WO2023168786A1 - 1,7-二氢-6h-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用 - Google Patents

1,7-二氢-6h-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用 Download PDF

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WO2023168786A1
WO2023168786A1 PCT/CN2022/087110 CN2022087110W WO2023168786A1 WO 2023168786 A1 WO2023168786 A1 WO 2023168786A1 CN 2022087110 W CN2022087110 W CN 2022087110W WO 2023168786 A1 WO2023168786 A1 WO 2023168786A1
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pulmonary fibrosis
compound
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hypoxanthine
dihydro
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黄文�
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四川大学华西医院
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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
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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

Definitions

  • the invention relates to the technical field of biomedicine, and in particular to the application of a 1,7-dihydro-6H-purin-6-one compound in the preparation of anti-pulmonary fibrosis drugs.
  • Pulmonary fibrosis is a fatal lung disease caused by various pathogenic factors. Its pathological manifestations include a large amount of extracellular matrix accumulation, fibroblast proliferation, lung tissue structure destruction, and inflammatory reactions. Pulmonary fibrosis has a higher mortality rate than most oncological diseases, with the average survival time after diagnosis being 2.8 years. Pulmonary fibrosis will form when pneumonia continues to develop and worsen. Pulmonary fibrosis is a manifestation of the worsening of interstitial pneumonia or other pneumonias. They are different development stages of the same type of disease. Therefore, it is crucial to find a drug that can reduce the inflammatory response in the lungs, prevent and treat pneumonia and pulmonary fibrosis, and block the transformation of mild pneumonia into severe pneumonia and pulmonary fibrosis.
  • Hypoxanthine (1,7-dihydro-6H-purin-6-one, Hypoxanthine), also known as “6-hydroxypurine", is a synthetic precursor of purine nucleotides in nucleic acids and is a naturally occurring Purine compounds. There are currently no reports that hypoxanthine compounds can block the development of pulmonary fibrosis and reverse pathological damage.
  • the purpose of the present invention is to propose the application of a 1,7-dihydro-6H-purin-6-one compound in the preparation of anti-pulmonary fibrosis drugs, so as to accelerate the process of developing new anti-pulmonary fibrosis drugs.
  • the many technical effects that can be produced by the preferred technical solutions of the present invention are described in detail below.
  • the 1,7-dihydro-6H-purin-6-one compound of the present invention in the preparation of anti-pulmonary fibrosis drugs.
  • the 1,7-dihydro-6H-purin-6-one compound has anti-pulmonary fibrosis properties. chemical activity, and the 1,7-dihydro-6H-purin-6-one compound has one of the following structures:
  • R 1 and R 2 are optionally H, C 1 -C 18 alkyl, halogen-substituted C 1 -C 18 alkyl, trifluoromethyl, sulfonyl, sulfonamide, sulfinyl, amino acid group, 2-[ Bis(pivaloyloxy)methoxy]phosphonomethoxyethyl, C 1 -C 18 fatty acid group, C 3 -C 12 heterocyclyl, C 1 -C 18 fatty acid; or R 1 , R 2 It is optionally a C 1 -C 18 alkyl group or fatty acid group substituted by an oxygen atom, a sulfur atom or a nitrogen atom.
  • the 1,7-dihydro-6H-purin-6-one compound is one or more of the following compounds:
  • the anti-pulmonary fibrosis drugs include drugs with the effect of preventing and treating pulmonary fibrosis and its complications.
  • the anti-pulmonary fibrosis drug is prepared by using 1,7-dihydro-6H-purin-6-one compound or its salt as the active ingredient and adding pharmaceutically acceptable excipients or auxiliary ingredients. preparations made.
  • the preparation is an oral preparation, an injection preparation or a nasal mucosal administration preparation.
  • the pulmonary fibrosis includes one or more of primary pulmonary fibrosis, secondary pulmonary fibrosis, idiopathic pulmonary fibrosis, interstitial pulmonary fibrosis and interstitial pneumonia. kind.
  • the pulmonary fibrosis includes one of bacterial pulmonary fibrosis, viral pulmonary fibrosis, mycoplasmal pulmonary fibrosis, chlamydial pulmonary fibrosis, immune pulmonary fibrosis and fungal pulmonary fibrosis. or more.
  • the pulmonary fibrosis includes pulmonary fibrosis caused by Streptococcus pneumoniae, pulmonary fibrosis caused by influenza A virus, pulmonary fibrosis caused by influenza B virus, pulmonary fibrosis caused by coronavirus, and One or more of the pulmonary fibrosis caused by the new coronavirus.
  • the pulmonary fibrosis also includes pulmonary fibrosis caused by Klebsiella pulmonary fibrosis, pulmonary fibrosis caused by Streptococcus pulmonary fibrosis, pulmonary fibrosis caused by resistant enterococci, and drug-resistant Enterococci.
  • pulmonary fibrosis caused by Staphylococcus aureus and pulmonary fibrosis caused by Acinetobacter baumannii are examples of pulmonary fibrosis caused by Klebsiella pulmonary fibrosis, pulmonary fibrosis caused by Streptococcus pulmonary fibrosis, pulmonary fibrosis caused by resistant enterococci, and drug-resistant Enterococci.
  • the application of the 1,7-dihydro-6H-purine-6-one compound provided by the invention in the preparation of anti-pulmonary fibrosis drugs is achieved by structurally modifying and transforming the 1,7-dihydro-6H-purine-6 -
  • the pharmacological activity of ketone compounds against pulmonary fibrosis was tested.
  • the pharmacological activity of this type of compounds was tested in various animal disease models, and data on the activity in preventing and treating different types of pulmonary fibrosis were provided, confirming that they all have good activity and effects. It is significantly better than the commonly used clinical positive drug nintedanib, and its effect is also better than that of hypoxanthine analogs A, B, and C.
  • the application of the 1,7-dihydro-6H-purin-6-one compound provided by the present invention in the preparation of anti-pulmonary fibrosis drugs can provide a new framework for the screening of new compounds for the preparation of anti-pulmonary fibrosis drugs, and provide a basis for the development of anti-pulmonary fibrosis drugs.
  • New lead compounds lay the theoretical foundation.
  • the application of the 1,7-dihydro-6H-purin-6-one compound provided by the present invention in the preparation of anti-pulmonary fibrosis drugs can significantly improve pulmonary fibrosis caused by viruses and bacteria. More importantly, the 1,7-dihydro-6H-purin-6-one compound provided by the present invention can improve the symptoms of early pulmonary fibrosis and reverse the symptoms of advanced pulmonary fibrosis.
  • hypoxanthine analogs A, B, and C are as follows:
  • hypoxanthine analogs A, B, and C were prepared as follows to prepare compounds 2 and 3.
  • This example describes the preparation method of Compound 1 to Compound 12 in detail.
  • Compound 1 to Compound 12 are prepared through one or more steps of alkylation, thiolation, and imidization of hypoxanthine.
  • This example provides methods for preparing 12 kinds of 1,7-dihydro-6H-purin-6-one compounds. All the prepared 1,7-dihydro-6H-purin-6-one compounds were analyzed by nuclear magnetic resonance spectroscopy and Mass spectrometry determined its structure.
  • This example is used to detect the anti-extensive pulmonary fibrosis activity of Compound 1 to Compound 12 prepared in Example 1.
  • mice SPF grade C57BL/6 mice (weighing about 22-25g) were randomly divided into several groups, including a blank control group, a model group, and nintedanib. Positive control group, hypoxanthine analog group A, hypoxanthine analog group B, hypoxanthine analog group C, compound group 1, compound group 2... compound group 12, 9 animals in each group, in standard environment Feed for 7 days. Before the start of the experiment, mice were anesthetized with pentobarbital, and then bleomycin (5 mg/kg) was introduced through tracheal inhalation to induce pulmonary fibrosis.
  • the model group In addition to the tracheal infusion of normal saline in mice in the blank control group, the model group, Nida Mice in the nibu positive control group, hypoxanthine analogue group A, hypoxanthine analogue group B, hypoxanthine analogue group C, and compound group 1, compound 2, and compound 12 were instilled into the trachea respectively. 5mg/kg bleomycin.
  • mice in the blank control group and the model group were given the same dose of normal saline in the drug group by gavage, and the nintedanib positive control group was given nintedanib (120 mg/kg), hypoxanthine analogues Group A, hypoxanthine analog group B, and hypoxanthine analog group C were given hypoxanthine analog A (120 mg/kg/d), hypoxanthine analog B (120 mg/kg/d), and hypoxanthine analog group respectively.
  • Purine analog C 120 mg/kg/d
  • compound group 1 compound group 2...
  • Compound group 12 were administered compound 1 (120 mg/kg/d) and compound 2 (120 mg/kg/d) prepared in Example 1 respectively.
  • mice 120mg/kg/d.
  • the mice were administered twice a day for 14 days. 2 hours after the last administration, the mice were anesthetized with 0.4% sodium pentobarbital solution (10 mL/kg). Blood was collected from the abdominal aorta to detect changes in blood routine, and lungs were collected. The tissue was stained with HE to evaluate the severity of pulmonary fibrosis, and Ashcroft score was performed. The results are shown in Table 2-1 and Table 2-2 below.
  • Compounds 1 to 12 prepared in Example 1 can significantly reduce the levels of neutrophils, lymphocytes and leukocytes in the blood of early pulmonary fibrosis, indicating that Compounds 1 to 12 have significant anti-inflammatory properties.
  • Sexual effect, and the effect is better than nintedanib, and the effect is also better than hypoxanthine analog A, hypoxanthine analog B and hypoxanthine analog C.
  • Compound 1 to Compound 12 prepared in Example 1 all significantly reduced the degree of lung fiber in pulmonary fibrosis model mice, indicating that Compound 1 to Compound 12 have significant anti-early pulmonary fibrosis effects, and the effect It is better than nintedanib tablets, and its effect is also better than that of hypoxanthine analog A, hypoxanthine analog B and hypoxanthine analog C.
  • mice SPF grade C57BL/6 mice (weighing about 22-25g) were randomly divided into several groups, including a blank control group, a model group, and nintedanib. Positive control group, hypoxanthine analog group A, hypoxanthine analog group B, hypoxanthine analog group C, compound group 1, compound group 2... compound group 12, 9 animals in each group, in standard environment Feed for 7 days. Before the start of the experiment, mice were anesthetized with pentobarbital, and then bleomycin (5 mg/kg) was introduced through tracheal inhalation to induce pulmonary fibrosis.
  • mice in the blank control group were instilled into the trachea respectively. 5mg/kg bleomycin.
  • mice in the blank control group and the model group were given the same dose of normal saline in the drug group by gavage, and the nintedanib positive control group was given nintedanib (120 mg/kg) and hypoxanthine analogues.
  • hypoxanthine analog group B and hypoxanthine analog group C were given hypoxanthine analog A (120 mg/kg/d), hypoxanthine analog B (120 mg/kg/d), and hypoxanthine analog group respectively.
  • Purine analog C 120 mg/kg/d
  • compound group 1, compound group 2... compound group 12 were respectively administered with compound 1 (120 mg/kg/d) and compound 2 (120 mg/kg/d) prepared in Example 1. ).
  • Compound 12 120mg/kg/d).
  • the mice were administered twice a day for 14 days. 2 hours after the last administration, the mice were anesthetized with 0.4% sodium pentobarbital solution (10 mL/kg). Blood was collected from the abdominal aorta to detect changes in blood routine, and lungs were collected. The tissue was stained with HE to evaluate the severity of pulmonary fibrosis, and Ashcroft score was performed. The results are shown in Table 2-3 and Table 2-4 below.
  • Compounds 1 to 12 prepared in Example 1 all significantly reduced the levels of neutrophils, lymphocytes and leukocytes in the blood of advanced pulmonary fibrosis model mice, indicating that Compounds 1 to 12 have significant
  • the anti-inflammatory effect is better than that of nintedanib tablets, and the effect is also better than that of hypoxanthine analog A, hypoxanthine analog B and hypoxanthine analog C.
  • This example is used to detect the activity of Compound 1 to Compound 12 prepared in Example 1 against pulmonary fibrosis caused by Streptococcus pneumoniae.
  • mice SPF grade C57BL/6 mice (weighing about 22-25g) were randomly divided into several groups, including a blank control group, a model group, and nintedanib-positive mice. Control group, hypoxanthine analog group A, hypoxanthine analog group B, hypoxanthine analog group C, compound group 1, compound group 2... compound group 12, 9 animals in each group, under standard environment Feed for 7 days. Before the start of the experiment, the mice were lightly anesthetized with ether inhalation, and then used nasal inhalation.
  • mice were intranasally instilled with normal saline, and the model group, nintedanib positive control group, hypoxanthine Mice in the analog group A, the hypoxanthine analog group B, the hypoxanthine analog group C, the compound group 1, the compound group 2, and the compound group 12 were respectively given 0.5 mL/kg Streptococcus pneumoniae liquid (concentration (1.0 ⁇ 10 9 CFU/mL), use a syringe needle to slowly infuse the above bacterial solution into the nasal cavity of the mouse, the infusion speed is about 0.05mL/min, and the next day, 5mg/kg bleomycin is given to the trachea to induce Pulmonary Fibrosis.
  • Streptococcus pneumoniae liquid concentration (1.0 ⁇ 10 9 CFU/mL)
  • the infusion speed is about 0.05mL/min
  • 5mg/kg bleomycin is given to the trachea to induce Pulmonary Fibrosis.
  • mice in the blank control group and model group were given the same dose of normal saline in the drug group by gavage, and the nintedanib positive control group was given nintedanib (120 mg/kg), Purine analogue group A, hypoxanthine analogue group B, and hypoxanthine analogue group C were given hypoxanthine analogue A (120 mg/kg/d) and hypoxanthine analogue B (120 mg/kg/d) respectively.
  • hypoxanthine analog C 120mg/kg/d
  • Compound 12 group were given compound 1 (120mg/kg/d) and compound 2 (120mg/d) prepared in Example 1 respectively.
  • mice were administered twice a day for 14 days. 2 hours after the last administration, the mice were anesthetized with 0.4% sodium pentobarbital solution (10 mL/kg). Blood was taken from the abdominal aorta to detect changes in blood routine, and lungs were taken. The tissue was stained with HE to evaluate the severity of pulmonary fibrosis, and Ashcroft score was performed. The results are shown in Table 3-1 and Table 3-2 below.
  • Compounds 1 to 12 prepared in Example 1 all significantly reduced the levels of leukocytes, neutrophils and lymphocytes in the blood, indicating that Compounds 1 to 12 have significant anti-Streptococcus pneumoniae-induced lung disease. Fibrotic activity, and the effect is better than nintedanib, and the effect is also better than hypoxanthine analog A, hypoxanthine analog B and hypoxanthine analog C. And it was found that no fibrotic lesions appeared in the lungs of mice in the intervention group of Compound 1 to Compound 12.
  • Compounds 1 to 12 prepared in Example 1 can significantly reduce the degree of pulmonary fibrosis in mice with a pulmonary fibrosis model induced by Streptococcus pneumoniae, indicating that Compounds 1 to 12 have significant anti-Streptococcus pneumoniae-induced pulmonary fibrosis model mice.
  • the effect of pulmonary fibrosis is better than that of nintedanib tablets, and the effect is also better than that of hypoxanthine analog A, hypoxanthine analog B and hypoxanthine analog C.
  • This example is used to detect the activity of Compound 1 to Compound 12 prepared in Example 1 against pulmonary fibrosis induced by influenza A virus.
  • mice C57BL/6 mice (22-25g) were randomly divided into several groups, namely blank control group, model group, nintedanib positive control group, Hypoxanthine analog group A, hypoxanthine analog group B, hypoxanthine analog group C, and compound group 1, compound group 2... compound group 12, 9 animals in each group.
  • the mice in the blank control group were intranasally instilled with normal saline, and the mice in the other groups were infected with the FM1 strain of influenza A H1N1 virus (30 ⁇ L) through intranasal instillation.
  • mice in the blank control group and the model group were given the same dose of normal saline in the drug group by gavage, and the nintedanib positive control group was given nintedanib (120 mg/kg), Purine analogue group A, hypoxanthine analogue group B, and hypoxanthine analogue group C were given hypoxanthine analogue A (120 mg/kg/d) and hypoxanthine analogue B (120 mg/kg/d) respectively.
  • hypoxanthine analog C 120mg/kg/d
  • compound 1 group compound 1 group
  • compound 2 group 120mg/d
  • Administration was continued for 14 days, and the mice were observed daily and their body weight and death were recorded.
  • blood was collected from the eyeballs to immediately detect the expression levels of NF- ⁇ B, TNF- ⁇ , IL-1, and IL-6 in the serum, and lung tissue was taken for HE detection and Ashcroft score.
  • Table 4 Table 4 below. -1 and Table 4-2.
  • Compounds 1 to 12 prepared in Example 1 all significantly reduced the levels of NF- ⁇ B, TNF- ⁇ , IL-1 ⁇ and IL-6 in serum, indicating that Compounds 1 to 12 have significant It has anti-influenza A virus-induced pulmonary fibrosis activity, and the effect is better than nintedanib, and the effect is also better than hypoxanthine analog A, hypoxanthine analog B and hypoxanthine analog C. And it was found that no fibrotic lesions appeared in the lungs of mice in the intervention group of Compound 1 to Compound 12.
  • Example 1 Compounds 1 to 12 prepared in Example 1 can significantly reduce the degree of pulmonary fibrosis in mice with pulmonary fibrosis model caused by influenza A virus, indicating that Compounds 1 to 12 have significant anti-influenza A virus properties.
  • Influenza virus causes pulmonary fibrosis, and the effect is better than that of nintedanib tablets, and also better than hypoxanthine analog A, hypoxanthine analog B and hypoxanthine analog C.
  • This example is used to detect the activity of Compound 1 to Compound 12 prepared in Example 1 against pulmonary fibrosis induced by influenza B virus.
  • mice C57BL/6 mice (22–25g) were randomly divided into several groups, namely blank control group, model group, nintedanib positive control group, Hypoxanthine analog group A, hypoxanthine analog group B, hypoxanthine analog group C, and compound group 1, compound group 2... compound group 12, 9 animals in each group.
  • the mice in the blank control group were intranasally instilled with normal saline, and the mice in the other groups were infected with the influenza B H7N9 strain (30 ⁇ L) through intranasal instillation.
  • 5 mg/kg bleomycin was administered to the trachea.
  • mice in the blank control group and the model group were given the same dose of normal saline in the drug group by gavage, and the nintedanib positive control group was given nintedanib (120 mg/kg), Purine analogue group A, hypoxanthine analogue group B, and hypoxanthine analogue group C were given hypoxanthine analogue A (120 mg/kg/d) and hypoxanthine analogue B (120 mg/kg/d) respectively. , hypoxanthine analog C (120mg/kg/d), compound 1 group, compound 2 group...
  • Compound 12 group were given compound 1 (120mg/kg/d) and compound 2 (120mg/d) prepared in Example 1 respectively. kg/d)... compound 12 (120 mg/kg/d). Administration was continued for 14 days, and the mice were observed daily and their body weight and death were recorded. On the last day of administration, blood was collected from the eyeballs to immediately detect the expression levels of NF- ⁇ B, TNF- ⁇ , IL-1, and IL-6 in the serum, and mouse lung tissue was taken for HE staining and Ashcroft scoring. The results are shown in Tables 5-1 and 5-2 below.
  • Compound 1 to Compound 12 prepared in Example 1 all significantly reduced the levels of NF- ⁇ B, TNF- ⁇ , IL-1 ⁇ and IL-6 in the serum of mice with pulmonary fibrosis, indicating that Compounds 1 to 12 have significant activity against pulmonary fibrosis caused by influenza B virus, and the effect is better than nintedanib, and the effect is also better than hypoxanthine analog A, hypoxanthine analog B and hypoxanthine Analog C. And it was found that no fibrotic lesions appeared in the lungs of mice in the intervention group of Compound 1 to Compound 12.
  • Example 2 It can be seen from Table 5-2 that Compounds 1 to 12 prepared in Example 1 can significantly reduce the degree of pulmonary fibrosis in mice with pulmonary fibrosis model caused by influenza B virus, indicating that Compounds 1 to 12 have significant anti-Influenza B effects.
  • the virus induces pulmonary fibrosis, and the effect is better than that of nintedanib tablets, and the effect is also better than that of hypoxanthine analog compound A, hypoxanthine analog B and hypoxanthine analog C.
  • This example is used to detect the activity of Compound 1 to Compound 12 prepared in Example 1 against coronavirus-induced pulmonary fibrosis.
  • mice C57BL/6 mice (22-25g) were randomly divided into several groups, namely the blank control group, the model group, the nintedanib positive control group, and the hypoxanthide group.
  • the mice in the blank control group were intranasally instilled with normal saline, and the mice in the other groups were infected with HcoV-OC43 coronavirus strain (30 ⁇ L) through intranasal instillation.
  • mice in the blank control group and the model group were given the same dose of normal saline in the drug group by gavage, and the nintedanib positive control group was given nintedanib (120 mg/kg), Purine analogue group A, hypoxanthine analogue group B, and hypoxanthine analogue group C were given hypoxanthine analogue A (120 mg/kg/d) and hypoxanthine analogue B (120 mg/kg/d) respectively.
  • hypoxanthine analog C 120mg/kg/d
  • compound 1 group compound 1 group
  • compound 2 group 120mg/d
  • Administration was continued for 14 days, and the mice were observed daily and their body weight and death were recorded.
  • blood was collected from the eyeballs to immediately detect the expression levels of NF- ⁇ B, TNF- ⁇ , IL-1, and IL-6 in the serum, and mouse lung tissue was taken for HE staining and Ashcroft scoring. The results are shown in Tables 6-1 and 6-2 below.
  • Compounds 1 to 12 prepared in Example 1 all significantly reduced the levels of NF- ⁇ B, TNF- ⁇ , IL-1 ⁇ and IL-6 in the serum of mice infected with coronavirus, indicating that Compounds 1 to Compound 12 has significant anti-coronavirus-induced pulmonary fibrosis activity, and its effect is better than that of nintedanib, and its effect is also better than that of hypoxanthine analog A, hypoxanthine analog B and hypoxanthine analog C. And it was found that no fibrotic lesions appeared in the lungs of mice in the intervention group of Compound 1 to Compound 12.
  • Compounds 1 to 12 prepared in Example 1 can significantly reduce the degree of pulmonary fibrosis in coronavirus-induced pulmonary fibrosis model mice, indicating that Compounds 1 to 12 have significant anti-pulmonary fibrosis effects. And the effect is better than that of nintedanib tablets, and the effect is also better than that of hypoxanthine analog A, hypoxanthine analog B and hypoxanthine analog C.
  • This example is used to detect the activity of Compound 1 to Compound 12 prepared in Example 1 against pulmonary fibrosis caused by novel coronavirus.
  • mice C57BL/6 mice (22–25g) were randomly divided into several groups, namely blank control group, model group, nintedanib positive control group, and sub-group.
  • the mice in the blank control group were instilled with normal saline through the nasal cavity, and the mice in the other groups were infected with the COVID-19 coronavirus strain (30 ⁇ L) through the nasal cavity.
  • mice in the blank control group and the model group were given the same dose of normal saline in the drug group by gavage, and the nintedanib positive control group was given nintedanib (120 mg/kg), Purine analogue group A, hypoxanthine analogue group B, and hypoxanthine analogue group C were given hypoxanthine analogue A (120 mg/kg/d) and hypoxanthine analogue B (120 mg/kg/d) respectively.
  • hypoxanthine analog C 120mg/kg/d
  • compound 1 group compound 1 group
  • compound 2 group 120mg/d
  • Administration was continued for 14 days, and the mice were observed daily and their body weight and death were recorded.
  • blood was collected from the eyeballs to immediately detect the expression levels of NF- ⁇ B, TNF- ⁇ , IL-1, and IL-6 in the serum, and mouse lung tissue was taken for HE staining and Ashcroft scoring. The results are shown in Tables 7-1 and 7-2 below.
  • This example is used to detect the activity of Compound 1 to Compound 12 prepared in Example 1 against mycoplasma-induced pulmonary fibrosis.
  • mice were randomly divided into several groups, namely, blank control group, model group, nintedanib positive control group, hypoxanthine analog group A, Hypoxanthine analog group B, hypoxanthine analog group C, and compound group 1, compound group 2... compound group 12. Before modeling, the mice were anesthetized with ether. The mice in the blank control group were instilled with 100 ⁇ L of physiological saline through the nasal cavity. The remaining groups were slowly instilled with the same volume of MPFH strain solution (containing 1 ⁇ 10 7 mL -1 ). Nasal cavity, inhale into the bronchus, and instill continuously for 3 days.
  • mice in the blank control group and the model group were given the same dose of normal saline in the drug group by gavage, and the nintedanib positive control group was given nintedanib (120 mg/kg), Purine analogue group A, hypoxanthine analogue group B, and hypoxanthine analogue group C were given hypoxanthine analogue A (120 mg/kg/d) and hypoxanthine analogue B (120 mg/kg/d) respectively.
  • hypoxanthine analog C 120mg/kg/d
  • compound 1 group compound 1 group
  • compound 2 group 120mg/d
  • Compound 12 group were given compound 1 (120mg/kg/d) and compound 2 (120mg/d) prepared in Example 1 respectively. kg/d)...Compound 12 (120 mg/kg/d), once a day, for 14 consecutive days. The mice were observed daily and their body weight and mortality were recorded. On the last day of administration, the mice were sacrificed, and blood was collected from the eyeballs, and the blood routine indicators to be detected were stored at -80°C.
  • Compounds 1 to 12 prepared in Example 1 can all reduce the levels of leukocytes, neutrophils and lymphocytes in the blood of mycoplasma-infected mice, indicating that Compounds 1 to 12 have anti-mycoplasma-infected lung Fibrotic activity, and the effect is better than nintedanib, and the effect is also better than hypoxanthine analog A, hypoxanthine analog B and hypoxanthine analog C. And it was found that no fibrotic lesions appeared in the lungs of mice in the intervention group of Compound 1 to Compound 12.
  • Compounds 1 to 12 prepared in Example 1 can significantly reduce the degree of pulmonary fibrosis in mice with a mycoplasma-induced pulmonary fibrosis model, indicating that Compounds 1 to 12 have significant anti-mycoplasma-induced pulmonary fibrosis effects.
  • the effect is better than that of nintedanib tablets, and the effect is better than that of hypoxanthine analog A, hypoxanthine analog B and hypoxanthine analog C.

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Abstract

一种1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用。在多种动物肺纤维化模型中测试了结构修饰与改造后的1,7-二氢-6H-嘌呤-6-酮化合物抗肺纤维化药理活性，证实其均有良好活性，效果明显优于临床常用的阳性药物尼达尼布，也优于次黄嘌类似物A、B、C。

Description

1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用 技术领域
本发明涉及生物医药技术领域，尤其涉及一种1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用。
背景技术
肺纤维化是各种致病因素作用下引发的一种致命性肺部疾病，病理变现为大量细胞外基质聚集、成纤维细胞增殖、肺组织结构破坏以及炎症反应等。肺纤维的死亡率高于大多数肿瘤疾病，确诊后的平均生存期为2.8年。肺炎不断发展、加重就会形成肺纤维化，肺纤维化是间质性肺炎或其它肺炎恶化的一个表现，它们是同一类疾病的不同发展时期。因此，找寻一种可以减少肺部炎症反应，防治肺炎、肺纤维化，阻断轻症肺炎向重症肺炎肺纤维化转化的药物对肺炎及肺纤维化的防治至关重要。
次黄嘌呤(1,7-二氢-6H-嘌呤-6-酮，Hypoxanthine)，也称“6-羟基嘌呤”，它是核酸的嘌呤核苷酸的合成前体，是一种天然存在的嘌呤类化合物。目前尚无次黄嘌类化合物可阻断肺纤维化发展，并逆转病理损伤的报道。
发明内容
本发明的目的是提出一种1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用，以加快研发新的抗肺纤维化药物的进程。本发明优选技术方案所能产生的诸多技术效果详见下文阐述。
为实现上述目的，本发明提供了以下技术方案：
本发明的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用，所述1,7-二氢-6H-嘌呤-6-酮化合物具有抗肺纤维化活性，并且所述1,7-二氢-6H-嘌呤-6-酮化合物具有如下结构之一：
Figure PCTCN2022087110-appb-000001
其中：
R 1、R 2任选为H、C 1-C 18烷基、卤素取代的C 1-C 18烷基、三氟甲基、磺酰基、磺酰胺、亚磺酰基、氨基酸基、2-[双(新戊酰氧基)甲氧基]膦酰甲氧基乙基、C 1-C 18脂肪酸基、C 3-C 12杂环基、C 1-C 18脂肪酸；或者R 1、R 2任选为氧原子、硫原子或氮原子取代的C 1-C 18的烷基或脂肪酸基。
根据一个优选实施方式，所述的1,7-二氢-6H-嘌呤-6-酮化合物为以下化合物中的一种或多种：
Figure PCTCN2022087110-appb-000002
根据一个优选实施方式，所述的抗肺纤维化药物包括具有防治肺纤维化及其并发症功效的药物。
根据一个优选实施方式，所述的抗肺纤维化药物是以1,7-二氢-6H-嘌呤-6-酮化合物或其盐为活性成分，加入药学上可接受的辅料或者辅助性成分制备而成的制剂。
根据一个优选实施方式，所述的制剂为口服制剂、注射制剂或鼻腔黏膜给药制剂。
根据一个优选实施方式，所述的肺纤维化包括原发性肺纤维化、继发性肺纤维化、特发性肺纤维化、肺间质纤维化和间质性肺炎中的一种或多种。
根据一个优选实施方式，所述的肺纤维化包括细菌性肺纤维化、病毒性肺纤维化、支原体肺纤维化、衣原体肺纤维化、免疫性肺纤维化和真菌性肺纤维 化中的一种或多种。
根据一个优选实施方式，所述的肺纤维化包括肺炎链球菌引发的肺纤维化、甲型流感病毒引发的肺纤维化、乙型流感病毒引发的肺纤维化、冠状病毒引发的肺纤维化和新冠状病毒引发的肺纤维化中的一种或多种。
根据一个优选实施方式，所述的肺纤维化还包括肺纤维化克雷伯菌引发的肺纤维化、肺纤维化链球菌引发的肺纤维化、耐万古肠球菌引发的肺纤维化、耐药金葡菌引发的肺纤维化和鲍曼不动杆菌引发的肺纤维化中的一种或多种。
本发明提供的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用至少具有如下有益技术效果：
本发明提供的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用，通过对结构修饰与改造后的1,7-二氢-6H-嘌呤-6-酮化合物进行抗肺纤维化药理活性的检测，在多种动物疾病模型中测试了该类化合物的药理活性，并提供了防治不同类型肺纤维化活性的数据，证实其均有良好活性，效果明显优于临床常用的阳性药物尼达尼布，效果也优于次黄嘌类似物A、B、C。即本发明提供的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用，可为制备抗肺纤维化药物的新化合物的筛选提供新型骨架，为开发新型先导化合物奠定理论基础。
具体的，本发明提供的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用，可显著改善病毒、细菌引发的肺纤维化。更为重要的是，本发明提供的1,7-二氢-6H-嘌呤-6-酮化合物可改善早期肺纤维化病症，并可逆转晚期肺纤维化的病症。
具体实施方式
为使本发明的目的、优点和技术方案更加清楚，下面将对本发明的技术方案进行详细的描述。显然，所描述的实施例仅仅是本发明的一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所得到的所有其它实施方式，包括对本发明的1,7-二氢-6H-嘌呤-6-酮化合物治疗肺纤维化的延伸研究，都属于本发明所保护的范围。
通过对天然产物药物化学和化学研究，已经开发出许多植物内源性化合物及衍生物。对天然产物结构进行修饰和改造，得到了许多具有优良药理药化活性的衍生物。本发明提供的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用，通过对结构修饰与改造后的1,7-二氢-6H-嘌呤-6-酮化合物进行抗肺纤维化药理活性的检测，在多种动物疾病模型中测试了该类化合物的药理活性，并提供了防治不同类型肺纤维化活性的数据，证实其均有良好活性，效果明显优于临床常用的阳性药物尼达尼布，效果也优于次黄嘌类似物A、B、C。即本发明提供的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用，可为制备抗肺纤维化药物的新化合物的筛选提供新型骨架，为开发新型先导化合物奠定理论基础。
次黄嘌类似物A、B、C的结构分别如下所示：
Figure PCTCN2022087110-appb-000003
次黄嘌类似物A、B、C按如下制备化合物2和化合物3的方法制备。
下面结合实施例1～8对本发明提供的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用进行详细说明。
实施例1
本实施例对化合物1～化合物12的制备方法进行详细说明。
根据一个优选实施方式，化合物1～化合物12是通过次黄嘌呤的烷基化、巯基化、亚胺基化中的一步或多步反应制得。
本实施例提供了12种1,7-二氢-6H-嘌呤-6-酮化合物的制备方法，所有制得的1,7-二氢-6H-嘌呤-6-酮化合物均通过核磁共振谱和质谱确定其结构。
化合物1～化合物3的制备
化合物1～化合物3分别具有如下结构：
Figure PCTCN2022087110-appb-000004
化合物1的合成路线如下所示：
Figure PCTCN2022087110-appb-000005
化合物2和化合物3的合成路线如下所示：
Figure PCTCN2022087110-appb-000006
化合物1～化合物3的相关谱图数据如下：
化合物1： 1H NMR(500MHz,Chloroform-d)δ8.43(d,J＝1.7Hz,1H),8.05(d,J＝5.4Hz,1H),4.44(heptd,J＝6.8,1.6Hz,1H),1.26(d,J＝6.6Hz,6H).HRMS(ESI-TOF)[M+H+]:179.09；found 179.10。
化合物2： 1H NMR(400MHz,Chloroform-d)δ13.21(s,1H),8.27(s,1H),7.92(s,1H),4.78(hept,J＝6.8Hz,1H),1.58(d,J＝6.8Hz,6H).HRMS(ESI-TOF)[M+H+]:179.09；found 179.10。
化合物3： 1H NMR(400MHz,DMSO-d6)δ8.35(d,J＝1.3Hz,2H),5.03(hept,J＝13.6,6.7Hz,2H),1.49(d,J＝6.8Hz,6H),1.39(d,J＝6.9Hz,6H).HRMS(ESI-TOF)[M+H+]:221.27；found 221.20。
化合物4～化合物12的制备
化合物4～化合物12分别具有如下结构：
Figure PCTCN2022087110-appb-000007
化合物4～化合物12按如上制备化合物2和化合物3的方法制备。
化合物4～化合物12的相关谱图数据如下：
化合物4： 1H NMR(500MHz,Chloroform-d)δ8.27(q,J＝1.2Hz,1H),8.06(d,J＝5.6Hz,1H),3.67(d,J＝1.2Hz,3H).HRMS(ESI-TOF)[M+H+]:151.05；found 151.10。
化合物5： 1H NMR(500MHz,Chloroform-d)δ7.92(s,1H),3.82(d,J＝0.5Hz,2H).HRMS(ESI-TOF)[M+H+]:151.05；found 151.10。
化合物6： 1H NMR(500MHz,Chloroform-d)δ8.22(q,J＝1.1Hz,1H),7.89(s,1H),3.79(d,J＝0.9Hz,3H),3.51(d,J＝1.1Hz,3H).HRMS(ESI-TOF)[M+H+]:165.07；found 165.10。
化合物7： 1H NMR(500MHz,Chloroform-d)δ8.51(t,J＝0.7Hz,1H),8.05(d,J＝5.4Hz,1H),2.93(qd,J＝7.1,0.9Hz,2H),1.21(t,J＝7.4Hz,3H).HRMS(ESI-TOF)[M+H+]:165.07；found 165.10。
化合物8： 1H NMR(500MHz,Chloroform-d)δ7.93(d,J＝1.2Hz,1H),4.20(qd,J＝5.9,0.8Hz,1H),1.64(d,J＝10.4Hz,2H).HRMS(ESI-TOF)[M+H+]:165.07；found 165.10。
化合物9： 1H NMR(500MHz,Chloroform-d)δ8.31(t,J＝1.1Hz,1H),7.89(t,J＝1.1Hz,1H),4.20(qd,J＝5.9,0.6Hz,2H),2.97(qd,J＝7.5,1.1Hz,2H),1.61(d,J＝11.6Hz,3H),1.20(t,J＝7.6Hz,3H).HRMS(ESI-TOF)[M+H+]:193.10；found 193.10。
化合物10： 1H NMR(500MHz,Chloroform-d)δ8.22(q,J＝0.9Hz,1H),7.91(d,J＝0.8Hz,1H),4.86(heptd,J＝5.2,0.9Hz,1H),3.51(d,J＝0.9Hz,3H),1.88(s,6H).HRMS(ESI-TOF)[M+H+]:193.10；found 193.10。
化合物11： 1H NMR(500MHz,Chloroform-d)δ8.31(d,J＝1.1Hz,1H),7.89(d,J＝0.5Hz,1H),4.84(heptd,J＝5.2,0.8Hz,1H),2.97(qd,J＝7.5,0.8Hz,2H),1.84(s,6H),1.20–1.13(m,3H).HRMS(ESI-TOF)[M+H+]:207.11；found 207.10。
化合物12： 1H NMR(500MHz,Chloroform-d)δ8.28(d,J＝1.9Hz,1H),7.83(s,1H),4.31(heptd,J＝6.5,1.5Hz,1H),3.65(d,J＝0.5Hz,3H),1.26(d,J＝6.6Hz,6H).HRMS(ESI-TOF)[M+H+]:193.10；found 193.10。
实施例2
本实施例用来检测实施例1制得的化合物1～化合物12抗广泛性肺纤维化的活性。
(1)化合物1～化合物12抗早期肺纤维化的活性。
实验方法：建立体内博来霉素引发的肺纤维化模型：将SPF级的C57BL/6小鼠(重约22～25g)随机平均分成若干组，包括空白对照组、模型组、尼达尼布阳性对照组、次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组、以及化合物1组、化合物2组……化合物12组，每组9只，在标准环境下饲养7天。实验开始前，使用戊巴比妥麻醉小鼠，然后利用气管吸入导入博来霉素(5mg/kg)引发肺纤维化，除空白对照组小鼠气管滴注生理盐水外，模型组、尼达尼布阳性对照组、次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组、以及化合物1组、化合物2组……化合物12组的小鼠分别气管滴注5mg/kg博来霉素。造模结束1周后，空白对照组和模型组小鼠给予药物组同等剂量的生理盐水灌胃服用，尼达尼布阳性对照组给予尼达尼布(120mg/kg)，次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组分别给予次黄嘌呤类似物A(120mg/kg/d)、次黄嘌类似物B(120mg/kg/d)、次黄嘌类似物C(120mg/kg/d)，化合物1组、化合物2组…… 化合物12组分别给予实施例1制得的化合物1(120mg/kg/d)、化合物2(120mg/kg/d)……化合物12(120mg/kg/d)。每天给药两次，给药14d，末次给药2h后，将小鼠用0.4％戊巴比妥钠溶液(10mL/kg)麻醉，在腹主动脉处取血并检测血常规变化，取肺组织进行HE染色，评价肺纤维严重程度，并进行Ashcroft评分，结果见下表2-1和表2-2。
表2-1早期肺纤维化炎性检测结果表
组别 白细胞(10 9/L) 中性粒细胞(10 9/L) 淋巴细胞(10 9/L)
空白对照组 4.42 1.31 5.51
模型组 56.12 41.09 57.52
尼达尼布阳性对照组 36.74 29.59 35.76
次黄嘌类似物A组 51.37 41.12 51.39
次黄嘌类似物B组 49.55 39.39 54.26
次黄嘌类似物C组 50.53 38.75 54.29
化合物1 4.19 0.95 5.09
化合物2 4.06 0.98 5.10
化合物3 3.87 0.90 5.01
化合物4 4.31 1.18 5.23
化合物5 4.26 1.10 5.59
化合物6 4.39 1.15 5.39
化合物7 4.07 1.20 5.30
化合物8 4.15 1.14 4.94
化合物9 4.06 1.50 5.10
化合物10 3.95 1.33 5.05
化合物11 4.01 1.25 5.25
化合物12 3.99 1.09 5.15
表2-2早期肺纤维化程度Ashcroft评分表
组别 Ashcroft评分
空白对照组 1.03
模型组 6.30
尼达尼布阳性对照组 3.84
次黄嘌类似物A组 5.86
次黄嘌类似物B组 5.56
次黄嘌类似物C组 5.04
化合物1 0.86
化合物2 0.94
化合物3 0.90
化合物4 1.15
化合物5 1.16
化合物6 1.24
化合物7 1.08
化合物8 1.10
化合物9 1.11
化合物10 1.09
化合物11 1.12
化合物12 1.14
从表2-1可知，实施例1制得的化合物1～化合物12均显著降低早期肺纤维化血液中的中性粒细胞、淋巴细胞和白细胞水平，表明化合物1～化合物12具有显著的抗炎性作用，且效果优于尼达尼布，效果也优于次黄嘌呤类似物A、次黄嘌呤类似物B和次黄嘌呤类似物C。
从表2-2可知，实施例1制得的化合物1～化合物12均显著降低肺纤维化模型小鼠肺纤维程度，表明化合物1～化合物12具有显著的抗早期肺纤维化的作用，且效果优于尼达尼布片，效果也优于次黄嘌呤类似物A、次黄嘌呤类似物B和次黄嘌呤类似物C。
(2)化合物1～化合物12抗晚期肺纤维化的活性。
实验方法：建立体内博来霉素引发的肺纤维化模型：将SPF级的C57BL/6小鼠(重约22～25g)随机平均分成若干组，包括空白对照组、模型组、尼达尼布阳性对照组、次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组、以及化合物1组、化合物2组……化合物12组，每组9只，在 标准环境下饲养7天。实验开始前，使用戊巴比妥麻醉小鼠，然后利用气管吸入导入博来霉素(5mg/kg)引发肺纤维化，除空白对照组小鼠气管滴注生理盐水外，模型组、尼达尼布阳性对照组、次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组、以及化合物1组、化合物2组……化合物12组的小鼠分别气管滴注5mg/kg博来霉素。造模结束3周后，空白对照组和模型组小鼠给予药物组同等剂量的生理盐水灌胃服用，尼达尼布阳性对照组给予尼达尼布(120mg/kg)，次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组分别给予次黄嘌呤类似物A(120mg/kg/d)、次黄嘌类似物B(120mg/kg/d)、次黄嘌类似物C(120mg/kg/d)，化合物1组、化合物2组……化合物12组分别给予实施例1制得的化合物1(120mg/kg/d)、化合物2(120mg/kg/d)……化合物12(120mg/kg/d)。每天给药两次，给药14d，末次给药2h后，将小鼠用0.4％戊巴比妥钠溶液(10mL/kg)麻醉，在腹主动脉处取血并检测血常规变化，取肺组织进行HE染色，评价肺纤维严重程度，并进行Ashcroft评分，结果见下表2-3和表2-4。
表2-3晚期肺纤维化炎性检测结果表
组别 白细胞(10 9/L) 中性粒细胞(10 9/L) 淋巴细胞(10 9/L)
空白对照组 4.31 1.39 5.65
模型组 79.22 67.36 79.71
尼达尼布阳性对照组 45.14 41.28 48.90
次黄嘌类似物A组 69.50 65.41 73.25
次黄嘌类似物B组 71.32 69.29 69.33
次黄嘌类似物C组 75.54 62.45 73.40
化合物1 4.20 1.12 5.15
化合物2 4.11 1.09 5.10
化合物3 3.95 1.01 5.01
化合物4 4.20 1.31 5.46
化合物5 4.15 1.19 5.95
化合物6 4.65 1.20 5.65
化合物7 4.53 1.31 5.13
化合物8 4.63 1.32 5.15
化合物9 4.71 1.15 5.19
化合物10 4.15 1.51 5.15
化合物11 4.20 1.40 5.15
化合物12 4.09 1.29 5.17
表2-4晚期肺纤维化程度Ashcroft评分表
组别 Ashcroft评分
空白对照组 1.08
模型组 6.77
尼达尼布阳性对照组 4.56
次黄嘌类似物A组 5.91
次黄嘌类似物B组 6.15
次黄嘌类似物C组 6.11
化合物1 1.01
化合物2 1.05
化合物3 0.94
化合物4 1.15
化合物5 1.11
化合物6 1.21
化合物7 1.05
化合物8 1.09
化合物9 1.03
化合物10 1.04
化合物11 1.19
化合物12 1.11
从表2-3可知，实施例1制得的化合物1～化合物12均显著降低晚期肺纤维化模型小鼠血液中的中性粒细胞、淋巴细胞和白细胞水平，表明化合物1～化合物12具有显著的抗炎性作用，且效果优于尼达尼布片，效果也优于次黄嘌呤类似物A、次黄嘌呤类似物B和次黄嘌呤类似物C。
从表2-4可知，实施例1制得的化合物1～化合物12均显著降低晚期肺纤 维化模型小鼠肺纤维化程度，表明化合物1～化合物12具有显著的抗晚期肺纤维化的作用，且效果优于尼达尼布片，效果也优于次黄嘌呤类似物A、次黄嘌呤类似物B和次黄嘌呤类似物C。
实施例3
本实施例用来检测实施例1制得的化合物1～化合物12抗肺炎链球菌引发的肺纤维化的活性。
实验方法：建立体内肺炎链球菌引发的肺纤维化模型：将SPF级的C57BL/6小鼠(重约22～25g)随机平均分成若干组，包括空白对照组、模型组、尼达尼布阳性对照组、次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组、以及化合物1组、化合物2组……化合物12组，每组9只，在标准环境下饲养7天。实验开始前，先用乙醚吸入的方式将小鼠轻度麻醉，然后利用鼻腔吸入法，除空白对照组小鼠鼻腔滴注生理盐水外，模型组、尼达尼布阳性对照组、次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组、以及化合物1组、化合物2组……化合物12组的小鼠分别给予0.5mL/kg肺炎链球菌菌液(浓度为1.0×10 9CFU/mL)，用注射器针头将上述菌液缓慢滴注进小鼠鼻腔，滴注速度约为0.05mL/min，第二天，气管给予5mg/kg的博来霉素引发肺纤维化。博来霉素造模两周后，空白对照组和模型组小鼠给予药物组同等剂量的生理盐水灌胃服用，尼达尼布阳性对照组给予尼达尼布(120mg/kg)，次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组分别给予次黄嘌呤类似物A(120mg/kg/d)、次黄嘌类似物B(120mg/kg/d)、次黄嘌类似物C(120mg/kg/d)，化合物1组、化合物2组……化合物12组分别给予实施例1制得的化合物1(120mg/kg/d)、化合物2(120mg/kg/d)……化合物12(120mg/kg/d)。每天给药两次，给药14d，末次给药2h后，将小鼠用0.4％戊巴比妥钠溶液(10mL/kg)麻醉，在腹主动脉处取血并检测血常规变化，取肺组织进行HE染色，评价肺纤维严重程度，并进行Ashcroft评分，结果见下表3-1和表3-2。
表3-1肺炎链球菌引发肺纤维化炎性检测结果表
组别 白细胞(10 9/L) 中性粒细胞(10 9/L) 淋巴细胞(10 9/L)
空白对照组 6.74 1.44 5.96
模型组 151.40 94.99 116.59
尼达尼布阳性对照组 98.23 75.50 80.30
次黄嘌类似物A组 161.24 97.10 118.25
次黄嘌类似物B组 159.31 91.73 109.89
次黄嘌类似物C组 153.35 85.30 110.45
化合物1 5.86 1.19 5.81
化合物2 5.90 1.35 5.80
化合物3 5.54 1.04 5.71
化合物4 6.87 1.58 6.91
化合物5 6.90 1.20 7.28
化合物6 5.95 1.15 7.52
化合物7 6.80 1.31 7.63
化合物8 6.96 1.32 9.12
化合物9 6.84 1.55 6.95
化合物10 6.95 1.69 7.65
化合物11 7.23 1.94 7.35
化合物12 7.15 1.81 6.99
表3-2肺炎链球菌引发肺纤维化程度Ashcroft评分表
组别 Ashcroft评分
空白对照组 1.02
模型组 6.19
尼达尼布阳性对照组 4.34
次黄嘌类似物A组 6.19
次黄嘌类似物B组 6.13
次黄嘌类似物C组 6.14
化合物1 1.12
化合物2 0.99
化合物3 0.95
化合物4 1.12
化合物5 1.10
化合物6 1.17
化合物7 1.34
化合物8 1.32
化合物9 1.28
化合物10 1.32
化合物11 1.43
化合物12 1.26
从表3-1可知，实施例1制得的化合物1～化合物12均显著降低血液中的白细胞、中性粒细胞和淋巴细胞水平，表明化合物1～化合物12具有显著的抗肺炎链球菌引发肺纤维化的活性，且效果优于尼达尼布，效果也优于次黄嘌呤类似物A、次黄嘌呤类似物B和次黄嘌呤类似物C。并且发现化合物1～化合物12干预组小鼠肺部未出现纤维化病变。
从表3-2可知，实施例1制得的化合物1～化合物12均显著降低肺炎链球菌引发肺纤维化模型小鼠肺纤维化程度，表明化合物1～化合物12具有显著的抗肺炎链球菌引发肺纤维化的作用，且效果优于尼达尼布片，效果也优于次黄嘌呤类似物A、次黄嘌呤类似物B和次黄嘌呤类似物C。
实施例4
本实施例用来检测实施例1制得的化合物1～化合物12抗甲型流感病毒引发肺纤维化的活性。
实验方法：建立体内甲型流感病毒引发的肺纤维化模型：随机将C57BL/6小鼠(22～25g)平分成若干组，分别为空白对照组、模型组、尼达尼布阳性对照组、次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组、以及化合物1组、化合物2组……化合物12组，每组9只。第1天，空白对照组小鼠经鼻腔滴注生理盐水，其它各组小鼠均经滴鼻感染甲型H1N1流感病毒FM1株(30μL)。第二天，气管给予5mg/kg的博来霉素引发其发生肺纤维化。造肺纤维化模型14天之后，空白对照组和模型组小鼠均给予药物组同等 剂量的生理盐水灌胃服用，尼达尼布阳性对照组给予尼达尼布(120mg/kg)，次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组分别给予次黄嘌呤类似物A(120mg/kg/d)、次黄嘌类似物B(120mg/kg/d)、次黄嘌类似物C(120mg/kg/d)，化合物1组、化合物2组……化合物12组分别给予实施例1制得的化合物1(120mg/kg/d)、化合物2(120mg/kg/d)……化合物12(120mg/kg/d)。连续给药14天，每日观察小鼠并记录其体重和死亡情况。最后一天，采用眼球取血的方式，立即检测血清中的NF-κB、TNF-α、IL-1、和IL-6表达水平，并取肺组织进行HE检测及Ashcroft评分，结果见下表4-1和表4-2。
表4-1甲型流感病毒引发肺纤维化炎性指标检测结果表
Figure PCTCN2022087110-appb-000008
Figure PCTCN2022087110-appb-000009
表4-2甲型流感病毒引发肺纤维化程度Ashcroft评分表
组别 Ashcroft评分
空白对照组 1.18
模型组 6.24
尼达尼布阳性对照组 4.63
次黄嘌类似物A组 6.11
次黄嘌类似物B组 6.28
次黄嘌类似物C组 6.16
化合物1 1.11
化合物2 1.12
化合物3 1.21
化合物4 1.21
化合物5 1.29
化合物6 1.22
化合物7 1.28
化合物8 1.31
化合物9 1.35
化合物10 1.26
化合物11 1.30
化合物12 1.25
从表4-1可知，实施例1制得的化合物1～化合物12均显著降低血清中的NF-κB、TNF-α、IL-1β和IL-6水平，表明化合物1～化合物12具有显著的抗甲型流感病毒引发肺纤维化的活性，且效果优于尼达尼布，效果也优于次黄嘌呤类似物A、次黄嘌呤类似物B和次黄嘌呤类似物C。并且发现化合物1～化合物12干预组小鼠肺部未出现纤维化病变。
从表4-2可知，实施例1制得的化合物1～化合物12均显著降低甲型流感病毒引发的肺纤维化模型小鼠肺纤维化程度，表明化合物1～化合物12具有显著的抗甲型流感病毒引发肺纤维化的作用，且效果优于尼达尼布片，效果也优 于次黄嘌呤类似物A、次黄嘌呤类似物B和次黄嘌呤类似物C。
实施例5
本实施例用来检测实施例1制得的化合物1～化合物12抗乙型流感病毒引发肺纤维化的活性。
实验方法：建立体内乙型流感病毒引发的肺纤维化模型：随机将C57BL/6小鼠(22–25g)平分成若干组，分别为空白对照组、模型组、尼达尼布阳性对照组、次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组、以及化合物1组、化合物2组……化合物12组，每组9只。第1天，空白对照组小鼠经鼻腔滴注生理盐水，其它各组小鼠均经滴鼻感染乙型H7N9流感病毒株(30μL)，第二天，气管给予5mg/kg的博来霉素引发其发生肺纤维化。造肺纤维化模型14天之后，空白对照组和模型组小鼠均给予药物组同等剂量的生理盐水灌胃服用，尼达尼布阳性对照组给予尼达尼布(120mg/kg)，次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组分别给予次黄嘌呤类似物A(120mg/kg/d)、次黄嘌类似物B(120mg/kg/d)、次黄嘌类似物C(120mg/kg/d)，化合物1组、化合物2组……化合物12组分别给予实施例1制得的化合物1(120mg/kg/d)、化合物2(120mg/kg/d)……化合物12(120mg/kg/d)。连续给药14天，每日观察小鼠并记录其体重和死亡情况。给药最后一天，采用眼球取血的方式，立即检测血清中的NF-κB、TNF-α、IL-1、和IL-6的表达水平，并取小鼠肺组织进行HE染色及Ashcroft评分，结果见下表5-1和5-2。
表5-1乙型流感病毒引发肺纤维化炎性指标检测结果表
Figure PCTCN2022087110-appb-000010
Figure PCTCN2022087110-appb-000011
表5-2乙型流感病毒引发肺纤维化程度Ashcroft评分表
组别 Ashcroft评分
空白对照组 1.21
模型组 6.58
尼达尼布阳性对照组 4.33
次黄嘌类似物A组 6.21
次黄嘌类似物B组 6.44
次黄嘌类似物C组 6.23
化合物1 1.12
化合物2 1.29
化合物3 1.18
化合物4 1.35
化合物5 1.14
化合物6 1.34
化合物7 1.20
化合物8 1.10
化合物9 1.36
化合物10 1.27
化合物11 1.31
化合物12 1.33
从表5-1可知，实施例1制得的化合物1～化合物12均显著降低均显著降低肺纤维化小鼠血清中的NF-κB、TNF-α、IL-1β和IL-6水平，表明化合物1～化合物12具有显著的抗乙型流感病毒引发肺纤维化的活性，且效果优于尼达尼布，效果也优于次黄嘌呤类似物A、次黄嘌呤类似物B和次黄嘌呤类似物C。并且发现化合物1～化合物12干预组小鼠肺部未出现纤维化病变。
从表5-2可知，实施例1制得的化合物1～化合物12均显著降低乙型流感病毒引发肺纤维化模型小鼠肺纤维化程度，表明化合物1～化合物12具有显著的抗乙型流感病毒引发肺纤维化的作用，且效果优于尼达尼布片，效果也优于次黄嘌呤类似物化合物A、次黄嘌呤类似物B和次黄嘌呤类似物C。
实施例6
本实施例用来检测实施例1制得的化合物1～化合物12抗冠状病毒引发肺纤维化的活性。
实验方法：建立体内冠状病毒引发的肺纤维化模型：随机将C57BL/6小鼠(22～25g)平分成若干组，分别为空白对照组、模型组、尼达尼布阳性对照组、次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组、以及化合物1组、化合物2组……化合物12组，每组9只。第1天，空白对照组小鼠经鼻腔滴注生理盐水，其它各组小鼠均经滴鼻感染HcoV-OC43冠状病毒株(30μL)。第二天，气管给予5mg/kg的博来霉素引发其发生肺纤维化。造肺纤维化模型14天之后，空白对照组和模型组小鼠均给予药物组同等剂量的生理盐水灌胃服用，尼达尼布阳性对照组给予尼达尼布(120mg/kg)，次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组分别给予次黄嘌呤类似物A(120mg/kg/d)、次黄嘌类似物B(120mg/kg/d)、次黄嘌类似物C(120mg/kg/d)，化合物1组、化合物2组……化合物12组分别给予实施例 1制得的化合物1(120mg/kg/d)、化合物2(120mg/kg/d)……化合物12(120mg/kg/d)。连续给药14天，每日观察小鼠并记录其体重和死亡情况。给药最后一天，采用眼球取血的方式，立即检测血清中的NF-κB、TNF-α、IL-1、和IL-6的表达水平，并取小鼠肺组织进行HE染色及Ashcroft评分，结果见下表6-1和6-2。
表6-1冠状病毒引发肺纤维化炎性指标检测结果表
Figure PCTCN2022087110-appb-000012
表6-2冠状病毒引发肺纤维化程度Ashcroft评分表
组别 Ashcroft评分
空白对照组 1.58
模型组 6.29
尼达尼布阳性对照组 4.51
次黄嘌类似物A组 6.33
次黄嘌类似物B组 6.53
次黄嘌类似物C组 6.38
化合物1 1.19
化合物2 1.06
化合物3 1.47
化合物4 1.33
化合物5 1.24
化合物6 1.12
化合物7 1.73
化合物8 1.14
化合物9 1.36
化合物10 1.45
化合物11 1.68
化合物12 1.21
从表6-1可知，实施例1制得的化合物1～化合物12均显著降低感染冠状病毒小鼠血清中的NF-κB、TNF-α、IL-1β和IL-6水平，表明化合物1～化合物12具有显著的抗冠状病毒引发肺纤维化的活性，且效果优于尼达尼布，效果也优于次黄嘌呤类似物A、次黄嘌呤类似物B和次黄嘌呤类似物C。并且发现化合物1～化合物12干预组小鼠肺部未出现纤维化病变。
从表6-2可知，实施例1制得的化合物1～化合物12均显著降低冠状病毒引发肺纤维化模型小鼠肺纤维化程度，表明化合物1～化合物12具有显著的抗肺纤维化作用，且效果优于尼达尼布片，效果也优于次黄嘌呤类似物A、次黄嘌呤类似物B和次黄嘌呤类似物C。
实施例7
本实施例用来检测实施例1制得的化合物1～化合物12抗新型冠状病毒引 发肺纤维化的活性。
实验方法：建立体内新型冠状病毒引发的肺纤维化模型：随机将C57BL/6小鼠(22–25g)平分成若干组，分别为空白对照组、模型组、尼达尼布阳性对照组、次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组、以及化合物1组、化合物2组……化合物12组，每组9只。第1天，空白对照组小鼠经鼻腔滴注生理盐水，其它各组小鼠均经滴注鼻腔感染COVID-19冠状病毒株(30μL)，第二天，气管给予5mg/kg的博来霉素引发其发生肺纤维化。造肺纤维化模型14天之后，空白对照组和模型组小鼠均给予药物组同等剂量的生理盐水灌胃服用，尼达尼布阳性对照组给予尼达尼布(120mg/kg)，次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组分别给予次黄嘌呤类似物A(120mg/kg/d)、次黄嘌类似物B(120mg/kg/d)、次黄嘌类似物C(120mg/kg/d)，化合物1组、化合物2组……化合物12组分别给予实施例1制得的化合物1(120mg/kg/d)、化合物2(120mg/kg/d)……化合物12(120mg/kg/d)。连续给药14天，每日观察小鼠并记录其体重和死亡情况。给药最后一天，采用眼球取血的方式，立即检测血清中的NF-κB、TNF-α、IL-1、和IL-6的表达水平，并取小鼠肺组织进行HE染色及Ashcroft评分，结果见下表7-1和7-2。
表7-1新型冠状病毒引发肺纤维化炎性指标检测结果表
Figure PCTCN2022087110-appb-000013
Figure PCTCN2022087110-appb-000014
表7-2新型冠状病毒引发肺纤维化程度Ashcroft评分表
组别 Ashcroft评分
空白对照组 1.68
模型组 6.37
尼达尼布阳性对照组 5.95
次黄嘌类似物A组 6.33
次黄嘌类似物B组 6.53
次黄嘌类似物C组 6.29
化合物1 1.15
化合物2 1.49
化合物3 1.51
化合物4 1.25
化合物5 1.11
化合物6 1.13
化合物7 1.16
化合物8 1.36
化合物9 1.42
化合物10 1.33
化合物11 1.88
化合物12 1.06
从表7-1可知，实施例1制得的化合物1～化合物12均显著降低血清中的 NF-κB、TNF-α、IL-1β和IL-6水平，表明化合物1～化合物12具有显著的抗新型冠状病毒引发肺纤维化的活性，且效果优于尼达尼布，效果也优于次黄嘌呤类似物A、次黄嘌呤类似物B和次黄嘌呤类似物C。并且发现化合物1～化合物12干预组小鼠肺部未出现纤维化病变。
从表7-2可知，实施例1制得的化合物1～化合物12均显著降低新型冠状病毒引发肺纤维化模型小鼠肺纤维化程度，表明化合物1～化合物12具有显著的抗新型冠状病毒引发肺纤维化的作用，且效果优于尼达尼布片，效果也优于次黄嘌呤类似物A、次黄嘌呤类似物B和次黄嘌呤类似物C。
实施例8
本实施例用来检测实施例1制得的化合物1～化合物12抗支原体引发肺纤维化的活性。
实验方法：建立体内支原体引发的肺纤维化模型：随机将BALB/c小鼠平均分成若干组，分别是空白对照组、模型组、尼达尼布阳性对照组、次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组、以及化合物1组、化合物2组……化合物12组。造模前先用乙醚将小鼠进行麻醉，空白对照组小鼠经鼻腔滴注100μL的生理盐水，其余各组均以同体积的MPFH菌株溶液(含1×10 7mL -1)缓慢滴注鼻腔，使其吸入进支气管，连续滴注3天。第四天，气管给予5mg/kg的博来霉素引发其发生肺纤维化。造肺纤维化模型14天之后，空白对照组和模型组小鼠均给予药物组同等剂量的生理盐水灌胃服用，尼达尼布阳性对照组给予尼达尼布(120mg/kg)，次黄嘌类似物A组、次黄嘌类似物B组、次黄嘌类似物C组分别给予次黄嘌呤类似物A(120mg/kg/d)、次黄嘌类似物B(120mg/kg/d)、次黄嘌类似物C(120mg/kg/d)，化合物1组、化合物2组……化合物12组分别给予实施例1制得的化合物1(120mg/kg/d)、化合物2(120mg/kg/d)……化合物12(120mg/kg/d)，每日1次，连续给药治疗14天。每日观察小鼠并记录其体重和死亡情况。给药最后一天，将小鼠进行处死，采用眼球取血的方式，-80℃保存待检测血常规指 标。同时，用生理盐水将肺部进行灌洗，分离收集灌洗液，检测白细胞计数及分类，并取肺组织进行HE染色以及纤维化程度Ashcroft评分，结果见下表8-1和8-2。
表8-1支原体引发肺纤维化炎性检测结果表
组别 白细胞(10 9/L) 中性粒细胞(10 9/L) 淋巴细胞(10 9/L)
空白对照组 7.76 22.58 73.25
模型组 116.62 232.52 568.32
尼达尼布阳性对照组 121.28 234.21 569.31
次黄嘌类似物A组 118.26 237.12 569.58
次黄嘌类似物B组 114.42 237.23 562.96
次黄嘌类似物C组 121.82 234.12 575.21
化合物1 6.58 20.39 72.28
化合物2 6.55 23.08 74.65
化合物3 6.39 23.32 74.11
化合物4 6.56 23.34 71.21
化合物5 6.48 21.68 74.61
化合物6 6.13 22.34 73.23
化合物7 7.36 21.44 73.16
化合物8 7.16 23.53 73.54
化合物9 6.84 24.12 72.12
化合物10 6.15 21.53 73.22
化合物11 6.34 22.62 73.72
化合物12 6.28 23.35 74.68
表8-2支原体引发肺纤维化程度Ashcroft评分表
组别 Ashcroft评分
空白对照组 1.32
模型组 6.18
尼达尼布阳性对照组 5.68
次黄嘌类似物A组 6.44
次黄嘌类似物B组 6.35
次黄嘌类似物C组 6.31
化合物1 1.11
化合物2 1.18
化合物3 1.28
化合物4 1.16
化合物5 1.12
化合物6 1.13
化合物7 1.41
化合物8 1.06
化合物9 1.22
化合物10 1.25
化合物11 1.33
化合物12 1.13
从表8-1可知，实施例1制得的化合物1～化合物12均可降低支原体感染小鼠血液中白细胞、中性粒细胞和淋巴细胞水平，表明化合物1～化合物12具有抗支原体感染合并肺纤维化的活性，且效果优于尼达尼布，效果也优于次黄嘌呤类似物A、次黄嘌呤类似物B和次黄嘌呤类似物C。并且发现化合物1～化合物12干预组小鼠肺部未出现纤维化病变。
从表8-2可知，实施例1制得的化合物1～化合物12均显著降低支原体引发肺纤维化模型小鼠肺纤维化程度，表明化合物1～化合物12具有显著的抗支原体引发肺纤维化的作用，且效果优于尼达尼布片，效果也优于次黄嘌呤类似物A、次黄嘌呤类似物B和次黄嘌呤类似物C。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应以所述权利要求的保护范围为准。

Claims (9)

  1. 一种1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用，所述1,7-二氢-6H-嘌呤-6-酮化合物具有抗肺纤维化活性，并且所述1,7-二氢-6H-嘌呤-6-酮化合物具有如下结构之一：
    Figure PCTCN2022087110-appb-100001
    其中：
    R 1、R 2任选为H、C 1-C 18烷基、卤素取代的C 1-C 18烷基、三氟甲基、磺酰基、磺酰胺、亚磺酰基、氨基酸基、2-[双(新戊酰氧基)甲氧基]膦酰甲氧基乙基、C 1-C 18脂肪酸基、C 3-C 12杂环基、C 1-C 18脂肪酸；或者R 1、R 2任选为氧原子、硫原子或氮原子取代的C 1-C 18的烷基或脂肪酸基。
  2. 根据权利要求1所述的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用，其特征在于，所述的1,7-二氢-6H-嘌呤-6-酮化合物为以下化合物中的一种或多种：
    Figure PCTCN2022087110-appb-100002
  3. 根据权利要求1或2所述的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用，其特征在于，所述的抗肺纤维化药物包括具有防治肺纤维化及其并发症功效的药物。
  4. 根据权利要求1或2所述的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤 维化药物中的应用，其特征在于，所述的抗肺纤维化药物是以1,7-二氢-6H-嘌呤-6-酮化合物或其盐为活性成分，加入药学上可接受的辅料或者辅助性成分制备而成的制剂。
  5. 根据权利要求4所述的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用，其特征在于，所述的制剂为口服制剂、注射制剂或鼻腔黏膜给药制剂。
  6. 根据权利要求1所述的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用，其特征在于，所述的肺纤维化包括原发性肺纤维化、继发性肺纤维化、特发性肺纤维化、肺间质纤维化和间质性肺炎中的一种或多种。
  7. 根据权利要求6所述的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用，其特征在于，所述的肺纤维化包括细菌性肺纤维化、病毒性肺纤维化、支原体肺纤维化、衣原体肺纤维化、免疫性肺纤维化和真菌性肺纤维化中的一种或多种。
  8. 根据权利要求7所述的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用，其特征在于，所述的肺纤维化包括肺炎链球菌引发的肺纤维化、甲型流感病毒引发的肺纤维化、乙型流感病毒引发的肺纤维化、冠状病毒引发的肺纤维化和新冠状病毒引发的肺纤维化中的一种或多种。
  9. 根据权利要求8所述的1,7-二氢-6H-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用，其特征在于，所述的肺纤维化还包括肺纤维化克雷伯菌引发的肺纤维化、肺纤维化链球菌引发的肺纤维化、耐万古肠球菌引发的肺纤维化、耐药金葡菌引发的肺纤维化和鲍曼不动杆菌引发的肺纤维化中的一种或多种。
PCT/CN2022/087110 2022-03-11 2022-04-15 1,7-二氢-6h-嘌呤-6-酮化合物在制备抗肺纤维化药物中的应用 WO2023168786A1 (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101896177A (zh) * 2007-12-13 2010-11-24 诺瓦提斯公司 用于治疗癌症的治疗剂的组合
CN109912600A (zh) * 2019-02-22 2019-06-21 四川大学华西医院 一种防治肺纤维化的咪唑并嘧啶类衍生物及其应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101896177A (zh) * 2007-12-13 2010-11-24 诺瓦提斯公司 用于治疗癌症的治疗剂的组合
CN109912600A (zh) * 2019-02-22 2019-06-21 四川大学华西医院 一种防治肺纤维化的咪唑并嘧啶类衍生物及其应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PAN, HAIXIAN: "Clinical Analysis of a Case of Idiopathic Pulmonary Fibrosis in Children", CHINESE COMMUNITY DOCTORS, vol. 9, no. 161, 31 July 2007 (2007-07-31), pages 73, XP009548998, ISSN: 1007-614X *
XIE QIANG-MIN: "Drug Therapy of Idiopathic Pulmonary Fibrosis", WORLD PHARMACY / WORLD CLINICAL DRUGS, SHANGHAI PHARMACEUTICAL INDUSTRY RESEARCH INSTITUTE; CHINA NATIONAL CHEMICAL PHARMACEUTICAL, CN, vol. 34, no. 1, 31 January 2013 (2013-01-31), CN , pages 1 - 6, XP093091363, ISSN: 1672-9188 *
XUE, JIANGBO: "Clinical Study of Azathioprine in Combination with Azithromycin in Patients with Idiopathic Pulmonary Fibrosis", CHINA MODERN DOCTOR, vol. 48, no. 24, 31 August 2010 (2010-08-31), pages 39, 55, XP009548999, ISSN: 1673-9701 *

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