WO2024041633A1 - Utilisation d'un composé pyrimidine à cycles fusionnés - Google Patents

Utilisation d'un composé pyrimidine à cycles fusionnés Download PDF

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WO2024041633A1
WO2024041633A1 PCT/CN2023/114914 CN2023114914W WO2024041633A1 WO 2024041633 A1 WO2024041633 A1 WO 2024041633A1 CN 2023114914 W CN2023114914 W CN 2023114914W WO 2024041633 A1 WO2024041633 A1 WO 2024041633A1
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pharmaceutically acceptable
formula
compound represented
acceptable salt
pharmaceutical composition
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PCT/CN2023/114914
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English (en)
Chinese (zh)
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王玉光
冯振华
张农
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广州再极医药科技有限公司
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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

Definitions

  • the present invention relates to the use of a fused ring pyrimidine compound in the preparation of medicines.
  • Fibrosis refers to a pathological process in which inflammation leads to necrosis of parenchymal cells in organs and abnormal increase and excessive deposition of extracellular matrix in tissues. In mild cases, it becomes fibrosis, and in severe cases, it causes tissue structure damage and organ sclerosis. Fibrosis can occur in a variety of organs and tissues, but is particularly prevalent in those frequently exposed to chemical and biological damage, including the lungs, skin, gastrointestinal tract, kidneys, and liver.
  • Pulmonary fibrosis is the end-stage change of a large group of lung diseases characterized by the proliferation of fibroblasts and the accumulation of large amounts of extracellular matrix, accompanied by inflammatory damage and tissue structure destruction. That is, the normal alveolar tissue is damaged and undergoes abnormal repair resulting in structural damage. Abnormalities (scarring). The cause of most pulmonary fibrosis patients is unknown (idiopathic). This group of diseases is called idiopathic interstitial pneumonia (IIP), which is a major category of interstitial lung diseases.
  • IIP idiopathic interstitial pneumonia
  • IIP interstitial interstitial pneumonia
  • IPF idiopathic pulmonary fibrosis
  • Pulmonary fibrosis seriously affects human respiratory function, manifesting as dry cough and progressive dyspnea. As the condition and lung damage worsen, the patient's respiratory function continues to deteriorate.
  • the incidence and mortality of idiopathic pulmonary fibrosis are increasing year by year.
  • the average survival time after diagnosis is only 2.8 years.
  • the mortality rate is higher than that of most tumors. It is called a "tumor-like disease”.
  • IPF idiopathic pulmonary fibrosis
  • COVID-19 coronavirus disease 2019 (COVID-19) epidemic ends, many patients are suffering from sequelae of chronic diseases (pulmonary fibrosis disease).
  • pulmonary fibrosis disease caused by severe COVID-19 has something in common with IPF.
  • the underlying host immune response and alveolar cell pathology characterize interstitial lung disease, and they show similar gene expression patterns in the lungs and blood (Saptarshi Sinha et al., eBioMedicine 2022;82:104185).
  • COVID-19 infection is the cause of acute exacerbation of idiopathic pulmonary fibrosis.
  • Idiopathic pulmonary fibrosis and pulmonary fibrosis after COVID-19 infection have pro-fibrotic processes, genetic characteristics, and effects on fibrosis in the physiological pathology inside and outside the cells.
  • the effects of chemotherapy are very similar (Peter M George, Lancet Respir Med. 2020; 8(8):807–815; Patrucco, F. et al. Microorganisms 2023, 11, 895).
  • a large-scale genome-wide association study (GWAS) has identified 20 genome-wide significant signals associated with the risk of IPF and also examined a genome-wide significant signal associated with severe COVID-19, finding that infection with pulmonary fibrosis is associated with infection with COVID-19.
  • WO2017012559A1 discloses a multi-target tyrosine kinase inhibitor, which includes a compound represented by the following formula, whose chemical name is N-[7-(4-fluoro-2-methoxyphenyl)-6-methyl Thieno[3,2-d]pyrimidin-2-yl]-1-(piperidin-4-yl)-1H-pyrazol-4-amine, and its potential to treat various types of tumors has been disclosed.
  • WO2019228171A1 discloses the crystal form of the compound with the following structure and its use in treating tumors.
  • the present invention provides the use of a compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing fibrotic diseases,
  • the pharmaceutically acceptable salts of the present invention are selected from, but are not limited to, fumarate, adipate, phosphate, tartrate, maleate, hydrochloride, citrate, sulfate, methanesulfonate, Benzenesulfonate and p-toluenesulfonate.
  • the pharmaceutically acceptable salt of the compound represented by formula I is a compound represented by formula Ia, which is N-[7-(4-fluoro-2-methoxyphenyl)- 6-Methylthieno[3,2-d]pyrimidin-2-yl]-1-(piperidin-4-yl)-1H-pyrazole-4-amine fumarate,
  • the fibrotic disease may be pulmonary fibrosis, liver cirrhosis, scleroderma, or renal fibrosis.
  • the fibrotic disease may be idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • the fibrotic disease may be pulmonary fibrotic disease caused by idiopathic interstitial pneumonia (IIP).
  • IIP idiopathic interstitial pneumonia
  • the fibrotic disease may be pulmonary fibrotic disease caused by coronavirus disease 2019 (COVID-19).
  • the fibrotic disease has one or more of the following characteristics:
  • the compound represented by Formula I or a pharmaceutically acceptable salt thereof is administered to human subjects at a total dose of 10-200 mg per day, and the frequency of administration can be once a day or twice a day. times, three times a day, preferably twice a day.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in a human subject at a total dose of 20-160 mg per day, such as 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg , 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg or 160mg, frequency of administration It can be once a day, twice a day, or three times a day, preferably twice a day.
  • the dosage of the compound represented by Formula I or a pharmaceutically acceptable salt thereof is 10-200 mg, such as 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg or 160mg;
  • the compound represented by Formula I or its pharmaceutically acceptable salt according to the present invention can be administered orally, parenterally, or transdermally.
  • the parenteral administration includes but is not limited to intravenous injection. , subcutaneous injection, intramuscular injection; oral administration is preferred.
  • the compound represented by Formula I or a pharmaceutically acceptable salt thereof is administered orally in human subjects, and the frequency of administration may be once a day, twice a day, or once a day. Three times a day, preferably twice a day, the compound represented by formula I or a pharmaceutically acceptable salt thereof is administered at a total dose of 20-160 mg per day.
  • the present invention also provides the use of a pharmaceutical composition in the preparation of drugs for treating or preventing fibrotic diseases.
  • the pharmaceutical composition contains a compound represented by formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutical agent.
  • Acceptable carrier, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is a therapeutically effective amount.
  • the pharmaceutical composition includes (a therapeutically effective amount) a compound represented by formula I-a and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be capsules, tablets, granules, injections, inhalants, etc.
  • the pharmaceutical composition is administered as described above.
  • the frequency of administration of the pharmaceutical composition is as described above.
  • the pharmaceutical composition is administered orally in human subjects, and the frequency of administration can be once a day, twice a day, three times a day, preferably twice a day,
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a total dose of 20-160 mg per day.
  • the present invention also provides a method for treating or preventing fibrotic diseases, which includes administering (a therapeutically effective amount) of a compound represented by Formula I or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need of treatment.
  • the fibrotic disease is defined as above.
  • the compound represented by formula I or its pharmaceutically acceptable salt or pharmaceutical composition is as described in any of the above solutions.
  • the compound represented by Formula I or a pharmaceutically acceptable salt thereof is administered to human subjects at a total dose of 10-200 mg per day, and the frequency of administration can be once a day or twice a day. times, three times a day, preferably twice a day.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in a human subject at a total dose of 20-160 mg per day, such as 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg , 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg or 160mg, frequency of administration It can be once a day, twice a day, or three times a day, preferably twice a day.
  • the dosage of the compound represented by Formula I or a pharmaceutically acceptable salt thereof is 10-200 mg, such as 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg or 160mg;
  • the administration method of the compound represented by formula I or its pharmaceutically acceptable salt or pharmaceutical composition according to the present invention can be oral administration, parenteral administration, or transdermal administration.
  • the parenteral administration includes: It is not limited to intravenous injection, subcutaneous injection, and intramuscular injection; oral administration is preferred.
  • the compound represented by Formula I or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered orally in human subjects, and the frequency of administration may be once a day, or once a day.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof is administered twice, three times a day, preferably twice a day, at a total dose of 20-160 mg per day.
  • the present invention also provides the use of a compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing coronavirus disease 2019 (COVID-19).
  • the coronavirus disease 2019 (COVID-19) may be a pulmonary fibrosis disease caused by coronavirus disease 2019 (COVID-19).
  • the COVID-19 has one or more of the following characteristics:
  • the compound represented by Formula I or a pharmaceutically acceptable salt thereof is administered to human subjects at a total dose of 10-200 mg per day, and the frequency of administration can be once a day or twice a day. times, three times a day, preferably twice a day.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in a human subject at a total dose of 20-160 mg per day, such as 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg , 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg or 160mg, frequency of administration It can be once a day, twice a day, or three times a day, preferably twice a day.
  • the dosage of the compound represented by Formula I or a pharmaceutically acceptable salt thereof is 10-200 mg, such as 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg or 160mg;
  • the compound represented by Formula I or its pharmaceutically acceptable salt according to the present invention can be administered orally, parenterally, or transdermally.
  • the parenteral administration includes but is not limited to intravenous injection. , subcutaneous injection, intramuscular injection; oral administration is preferred.
  • the compound represented by Formula I or a pharmaceutically acceptable salt thereof is administered orally in human subjects, and the frequency of administration may be once a day, twice a day, or once a day. Three times a day, preferably twice a day, the compound represented by formula I or a pharmaceutically acceptable salt thereof is administered at a total dose of 20-160 mg per day.
  • the present invention also provides the use of a pharmaceutical composition in the preparation of medicines for treating or preventing coronavirus disease 2019 (COVID-19).
  • the pharmaceutical composition contains a compound represented by formula I or a pharmaceutically acceptable salt thereof. and at least one pharmaceutically acceptable carrier, and the compound represented by Formula I or a pharmaceutically acceptable salt thereof is a therapeutically effective amount.
  • the pharmaceutical composition includes (a therapeutically effective amount) a compound represented by formula I-a and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be capsules, tablets, granules, injections, inhalants, etc.
  • the administration mode of the pharmaceutical composition is as described above.
  • the administration frequency of the pharmaceutical composition is as described above.
  • the pharmaceutical composition is administered orally in human subjects, and the frequency of administration can be once a day, twice a day, three times a day, preferably twice a day,
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a total dose of 20-160 mg per day.
  • the coronavirus disease 2019 (COVID-19) may be a pulmonary fibrosis disease caused by coronavirus disease 2019 (COVID-19).
  • the present invention also provides a method for treating or preventing coronavirus disease 2019 (COVID-19), comprising administering (a therapeutically effective amount) of a compound represented by formula I or a pharmaceutically acceptable compound thereof to a subject in need of treatment Salt or pharmaceutical composition.
  • the compound represented by formula I or its pharmaceutically acceptable salt or pharmaceutical composition is as described in any of the above solutions.
  • the coronavirus disease 2019 (COVID-19) may be a pulmonary fibrosis disease caused by coronavirus disease 2019 (COVID-19).
  • the compound represented by Formula I or a pharmaceutically acceptable salt thereof is administered to human subjects at a total dose of 10-200 mg per day, and the frequency of administration can be once a day or twice a day. times, three times a day, preferably twice a day.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in a human subject at a total dose of 20-160 mg per day, such as 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg , 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg or 160mg, frequency of administration It can be once a day, twice a day, or three times a day, preferably twice a day.
  • the dosage of the compound represented by Formula I or a pharmaceutically acceptable salt thereof is 10-200 mg, such as 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg or 160mg;
  • the administration method of the compound represented by formula I or its pharmaceutically acceptable salt or pharmaceutical composition according to the present invention can be oral administration, parenteral administration, or transdermal administration.
  • the parenteral administration includes: It is not limited to intravenous injection, subcutaneous injection, and intramuscular injection; oral administration is preferred.
  • the compound represented by Formula I or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered orally in human subjects, and the frequency of administration may be once a day, or once a day.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof is administered twice, three times a day, preferably twice a day, at a total dose of 20-160 mg per day.
  • the present invention also provides a substance X for treating coronavirus disease 2019 (COVID-19).
  • the substance X is a compound represented by formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.
  • the coronavirus disease 2019 (COVID-19) may be a pulmonary fibrosis disease caused by coronavirus disease 2019 (COVID-19).
  • the coronavirus disease 2019 (COVID-19) has one or more of the following characteristics:
  • the compound represented by formula I or its pharmaceutically acceptable salt or pharmaceutical composition is as described in any of the above solutions.
  • the pharmaceutically acceptable salts include but are not limited to: fumarate, adipate, phosphate, tartrate, maleate, Hydrochloride, citrate, sulfate, mesylate, benzenesulfonate and p-toluenesulfonate.
  • the medicine for treating or preventing fibrotic diseases can be in conventional dosage forms in the field, such as capsules, tablets, granules, injections, etc.
  • treatment refers to therapeutic therapy.
  • treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that causes or causes the condition or (b) ) one or more biological manifestations of a condition, (3) amelioration of one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slow the progression of a condition or one or more biological manifestations of a condition.
  • prevention refers to the reduction of the risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a subject.
  • the “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by one skilled in the art.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that compound I or its pharmaceutically acceptable salt has good preventive or therapeutic effects on pulmonary fibrosis disease.
  • Figure 1 shows the effect of compound MAX-40279-01 on the body weight of the pulmonary fibrosis mouse model caused by bleomycin (BLM). Compared with the model group, **P ⁇ 0.01, *P ⁇ 0.05.
  • Figure 2 shows the effect of compound MAX-40279-01 on the lung weight and organ coefficient of the pulmonary fibrosis mouse model caused by bleomycin (BLM). Compared with the model group, **P ⁇ 0.01, *P ⁇ 0.05.
  • Figure 3 shows the effect of compound MAX-40279-01 on the pathological scores of the pulmonary fibrosis mouse model caused by bleomycin (BLM). Compared with the model group, **P ⁇ 0.01, *P ⁇ 0.05.
  • Figure 4 shows the effect of compound MAX-40279-01 on the Masson staining score of the pulmonary fibrosis mouse model caused by bleomycin (BLM) (Masson’s, 200X).
  • Figure 5 shows the effect of compound MAX-40279-01 on lung lavage fluid cytokines (TNF- ⁇ , IL1- ⁇ , TGF- ⁇ , IFN- ⁇ ) in a mouse model of pulmonary fibrosis caused by bleomycin (BLM). , compared with the model group, **P ⁇ 0.01, *P ⁇ 0.05.
  • Figure 6 shows the effect of compound MAX-40279-01 on lung hydroxyproline in the mouse model of pulmonary fibrosis caused by bleomycin (BLM). Compared with the model group, **P ⁇ 0.01, *P ⁇ 0.05.
  • Figure 7 shows the effect of compound MAX-40279-01 on the body weight of the pulmonary fibrosis rat model caused by bleomycin (BLM). Compared with the model group, **P ⁇ 0.01, *P ⁇ 0.05.
  • Figure 8 shows the effect of compound MAX-40279-01 on the lung weight and organ coefficient of the pulmonary fibrosis rat model caused by bleomycin (BLM). Compared with the model group, **P ⁇ 0.01, *P ⁇ 0.05.
  • Figure 9 shows the effect of compound MAX-40279-01 on structural changes in the lung tissue of rats with pulmonary fibrosis caused by bleomycin (BLM) (HE staining, 200X).
  • Figure 10 shows the effect of compound MAX-40279-01 on the Szapiel pathological score of the pulmonary fibrosis rat model caused by bleomycin (BLM).
  • Figure 11 shows the effect of compound MAX-40279-01 on the Masson staining score of the pulmonary fibrosis rat model caused by bleomycin (BLM) (Masson’s, 200X).
  • Figure 12 shows the effect of compound MAX-40279-01 on the pathological scores of the pulmonary fibrosis rat model caused by bleomycin (BLM). Compared with the model group, **P ⁇ 0.01, *P ⁇ 0.05.
  • Figure 13 shows the effect of compound MAX-40279-01 on cytokines (TNF- ⁇ , IL1- ⁇ , TGF- ⁇ , IFN- ⁇ ) in the lung lavage fluid of a rat model of pulmonary fibrosis caused by bleomycin (BLM). , compared with the model group, **P ⁇ 0.01, *P ⁇ 0.05.
  • Figure 14 shows the effect of compound MAX-40279-01 on pulmonary hydroxyproline in the rat model of pulmonary fibrosis caused by bleomycin (BLM). Compared with the model group, **P ⁇ 0.01, *P ⁇ 0.05.
  • Compound MAX-40279-01 synthesized according to the method disclosed in WO2019/228171A1.
  • C57BL/6 male mice were continued to be raised until their weight reached about 24g. After anesthesia, they were fixed on the operating table. After disinfecting the neck with alcohol cotton, the muscles were separated layer by layer to expose the trachea. After injecting a dose of bleomycin (BLM) 3.5mg/kg (20ul/10g body weight) into the needle, quickly stand the animal upright, then rotate it along the long axis of the body for 1 minute to evenly distribute the solution in the lungs, suture the incision, and disinfect Then put it back in the cage. In the sham operation group, the trachea was exposed, and normal saline was used instead of bleomycin solution to perform the same operation.
  • BLM bleomycin
  • the bleomycin mice are randomly divided into three groups according to body weight: model group, 1.2 mg/kg DEX group, 50 mg/kg Nintedanib group, 300 mg/kg Pirfenidone group, 20mg/kg MAX-40279-01 group, 15mg/kg MAX-40279-01 group, 10mg/kg MAX-40279-01 group, 5mg/kg MAX-40279-01 group, 10 animals in each group, and blank control All groups were treated together 7 days after modeling, for a total of 21 days, and the model group and blank control group were given corresponding solvents.
  • the grouping situation is shown in Table 1 below:
  • the general condition of the animals was observed every day, and the body weight was recorded once every 7 days.
  • lung tissue organ coefficient lung tissue weight/body weight
  • take 1 ml of normal saline to repeatedly lavage the lungs, and collect the lung lavage fluid to detect inflammatory cells and inflammatory factors.
  • the other lung was injected with 10% formaldehyde solution through the bronchus until the pleura was flattened and then the bronchus was ligated. After the lung tissue was fixed, the lung tissue was collected longitudinally from the lung apex to the lung base for pathological examination (HE staining, Masson staining and pathological scoring). Ashcroft score, the scoring criteria are shown in Table 2 below:
  • lung lavage fluid to detect inflammatory factors: TGF- ⁇ , IL-1 ⁇ , TNF- ⁇ and IFN- ⁇ .
  • Collagen generally measures the collagen content in lung tissue, which can be determined by detecting the hydroxyproline content in lung tissue).
  • mice After mice were modeled, the body weight of the model group was lower than that of the blank group, and there was a statistically significant difference (P ⁇ 0.01), indicating that bleomycin modeling would reduce the weight of mice.
  • the modeling mice were weighed and divided into groups 7 days after modeling, and there was no difference in body weight among the mice in each administration group.
  • mice in the 15mg/kg MAX-40279-01 group and the Pirfenidone group lost less weight, which was significantly different from the body weight of the model group (P ⁇ 0.01 or P ⁇ 0.05); after three weeks of administration, The body weight of the two doses (20mg/kg and 15mg/kg) of MAX-40279-01 group was significantly improved compared with the model group (P ⁇ 0.05), achieving the same effect as the Pirfenidone group, and was more effective than the Nintedanib group. Excellent effect. See Table 3 and Figure 1.
  • the Ashcroft Score standard after mouse modeling, the lungs of the animals in the model group were completely occluded, the alveoli were almost covered by fibrous masses, accompanied by fibrotic masses, most of which affected more than 50% of the area, and the alveolar structure could not be identified.
  • the pathological scores of the two doses of MAX-40279-01 (15mg/kg and 10mg/kg) and Nintedanib groups were significantly lower than those of the model group (P ⁇ 0.05).
  • the pathological score of the high-dose MAX-40279-01 (20mg/kg) group was significantly lower than that of the model group (P ⁇ 0.01), and the therapeutic effect was significantly better than that of the Pirfenidone group and Nintedanib group. See Table 6, Figure 3 and Figure 4.
  • the TNF- ⁇ in the mouse model group was higher than that in the blank group, and there was a statistically significant difference (P ⁇ 0.01).
  • the three doses of MAX-40279-01 (20mg/kg, 15mg/kg and 10mg/kg) groups as well as the DEX group and Nintedanib group showed a significant reduction in TNF- ⁇ content, with statistically significant differences. (P ⁇ 0.01). See Table 7 and Figure 5.
  • the TGF- ⁇ in the mouse model group was higher than that in the blank group, and there was a statistically significant difference (P ⁇ 0.01).
  • the three doses of MAX-40279-01 (20mg/kg, 15mg/kg and 10mg/kg) group, DEX group, Pirfenidone and Nintedanib group all showed a significant reduction in TGF- ⁇ content, statistically There is a significant difference (P ⁇ 0.01). See Table 7 and Figure 5.
  • IL1- ⁇ in the mouse model group was higher than that in the blank group, with a statistically significant difference (P ⁇ 0.01).
  • the four doses of MAX-40279-01 (20mg/kg, 15mg/kg, 10mg/kg and 5mg/kg) groups as well as the DEX group and Nintedanib group showed a significant reduction in IL1- ⁇ (P ⁇ 0.01 or P ⁇ 0.05). See Table 7 and Figure 5.
  • IFN- ⁇ in the mouse model group was lower than that in the blank group, with a statistically significant difference (P ⁇ 0.01).
  • Two doses of MAX-40279-01 (20 and 15 mg/kg) groups as well as the DEX group and Nintedanib group showed significant upregulation of IFN- ⁇ (P ⁇ 0.01 or P ⁇ 0.05). See Table 7 and Figure 5.
  • the hydroxyproline in the mouse model group was higher than that in the blank group, and there was a statistically significant difference (P ⁇ 0.01).
  • the hydroxyproline content of mouse lung tissue in all doses of MAX-40279-01 groups (20mg/kg, 15mg/kg, 10mg/kg and 5mg/kg) as well as the DEX group, Nintedanib and Pirfenidone groups Significantly reduced (P ⁇ 0.01 or P ⁇ 0.05).
  • three doses of MAX-40279-01 groups (20mg/kg, 15mg/kg and 10mg/kg) achieved equivalent or even better effects than the Nintedanib and Pirfenidone groups. See Table 8 and Figure 6.
  • Compound MAX-40279-01 can improve the weight loss of mice after BLM modeling; reduce the lung organ coefficient and lung weight of model mice; improve the lung microstructure of animals in the model group and reduce fibrotic masses; reduce the size of the model mice.
  • Compound MAX-40279-01 synthesized according to the method disclosed in WO2019/228171A1.
  • 160 SD male rats were adaptively raised and continued to be raised until the weight reached about 240g. After anesthesia, they were fixed on the operating table. After disinfecting the neck with alcohol cotton, the muscles were separated layer by layer to expose the trachea. needle, after injecting a dose of bleomycin 2.5mg/kg (20ul/100g body weight), quickly stand the animal upright, then rotate it along the long axis of the body for 1 minute to evenly distribute the solution in the lungs, suture the incision, and return it to the cage after disinfection middle. In the sham operation group, the trachea was exposed, and normal saline was used instead of bleomycin solution to perform the same operation. After the animals wake up, the blank group and the model group are raised separately.
  • the bleomycin rats are randomly divided into three groups according to body weight: model group, 0.6 mg/kg DEX (dexamethasone) group, and 25 mg/kg Nintedanib group. , 150mg/kg Pirfenidone group, 10mg/kg MAX-40279-01 group, 7.5mg/kg MAX-40279-01 group, 5mg/kg MAX-40279-01 group, 2.5mg/kg MAX-40279-01 group, each Ten animals were enrolled in the group, and they were treated together with the blank control group 7 days after the modeling, for a total of 21 days. The model group and the blank control group were given corresponding solvents. The grouping situation is shown in Table 9 below:
  • the general condition of the animals was observed every day, and the body weight was recorded once every 7 days.
  • lung tissue organ coefficient lung tissue weight/body weight
  • the other lung was injected with 10% formaldehyde solution through the bronchus until the pleura was flattened and then the bronchus was ligated.
  • the lung tissue was collected longitudinally from the lung apex to the lung base for pathological examination (HE staining, Masson staining and pathological scoring). Szapiel scoring system and Ashcroft score, the scoring standards are as follows in Table 10:
  • lung lavage fluid to detect inflammatory cells and inflammatory factors: TGF- ⁇ and IL-1 ⁇ , TNF- ⁇ and IFN- ⁇ .
  • Collagen generally measures the collagen content in lung tissue, which can be determined by detecting the hydroxyproline content in lung tissue).
  • the body weight of the model group was lower than that of the blank group, with a statistically significant difference (P ⁇ 0.01), indicating that BLM modeling reduced the body weight of rats.
  • the model rats were weighed and divided into groups 7 days after the modeling, and there was no difference in the body weight of the rats in each administration group. Seven days after administration, the weight of rats in the 10 mg/kg and 7.5 mg/kg MAX-40279-01 groups decreased less. Among them, the weight of rats in the 7.5 mg/kg MAX-40279-01 group was lower than that of the model group.
  • the results of calculating the lung organ coefficient showed that the lung organ coefficient of the blank control group was smaller than that of the model group, with a very significant difference (P ⁇ 0.01). All doses of MAX-40279-01 (10mg/kg, 7.5mg/kg, 5mg/ kg and 2.5mg/kg) groups and the Pirfenidone group, the lung tissue of rats was smaller than that of the model group, with significant differences (P ⁇ 0.01 or P ⁇ 0.05). 0.6mg/kg DEX Due to the smaller body weight of rats, the organ coefficient was higher than that of the model group, and there was a significant difference compared with the model group (P ⁇ 0.05). See Table 13 and Figure 8.
  • Preliminary scoring was carried out according to the Szapiel scoring system standards. Compared with the blank group, the lungs of the animals in the model group had diffuse inflammatory infiltration and exudation, and most of the affected areas reached more than 50%.
  • the TNF- ⁇ in the rat model group was higher than that in the blank group, and there was a statistically significant difference (P ⁇ 0.01).
  • the three doses of MAX-40279-01 groups (10mg/kg, 7.5mg/kg and 5mg/kg) as well as the DEX group, Nintedanib group and Pirfenidone group significantly reduced the alveolar lavage of rats.
  • the TGF- ⁇ in the rat model group was higher than that in the blank group, and there was a statistically significant difference (P ⁇ 0.01).
  • the three doses of MAX-40279-01 groups (10mg/kg, 7.5mg/kg and 5mg/kg) as well as the DEX group, Nintedanib group and Pirfenidone group were all Significantly reduced TGF- ⁇ in alveolar lavage fluid of rats (P ⁇ 0.01). See Table 16 and Figure 13.
  • the IL1- ⁇ in the rat model group was higher than that in the blank group, and there was a statistically significant difference (P ⁇ 0.01).
  • three doses of MAX-40279-01 groups (10 mg/kg, 7.5 mg/kg and 5 mg/kg) and the DEX group significantly reduced IL1- ⁇ in the alveolar lavage fluid of rats (P ⁇ 0.01 or P ⁇ 0.05), but there was no difference between the Nintedanib group and Pirfenidone group compared with the model group (P>0.05). See Table 16 and Figure 13.
  • the IFN- ⁇ in the rat model group was lower than that in the blank group, and there was a statistically significant difference (P ⁇ 0.01).
  • the two doses of MAX-40279-01 groups (10mg/kg and 7.5mg/kg) and the DEX group significantly increased the IFN- ⁇ in the alveolar lavage fluid of rats (P ⁇ 0.05) , but there was no difference between the Nintedanib group and Pirfenidone group compared with the model group (P>0.05). See Table 16 and Figure 13.
  • the hydroxyproline content of the rat model group was higher than that of the blank group, and there was a statistically significant difference (P ⁇ 0.01).
  • the three doses of MAX-40279-01 groups (10mg/kg, 7.5mg/kg and 5mg/kg) as well as the DEX group, Nintedanib group and Pirfenidone group all significantly reduced the levels of hydroxypredose in rat lung tissue.
  • Amino acid content (P ⁇ 0.01). See Table 17 and Figure 14.
  • Compound MAX-40279-01 can well improve the weight loss induced by bleomycin (BLM) modeling in rats; reduce the lung organ coefficient and lung weight of model rats; and well improve the lungs of animals in the model group.
  • MBM bleomycin
  • Microstructure reduce fibrotic masses; reduce TNF- ⁇ , TGF- ⁇ , IL1- ⁇ , and increase the content of IFN- ⁇ in the lungs of model rats; reduce the content of hydroxyproline in the lungs of model rats ;

Abstract

L'invention concerne l'utilisation d'un composé pyrimidine à cycles fusionnés ou d'un sel pharmaceutiquement acceptable de celui-ci. La structure du composé pyrimidine à cycles fusionnés est représentée par la formule I. Le composé pyrimidine à cycles fusionnés peut être utilisé pour préparer un médicament pour traiter ou prévenir des maladies fibrotiques ou la maladie à coronavirus 2019 (COVID-19).
PCT/CN2023/114914 2022-08-25 2023-08-25 Utilisation d'un composé pyrimidine à cycles fusionnés WO2024041633A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106366093A (zh) * 2015-07-21 2017-02-01 广州再极医药科技有限公司 稠环嘧啶类化合物、中间体、其制备方法、组合物和应用
CN110551142A (zh) * 2018-05-31 2019-12-10 上海再极医药科技有限公司 一种稠环嘧啶类化合物的盐、晶型及其制备方法和应用
CN113384582A (zh) * 2020-03-13 2021-09-14 广州再极医药科技有限公司 稠环嘧啶化合物在制备治疗癌症的药物中的应用
WO2021247601A1 (fr) * 2020-06-02 2021-12-09 Model Medicines, Inc. Méthodes et compositions de traitement d'infections virales à arn
US20220117966A1 (en) * 2019-02-27 2022-04-21 Astrazeneca Ab Method of treating fibrosis

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106366093A (zh) * 2015-07-21 2017-02-01 广州再极医药科技有限公司 稠环嘧啶类化合物、中间体、其制备方法、组合物和应用
CN110551142A (zh) * 2018-05-31 2019-12-10 上海再极医药科技有限公司 一种稠环嘧啶类化合物的盐、晶型及其制备方法和应用
US20220117966A1 (en) * 2019-02-27 2022-04-21 Astrazeneca Ab Method of treating fibrosis
CN113384582A (zh) * 2020-03-13 2021-09-14 广州再极医药科技有限公司 稠环嘧啶化合物在制备治疗癌症的药物中的应用
WO2021247601A1 (fr) * 2020-06-02 2021-12-09 Model Medicines, Inc. Méthodes et compositions de traitement d'infections virales à arn

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