diluted with normal saline for injection and administered by intravenous infusion after preparation according to the clinical protocol.
  • the placebo of this study is 0.9% sodium chloride injection, which is provided in the form of an independent glass vial with the same label, each 10mL, and the storage conditions are the same as those of the study drug, and they are all refrigerated at 2°C-8°C. Placebos must be administered according to the same procedures and guidelines as for compounds of formula II.
  • index detections are all routine detections in the art, and those skilled in the art know how to obtain the detection indexes.
  • CRP C-reactive protein
  • ALT lactate dehydrogenase
  • LH lactate dehydrogenase
  • SOFA Sequential Organ Failure Assessment Score
  • the improvement or return of PaO2/FiO2 to normal levels can reflect the improvement or relief of the patient's respiratory status (such as respiratory distress, hypoxemia, acute respiratory distress syndrome and other symptoms) to a certain extent.
  • the improvement of C-reactive protein (CRP) and the improvement of lactate dehydrogenase (LDH) can reflect the improvement of the patient's infection degree (such as sepsis, septic shock and other symptoms) to a certain extent, and the reduction of SOFA score can To a certain extent, it reflects the improvement of the patient's organ damage or failure.
  • the improvement of alanine aminotransferase (ALT) may reflect the improvement of liver injury to some extent.
  • the improvement of one or more indicators can reflect the overall symptoms of patients due to 2019-nCoV infection.
  • related diseases or conditions including pneumonia, organ damage, respiratory distress, hypoxemia, thrombosis and embolism, microcirculatory disturbances, acute respiratory distress syndrome, sepsis, septic shock and multiple organ failure, etc.).
  • the clinical research results show that the compound of formula II is safe and has a therapeutic effect on related diseases or conditions caused by 2019-nCoV infection.

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Abstract

一种聚阴离子纤维二糖苷类化合物的应用，如式II所示的化合物在制备治疗2019-nCoV感染引发的相关疾病或病症的药物中的应用。该类化合物不仅安全，还可以明显改善2019-nCoV感染引发的相关疾病或病症，同时对于其他原因导致的急性呼吸窘迫综合征也可达到治疗效果。

Description

一种聚阴离子纤维二糖苷类化合物的应用
本申请要求申请日为2020/12/1的中国专利申请202011384873.9的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种聚阴离子纤维二糖苷类化合物的应用。
背景技术
新型冠状病毒肺炎(Corona Virus Disease 2019)为新发急性呼吸道传染病，由SARS-CoV-2(又称2019-nCoV)引发，其自2019年12月底爆发，截至当前已经造成全球超2亿人感染，超400万人死亡，目前已成为全球性重大公共卫生事件，对全球也带来了重大的影响。
根据我国的2021年发布的新型冠状病毒肺炎诊疗方案(试行第八版修订版)，2019新型冠状病毒感染的肺炎根据病情的轻重程度可分为轻型、普通型、重型和危重型。轻型临床症状轻微，仅表现为低热、轻微乏力等，无肺炎表现。普通型具有发热、呼吸道等症状(咳嗽、咽痛、鼻塞、气促、乏力等)，影像学可见肺炎表现。重型表现出呼吸困难、气促、低氧血症、嗜睡、惊厥；严重者可快速进展为急性呼吸窘迫综合征、脓毒症、脓毒症休克及多器官功能衰竭，甚至死亡。
急性呼吸窘迫综合征的病理学研究发现，在肺泡与肺间质内聚积的水肿液中存在大量蛋白及多种炎症细胞，而其中以中性粒细胞为主。中性粒细胞的激活和募集被认为在急性呼吸窘迫综合征的进展中起到作用。
患者感染新型冠状病毒后，由于病毒损伤与炎症过激导致的免疫损伤相互交织，会出现以肺部损伤为主，全身多器官受累的临床病理表现，特别是重症患者，表现为急性呼吸窘迫综合征，并可发展为脓毒症、脓毒性休克、多器官功能衰竭，甚至死亡。针对于疫情防控，除了需要有效的疫苗和抗病 毒药物进行防治之外，同样迫切需要针对病毒感染引发的机体免疫损伤进行治疗的“救命药”。
发明内容
本发明所要解决的技术问题是现有的治疗急性呼吸窘迫综合征、新型冠状病毒肺炎的药物的结构单一，为此，本发明提供了一种聚阴离子纤维二糖苷类化合物的应用。该类化合物不仅安全，还可以明显改善2019-nCoV感染引发的相关疾病或病症，同时对于其他原因导致的急性呼吸窘迫综合征也可达到治疗效果。
本发明第一方面提供了一种式II化合物(1-O-甲基2,2',3,3',4',6,6'-七-O-磺酰基-β-纤维二糖苷七钠盐)在制备治疗2019-nCoV感染引发的相关疾病或病症的药物中的应用；
Figure PCTCN2021134613-appb-000001
本发明所述的“2019-nCoV”是指世界卫生组织命名的2019新型冠状病毒，又称为SARS-CoV-2(severe acute respiratory syndrome coronavirus 2)。本发明所述的2019-nCoV包含各种毒株，例如NCBI或GISAID(全球共享流感数据倡议组织)收录的所有毒株，尤其包括传播性、致病性或免疫逃逸性等较强的重要变异株，例如WHO指定的Alpha、Beta、Gamma、Delta，Eta、Iota、Kappa、Lambda或Omicron变异株，及后续被指定的重要变异株。
本发明所述的2019-nCoV感染引发的相关疾病或病症包括但不限于：肺炎、器官损伤、呼吸窘迫、低氧血症、血栓形成和栓塞、微循环障碍、急性呼吸窘迫综合征、急性呼吸衰竭、脓毒症、脓毒症休克、多器官功能衰竭、 发热、呼吸道等症状(咳嗽、咽痛、鼻塞、气促、乏力等)、呼吸困难、嗜睡和惊厥中的一种或多种；优选地，其中所述肺炎为COVID-19，更优选为重型或危重型COVID-19。进一步地，所述的急性呼吸窘迫综合征可为脂多糖引发的急性呼吸窘迫综合征。
本领域技术人员应当理解，不同国家或者组织对于COVID-19临床分型的定义及鉴定可能存在差异，本申请包括被不同国家或组织定义的所有重型或危重型COVID-19的临床分型(英文表达为Severe COVID-19或Severe COVID-19 pneumonia)，例如我国《新型冠状病毒肺炎诊疗方案(试行第八版修订版)》。
本发明所使用的“COVID-19”是指2019-nCoV感染感染所引发的肺炎。
器官损伤包括但不限于：肺损伤、肾损伤、心肌损伤和肝损伤种的一种或多种。所述的肺损伤可包括：肺毛细血管内皮细胞损伤和/或肺泡上皮细胞损伤。
急性呼吸窘迫综合症的病理基础是弥漫性肺泡损伤，病理特点是由炎症引发肺组织毛细血管内皮细胞受到广泛性的损伤，从而导致毛细血管的渗出增加；以及肺泡上皮细胞损伤，导致肺通透性增加，肺泡和肺间质充满富含蛋白质的肺水肿液、透明膜形成及炎症细胞浸润，导致通气/血液比例严重失调。急性呼吸窘迫综合症临床表现为呼吸窘迫和顽固型的低氧血症，肺部影像学表现为非均一性的渗出性病变，一般认为该病的早期阶段为急性肺损伤，中度或重度称为急性呼吸窘迫综合症。
脓毒症一般指机体对感染(如2019-nCoV)产生全身过度激活的炎症反应而导致危及生命的多器官功能障碍，进一步可发展为脓毒症状休克和多脏器功能衰竭；所述多脏器功能衰竭包括但不限于：肺功能衰竭，肾脏功能衰竭和肝功能衰竭。
本发明第二方面还提供一种药物组合物在制备药物中的应用；
所述的药物组合物包括式II化合物(1-O-甲基2,2',3,3',4',6,6'-七-O-磺酰 基-β-纤维二糖苷七钠盐)和药学上可接受的辅料；
Figure PCTCN2021134613-appb-000002
所述的药物为治疗2019-nCoV感染引发的相关疾病或病症的药物。
进一步地，所述的2019-nCoV感染引发的相关疾病或病症如上所述，例如重型或危重型COVID-19，又例如脂多糖引发的急性呼吸窘迫综合征。
所述的药物组合物可通过固体或液体形式配制以用于给药，包括但不限于：注射(如经皮下、肌肉内、静脉内或硬膜外注射)、黏膜、经皮或局部给药、经鼻或口腔吸入给药和眼部给药等方式。
本领域中，药学上可接受的辅料包括但不限于：稀释剂、填充剂、崩解剂、润湿剂、润滑剂、pH值调节剂、缓冲剂、着色剂、调味剂、防腐剂或其它常规添加剂。
在本发明的一个实施方案中，所述药物组合物可为注射用药物组合物。进一步地，所述注射用药物组合物可制备成粉末或浓溶液的形式(本领域人员理解，所述粉末和浓度液一般为无菌)，使用时可将所述的粉末或浓溶液溶解或分散于药学上可接受的载体中用于临床使用。所述药学上可接受的载体可为溶剂或分散介质，包括但不限于：水、林格氏溶液、等渗盐水、磷酸盐缓冲液、乙醇或多元醇等。
在本发明的一些实施方案中，所述浓溶液的pH约为7.0～8.0，进一步为7.4～7.6，更进一步为7.5，可通过加入缓冲液调节pH，所述的缓冲液可选自磷酸盐缓冲液、柠檬酸盐缓冲液和醋酸盐缓冲液。
在本发明的一些实施方案中，所述浓溶液中的如式II化合物的浓度可为50-500mg/mL的，进一步为60-100mg/ml，优选地为65-85mg/mL，更优选地为68-80mg/ml(例如，70mg/ml)，可按照临床方案稀释后静脉输注给药，所述稀释可采用如下试剂进行稀释：水，林格氏溶液，等渗盐水等。
在一些具体实施方式中，所述浓溶液在临床使用(即浓溶液稀释后的溶液)时输注速度可为15～120mg/hr，优选为20～90mg/hr，例如：25mg/hr、30mg/hr、35mg/hr、40mg/hr、45mg/hr、50mg/hr、55mg/hr、58.3mg/hr、60mg/hr、65mg/hr、70mg/hr、75mg/hr、80mg/hr、87.5mg/hr或90mg/hr；输注时间可为1-120hr，例如：2hr、4hr、6hr、8hr、10hr、12hr、24hr、36hr、48hr、60hr、72hr、84hr、96hr、108hr等。所述数值包括所有点值的中间值。
在本发明的一些实施方案中，所述的药物组合物可以以气雾剂的形式或通过雾化直接给予受试者的气道。为了用作气溶胶，本发明药物可接受组合物的溶液或悬浮液可以与合适的推进剂，例如烃类推进剂如丙烷，丁烷或异丁烷以及常规助剂一起包装在加压气溶胶容器中。这种组合物也可以以非加压形式给药，例如在喷雾器或雾化器中。
本发明第三方面还提供了一种式II化合物(1-O-甲基2,2',3,3',4',6,6'-七-O-磺酰基-β-纤维二糖苷七钠盐)在制备治疗急性呼吸窘迫综合征或急性呼吸衰竭的药物中的应用；
Figure PCTCN2021134613-appb-000003
进一步地，所述的急性呼吸窘迫综合征可为感染引发的急性呼吸窘迫综合征或脂多糖引发的急性呼吸窘迫综合征，又可为2019-nCoV感染引发的急性呼吸窘迫综合征。
本发明第四方面还提供了一种治疗如上所述的2019-nCoV感染引发的相关疾病或病症的方法，其包括给予患者治疗有效量的式II化合物(1-O-甲基2,2',3,3',4',6,6'-七-O-磺酰基-β-纤维二糖苷七钠盐)；
Figure PCTCN2021134613-appb-000004
进一步地，所述的2019-nCoV感染引发的相关疾病或病症例如COVID-19，又例如重型或危重型COVID-19。
进一步地，所述的2019-nCoV感染引发的相关疾病或病症例如急性呼吸窘迫综合征或急性呼吸衰竭，又例如脂多糖引发的急性呼吸窘迫综合征。
优选地，采用静脉连续输注给药，输注速度可为15～120mg/hr，优选为20～90mg/hr，例如：25mg/hr、30mg/hr、35mg/hr、40mg/hr、45mg/hr、50mg/hr、55mg/hr、58.3mg/hr、60mg/hr、65mg/hr、70mg/hr、75mg/hr、80mg/hr、87.5mg/hr或90mg/hr；输注时间可为1-120hr，例如：2hr、4hr、6hr、8hr、10hr、12hr、24hr、36hr、48hr、60hr、72hr、84hr、96hr、108hr等。所述数值包括所有点值的中间值。
本发明第五方面还提供了一种治疗急性呼吸窘迫综合征或急性呼吸衰竭的方法，其包括给予患者治疗有效量的式II化合物(1-O-甲基2,2',3,3',4',6,6'-七-O-磺酰基-β-纤维二糖苷七钠盐)；
Figure PCTCN2021134613-appb-000005
进一步地，所述的急性呼吸窘迫综合征可为感染引发的急性呼吸窘迫综合征或脂多糖引发的急性呼吸窘迫综合征，又可为2019-nCoV感染引发的急性呼吸窘迫综合征。
急性呼吸窘迫综合征是一种可由多种病因引起的非心源性的以进行性 呼吸困难和顽固性低氧血症为主要表现的临床综合征，发病率高，且危害大，目前还没有公认有效的药物治疗方法，是临床治疗急需解决的一大难题。引发急性呼吸窘迫综合征的病因众多，可以分为肺内原因：细菌性或病毒性肺炎(包括冠状病毒性肺炎)、胃内容物误吸、肺挫伤、毒性吸入、溺水等，以及肺外原因：脓毒症、胰腺炎、严重创伤、大量输血和烧伤等，但其共同的病理基础都是弥漫性肺泡损伤，临床表现以进行性呼吸窘迫和难治性低氧血症为主要特征。急性呼吸窘迫综合征的病理学研究早已发现，在肺泡与肺间质内积聚的水肿液中存在大量蛋白及多种炎症细胞，而其中以中性粒细胞为主。
在本发明的一些实施方式中，所述的急性呼吸窘迫综合征为感染或非感染引发的急性呼吸窘迫综合征；所述的感染包括但不限于病毒、细菌、真菌、支原体或衣原体感染。所述细菌包括但不限于肺炎链球菌，葡萄球菌或肺炎克列波杆菌。所述病毒包括但不限于流感病毒、副流感病毒或冠状病毒(例如2019-nCoV)。所述的真菌包括但不限于曲菌放线菌。
在一些具体实施方案中，本发明还进一步提供了一种治疗急性呼吸窘迫综合征的方法，包括给予患者治疗有效量的式II所示的聚阴离子纤维二糖苷类化合物。优选地，采用静脉连续输注给药，输注速度可为15～120mg/hr，优选为20～90mg/hr，例如：25mg/hr、30mg/hr、35mg/hr、40mg/hr、45mg/hr、50mg/hr、55mg/hr、58.3mg/hr、60mg/hr、65mg/hr、70mg/hr、75mg/hr、80mg/hr、87.5mg/hr或90mg/hr；输注时间可为1-120hr，例如：2hr、4hr、6hr、8hr、10hr、12hr、24hr、36hr、48hr、60hr、72hr、84hr、96hr、108hr等。所述数值包括所有点值的中间值。
术语“C 1-6烷基”表示具有具体指定的碳原子数(例如一个、两个、三个、四个、五个或六个碳原子)的直链或支链烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、己基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基 丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基。
术语“治疗有效量”是指给予患者的、足以有效治疗疾病的化合物的量。治疗有效量将根据化合物、疾病种类、疾病的严重度、患者的年龄等变化，但可由本领域技术人员视情况调整。
术语“治疗”是指下述任一情形：(1)缓解疾病的一种或多种生物学表现；(2)干扰引发疾病的生物级联中的一个或多个点；(3)减缓疾病的一种或多种生物学表现发展。
术语“患者”是指已经或即将接受治疗的任何动物，优选哺乳动物，最优选人类。哺乳动物包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人类等。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的式II化合物不仅安全，还可以明显改善2019-nCoV感染引发的相关疾病或病症，同时对于其他原因导致的急性呼吸窘迫综合征也可达到治疗效果。
附图说明
图1为式II化合物对急性呼吸窘迫综合征模型大鼠肺组织炎症病变程度的影响。
具体实施方式
下面结合实施例对本发明作进一步详细、完整地说明，但不应视为对本发明的限定。以下所用试剂或设备均为市售品种，如无特殊说明，均按照说 明书操作，在此不做赘述。
实施例1 评价式II化合物对急性呼吸窘迫综合征的治疗效果
动物种属：雄性Sprague-Dawley大鼠(SD大鼠)
动物等级：SPF级
造模开始时年龄：6～8周龄。
造模开始时体重：195～270g。
1.1动物分组与造模：
动物分组：将检疫合格的56只雄性动物，根据分组前测定的体重，将动物随机分为正常对照组、模型对照组、供试品低剂量组、供试品中剂量组、供试品高剂量组；正常对照组8只，其余各组均为12只/组。
试验批次：本试验分两批次进行。第1批次为每组前一半动物数，第2批次为每组后一半动物数。每批次动物的模型构建、给药、指标检测等均一致。
模型构建：
D0各组动物根据体重，抽取造模试剂(脂多糖，LPS)，腹腔注射给予脂多糖(0.8mg/kg，400μL/kg)。
D1：腹腔注射16h(±30min)后，异氟烷吸入麻醉，各组动物气管内雾化给予脂多糖(5mg/kg，1000μL/kg)。
腹腔注射脂多糖(LPS)：根据最近称量的动物体重，采用一次性微量注射器抽取每只动物给予脂多糖的量，腹腔注射给予脂多糖。给予脂多糖体积保留至整数位，脂多糖体积介于两个分度容量线之间时，按上位分度值吸取。
气道内雾化脂多糖(LPS)：动物异氟烷吸入麻醉，然后固定于呈45°放置的大鼠固定器上，使用小动物麻醉咽喉镜，压住动物舌根部，暴露声门，将抽取定量的脂多糖(LPS)溶液的肺部微型液体雾化器针头(钝性)轻柔的插入气管内，然后快速推动活塞，将LPS溶液雾化进入肺脏，快速拔出针 头，从固定器上取下动物，头部朝上，左右旋转，使LPS尽可能的均匀分布于各肺叶。给予脂多糖体积保留至小数后1位，脂多糖体积介于两个分度容量线之间时，按上位分度值吸取。
1.2供试品剂量及方法
动物模型构建后，按照下表进行供试品及对照品进行给药。详见下表：
供试品为式II化合物(1-O-甲基2,2',3,3',4',6,6'-七-O-磺酰基-β-纤维二糖苷七钠盐)，将式II化合物配置成为70mg/mL的储存液(溶剂为pH 7.5的磷酸盐缓冲液)，给药前，使用氯化钠注射液将70mg/mL的储存液稀释成1mg/mL、5mg/mL、20mg/mL的供试品溶液。
正常对照组和模型对照组静脉注射给予氯化钠注射液。
表1给药剂量
Figure PCTCN2021134613-appb-000006
给药途径：组1～组5：尾静脉注射。
给药频率及时间：组1～组5：D1、D2：上午9:00～10:30、13:00～14:30、16:00～17:30；D3(给药2次)：上午8:30～10:00、11:00～12:30。
1.3试验观察与数据收集
1.3.1一般临床观察
动物检疫期及给药期间每天观察2次(上午和下午各1次)。观察内容： 精神状态、行为活动、死亡、呼吸、分泌物、粪便性状及其他异常情况。
1.3.2体重
动物接收，分组前，造模当天、供试品给药当天称重；动物发现死亡或濒死安乐死时也进行称重。
1.3.3存活率
计划安乐死后，计算试验周期内各组动物存活数与每组总动物数的比值。
存活率(％)＝组存活动物数/组总动物数×100％。
1.3.4血气检测
检测时间：D3最后1次给药结束约2h后
样品采集：大鼠腹腔注射水合氯醛(350mg/kg，100mg/mL)实施麻醉，腹中线纵向切开，分离腹主动脉，采用动脉采血器采集动脉血约0.5mL，采血器于手掌内搓动注射器及上下颠倒各5秒，绝对不能回抽采血器进行血液混匀处理。
检测方法：动脉血采集后，轻柔的将针头插入测试卡的血液注入口中，将血液缓慢推入，并加满样品加注管，当血液到达加样位时，停止加样，扣上盖子，血液会自动进入测试管内，将测试卡插入血气分析仪中，等待检测结果。
检测指标：PO2(mmHg)、PCO2(mmHg)、pH、sO2％。
1.3.5血浆组蛋白浓度检测
D3分别收集腹主动脉血和静脉血各约1mL，装在枸橼酸钠抗凝的采样管中。血样采集后湿冰暂存，2h内4℃3000rpm离心，分离血浆分别装在标有动脉血浆和静脉血浆的冻存管中，-70℃冻存，试验结束，按照试剂盒要求步骤进行血浆组蛋白浓度检测。
1.3.6血细胞计数
D3收集腹主静脉血1mL，装在含有EDTA-K 2抗凝剂的采样管中。采用
Figure PCTCN2021134613-appb-000007
2120系列血液分析仪进行血细胞计数。检测参数指标如下：
血细胞计数
Figure PCTCN2021134613-appb-000008
1.3.7肺灌洗液(BALF)检测
样本采集：动物安乐死后，剪开颈部和胸部皮肤及组织暴露气管、支气管及肺脏，分离右肺支气管，并结扎。在气管下穿缝合线，并在甲状软骨下适当位置于气管软骨环之间做1/2切口，将气管插管沿切口处向气道内缓慢插入至左侧支气管处，用穿好的缝合线在切口向心方向的适当部位将插管与 气管扎紧固定。用注射器吸取3mL的PBS缓冲液缓慢注入，进行肺泡灌洗，反复灌洗3次，每次冲洗停留约10s，收集灌洗液于合适容量的离心管中(不低于2.1mL，最终以实际收集量为准)。
BALF处理：将收集的灌洗液，每只动物保留2mL(多余部分按照医疗垃圾处理)，于4℃，约2000rpm条件下，离心10min。上清液分装至2管，均于-70℃以下保存待用(试验结束后寄送委托方或按照其他方式进行处理)。沉淀用1mL PBS缓冲液重悬，用于白细胞总数及分类计数。
灌洗液组蛋白浓度检测：试验结束，将肺灌洗液上清，按照试剂盒要求步骤进行肺灌洗液组蛋白浓度检测。
白细胞分类检测：重悬后的肺灌洗液，采用全自动血球分析仪进行白细胞计数及分类。
1.3.8动物安乐死
根据AVMA Guidelines for the Euthanasia of Animals:2013 Edition(the American Veterinary Medical Association,2013)，D3所有动物腹腔注射水合氯醛(350mg/kg，100mg/mL)实施麻醉，腹主动脉放血实施安乐死。濒死动物采用异氟烷麻醉后，腹主动脉放血实施安乐死。
1.3.9组织病理学检查
大体观察：各组所有动物(包括发现死亡、濒死安乐死动物)均进行解剖，并保存组织。发现动物非工作时间死亡后放置2-8℃冰箱保存，并于24小时内尽快进行解剖。解剖并留取组织后，动物尸体按医疗垃圾处理。
尸检过程中，观察动物肺脏、气管及支气管是否异常。剪取右肺中叶，用于计算湿/干重比值。剩余右肺组织及支气管置于10％中性缓冲福尔马林溶液中固定、石蜡包埋、切片、制片、HE染色进行肺组织病理形态学观察，使用标准术语诊断和分类，按4分级法(轻微，轻度，中度，重度)对肺组织进行病理学检测。
1.3.10肺脏湿干重比
用纸巾将右肺中叶组织表面血液、组织液等异物擦拭干净，并称重，然后将右肺中叶组织置于60℃烘箱72h再次称重，计算湿/干重比值。
肺脏湿干重比＝右肺中叶湿重/干重
1.3.11数据采集和统计分析
数据采集：数据采用系统生成和人工记录的方式采集。
数据分析：本试验采用统计学软件SPSS 13.0和或GraphPad Prism 5对数据进行处理。所有统计分析采用双尾分析，统计学水平设在P≤0.05。各指标均以“平均数±标准差”表示，并按下列过程分析：首先用Levene’s Test对数据进行均一性检验，如果数据均一(P>0.05)，则进行单因素方差分析(ANOVA)；如果方差分析显著(P≤0.05)，则模型对照组与其它各组间的差异进行Dunnett’s多重比较。如果Levene’s Test的结果显著(P≤0.05)，则进行Kruskal-wallis非参数检验。如果Kruskal-wallis非参数检验结果显著(P≤0.05)，则进一步采用Mann-Whitney U检验进行两两比较。
1.4实验结果
造模情况：显微镜下可见模型对照组动物肺泡腔、血管、肺泡壁炎细胞浸润/肺泡壁间隔增厚，肺泡内出血(伴或不伴血红蛋白结晶)等病理学改变；模型对照组动物的肺灌洗中WBC、Neut、组蛋白分别由正常对照组0.32±0.22、0.04±0.02、0.039±0.012升高至9.41±2.01、5.17±1.90、0.835±0.380；肺脏湿干比值由正常对照组1.17±0.09升高至2.26±0.51；PO2、sO2％分别由正常对照组103.3±5.9、98.4±0.5降低至77.5±11.4、95.3±2.5；且以上指标均具有统计学差异。综上所述，在本试验条件下，认为腹腔注射联合气道内雾化给予造模试剂脂多糖(LPS)构建急性呼吸窘迫综合征模型成功。
存活率：试验过程中未发现动物死亡，各组动物存活率均为100％。数据详见附表：表6。
肺灌洗液检测：供试品低、中、高剂量组动物肺灌洗液中的白细胞总数及分类指标均值，与模型对照组WBC指标均值(9.41±2.01)比较，分别降 低至(2.88±1.50)、(0.91±0.45)及(0.59±0.49)；与模型对照组Neut指标均值(5.17±1.90)比较，分别降低至(1.45±1.13)、(0.50±0.43)及(0.30±0.26)；Lymph、Mono指标均值也明显较低；且均具有统计学差异。数据详见附表：表2。
血气分析检测：供试品低、中、高剂量组动物的相应血气分析指标均值，与模型对照组PO2指标均值(77.5±11.4)比较，分别升高至(88.4±8.6)、(90.3±6.4)及(92.3±9.2)，与模型对照组sO2％指标均值(95.3±2.5)比较，分别升高至(97.2±1.1)、(97.4±0.8)及(97.3±1.2)，且均具有统计学差异；PCO2和pH指标均未见统计学差异。数据详见附表：表3。
组蛋白检测：供试品低、中、高剂量组动物的组蛋白指标均值，与模型对照组肺灌洗液组蛋白指标均值(0.835±0.380)比较，分别降低至(0.686±0.452)、(0.415±0.445)及(0.449±0.606)，且供试品中、高剂量组均具有统计学差异；与模型对照组动脉血浆组蛋白指标均值(0.164±0.093)比较，分别降低至(0.126±0.039)、(0.117±0.062)及(0.091±0.035)，且供试品高剂量组具有统计学差异；与模型对照组静脉血浆组蛋白指标均值(0.074±0.019)比较，分别降低至(0.073±0.046)、(0.057±0.008)及(0.049±0.009)，且供试品中、高剂量组均具有统计学差异。数据详见附表：表4。
肺脏湿干比检测：供试品低、中、高剂量组动物的肺脏湿干比指标均值，与模型对照组(2.26±0.51)比较，分别降低至(1.97±0.33)、(1.85±0.20)及(1.61±0.43)，且供试品中、高剂量组均具有统计学差异。数据详见附表：表5。
血细胞计数：与模型对照组动物相应指标比较，供试品低、中、高剂量组动物的WBC、Lymph、PLT等指标均值升高，Neut、Mono、LUC等指标均值均降低，且具有统计学差异。数据详见附表：表7。
病理学检测：本试验过程中，造模动物均观察到肺脏炎症，炎症主要表 现为：中性粒细胞为主的炎细胞(肺泡腔、血管、肺泡壁)，肺泡壁间隔增厚，肺泡内出血(伴或不伴血红蛋白结晶)。给药组动物的炎症程度明显低于模型对照组，说明供试品降低了炎症的程度，各个给药组的动物的炎症存在剂量关系，随着剂量的升高，炎症的病变程度逐渐降低。数据详见附图：图1(1、正常对照组动物肺组织病理学检测未见病理学改变，故未在图中显示；2、每组进行病理学检查的肺叶数＝每组动物数(12只)×每只动物病理学检查肺叶数(3叶：右上叶、右下叶及副叶)，每组均为36叶)。
表2对急性呼吸窘迫综合征模型大鼠肺灌洗液(BALF)中白细胞总数及分类的影响(
Figure PCTCN2021134613-appb-000009
n＝8/12)
Figure PCTCN2021134613-appb-000010
注：1、动物数：正常对照组8只，其余各组均为12只；2、与模型对照组比较，“*”表示p≤0.05；3、Levene’s Test检验WBC、Neut、Lymph、Mono指标不均一，采用Kruskal-wallis非参数检验进行统计分析。
表3对急性呼吸窘迫综合征模型大鼠血气分析的影响(
Figure PCTCN2021134613-appb-000011
n＝8/12)
组别 PH PCO2(mmHg) PO2(mmHg) sO 2％
正常对照组 7.477±0.054 34.33±3.02 103.3±5.9* 98.4±0.5*
模型对照组 7.437±0.033 37.14±4.31 77.5±11.4 95.3±2.5
供试品低剂量组 7.463±0.052 36.26±4.86 88.4±8.6* 97.2±1.1*
供试品中剂量组 7.450±0.035 36.23±4.09 90.3±6.4* 97.4±0.8*
供试品高剂量组 7.437±0.045 37.20±3.70 92.3±9.2* 97.3±1.2*
注：1、动物数：正常对照组8只，其余各组均为12只；2、与模型对照组比较，“*”表示p≤0.05；3、Levene’s Test检验sO 2％指标不均一，采用Kruskal-wallis非参数检验进行统计分析。
表4对急性呼吸窘迫综合征模型大鼠组蛋白的影响(
Figure PCTCN2021134613-appb-000012
n＝8/12；Median)
Figure PCTCN2021134613-appb-000013
注：1、动物数：正常对照组8只，其余各组均为12只；2、与模型对照组比较，“*”表示p≤0.05；3、Levene’s Test检验肺灌洗液组蛋白、静脉血浆组蛋白指标不均一，采用Kruskal-wallis非参数检验进行统计分析。
表5对急性呼吸窘迫综合征模型大鼠肺脏湿干比值的影响(
Figure PCTCN2021134613-appb-000014
n＝8/12)
组别 湿干比值
正常对照组 1.17±0.09*
模型对照组 2.26±0.51
供试品低剂量组 1.97±0.33
供试品中剂量组 1.85±0.20*
供试品高剂量组 1.61±0.43*
注：1、动物数：正常对照组8只，其余各组均为12只；2、与模型对 照组比较，“*”表示p≤0.05；3、Levene’s Test检验肺脏湿干比指标不均一，采用Kruskal-wallis非参数检验进行统计分析。
表6对急性呼吸窘迫综合征模型大鼠存活率的影响
组别 造模动物数(只) 组内存活动物数(只) 存活率(％)
正常对照组 8 8 100.0
模型对照组 12 12 100.0
供试品低剂量组 12 12 100.0
供试品中剂量组 12 12 100.0
供试品高剂量组 12 12 100.0
备注：1、存活率(％)＝组存活动物数/组总动物数×100％。
表7对急性呼吸窘迫综合征模型大鼠血细胞计数的影响(
Figure PCTCN2021134613-appb-000015
n＝8/12)
Figure PCTCN2021134613-appb-000016
Figure PCTCN2021134613-appb-000017
注：1、动物数：正常对照组8只，其余各组均为12只；2、与模型对照组比较，“*”表示p≤0.05；3、Levene’s Test检验Neut、Mono、LUC、HCT、PLT指标不均一，采用Kruskal-wallis非参数检验进行统计分析。
实施例2式II化合物的临床研究
本研究是一项随机、开放标签、多中心的临床研究，旨在评价式II化合物持续输注制剂在重度2019冠状病毒病肺炎(sever COVID-19 Pneumonia)患者中的安全性和疗效。受试者将以2:2:1的比例随机分为三个队列，接受持续输注式II化合物，以58.3mg/小时或87.5mg/小时持续3天(72小时)， 或接受适当的标准护理(安慰剂为0.9％氯化钠注射液)。式II化合物治疗组的所有受试者也将接受标准护理作为背景治疗。
将式II化合物配置成为无菌浓缩溶液(70mg/mL，溶剂为pH 7.5的磷酸盐缓冲液)，装于配有橡胶塞和密封盖的10mL玻璃瓶中，2℃-8℃下冷藏保存。临用前，使用注射用生理盐水稀释，并按照临床方案配制后静脉输注给药。
此项研究的安慰剂为0.9％氯化钠注射液，以标签相同的独立玻璃西林瓶形式提供，每支10mL，储存条件与研究用药相同，均在2℃-8℃下冷藏保存。安慰剂必须按照与式II化合物相同的程序和操作指南进行给药。
本研究探索了：1)不良事件和严重不良事件的发生率；2)不良事件导致治疗终止率；3)心电图异常；4)实验室检查异常；5)生命体征和体格检查异常各种不良事件发生率，包括症状或体征异常和实验室检查异常。以1)与基线相比，给药后、PaO2/FiO2的变化；2)与基线相比，给药后c反应蛋白(CRP)、丙氨酸转氨酶(ALT)、乳酸脱氢酶(LDH)等生物学指标的变化；3)与基线相比，给药后SOFA评分的变化；4)30天内生存时间；5)30天内脱机后生存时间；6)30天内住院时间；7)30天内ICU住院时间；8)30天内有创机械通气时间。
上述指标检测均为本领域常规检测，本领域技术人员均知如何获取所述检测指标。
临床研究中几乎未发现与受试药物相关的不良反应事件或严重不良反应。给予式II化合物后，患者的临床症状得到了一定的改善，所述的改善包括一种或者多种如下所示的生物学或临床指标的改善：C-反应蛋白(CRP)、丙氨酸转氨酶(ALT)、乳酸脱氢酶(LDH)或PaO2/FiO2等生物学指标得到改善(或可恢复到正常水平)，序贯器官衰竭估计评分(SOFA)降低(如可降低到1或0)，机械通气的使用及使用时间的降低，住院时间或ICU住院时间减少，及死亡率降低等。
PaO2/FiO2得到改善或恢复到正常水平可一定程度上反映患者的呼吸状况(如呼吸窘迫、低氧血症、急性呼吸窘迫综合征等症状)有一定的改善或者缓解。C-反应蛋白(CRP)的改善，乳酸脱氢酶(LDH)的改善可一定程度上反映患者的感染程度(如脓毒症，脓毒症休克等症状)有所改善，SOFA评分的降低可一定程度上反映患者的器官损伤或衰竭的改善。丙氨酸转氨酶(ALT)的改善可一定程度上反映对肝损伤的改善。住院时间的降低，ICU住院时间的减低，机械通气的使用及时间的降低，无呼吸机存活时间的延长等一种或多种指标的改善可在一定程度上整体反映患者由于2019-nCoV感染引发的相关疾病或病症有改善或治疗效果(包括肺炎、器官损伤、呼吸窘迫、低氧血症、血栓形成和栓塞、微循环障碍、急性呼吸窘迫综合征、脓毒症、脓毒症休克和多器官功能衰竭等)。
临床研究结果显示式II化合物安全性好，对于2019-nCoV感染引发的相关疾病或病症具有治疗效果。
尽管本申请已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。本发明的保护范围由所附权利要求书限定。

Claims (15)

  1. 一种式II化合物在制备治疗2019-nCoV感染引发的相关疾病或病症的药物中的应用；
    Figure PCTCN2021134613-appb-100001
  2. 如权利要求1所述的应用，其特征在于，所述的2019-nCoV感染引发的相关疾病或病症包括但不限于：肺炎、器官损伤、呼吸窘迫、低氧血症、血栓形成和栓塞、微循环障碍、急性呼吸窘迫综合征、急性呼吸衰竭、脓毒症、脓毒症休克、多器官功能衰竭、发热、呼吸道等症状、呼吸困难、嗜睡和惊厥中的一种或多种。
  3. 如权利要求2所述的应用，其特征在于，所述的应用满足下列条件中的一个或两个：
    a)所述的肺炎为COVID-19；优选地，所述COVID-19为重型或危重型COVID-19；
    b)所述的急性呼吸窘迫综合征可为脂多糖引发的急性呼吸窘迫综合征。
  4. 一种药物组合物在制备药物中的应用；
    所述的药物组合物包括式II化合物和药学上可接受的辅料；
    Figure PCTCN2021134613-appb-100002
    所述的药物为治疗2019-nCoV感染引发的相关疾病或病症的药物。
  5. 如权利要求4所述的应用，其特征在于，所述的药物组合物为注射用药物组合物；优选地，所述的注射用药物组合物为粉末或浓溶液的形式。
  6. 如权利要求5所述的应用，其特征在于，所述的浓溶液的pH为7.0～8.0，优选为7.4～7.6，更进一步为7.5。
  7. 如权利要求6所述的应用，其特征在于，所述的浓溶液通过加入缓冲液调节pH，所述的缓冲液可选自磷酸盐缓冲液、柠檬酸盐缓冲液和醋酸盐缓冲液。
  8. 如权利要求4所述的应用，其特征在于，所述的2019-nCoV感染引发的相关疾病或病症包括但不限于：肺炎、器官损伤、呼吸窘迫、低氧血症、血栓形成和栓塞、微循环障碍、急性呼吸窘迫综合征、急性呼吸衰竭、脓毒症、脓毒症休克、多器官功能衰竭、发热、呼吸道等症状、呼吸困难、嗜睡和惊厥中的一种或多种。
  9. 如权利要求8所述的应用，其特征在于，所述的应用满足下列条件中的一个或两个：
    c)所述的肺炎为COVID-19；优选地，所述COVID-19为重型或危重型COVID-19；
    d)所述的急性呼吸窘迫综合征可为脂多糖引发的急性呼吸窘迫综合征。
  10. 如权利要求5～9中任一项所述的应用，其特征在于，所述的浓溶液中，所述的式II化合物的浓度可为50-500mg/mL，进一步为60-100mg/ml，优选地为65-85mg/mL，更优选地为68-80mg/ml。
  11. 如权利要求10所述的应用，其特征在于，所述的注射用药物组合物通过静脉连续输注给药，输注速度为15～120mg/hr，输注时间为1-120hr。
  12. 一种式II化合物在制备治疗急性呼吸窘迫综合征或急性呼吸衰竭的药物中的应用；
    Figure PCTCN2021134613-appb-100003
    其中，所述的急性呼吸窘迫综合征可为感染引发的急性呼吸窘迫综合征 或脂多糖引发的急性呼吸窘迫综合征，又可为2019-nCoV感染引发的急性呼吸窘迫综合征。
  13. 一种治疗2019-nCoV感染引发的相关疾病或病症的方法，其包括给予患者治疗有效量的式II化合物；
    Figure PCTCN2021134613-appb-100004
    其中，所述的2019-nCoV感染引发的相关疾病或病症包括但不限于：肺炎、器官损伤、呼吸窘迫、低氧血症、血栓形成和栓塞、微循环障碍、急性呼吸窘迫综合征、急性呼吸衰竭、脓毒症、脓毒症休克、多器官功能衰竭、发热、呼吸道等症状、呼吸困难、嗜睡和惊厥中的一种或多种。
  14. 如权利要求13所述的方法，其特征在于，所述的应用满足下列条件中的一个或两个：
    e)所述的肺炎为COVID-19；优选地，所述COVID-19为重型或危重型COVID-19；
    f)所述的急性呼吸窘迫综合征可为脂多糖引发的急性呼吸窘迫综合征。
  15. 一种治疗急性呼吸窘迫综合征或急性呼吸衰竭的方法，其包括给予患者治疗有效量的式II化合物；
    Figure PCTCN2021134613-appb-100005
    其中，所述的急性呼吸窘迫综合征可为感染引发的急性呼吸窘迫综合征或脂多糖引发的急性呼吸窘迫综合征，又可为2019-nCoV感染引发的急性呼吸窘迫综合征。
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