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WO2025139398A1 - Composition pharmaceutique pour le traitement d'une maladie inflammatoire pulmonaire, sa préparation, et son utilisation - Google Patents

Composition pharmaceutique pour le traitement d'une maladie inflammatoire pulmonaire, sa préparation, et son utilisation Download PDF

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Publication number
WO2025139398A1
WO2025139398A1 PCT/CN2024/130814 CN2024130814W WO2025139398A1 WO 2025139398 A1 WO2025139398 A1 WO 2025139398A1 CN 2024130814 W CN2024130814 W CN 2024130814W WO 2025139398 A1 WO2025139398 A1 WO 2025139398A1
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WIPO (PCT)
Prior art keywords
matrine
component
components
celery
extract
Prior art date
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English (en)
Chinese (zh)
Inventor
沈涛
管悦琴
许振鹏
彭广程
刘明杰
李国辉
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Jiuhua Huayuan Pharmaceutical Co Ltd
Shandong University
Original Assignee
Jiuhua Huayuan Pharmaceutical Co Ltd
Shandong University
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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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present application relates to the technical field of pneumonia pharmaceutical compositions, and in particular to a pharmaceutical composition for treating pulmonary inflammatory diseases, and a preparation and application thereof.
  • Oxidative stress caused by harmful substances can stimulate alveolar macrophages to secrete a variety of cytokines, such as interleukin-8 (IL-8) and tumor necrosis factor- ⁇ (TNF- ⁇ ), promote the release of proteases, promote epithelial permeability and increase the content of lipid peroxides.
  • cytokines such as interleukin-8 (IL-8) and tumor necrosis factor- ⁇ (TNF- ⁇ )
  • IL-8 and TNF- ⁇ tumor necrosis factor- ⁇
  • These factors lead to the retention and activation of neutrophils in the airways and lungs, and lead to a significant increase in the release of inflammatory factors, further exacerbating the inflammatory response in the airways, lungs and the whole body.
  • Respiratory diseases are closely related to inflammatory responses. From the perspective of treating inflammation, developing drugs to treat respiratory diseases is an effective strategy.
  • Acute or chronic inflammatory diseases can cause the body to produce a large amount of nitric oxide (NO).
  • NO nitric oxide
  • the continuous presence of high levels of NO in the human body can directly damage DNA and proteins and lead to tissue damage. Therefore, the NO production inhibition activity can reflect the anti-inflammatory activity of the compound.
  • Quinone reductase (QR) is a phase II detoxification enzyme that can catalyze the reduction of quinone substances and eliminate reactive oxygen in the body. It is generally believed that phase II detoxification enzymes are mainly responsible for the metabolic detoxification of harmful oxidants and chemical carcinogens. Therefore, QR-induced activity can reflect the inhibitory effect of the compound on inflammatory response and oxidative stress, as well as the preventive effect on inflammatory-related diseases such as COPD and pneumonia.
  • CD4 cells differentiate into mature CD4 cells, and then differentiate into different cell subtypes, including Th1, Th2, Th17 and regulatory Treg cells.
  • Different cell subtypes secrete different cytokines and chemokines, which mediate (or inhibit) the recruitment of inflammatory cells to the site of infection. This promotes (or inhibits) the progression of chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), lung cancer, cystic fibrosis and asthma.
  • COPD chronic obstructive pulmonary disease
  • exogenous particulate matter or cigarette smoke can cause intestinal inflammatory responses and changes in the composition of intestinal flora.
  • derived components of the intestinal flora or their metabolites can cause damage to the intestinal barrier, leading to local and systemic immune responses, which in turn affect the immune response and pathological damage of the lungs.
  • the interaction between the lung and the intestine is bidirectional.
  • the lungs can also regulate the intestinal microbiota through lymphocyte migration and inflammatory cells. Cytokines and other factors affect the intestine.
  • Thesium chinense Turcz. is a plant of the genus Thesium in the family Santalaceae. The whole plant is used as medicine. It tastes spicy, slightly bitter, and cold in nature. It enters the spleen, kidney, and lung meridians. It has the effects of clearing away heat and detoxifying, tonifying the kidney and astringing semen.
  • the research on the chemical components of Thesium chinense Turcz. is relatively weak. More than 60 compounds have been reported in the literature, including flavonoids, alkaloids, organic acids, terpenes and other chemical components. The material basis and mechanism of action of Thesium chinense in treating inflammatory diseases are still unclear.
  • the celery alkaloid components mainly include celery alkaloid I, celery alkaloid II, and celery alkaloid III.
  • celery alkaloid I has anti-inflammatory and anti-diabetic activities.
  • Celery alkaloid II has anti-inflammatory, antioxidant, neuroprotective, anti-osteoporosis, anti-cancer and other effects.
  • Celery alkaloid III has anti-inflammatory, antioxidant, osteoporosis treatment, anti-cancer and other effects. It can be seen that celery alkaloid components have broad application prospects in the field of new drug research and development.
  • Celery alkaloid I, celery alkaloid II and celery alkaloid III are the main components in celery, but the purification is difficult.
  • celery alkaloid I celery alkaloid II
  • celery alkaloid III pure products from celery.
  • celery alkaloid components have poor water solubility and low bioavailability. Only 3 alkaloids were found in the early literature from celery, but the content was extremely low, among which sophocarpine was a matrine component.
  • Matrine components belong to a type of quinolizidine alkaloids, and their molecular skeleton is composed of two quinolizidine rings fused together. This type of alkaloids is widely found in the leguminous plants Sophora flavescens, Sophora alopecuroides and Sophora root. Representative compounds include matrine, sophoridine, sophorocarpine, sophoramine, sophorolamine, etc. Matrine has a variety of pharmacological activities, such as anti-tumor, anti-arrhythmic, anti-diabetic, immunosuppressive, anti-inflammatory, antibacterial, antiviral, antiparasitic, anti-fibrotic and neuroprotective. Matrine alkaloids are used in clinical practice because of their wide range of pharmacological activities, but their toxicity, which cannot be ignored, limits their development as therapeutic drugs, especially their long-term use will cause liver and kidney damage.
  • the purpose of the embodiments of the present application is to provide a pharmaceutical composition for treating pulmonary inflammatory diseases, and its preparation and application, so as to solve the technical problem that there is no drug in the prior art that can effectively treat pulmonary inflammatory diseases.
  • the present application provides a pharmaceutical composition for treating pulmonary inflammatory diseases, comprising the following components:
  • R 6 , R 7 , and R 8 are independently selected from one of the following groups: H, OH, OCH 3 , and CH 3 COO.
  • the pharmaceutical composition comprises the following components:
  • the celery scutellariae component 60-66 parts The celery scutellariae component 60-66 parts,
  • the calendula component is selected from at least one of calendula I, calendula II, calendula III, calendula A, and calendula B;
  • the matrine component is selected from at least one of matrine, sophoracarpine, lycopodipine A, and lycopodipine B.
  • the pharmaceutical composition comprises the following components:
  • the method for extracting celastrol A and celastrol B comprises the following steps:
  • the whole herb After the dried whole herb of Herba Lycopodii is crushed, the whole herb is soaked at 20-40°C for 1-10 hours, and then the whole herb is extracted by heating and refluxing with 60-80% ethanol to obtain an extract; the extract is filtered and concentrated in sequence to obtain a total extract;
  • the second eluted product E7d was separated by a normal silica gel column, and the eluent was a dichloromethane/methanol eluent with a volume ratio of 0.1 to 30:1 for gradient elution, and 8 parts were collected in chronological order to obtain the third eluted products E7a-h;
  • the total alkaloid extract was separated by a normal phase silica gel column, and eluted with a petroleum ether/dichloromethane/ammonia water eluent in a volume ratio of 1:1:0.02-0.03; then gradient elution was performed with a dichloromethane/methanol eluent in a volume ratio of 6-97:3-4, and 10 parts were collected in chronological order to obtain the fourth elution product S1-S10;
  • the fourth elution product S5 is purified by Sephadex LH-20 column chromatography using methanol as eluent, and the purified S5 is separated by HPLC, wherein a mobile phase having a pH of 3 to 4 and a methanol volume percentage of 5% to 10% is used for elution;
  • the extraction process of the lycopodiola cruenta I, the lycopodiola cruenta II and the lycopodiola cruenta III comprises the following steps:
  • the dried whole herb of hyssop is crushed and soaked at 20-40° C. for 1-10 hours, and then heated and refluxed with an ethanol aqueous solution with a mass percentage of 60-80%; the extract is filtered and concentrated to obtain a total extract;
  • the extract After adding water to the ethyl acetate extract, the extract is passed through an MCI column, and then eluted with methanol-water solutions with a mass percentage of 20%-30%, 40%-50%, and 60%-70% in sequence to obtain a first fraction, a second fraction, and a third fraction in sequence;
  • the first fraction is then eluted with pure water, ethanol-water solution with a mass percentage of 20%-30%, 40%-50%, 60%-70%, and pure ethanol in sequence to obtain component a, component b, component c, component d, and component e in sequence;
  • the c component is purified by gel chromatography column, with methanol as eluent, and recrystallized to obtain celastrol II;
  • the third fraction is purified by gel chromatography column with methanol as eluent, and recrystallized to obtain celastrol III.
  • the present application provides a preparation for inflammatory diseases of the lungs, wherein the mass percentage of the above-mentioned pharmaceutical composition as an effective component in the preparation is 0.1%-99.9%, and the rest is a pharmaceutically acceptable excipient; wherein the dosage form of the preparation is tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, oral liquids, lozenges, granules, electuary, pills, powders, ointments, pills, suspensions, powders, injections, suppositories, creams, sprays, drops or patches.
  • the pharmaceutical composition provided by the present application mainly includes scutellaria baicalensis components and matrine components.
  • the scutellaria baicalensis components have QR inducing activity, can inhibit LPS-induced excessive production of NO in RAW264.7 mouse macrophages, reduce LPS-induced pathological changes in mouse lung tissue, inhibit the increase of inflammatory factor IL-1 ⁇ in the alveolar lavage fluid of mice induced by LPS, and can reduce the number of inflammatory cells in the blood of mice, thereby exerting a lung protective effect and reducing lung inflammation.
  • the synergistic effect of chelidonin components and matrine components, the two play a role in treating lung diseases through different mechanisms of action.
  • chelidonin components have a new mechanism for treating acute lung injury by regulating ferroptosis-related pathway proteins SLC7A11 and GPX4, while matrine components can inhibit the excessive activation of NLRP3 inflammasomes and inhibit NF-kB activation; the two synergistically play a lung protective effect through different mechanisms of action; and the combination of chelidonin and matrine components with key inflammatory regulatory proteins has a better anti-inflammatory effect. Therefore, the two components have an interaction of "enhancing efficacy and reducing toxicity, complementary mechanisms, and mutual solubility", which is conducive to wide application.
  • the beneficial effect of the second aspect provided by the embodiment of the present application is: providing a preparation for inflammatory lung diseases, wherein the mass percentage of the above-mentioned pharmaceutical composition as an effective component in the preparation is 0.1%-99.9%; therefore, the provided preparation has the effects of alleviating lung inflammation, protecting the lungs, having excellent anti-inflammatory effects, and is conducive to wide application.
  • the third aspect of the beneficial effect provided by the embodiments of the present application is that the pharmaceutical composition for treating inflammatory lung diseases has excellent anti-inflammatory effects, can effectively reduce lung inflammation, and can be widely used in the preparation of drugs for chronic obstructive pulmonary disease, acute lung injury or lower respiratory tract infection.
  • FIG1 is a schematic diagram of the structure of celastrol I.
  • FIG2 is a schematic diagram of the structure of celastrol II.
  • FIG3 is a schematic diagram of the structure of celastrol III.
  • FIG. 4 is a schematic diagram of the structure of celastrol A.
  • FIG5 is a schematic diagram of the structure of celastrol B.
  • FIG6 is a schematic diagram of the structure of matrine.
  • FIG. 7 is a schematic diagram of the structure of sophocarpine.
  • FIG8 is a schematic diagram of the structure of cyperine A.
  • FIG9 is a schematic diagram of the structure of cyperine B.
  • Figure 10 is a graph showing the anti-inflammatory effects of different drug compositions, indicating that each composition can inhibit the excessive production of NO in RAW264.7 mouse macrophages induced by LPS in a dose-dependent manner and exert an anti-inflammatory effect, wherein Figure A is a graph showing the anti-inflammatory effects of the composition of Example 3, Figure B is a graph showing the anti-inflammatory effects of the composition of Example 4, Figure C is a graph showing the anti-inflammatory effects of the composition of Example 5, Figure D is a graph showing the anti-inflammatory effects of the composition of Example 6, Figure E is a graph showing the anti-inflammatory effects of the composition of Example 7, and Figure F is a graph showing the anti-inflammatory effects of the composition of Example 8.
  • Figure 11 is a bar graph of the results of the NO production inhibition experiment, indicating that the chelidonin components can dose-dependently inhibit the excessive production of NO in LPS-induced RAW264.7 mouse macrophages, wherein Figure A is a bar graph of the NO production inhibition experiment results of chelidonin III, Figure B is a bar graph of the NO production inhibition experiment results of chelidonin A, and Figure C is a bar graph of the NO production inhibition experiment results of chelidonin B.
  • Figure 12 is a bar graph of the results of the QR-induced activity experiment, indicating that the chelidonin components have an inhibitory effect on oxidative stress
  • Figure A is a bar graph of the QR-induced activity experimental results of chelidonin III
  • Figure B is a bar graph of the QR-induced activity experimental results of chelidonin A
  • Figure C is a bar graph of the QR-induced activity experimental results of chelidonin B.
  • FIG. 13 shows the effect of celastrol A, a component of celastrol, on the transcriptome of human bronchial epithelial Beas-2B cells.
  • FIG. 14 shows the effect of scutellarine A, a component of the matrine class, on the transcriptome of human bronchial epithelial Beas-2B cells.
  • Figure 15 shows the potential anti-inflammatory functional genes (targets) of cleomelanin A, a component of cleomelanin, and cleomelanine A, a component of matrine.
  • FIG 16 is a photograph of H&E staining of mouse lung tissue, indicating that the basidiospermide components in the drug composition, namely basidiospermide I (BS1), basidiospermide II (BS2) and basidiospermide III (BS3), and the matrine component matrine (MR) and the combination of the two components (BS3+MR) can all reduce LPS-induced pathological changes in mouse lung tissue, and the effect of the combination group is more obvious.
  • basidiospermide I basidiospermide I
  • BS2 basidiospermide II
  • BS3 basidiospermide III
  • MR matrine component matrine
  • BS3+MR the combination of the two components
  • the concentration of the positive control drug DEX is 1 mg/kg
  • the concentration of LPS is 10 mg/kg
  • the concentrations of BS1, BS2, BS3 and MR are all 20 mg/kg
  • the concentration of the drug composition (BS3+MR) is 20 mg/kg of BS3 and 20 mg/kg of MR.
  • Figure 17 is a bar graph of the results of enzyme-linked immunosorbent assay, indicating that the basidiophore components in the drug composition, namely basidiophore I (BS1), basidiophore II (BS2) and basidiophore III (BS3), and the matrine component matrine (MR) and the combination of the two components (BS3+MR) can inhibit the increase of the inflammatory factor IL-1 ⁇ in the alveolar lavage fluid of mice induced by LPS, and the activity of the combination is significantly enhanced.
  • basidiophore components in the drug composition namely basidiophore I (BS1), basidiophore II (BS2) and basidiophore III (BS3)
  • MR matrine component matrine
  • MR matrine component matrine
  • IL-1 ⁇ the combination of the two components
  • the concentration of the positive control drug DEX is 1 mg/kg
  • the concentration of LPS is 10 mg/kg
  • the concentrations of BS1, BS2, BS3 and MR are all 20 mg/kg
  • the concentration of the drug composition (BS3+MR) is 20 mg/kg of BS3 and 20 mg/kg of MR.
  • Figure 18 is a scatter plot of the blood routine test results in mice, indicating that the basidiospermum officinale components in the drug composition, namely basidiospermum officinale I (BS1), basidiospermum officinale II (BS2) and basidiospermum officinale III (BS3), and the matrine component matrine (MR) and the combination of the two components (KF+MR) can all reduce the number of inflammatory cells in the blood of mice, among which the activity of the combination is significantly enhanced.
  • BS1 basidiospermum officinale I
  • BS2 basidiospermum officinale II
  • BS3 basidiospermum officinale III
  • MR matrine component matrine
  • KF+MR the combination of the two components
  • the concentration of the positive control drug DEX is 1 mg/kg
  • the concentration of LPS is 10 mg/kg
  • the concentrations of BS1, AG, BS3 and MR are all 20 mg/kg
  • the concentration of the drug composition (BS3+MR) is 20 mg/kg of BS3 and 20 mg/kg of MR.
  • FIG19 is a bar graph of qRT-PCR results, indicating that the basidiosyl components of the pharmaceutical composition, basidiosyl I (BS1), basidiosyl II (BS2) and basidiosyl III (BS3), and the matrine component matrine (MR) and the combination of the two components (BS3+MR) can reduce the increase in the mRNA level of inflammatory factors in the lung tissue of mice, wherein the activity of the composition is
  • the concentration of the positive control drug DEX was 1 mg/kg
  • the concentration of LPS was 10 mg/kg
  • the concentrations of BS1, BS2, BS3 and MR were all 20 mg/kg
  • the concentration of the drug composition (BS3+MR) was 20 mg/kg of BS3 and 20 mg/kg of MR.
  • Figure 20 is a bar graph of Western Blot and qRT-PCR results, indicating that the scutellariae components in the drug composition can regulate the ferroptosis-related pathway proteins SLC7A11 and GPX4 and their mRNA levels.
  • the concentration of the positive control drug DEX was 1 mg/kg
  • the concentration of LPS was 10 mg/kg
  • the concentrations of BS1, BS2, BS3 and MR were all 20 mg/kg.
  • FIG. 22 is a bar graph of the results of enzyme-linked immunosorbent assay, indicating that both scutellariae components and matrine components can inhibit the production of CS-induced inflammatory factors IL-1 ⁇ and TNF- ⁇ in the lungs of mice.
  • FIG. 23 is a bar graph of the results of routine blood tests in mice, indicating that both the scutellariae fractions and the matrine fractions reduced the number of inflammatory cells in the peripheral blood of mice induced by CS.
  • FIG. 24 is a bar graph of flow cytometry results, indicating that celery alkaloid components and matrine components inhibit the proportion of Th1 cells in CS-induced mouse lung tissue and improve the balance between Th1 and Th2.
  • FIG. 25 is a bar graph of flow cytometry results, indicating that celastrol components and matrine components inhibited the proportion of Th17 cells in CS-induced mouse lung tissue and improved the balance between Th17 and Treg.
  • Figure 26 is a bar graph of the results of improving intestinal flora, indicating that the chelidonide components can improve the composition of intestinal flora, among which the chelidonide components mainly improve the murinus species in the Lactobacillus genus, while the matrine components mainly improve COPD through the caecimuris and vulgatus species in the Bacteroides genus.
  • Figure 27 is a line graph of cell survival rate, indicating that the combination of BS3 and BSA with matrine (MR) can reduce the toxicity of MR to liver cells, wherein the combination ratio of BS3 and BSA to MR is 1:1.
  • Figure 28 is a line graph of cellular reactive oxygen species levels, indicating that the combination of basidiospermum nitrosum III (BS3) and basidiospermum nitrosum A (BSA) with matrine (MR), a component of the matrine class, can reduce the ability of MR to induce reactive oxygen species in liver cells.
  • the combination ratio of BS3 and BSA to MR is 1:1.
  • FIG. 29 is a 1 H NMR spectrum of celastrol A.
  • FIG. 30 is a 13 C NMR spectrum of celastrol A.
  • FIG. 31 is a 1 H NMR spectrum of celastrol B.
  • FIG. 32 is a 13 C NMR spectrum of celastrol B.
  • first and second are only used for the purpose of convenience of description, and cannot be understood as indicating or implying relative importance or implicitly indicating the number of technical features.
  • the meaning of “multiple” is two or more, unless otherwise clearly and specifically defined.
  • the first aspect of the present application provides a pharmaceutical composition for treating pulmonary inflammatory diseases, comprising the following components:
  • the extraction method of the lycopodipine A and the lycopodipine B is:
  • the whole herb of the herb is crushed, it is extracted with a hydrochloric acid aqueous solution with a mass percentage concentration of 0.1-0.5 mol/L (after the acid water extraction, the alkaloids are dissolved in the acid water in the form of salts, and the alkaloids are precipitated by adding alkali, which is conducive to the full extraction of dichloromethane), the extract is adjusted to alkaline, and then the dichloromethane is used for repeated extraction, and the total alkaloid extract is obtained after reduced pressure concentration;
  • the fourth elution product S5 is purified by Sephadex LH-20 column chromatography using methanol as eluent, and the purified S5 is separated by HPLC, wherein a mobile phase having a pH of 3 to 4 and a methanol volume percentage of 5% to 10% is used for elution;
  • the extract After adding water to the ethyl acetate extract, the extract is passed through an MCI column, and then eluted with methanol-water solutions with a mass percentage of 20%-30%, 40%-50%, and 60%-70% in sequence to obtain a first fraction, a second fraction, and a third fraction in sequence;
  • the first fraction is then eluted with pure water, ethanol-water solution with a mass percentage of 20%-30%, 40%-50%, 60%-70%, and pure ethanol in sequence to obtain component a, component b, component c, component d, and component e in sequence;
  • component b is purified by gel chromatography column, with methanol as eluent, and recrystallized to obtain celastrol I (purity>98%);
  • the c component is purified by gel chromatography column, with methanol as eluent, and recrystallized to obtain celastrol II (purity>98%);
  • the third fraction was purified by gel chromatography using methanol as the eluent, and recrystallized to obtain celastrol III (purity>98%).
  • the MCI column is an MCI gel column, which is a small-pore resin gel column (polystyrene-based reverse-phase resin filler).
  • the macroporous resin column is an AB-8 macroporous resin column; and the gel chromatography column is a Sephadex LH-20 gel chromatography column.
  • the second aspect of the embodiment of the present application provides a preparation for pulmonary inflammatory diseases, wherein the mass percentage of the above-mentioned pharmaceutical composition as an effective component in the preparation is 0.1%-99.9%, and the rest is a pharmaceutically acceptable excipient; wherein the dosage form of the preparation is tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, oral liquids, lozenges, granules, electuary, pills, powders, ointments, pills, suspensions, powders, injections, suppositories, creams, sprays, drops or patches.
  • the beneficial effect of the second aspect provided by the embodiment of the present application is: providing a preparation for inflammatory lung diseases, wherein the mass percentage of the above-mentioned pharmaceutical composition as an effective component in the preparation is 0.1%-99.9%; therefore, the provided preparation has the effects of alleviating lung inflammation, protecting the lungs, having excellent anti-inflammatory effects, and is conducive to wide application.
  • composition of the present application is prepared into a unit dose pharmaceutical preparation form, wherein the unit dose form refers to the unit of the preparation, such as each tablet of a tablet, each capsule of a capsule, each bottle of an oral solution, each bag of granules, and the like.
  • the preparation for oral administration may contain common excipients, binders, fillers, diluents, tableting agents, lubricants, disintegrants, colorants, flavoring agents and wetting agents, and the tablets may be coated if necessary.
  • the third aspect of the embodiments of the present application provides the use of the above-mentioned pharmaceutical composition for treating pulmonary inflammatory diseases in the preparation of drugs for chronic obstructive pulmonary disease, acute lung injury or lower respiratory tract infection.
  • the third aspect of the beneficial effect provided by the embodiments of the present application is that the pharmaceutical composition for treating inflammatory lung diseases has excellent anti-inflammatory effects, can effectively reduce lung inflammation, and can be widely used in the preparation of drugs for chronic obstructive pulmonary disease, acute lung injury or lower respiratory tract infection.
  • the lycopodiola cruciferol A and lycopodiola cruciferol B in the lycopodiola cruciferol provided in the present application can be prepared by the following method:
  • the ethyl acetate portion was first separated by normal phase silica gel column chromatography using petroleum ether/ethyl acetate as eluent. (1:0 ⁇ 0:1) and ethyl acetate/methanol (1:0 ⁇ 0:1) to obtain 8 parts (E1-E8); the E7 part was first subjected to MCI column chromatography to remove part of the pigment, and methanol/water (3:7 ⁇ 1:0) was used as the eluent to obtain 8 parts (E7a-h); the E7d part was separated by normal phase silica gel column chromatography (dichloromethane/methanol, 30:1 ⁇ 0:1) to obtain 6 parts (E7d1-6); the E7d5 part was separated and purified by Sephadex LH-20 gel and C18 reverse phase silica gel to obtain compounds celastrol A (purity of 99%, yield of 68%) and celastrol B (purity of 99%, yield of 71%).
  • a batch of dried and crushed whole herb materials of Herba Lycopodii were extracted with a 0.3 mol/L hydrochloric acid aqueous solution; the extract was adjusted to pH 10 with a 1.32 mol/L sodium hydroxide aqueous solution, then extracted four times with dichloromethane, and concentrated under reduced pressure to obtain a total alkaloid extract.
  • the total alkaloid extract was separated by normal phase silica gel column, and the eluent was petroleum ether/dichloromethane/ammonia water (1:1:0.03) and dichloromethane/methanol (97:3 ⁇ 6:4), and a total of 10 parts (S1-S10) were obtained, and the S5-S7 parts were selected for further system separation; the S5 part was separated by C 18 reverse phase silica gel column chromatography (methanol/water, 0:1 ⁇ 1:0), and a total of 6 parts (S5a-f) were obtained.
  • the dried whole herb of Herba Lycopodiellae was crushed and soaked at room temperature for 3 hours, and then extracted with 75% ethanol for 3 times, each time for 3 hours; after filtering the extract, the extract was vacuum concentrated on a rotary evaporator to obtain a total extract.
  • the total extract was suspended in water and extracted four times with equal volumes of petroleum ether, dichloromethane and ethyl acetate to obtain organic layers.
  • the ethyl acetate layer was dissolved in water and passed through an MCI column, eluted with 30%, 50%, and 70% methanol-water to remove the pigment and some impurities.
  • the 30% methanol-water fraction (A) and the 70% methanol-water fraction (B) were used for further separation.
  • the A fraction was separated by D101 macroporous resin column chromatography, and gradient elution was performed with pure water, 30% ethanol-water, 50% ethanol-water, 70% ethanol-water and pure ethanol for 3 column volumes respectively.
  • the 30% ethanol-water fraction (C) and the 50% ethanol-water fraction (D) were used for further purification; the C fraction was purified by Sephadex LH-20 gel chromatography column with methanol as the eluent, and finally recrystallized at 4°C using methanol as the solvent to obtain high-purity celery scutellarin I with a purity of 99% and a yield of 72%;
  • Fraction B was purified by Sephadex LH-20 gel chromatography column with methanol as eluent and finally recrystallized to obtain high-purity celastrol III with a purity of 98% and a yield of 51%.
  • the A fraction was separated by AB-8 macroporous resin column chromatography, and gradient eluted with pure water, 30% ethanol-water, 50% ethanol-water, 70% ethanol-water and pure ethanol for 3 column volumes each.
  • the 30% ethanol-water fraction (C) and the 50% ethanol-water fraction (D) were used for further purification.
  • the C fraction was purified by Sephadex LH-20 gel chromatography column with methanol as the eluent to obtain celastrol I with a purity of 83% and a yield of 89%.
  • the D fraction was purified by Sephadex LH-20 gel chromatography column with methanol as the eluent to obtain cyperine II with a purity of 76% and a yield of 85%.
  • the dried whole herb of Herba Lycopodiellae was crushed and soaked at room temperature for 3 hours, and then extracted with 75% ethanol under reflux for 3 times, each time for 3 hours. After filtering the extract, the extract was vacuum concentrated on a rotary evaporator to obtain a total extract.
  • the total extract was suspended with water in a volume ratio of 1:5, and extracted four times with petroleum ether, dichloromethane and ethyl acetate in a volume 6 times that of the total extract to obtain organic layers.
  • the ethyl acetate portion was first separated by normal phase silica gel column chromatography using petroleum ether/ethyl acetate (1:0 ⁇ 0:1) and ethyl acetate/methanol (1:0 ⁇ 0:1) as eluents to obtain 8 portions (E1-E8); the E7 portion was first subjected to MCI column chromatography to remove part of the pigment using methanol/water (3:7 ⁇ 1:0) as eluent to obtain 8 portions (E7a-h); the E7d portion was separated by normal phase silica gel column chromatography (dichloromethane/methanol, 30:1 ⁇ 0:1) to obtain 6 portions (E7d1-6); the E7d5 portion was separated and purified by Sephadex LH-20 gel to obtain compounds celastrol A (purity of 67%, yield of 88%) and celastrol B (purity of 71%, yield of 83%).
  • Cleome A and Cleome B can be prepared by the following method:
  • the dried whole herb of Herba Lycopodii was crushed and soaked at room temperature for 3 hours, and then extracted with water under reflux for 3 times, each time for 3 hours. After filtering the extract, the extract was vacuum concentrated on a rotary evaporator to obtain a total extract.
  • the total extract was suspended with water in a volume ratio of 1:5, and extracted four times with petroleum ether, dichloromethane and ethyl acetate in a volume 6 times that of the total extract to obtain organic layers.
  • the ethyl acetate portion was first separated by normal phase silica gel column chromatography using petroleum ether/ethyl acetate (1:0 ⁇ 0:1) and ethyl acetate/methanol (1:0 ⁇ 0:1) as eluents to obtain 8 portions (E1-E8); the E7 portion was first subjected to MCI column chromatography to remove part of the pigment using methanol/water (3:7 ⁇ 1:0) as eluent to obtain 8 portions (E7a-h); the E7d portion was separated by normal phase silica gel column chromatography (dichloromethane/methanol, 30:1 ⁇ 0:1) to obtain 6 portions (E7d1-6); the E7d5 portion was separated and purified by Sephadex LH-20 gel to obtain compounds celastrol A (purity of 65%, yield of 46%) and celastrol B (purity of 58%, yield of 41%).
  • Lycopodipine A and Lycopodipine B can be prepared by the following method:
  • a batch of dried and crushed whole herb materials of Herba Lycopodii were extracted with a 0.3 mol/L hydrochloric acid aqueous solution; the extract was adjusted to pH 10 with a 1.32 mol/L sodium hydroxide aqueous solution, then extracted four times with dichloromethane, and concentrated under reduced pressure to obtain a total alkaloid extract.
  • the total alkaloid extract was separated by normal phase silica gel column, and the eluent was petroleum ether/dichloromethane/ammonia water (1:1:0.03) and dichloromethane/methanol (97:3 ⁇ 6:4), and a total of 10 parts (S1-S10) were obtained, and the S5-S7 parts were selected for further system separation; the S5 part was separated by C 18 reverse phase silica gel column chromatography (methanol/water, 0:1 ⁇ 1:0), and a total of 6 parts (S5a-f) were obtained.
  • the S5f part was first purified by Sephadex LH-20 column chromatography, and the eluent was pure methanol, and the compounds scutellarine A (purity of 67%, yield of 79%) and scutellarine B (purity of 72%, yield of 76%) were obtained.
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • the compound is a yellow oily substance, soluble in methanol.
  • dichloromethane/methanol as the developing solvent at a ratio of 4:1, and adding a drop of glacial acetic acid, the thin layer chromatography was developed, and dark spots were displayed under a 254nm ultraviolet lamp.
  • p-anisaldehyde-concentrated sulfuric acid solution and heating for color development yellow spots were observed, indicating that it is a flavonoid substance with an R f value of 0.38.
  • HRESIMS showed that its quasi-molecular ion [M+H] + peak m/z 879.1991 (calculated value 879.1978), and its molecular formula was deduced to be C 42 H 38 O 21 .
  • H-1′′′′/C-3′′ and H-1′′′′′/C-2′′′′ in the HMBC spectrum determined the connection mode of the two sugars.
  • the relative configuration of the compound was inferred from this, and the structure of the compound was similar to that of the compound balsamiside A reported in the literature, with the main difference being the different connection positions of the two sugars.
  • C-2 and C-3 are two chiral carbons, and their absolute configuration was determined by comparing the ECD spectrum of the compound with the literature.
  • the ECD spectrum showed a positive cotton effect at 320nm and a negative cotton effect at 288nm.
  • the biflavonoid structure of this compound is the same as the structure of the hydrolysis product of the compound balsamiside A reported in the literature, and its cotton effect is basically the same, so its absolute configuration is determined to be 2S, 3S.
  • this compound is [(2S,3S)-2,3-epoxy-5,7,4′-trihydroxyflavanone]-(3 ⁇ 8)-kaempferol3′′-O- ⁇ -L-rhamnopyranosyl-(1 ⁇ 2)- ⁇ -D-glucopyranoside, named kaempferol A.
  • the compound is a yellow oily substance, soluble in methanol.
  • dichloromethane/methanol as the developing solvent at a ratio of 4:1, and adding a drop of glacial acetic acid, the thin layer chromatography was developed, and dark spots were displayed under a 254nm ultraviolet lamp.
  • p-anisaldehyde-concentrated sulfuric acid solution and heating for color development yellow spots were observed, indicating that it is a flavonoid substance with an R f value of 0.38.
  • HRESIMS showed that its quasi-molecular ion [M+H] + peak m/z 879.1991 (calculated value 879.1978), and its molecular formula was deduced to be C 42 H 38 O 21 .
  • the 1D NMR and 2D NMR spectra of the compound are basically consistent with those of kaempferol A, confirming that they have the same planar structure and should be a pair of diastereomers. The only difference between the two is the absolute configuration of C-2 and C-3.
  • the ECD spectrum shows that the compound has a negative cotton effect at 320nm and a positive cotton effect at 288nm, which is opposite to kaempferol A, indicating that the absolute configurations of the two compounds at C-2 and C-3 are opposite.
  • the structure of the compound is [(2R,3R)-2,3-epoxy-5,7,4′-trihydroxyflavanone]-(3 ⁇ 8)-kaempferol3′′-O- ⁇ -L-rhamnopyranosyl-(1 ⁇ 2)- ⁇ -D-gluco-pyranoside, named kaempferol B.
  • Table 1 1 H (600 MHz) and 13 C (150 MHz) data (CD 3 OD) of celery scutellarin A and celery scutellarin B
  • the compound is a colorless solid, soluble in methanol. Petroleum ether/ethyl acetate was used as the developing solvent at a ratio of 1:1, and a drop of glacial acetic acid was added. Thin layer chromatography was developed and dark spots were displayed under a 254nm ultraviolet lamp. The modified potassium bismuth iodide reagent was used to detect the presence of The color was developed by a reagent and an orange-red spot was observed with an R f value of 0.34. HRESIMS showed that its quasi-molecular ion [M+H] + peak m/z 247.1805 (calculated value 247.1805), and its molecular formula was deduced to be C 15 H 22 N 2 O with an unsaturation of 6.
  • the NOESY spectrum showed related signals of H-17b/H-7 and H-11; H-3b/H-5 and H-6; H-6/H-8b and H-11/H-8a, indicating that H-7 and H-11 were ⁇ -configuration, and H-5 and H-6 were ⁇ -configuration, thus determining the relative configuration of the compound. Based on the relative configuration of the compound, it was judged to be a new compound.

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Abstract

L'invention concerne une composition pharmaceutique pour le traitement d'une maladie inflammatoire pulmonaire, sa préparation, et son utilisation. La composition pharmaceutique contient les composants suivants : 1 à 100 parties d'un composant thésine et 1 à 20 parties d'un composant matrine, le composant thésine étant choisi parmi un ou une combinaison des composants thésine I, thésine II, thésine III, thésine A et thésine B, et le composant matrine étant choisi parmi un ou une combinaison des composants matrine, sophocarpine, alcaloïde thésium A et alcaloïde thésium B. Le composant thésine réduit la toxicité du composant matrine à des concentrations élevées, peut inhiber la toxicité hépatorénale provoquée par le composant matrine, et peut inhiber la génération de ROS provoquée par le composant matrine.
PCT/CN2024/130814 2023-12-28 2024-11-08 Composition pharmaceutique pour le traitement d'une maladie inflammatoire pulmonaire, sa préparation, et son utilisation Pending WO2025139398A1 (fr)

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