Use of QX77, AR7 and CA77.1 in the prevention and / or treatment of pneumoconiosis

Abstract

Disclosed is a use of a compound represented by formula (I), formula (II) or formula (III) or a tautomer, a stereoisomer, a solvate or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating pneumoconiosis. The compound represented by formula (I), formula (II) or formula (III) can effectively prevent and / or treat pneumoconiosis, especially silicosis.

Description

Technical Field

[0001] This invention relates to the fields of medicine and biology. Specifically, this application relates to the use of QX77, AR7, and CA77.1 in the prevention and / or treatment of pneumoconiosis, and more specifically, to combined drugs or kits and their uses, and methods for the prevention and / or treatment of pneumoconiosis. Background Technology

[0002] Pneumoconiosis is a group of occupational lung diseases characterized by diffuse fibrosis of the lungs, caused by long-term inhalation of industrial inorganic dust (including silica-containing dust, coal dust, asbestos dust, graphite dust, carbon black dust, etc.). It is well-known in the field that pneumoconiosis is one of the most prevalent and serious occupational diseases in my country and globally. Its long course, irreversible progression, and poor prognosis seriously threaten the health of working-age populations and place a heavy burden on social medical systems and families.

[0003] Although the composition and physicochemical properties of different types of industrial inorganic dust vary, the core pathogenic mechanism of pneumoconiosis is common. Current research indicates that this pathogenic process can be summarized as follows: inhaled dust particles are deposited in the alveolar tissue after passing through the respiratory tract and are phagocytosed by alveolar macrophages. Because these dust particles are difficult to biodegrade, alveolar macrophages undergo continuous activation and necrosis. The necrotic macrophages release the phagocytosed dust particles, which are then phagocytosed again by new alveolar macrophages, forming a vicious cycle of "phagocytosis-necrosis-rephagocytosis." During this process, the continuously released inflammatory factors, reactive oxygen species, and proteases activate fibroblasts in the lung tissue, promoting abnormal proliferation and excessive secretion of extracellular matrix (mainly collagen), ultimately leading to diffuse pulmonary fibrosis, destruction of lung tissue structure, and irreversible loss of lung function.

[0004] Clinically, common types of pneumoconiosis include silicosis (caused by inhaling free silica dust), coal worker's pneumoconiosis (caused by inhaling coal dust), and asbestosis (caused by inhaling asbestos fibers). Among these, silicosis has the highest incidence, the fastest progression, and the worst prognosis. Clinical consensus confirms that the persistent presence of free silica crystals in the lesion area of ​​silicosis patients leads to the formation of typical silicotic nodules. This area generates extreme oxidative stress and a toxic microenvironment, further accelerating the process of pulmonary fibrosis and severely shortening the patient's survival.

[0005] Currently, clinical treatments for pneumoconiosis mainly include symptomatic supportive care, whole lung lavage, conventional anti-inflammatory therapy, antioxidant therapy, and anti-fibrotic drug intervention. However, the overall treatment effect is limited, and there is still no specific treatment plan that can effectively stop or reverse the progression of pulmonary fibrosis. Whole lung lavage can only remove dust particles that have not been deposited in the respiratory tract, but cannot remove dust particles that have been deposited in the alveolar tissue and formed lesions; conventional anti-inflammatory and antioxidant therapies can only temporarily relieve symptoms and cannot break the vicious cycle of "phagocytosis-necrosis-re-phagocytosis," let alone repair damaged alveolar epithelial cells.

[0006] It is important to note that pneumoconiosis (especially silicosis) and idiopathic pulmonary fibrosis (IPF) have fundamentally different pathogenesis, and their treatment strategies cannot be directly equated. The etiology of IPF is not yet clear, but its core pathological mechanism is believed to be repeated damage and abnormal repair of alveolar epithelial cells, with inflammatory response not being the main driving factor for its progression. In contrast, pneumoconiosis has a clear exogenous pathogenic factor—the continuous physical stimulation and chemical toxicity of industrial inorganic dust particles. Its pulmonary fibrosis process is directly related to the long-term retention of dust particles in lung tissue and repeated necrosis of alveolar macrophages, belonging to "chronic damaging fibrosis caused by continuous stimulation of exogenous foreign bodies," which is fundamentally different from the "spontaneous epithelial repair disorder fibrosis" of IPF.

[0007] Based on the aforementioned mechanistic differences, some treatment strategies used to treat IPF are ineffective in pneumoconiosis. Regarding the efficacy of antifibrotic drugs (pirfenidone, nintedanib) in pneumoconiosis, existing clinical research evidence is insufficient and inconsistent. For example, a phase III clinical trial of pirfenidone in pneumoconiosis showed that it could delay the decline in lung function (NCT03845062, 2025), but direct evidence is still lacking regarding its effects on the core pathological aspects of pneumoconiosis, such as persistent dust retention, macrophage circulation damage, and an extremely toxic microenvironment. Nintedanib is recommended in the "Chinese Expert Consensus on the Treatment of Pneumoconiosis (2024 Edition)" for antifibrotic treatment of patients with rapidly progressive silicosis; however, this recommendation is mainly based on the extrapolation of its antifibrotic mechanism, and specific clinical studies for pneumoconiosis patients (such as trials for asbestosis and coal worker's pneumoconiosis) have been terminated or withdrawn due to recruitment difficulties. Therefore, the long-term efficacy and safety of existing antifibrotic drugs for pneumoconiosis still require more clinical data verification, and they cannot solve the problems unique to pneumoconiosis, such as the continuous dust retention and the resulting macrophage circulation damage.

[0008] Therefore, the treatment of pneumoconiosis (especially silicosis) faces unique challenges in its pathological microenvironment: the persistent presence of dust particles triggers a vicious cycle of "phagocytosis-necrosis-rephagocytosis," extreme oxidative stress, and the continuous release of toxic mediators, making it difficult for conventional anti-fibrotic or anti-inflammatory treatment strategies to fundamentally halt disease progression. Therefore, there is an urgent need in this field to develop a drug that can tolerate and overcome the extreme pathological microenvironment induced by dust. This drug not only needs to effectively inhibit the abnormal deposition of collagen in lung tissue but also needs to repair and regenerate damaged alveolar epithelial cells in the microenvironment of both physical and chemical toxicity caused by the persistent presence of dust particles, thereby delaying, preventing, or even reversing the pulmonary fibrosis process of pneumoconiosis and overcoming the technical bottlenecks that existing treatments cannot overcome. Summary of the Invention

[0009] The present invention aims to at least partially address at least one of the technical problems existing in the prior art. To this end, the present invention provides the use of compound QX77 and its structural analogues AR7 and CA77.1 in the preparation of medicaments for the prevention and / or treatment of pneumoconiosis.

[0010] This invention is based on the following discoveries of the inventors: The applicant's earlier application (application number CN202510922585.0) disclosed compounds of formula (I), (II), or (III) that can treat pulmonary fibrosis by activating the nuclear receptor Nur77 (see Examples 1-2 of that earlier application). However, that earlier application only relates to chemically induced (bleomycin) or idiopathic pulmonary fibrosis models and does not address pneumoconiosis, a disease with a unique pathological microenvironment. Pneumoconiosis is caused by long-term inhalation of inorganic dust, and its lesions involve continuous physical friction and cytotoxic damage, forming a vicious cycle of "macrophage phagocytosis-necrosis-rephagocytosis". The efficacy of conventional antifibrotic drugs (including pirfenidone and nintedanib, which are approved for idiopathic pulmonary fibrosis) in this extreme microenvironment needs further verification and is still in the exploratory stage.

[0011] The core pathology of silicosis is the physical damage and fibrotic process caused by the persistent presence of dust particles. Simple anti-inflammatory strategies cannot effectively inhibit the formation of silicotic nodules or promote the repair of damaged alveolar epithelium. The Nur77 activation pathway used in this invention provides a therapeutic mechanism that is completely different from conventional anti-inflammatory or single-target anti-fibrotic strategies by directly inhibiting fibroblast activation and promoting epithelial repair.

[0012] (II) The unique mechanism and effects of the compounds of this invention The inventors demonstrated through surface plasmon resonance experiments that QX77 can directly bind to the nuclear receptor Nur77 (Kd=2.56μM) and effectively activate its transcriptional activity (see Examples 1-2 of the prior application). Based on this, the inventors further verified the therapeutic effects of this type of compound in a silica (SiO2)-induced silicosis animal model.

[0013] Surprisingly, the compounds shown in formula (I), formula (II), or formula (III) not only possess conventional anti-fibrotic activity but also exhibit a unique ability to resist both physical and toxic damage from silica. Specifically: (1) Inhibition of silicosis nodule formation and collagen deposition: In a toxic microenvironment where free silica dust is continuously present, the compound of this application can effectively improve pathological damage to lung tissue, significantly inhibit the deposition of collagen in the lung matrix, and specifically reduce the formation and expansion of characteristic silicosis nodules.

[0014] (2) Promoting the repair and regeneration of damaged alveolar epithelium: Silica crystals induce severe oxidative stress and DNA double-strand breaks, leading to extensive damage to alveolar epithelial cells (especially AT1 cells). Conventional regeneration-promoting methods are ineffective in lesions containing persistent sources of damage. However, the compound of this application can still significantly downregulate the expression of the DNA damage marker γ-H2AX in lesions where silica dust is persistent, and effectively reverse the decline of AT1 cell markers (Hopx, Caveolin1), thus strongly promoting the survival, differentiation and regeneration of damaged alveolar epithelial cells.

[0015] This powerful tissue repair capability under the continuous damage of silica dust is something that those skilled in the art cannot predict from conventional aseptic or endogenous pulmonary fibrosis models, offering the possibility of truly reversing the course of pneumoconiosis. This invention, by activating Nur77, simultaneously achieves the dual functions of "anti-fibrosis" and "promoting epithelial repair," providing a fundamental treatment strategy targeting the unique pathological microenvironment of silicosis.

[0016] (iii) Reasonable expectations of structural analogues Based on the binding activity of QX77 and Nur77 and their definite anti-fibrotic and repair-promoting effects in a silicosis model, the inventors further tested structural analogs AR7 and CA77.1, which have the same core framework. Experimental results showed that AR7 and CA77.1 could also activate Nur77 in vitro (see Example 1 of the prior application), and exhibited similar activities to QX77 in improving lung tissue pathology, reducing collagen deposition, and promoting epithelial repair in a silica-induced silicosis model (see Example 1 of this application). Therefore, those skilled in the art can reasonably expect that other structural analogs of formula (I), (II), or (III) can also be used for the prevention and / or treatment of pneumoconiosis (especially silicosis).

[0017] In a first aspect, the present invention provides the use of a compound of formula (I), formula (II) or formula (III) or a tautomer, stereoisomer, solvate or pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of pneumoconiosis.

[0018] (I);

[0019] (II);

[0020] (III).

[0021] According to embodiments of the present invention, the compounds represented by formula (I), formula (II) or formula (III) above, or their tautomers, stereoisomers, solvates, or pharmaceutically acceptable salts, can effectively prevent and / or treat pneumoconiosis, especially silicosis.

[0022] In a second aspect, the present invention provides a pharmaceutical composition. According to embodiments of the present invention, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I), formula (II) or formula (III) or a tautomer, stereoisomer, solvate, or pharmaceutically acceptable salt thereof as an active ingredient;

[0023] (I);

[0024] (II);

[0025] (III).

[0026] According to embodiments of the present invention, the above-described pharmaceutical compositions comprising a therapeutically effective amount of the compound represented by formula (I), formula (II) or formula (III) or its tautomers, stereoisomers, solvates, or pharmaceutically acceptable salts thereof can effectively prevent and / or treat pneumoconiosis, especially silicosis.

[0027] In a third aspect of the invention, the invention proposes the use of the pharmaceutical composition described in the second aspect of the invention in the preparation of a medicament for the prevention and / or treatment of pneumoconiosis.

[0028] In a fourth aspect, the present invention provides a combination drug or cassette. According to an embodiment of the present invention, the combination drug or cassette comprises: a first active ingredient, which is a compound of formula (I), formula (II) or formula (III) or a tautomer, stereoisomer, solvate, or pharmaceutically acceptable salt thereof;

[0029] (I);

[0030] (II);

[0031] (III).

[0032] According to embodiments of the present invention, the above-described combined drugs or kits can effectively prevent and / or treat pneumoconiosis, especially silicosis.

[0033] According to an embodiment of the present invention, the combined drug or cassette further comprises: a second active ingredient, the second active ingredient being selected from one or more other drugs for relieving silicosis symptoms.

[0034] According to an embodiment of the present invention, the second active ingredient is selected from antitussive and bronchodilator drugs, bronchodilators, glucocorticoids, anti-infective drugs or pulmonary lavage fluid.

[0035] In a fifth aspect of the invention, the invention provides for the use of the combined medicament or medicament described in the fourth aspect in the preparation of a medicament for the prevention and / or treatment of silicosis.

[0036] In a sixth aspect of the invention, a method for preventing and / or treating pneumoconiosis is provided. According to an embodiment of the invention, the method comprises administering to a subject a pharmaceutically acceptable dose of a compound of formula (I), formula (II), or formula (III) or a tautomer, stereoisomer, solvate, or pharmaceutically acceptable salt thereof, or the combination drug or cassette described in the fourth aspect;

[0037] (I);

[0038] (II);

[0039] (III).

[0040] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Attached Figure Description

[0041] The above and / or additional aspects and advantages of this application will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which: Figure 1 The figures show the results of establishing a mouse silica (SiO2)-induced silicosis model, the drug administration regimen, and the effects of QX77 on macroscopic indicators and collagen content in mice, as described in Example 1 of this invention. Figure 1 A is a schematic diagram of the experimental procedure in which 8-week-old male C57BL / 6 mice were given SiO2 (100 mg / kg) or PBS via intravenous drip on day 1, and then continuously administered QX77 (20 mg / kg / d) or corn oil by gavage for 31 days after day 14. Figure 1 B is a graph showing the changes in mouse body weight during modeling and drug administration; Figure 1 C is a graph showing the statistical results of the lung-to-body ratio (lung weight / body weight) calculated by weighing the mouse lung tissue at the time of sample collection; Figure 1 Figure D shows the statistical results of collagen content in mouse lung tissue detected using a hydroxyproline assay kit.

[0042] Figure 2 This image shows the histological staining and quantitative analysis results of QX77 in improving lung tissue pathological damage and reducing collagen deposition in a mouse silicosis model, as described in Example 1 of this invention. (The image likely shows the results of the analysis.) Figure 2 A shows HE-stained images of mouse lung tissue (the original panoramic scale bar is 700 μm, and the scale bar of the magnified image is 50 μm) and statistical results of assessing the integrity and severity of damage of mouse alveolar structure according to the Ashcroft scoring criteria. Figure 2 B shows a Sirius red stained image of mouse lung tissue (the original panoramic scale bar is 700 μm, and the scale bar of the magnified image is 50 μm) and a statistical result of quantitative analysis of the collagen matrix deposition area in mouse lungs using ImageJ software.

[0043] Figure 3 This is a qRT-PCR detection result of QX77 inhibiting the lung fibrosis process in a mouse silicosis model in this embodiment of the invention. The figure shows the relative mRNA expression levels of lung fibrosis-related indicators (COL1A1, COL3A1, SPP1, PDPN, Timp1, Fibronectin, Tenascin-c, MMP2, and TGF-β) obtained after extracting mRNA from mouse lung tissue (β-actin was used as an internal reference gene and normalized with the control group).

[0044] Figure 4 This is a graph showing the detection results of QX77's effect on reducing alveolar epithelial cell damage and promoting regeneration in mice, as described in this embodiment of the invention. Wherein: Figure 4 Figure A shows the protein expression level of γ-H2AX, a marker of DNA damage in mouse lung epithelial cells, as detected by Western blotting after extracting proteins from mouse lung tissue. Figure 4 B shows the relative expression levels of alveolar epithelial cell markers (Hopx, Caveolin1, Sftpc) detected by qRT-PCR after extracting mRNA from mouse lung tissue (calculated using the 2–ΔΔCt method with β-actin as an internal reference).

[0045] (Note: In the statistical analysis of all the quantitative data above, n=6, one-way ANOVA was used. In the figure, p<0.05 (*) indicates statistical significance, p<0.01 (**) indicates high significance, p<0.001 (***) and p<0.0001 (****) indicate extremely significant, and ns indicates no significant difference.) Detailed Implementation The embodiments of this application are described in detail below. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application.

[0046] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this application, unless otherwise stated, "multiple" means two or more.

[0047] Detailed description of the invention Definitions and General Terms In this document, the terms “comprising” or “including” are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.

[0048] In this document, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0049] In this document, the term "pharmaceutically acceptable" or "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals to which it is treated. Preferably, "pharmaceutically acceptable" as used herein means approved by a federal regulatory agency or national government, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, particularly in humans.

[0050] In this document, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic or organic acid that retains the bioavailability of the free base without other side effects. "Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic or organic base that retains the bioavailability of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are also contemplated in this invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used for the identification, characterization, or purification of the compounds of this invention.

[0051] In this document, the term "amine salt" refers to the product obtained by neutralizing an alkyl primary amine, secondary amine, or tertiary amine with an acid. The acid includes the inorganic or organic acids described in this application.

[0052] In this paper, the term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0053] Depending on the choice of raw materials and methods, the compounds of the present invention can exist as one or a mixture of possible isomers, for example as purely optical isomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral centers (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the plane-polarized rotation induced by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory.

[0054] When the bonds of the chiral carbon in the formulas of this invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The illustration of racemic or enantiomerically pure compounds in this document is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. The absolute configuration of a stereocenter is represented by wedge-shaped and dashed bonds.

[0055] In this document, the term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds of this invention can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0056] In this document, the term "solvent" refers to a compound of the present invention or a salt thereof comprising a stoichiometric or nonstoichiometric solvent bound by intermolecular noncovalent forces, and a hydrate when the solvent is water.

[0057] In this document, the term "pharmaceutical composition" generally refers to a unit dosage form and can be prepared by any method well known in the pharmaceutical industry. All methods involve the step of combining the active ingredient with a carrier constituting one or more adjunct components. Typically, compositions are prepared by uniformly and sufficiently combining the active compound with a liquid carrier, a finely chopped solid carrier, or both.

[0058] In this document, the term "treatment" refers to the use of a drug to achieve a desired pharmacological and / or physiological effect. This effect may be preventative in terms of complete or partial prevention of a disease or its symptoms, and / or therapeutic in terms of partial or complete cure of a disease and / or adverse effects caused by the disease. As used herein, "treatment" encompasses diseases in mammals, particularly humans, including: (a) prevention of disease or the onset of a condition in individuals susceptible to disease but not yet diagnosed with it; (b) suppression of disease, such as inhibiting disease progression; or (c) alleviating disease, such as reducing symptoms associated with the disease. As used herein, "treatment" encompasses any use of a drug to treat, cure, alleviate, improve, reduce, or suppress a disease in an individual, including but not limited to the administration of the drugs described herein to individuals in need.

[0059] In this paper, the term "silicosis" specifically refers to a systemic disease caused by long-term inhalation of dust containing free silica, leading to dust retention in the lungs and a series of physical damage, macrophage necrosis, and the formation of silicotic nodules as the main pathological feature. In the context of this application, silicosis is an occupational disease with a clearly identifiable exogenous physical pathogen, and its pathogenesis, disease progression, and microenvironmental characteristics are significantly different from ordinary pulmonary fibrosis (such as idiopathic pulmonary fibrosis IPF) caused by endogenous biological abnormalities or idiopathic factors.

[0060] In this paper, the term "regulation" includes positive regulation (e.g., maintenance, upregulation, or activation) and negative regulation (e.g., downregulation or inhibition).

[0061] Detailed description of the use of the present invention QX77, AR7, and CA77.1 in the prevention and / or treatment of pneumoconiosis. This invention proposes the use of QX77, AR7, and CA77.1 in the prevention and / or treatment of pneumoconiosis, combined drugs or kits and their uses, and methods for the prevention and / or treatment of pneumoconiosis, which will be described in detail below.

[0062] use In a first aspect, the present invention provides the use of a compound of formula (I), formula (II) or formula (III) or a tautomer, stereoisomer, solvate or pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of pneumoconiosis.

[0063] (I);

[0064] (II);

[0065] (III).

[0066] According to embodiments of the present invention, the compounds represented by formula (I), formula (II) or formula (III) above, or their tautomers, stereoisomers, solvates, or pharmaceutically acceptable salts, can effectively prevent and / or treat pneumoconiosis, especially silicosis.

[0067] According to an embodiment of the present invention, the pneumoconiosis is selected from at least one of silicosis, coal worker's pneumoconiosis, asbestosis, welder's pneumoconiosis and cement pneumoconiosis.

[0068] According to an embodiment of the present invention, the pneumoconiosis is silicosis.

[0069] According to an embodiment of the present invention, the silicosis is a pathological injury induced by long-term inhalation of dust containing free silica.

[0070] According to embodiments of the present invention, the treatment of silicosis includes reducing the area of ​​silicotic nodules in lung tissue; reducing the hydroxyproline content in lung tissue; alleviating alveolar septal thickening and / or collagen deposition; alleviating DNA damage to lung tissue cells; and promoting the repair and regeneration of alveolar epithelial cells, or one or more of the following:

[0071] According to embodiments of the present invention, the dosage of the compound represented by formula (I), formula (II) or formula (III) or its tautomers, stereoisomers, solvates, or pharmaceutically acceptable salts is about 1.0 mg to 100.0 mg, for example 1.0 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 35.0 mg, 40.0 mg, 45.0 mg, 50.0 mg, 55.0 mg, 60.0 mg, 65.0 mg, 70.0 mg, 75.0 mg, 80.0 mg, 85.0 mg, 90.0 mg, 95.0 mg, 100.0 mg, or any two values ​​therebetween, as a range between endpoints, exemplarily 20.0 mg to 100.0 mg.

[0072] In this document, the term "about" or "approximately" refers to an acceptable error for a particular value, as determined by those skilled in the art, which depends in part on how the value is measured or determined. In some embodiments, the term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In some embodiments, the term "about" or "approximately" refers to within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.

[0073] In this document, the dosage of the compound represented by formula (I), formula (II) or formula (III) or its tautomers, stereoisomers, solvates or pharmaceutically acceptable salts is approximately 20.0 mg to 100.0 mg. The dosing frequency can be adjusted according to actual needs, including but not limited to once a week, once every two days, once a day, twice a day (i.e., BID), three times a day, etc. The dosage is set based on the dosage of a person of normal weight and can be adjusted according to the weight and condition of different people. All of these are within the protection scope of this invention.

[0074] According to embodiments of the present invention, the dosage form of the drug includes oral formulations, injectable formulations, or inhaled formulations.

[0075] According to embodiments of the present invention, the inhalation formulation includes a nebulized inhaler, a dry powder inhaler, or an aerosol.

[0076] In a second aspect, the present invention provides a pharmaceutical composition. According to embodiments of the present invention, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I), formula (II) or formula (III) or a tautomer, stereoisomer, solvate, or pharmaceutically acceptable salt thereof as an active ingredient;

[0077] (I);

[0078] (II);

[0079] (III).

[0080] According to embodiments of the present invention, the above-described pharmaceutical compositions comprising a therapeutically effective amount of the compound represented by formula (I), formula (II) or formula (III) or its tautomers, stereoisomers, solvates, or pharmaceutically acceptable salts thereof can effectively prevent and / or treat pneumoconiosis, especially silicosis.

[0081] According to embodiments of the present invention, the compounds represented by formula (I), formula (II) or formula (III) above, or their tautomers, stereoisomers, solvates, or pharmaceutically acceptable salts, can effectively prevent and / or treat pneumoconiosis, especially silicosis.

[0082] According to embodiments of the present invention, the dosage of the compound represented by formula (I), formula (II) or formula (III) or its tautomers, stereoisomers, solvates or pharmaceutically acceptable salts is about 1.0 mg to 100.0 mg, exemplarily 20.0 mg to 100.0 mg.

[0083] According to embodiments of the present invention, the dosage form of the drug includes oral formulations, injectable formulations, or inhaled formulations.

[0084] According to embodiments of the present invention, the inhalation formulation includes a nebulized inhaler, a dry powder inhaler, or an aerosol.

[0085] In some preferred embodiments, the pharmaceutical compositions of the present invention are formulated as inhaled preparations (such as nebulized inhalers or dry powder inhalers). Since the core of silicosis lies in the local microenvironmental toxicity caused by free silica within the alveoli, inhalation allows the active compound to bypass the first-pass effect and be delivered directly at high concentrations to the deep alveoli and silicotic nodule lesions. This delivery method not only increases the effective drug concentration in the local toxic microenvironment but also maximizes the protection of alveolar epithelial cells and promotes their in situ repair.

[0086] In a third aspect of the invention, the invention proposes the use of the pharmaceutical composition described in the second aspect of the invention in the preparation of a medicament for the prevention and / or treatment of pneumoconiosis.

[0087] According to an embodiment of the present invention, the pneumoconiosis is selected from at least one of silicosis, coal worker's pneumoconiosis, asbestosis, welder's pneumoconiosis and cement pneumoconiosis.

[0088] According to an embodiment of the present invention, the pneumoconiosis is silicosis.

[0089] According to an embodiment of the present invention, the silicosis is a pathological injury induced by long-term inhalation of dust containing free silica.

[0090] According to embodiments of the present invention, the treatment of silicosis includes reducing the area of ​​silicotic nodules in lung tissue; reducing the hydroxyproline content in lung tissue; alleviating alveolar septal thickening and / or collagen deposition; alleviating DNA damage to lung tissue cells; and promoting the repair and regeneration of alveolar epithelial cells, or one or more of the following:

[0091] According to embodiments of the present invention, the dosage of the compound represented by formula (I), formula (II) or formula (III) or its tautomers, stereoisomers, solvates or pharmaceutically acceptable salts is about 1.0 mg to 100.0 mg, exemplarily 20.0 mg to 100.0 mg.

[0092] According to embodiments of the present invention, the final concentration of the compound represented by formula (I), formula (II), or formula (III), or its tautomers, stereoisomers, solvates, or pharmaceutically acceptable salts thereof, is approximately 0.1 μM to 50.0 μM, for example 0.1 μM, 0.5 μM, 1 μM, 2.0 μM, 2.5 μM, 3.0 μM, 3.5 μM, 4.0 μM, 4.5 μM, 5.0 μM, 5.5 μM. μM, 6.0 μM, 7.0 μM, 8.0 μM, 9.0 μM, 10.0 μM, 11.0 μM, 12.0 μM, 13.0 μM, 14.0 μM, 15.0 μM, 16.0 μM, 17.0 μM, 18.0 μM, 19.0 μM, 20.0 μM, 21.0 μM, 22.0 μM, 23.0 μM, 24.0 μM, 25.0 μM, 30.0 μM, 35.0 μM, 40.0 μM, 45.0 μM, 50.0 μM, or a range of any two values ​​between them, for example, 2.0 μM to 50.0 μM.

[0093] In this document, the term "final concentration used" refers to the final concentration added for the purpose of preventing and / or treating silicosis. For example, when culturing cells in vitro, the final concentration used is the final concentration in the cell culture medium.

[0094] According to embodiments of the present invention, the final concentration of the compound represented by formula (I), formula (II) or formula (III) or its tautomer, stereoisomer, solvate, or pharmaceutically acceptable salt is approximately 2.5 μM to 20.0 μM.

[0095] Combined drugs or pillboxes and their uses In a fourth aspect, the present invention provides a combination drug or cassette. According to an embodiment of the present invention, the combination drug or cassette comprises: a first active ingredient, which is a compound of formula (I), formula (II) or formula (III) or a tautomer, stereoisomer, solvate, or pharmaceutically acceptable salt thereof;

[0096] (I);

[0097] (II);

[0098] (III).

[0099] According to embodiments of the present invention, the above-described combined drugs or kits can effectively prevent and / or treat pneumoconiosis, especially silicosis.

[0100] According to an embodiment of the present invention, the combined drug or cassette further includes a second active ingredient, the second active ingredient being selected from one or more other drugs for relieving symptoms of pneumoconiosis.

[0101] According to an embodiment of the present invention, the second active ingredient is selected from antitussive and bronchodilator drugs, bronchodilators, glucocorticoids, anti-infective drugs or pulmonary lavage fluid.

[0102] use In a fifth aspect, the present invention provides the use of the combined drug or cassette described in the fourth aspect in the preparation of a medicament for the prevention and / or treatment of pneumoconiosis. As is known from the foregoing, the use of the aforementioned combined drug or cassette can effectively prevent and / or treat pneumoconiosis, especially silicosis.

[0103] According to an embodiment of the present invention, the pneumoconiosis is selected from at least one of silicosis, coal worker's pneumoconiosis, asbestosis, welder's pneumoconiosis and cement pneumoconiosis.

[0104] According to an embodiment of the present invention, the pneumoconiosis is silicosis.

[0105] According to an embodiment of the present invention, the silicosis is a pathological injury induced by long-term inhalation of dust containing free silica.

[0106] According to embodiments of the present invention, the treatment of silicosis includes reducing the area of ​​silicotic nodules in lung tissue; reducing the hydroxyproline content in lung tissue; alleviating alveolar septal thickening and / or collagen deposition; alleviating DNA damage to lung tissue cells; and promoting the repair and regeneration of alveolar epithelial cells, or one or more of the following:

[0107] Methods for preventing and / or treating pneumoconiosis In a sixth aspect of the invention, a method for preventing and / or treating pneumoconiosis is provided. According to an embodiment of the invention, the method comprises administering to a subject a pharmaceutically acceptable dose of a compound of formula (I), formula (II), or formula (III) or a tautomer, stereoisomer, solvate, or pharmaceutically acceptable salt thereof, or the combination drug or cassette described in the fourth aspect;

[0108] (I);

[0109] (II);

[0110] (III).

[0111] According to an embodiment of the present invention, the pneumoconiosis is selected from at least one of silicosis, coal worker's pneumoconiosis, asbestosis, welder's pneumoconiosis and cement pneumoconiosis.

[0112] According to an embodiment of the present invention, the pneumoconiosis is silicosis.

[0113] According to an embodiment of the present invention, the silicosis is a pathological injury induced by long-term inhalation of dust containing free silica.

[0114] According to embodiments of the present invention, the treatment of silicosis includes reducing the area of ​​silicotic nodules in lung tissue; reducing the hydroxyproline content in lung tissue; alleviating alveolar septal thickening and / or collagen deposition; alleviating DNA damage to lung tissue cells; and promoting the repair and regeneration of alveolar epithelial cells, or one or more of the following:

[0115] According to embodiments of the present invention, the dosage of the compound represented by formula (I), formula (II) or formula (III) or its tautomers, stereoisomers, solvates or pharmaceutically acceptable salts is about 1.0 mg to 100.0 mg, exemplarily 20.0 mg to 100.0 mg.

[0116] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0117] The following will explain the solution of this application with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0118] The materials and methods used in the following embodiments are as follows: 1. Experimental Materials 1.1 Compounds QX77, AR7 and CA77.1 were purchased from MedChemExpress.

[0119] 1.2 Laboratory Animals The animals used in this invention were male C57BL / 6 mice, 6-8 weeks old, SPF grade, purchased from Hangzhou Medical College and housed in the SPF environmental laboratory of the Experimental Animal Center of Xiamen University. All animal experimental procedures complied with the "National Regulations on the Management of Experimental Animals" and the "Xiamen University Regulations on the Management of Experimental Animals (Trial Implementation)" and other relevant regulations and management systems.

[0120] 1.3 The primer sequences for qRT-PCR are shown in the table below.

[0121] 2. Data Statistics and Analysis All data in this invention are expressed as mean ± standard error (SEM), and GraphPad Prism software was used for data processing, analysis, and visualization. Statistical analysis was performed using t-tests or one-way ANOVA. p < 0.05 (*) was considered statistically significant, p < 0.01 (**) was highly significant, p < 0.001 (***) and p < 0.0001 (****) were extremely significant, and ns indicated no significance.

[0122] Example 1: Inhibitory effects of QX77 and its analogues AR7 and CA77.1 on fibrosis and repair of lung epithelial cell damage in a mouse model of silica-induced silicosis (pneumoconiosis). Silica (SiO2) is a major pathogenic factor in silicosis (the most common type of pneumoconiosis). Unlike general endogenous irritants, silica crystals that enter the lungs cannot be degraded by the body, creating a persistent physical friction and cytotoxic microenvironment. Long-term inhalation of silica dust can induce inflammatory responses and activate signaling pathways such as TGF-β, promoting fibroblast proliferation and extracellular matrix deposition, ultimately leading to silicotic nodules and diffuse pulmonary fibrosis with extremely specific pathological characteristics. In this study, a mouse silicosis model was established by a single intratracheal instillation of silica suspension to evaluate the inhibitory effects of QX77 and its analogues AR7 and CA77.1 on fibrosis in pneumoconiosis and their repair effects on lung epithelial cell damage in a silica-toxic microenvironment.

[0123] Eight-week-old SPF-grade male C57BL / 6 mice were selected and, after one week of acclimatization, randomly divided into a control group, a model group (SiO2), and drug-treated groups (SiO2+QX77, SiO2+AR7, SiO2+CA77.1). Mice in the model and drug-treated groups were anesthetized with isoflurane inhalation, fixed in a supine position, and the glottis was exposed. A silica suspension (50 μL, 100 mg / kg) was slowly instilled into the trachea using a microsyringe. The control group received an equal volume of sterile saline. After instillation, the mice were rotated upright to ensure even distribution of silica in both lungs. On day 14 after model establishment, administration of the drug to the model groups began. The drug-treated groups received QX77, AR7, or CA77.1 (20 mg / kg, dissolved in corn oil) once daily; the model and control groups received an equal volume of corn oil via gavage daily. Samples were collected and analyzed after 30 days of continuous administration.

[0124] (1) During modeling and drug administration, the weight of mice was measured every 2 days, and a weight change curve was plotted. This example demonstrates the results of QX77. The results are shown in [link to example]. Figure 1 A. The results showed that, compared with the control group, the body weight of mice in the model group decreased significantly (approximately 20%) after silica instillation, followed by a slow recovery, reflecting the toxic consumption due to the continued presence of free silica dust. However, after administration began on day 14, the body weight recovery of mice in the QX77-treated group was significantly better than that of the model group. The wet weight of lung tissue was measured at sample collection, and the lung-to-body ratio (lung weight / body weight) was calculated. The results are shown in […]. Figure 1 B. The results showed that silica-induced lung-to-body ratio significantly increased in mice, while QX77 significantly reduced the lung-to-body ratio in silicosis mice. Further lung tissue was collected for hydroxyproline content detection; the results are shown below. Figure 1 C. The hydroxyproline content in the model group was significantly higher than that in the control group, while QX77 treatment significantly reduced silica-induced hydroxyproline content, indicating that QX77 can effectively inhibit silica-induced collagen deposition.

[0125] (2) Paraffin sections of mouse lung tissue were prepared, followed by hematoxylin-eosin (HE) staining and Sirius red staining. This example demonstrates the results of QX77. HE staining results (see...) Figure 2 A) The results showed that the alveolar structure in the control group was clear, without inflammatory cell infiltration or fibrosis. The silica model group exhibited typical silicosis pathological changes, with significantly thickened alveolar septa, typical silicotic nodule formation, accompanied by extensive inflammatory cell infiltration and disordered lung parenchymal structure. In contrast, the QX77-treated group significantly improved the alveolar structure, specifically inhibiting the further expansion and deterioration of silicotic nodules, and significantly reducing inflammatory cell infiltration. Sirius red staining results showed no obvious abnormalities in the lung tissue of the control group. In contrast, the model group showed a significant increase in red collagen fibers in the lung tissue, which filled the mouse lung tissue in sheets. The QX77-treated group significantly reduced the staining area and depth of red collagen fibers, indicating that QX77 can effectively inhibit silica-induced collagen deposition in lung tissue.

[0126] (3) QX77 and its analogues AR7 and CA77.1 compounds can improve the expression of fibrosis-related genes in silica-induced mouse lung tissue.

[0127] Lung tissue was collected from the mice described above, and total RNA was extracted. The expression levels of COL1A1, COL3A1, SPP1, PDPN, Timp1, Fibronectin, Tenascin-c, MMP2, and TGF-β were detected using qRT-PCR. This example demonstrates the results for QX77. The results are shown in [link to results]. Figure 3 .

[0128] The results showed that, compared with the control group, the expression levels of fibrosis-related genes in the lung tissue of the silica model group were significantly upregulated; while QX77 treatment could significantly inhibit the expression of the above-mentioned fibrosis markers and pro-fibrosis factors induced by silica, indicating that QX77 inhibited lung tissue damage and fibrosis process in silicosis.

[0129] (4) QX77 and its analogues AR7 and CA77.1 compounds can tolerate and inhibit silica-induced damage to lung epithelial cells and promote their repair in a silica-toxic microenvironment.

[0130] γ-H2AX is a highly sensitive marker of DNA double-strand breaks and can be used to sensitively detect the degree of cell and DNA damage induced by silica physical toxicity. The expression level of γ-H2AX in mouse lung tissue was detected by Western blotting; the results are shown below. Figure 4A. The results showed that the model group significantly overexpressed γ-H2AX, indicating severe damage to its lung tissue cells; while the QX77 administration group, even in an environment containing free silica, could still significantly downregulate the expression of γ-H2AX, reducing the degree of damage to lung tissue cells.

[0131] Furthermore, the differentiation of lung epithelial cells from AT2 to AT1 is a crucial step in the repair and regeneration of alveolar cells after injury. Using the aforementioned mouse tissues, the expression levels of AT1 cell markers (Ager, Hopx, caveolin1) and key differentiation transcription factors (Nkx2-1, Cebpa, and YAP) were detected by qRT-PCR. This example exemplifies the results obtained with QX77; the results are shown below. Figure 4 B. The results showed that the expression of markers such as Hopx and caveolin1 in the silica model group was significantly lower than that in the control group, suggesting that AT1 cells were damaged during silicosis; while compound QX77 could significantly restore the expression of the above markers.

[0132] In summary, the results indicate that QX77 and its analogues AR7 and CA77.1 can significantly inhibit silica-induced silicosis and reduce pulmonary collagen deposition. Furthermore, they can promote the survival and regeneration of alveolar epithelial cells in the physical and toxic microenvironment where silica is present, thus demonstrating a significant therapeutic effect on pneumoconiosis.

[0133] Comparative Example: A comparative experiment on the efficacy of compound QX77 of the present invention and first-line clinical IPF treatment drugs in a silicosis model. This embodiment aims to evaluate the efficacy advantages of compound QX77 of the present invention in a silica-induced silicosis model compared to pirfenidone (PFD), a currently clinically recognized first-line drug for the treatment of idiopathic pulmonary fibrosis (IPF), particularly its repair effect on silicosis-specific pathological damage. The anti-fibrotic effect of pirfenidone is mainly achieved through downregulation of TGF-β, inhibition of inflammatory factors (such as TNF-α), and anti-oxidative stress. Its mechanism of action overlaps to some extent with that of compound QX77 of the present invention (which regulates the TGF-β / Smad pathway), making it suitable for comparing the strength of their anti-fibrotic activity and the extent of lung tissue pathological damage.

[0134] Literature reports that pirfenidone showed efficacy in early silicosis models (silica model) with administration on the first day after injection at a dose of 100 mg / kg. In late silicosis models (silica model), administration at doses of 200 mg / kg and 400 mg / kg, starting fourteen days after injection, was effective. In contrast, the compound QX77 used in this comparative example, administered at a dose of 20 mg / kg fourteen days after injection (late silicosis model), showed significant efficacy. To further compare efficacy, the inventors conducted this comparative experiment. An SPF-grade C57BL / 6 male mouse of approximately 8 weeks of age was selected, and a silicosis model was established using the same method as in Example 1: intratracheal instillation of silica suspension (100 mg / kg). On day 14 of modeling, oral administration began, and participants were randomly divided into: a control group, a model group (SiO2), different dose groups of QX77 (e.g., 10 mg / kg, 20 mg / kg, 40 mg / kg, 80 mg / kg), and a pirfenidone group (300 mg / kg). Medication was administered once daily after 14 days of silica infusion. The model group and control group received an equal volume of solvent. Samples were collected after 30 days of continuous administration.

[0135] 1. The detection indicators are as follows: (1) Changes in mouse body weight and lung-to-body ratio; (2) Hydroxyproline content in lung tissue; (3) HE staining and Sirius red staining and quantitative analysis; (4) qRT-PCR detection of mRNA expression of Col1a1, Timp1, TGF-β, etc.; (5) Western Blot detection of γ-H2AX protein level; (6) qRT-PCR detection of expression of AT1 cell markers Hopx and Ager.

[0136] 2. Results: Dosage studies showed that QX77 at a dose of 20 mg / kg (administered starting on day 14 post-modeling) significantly reduced lung-to-body ratio, hydroxyproline content, and collagen deposition area. However, literature reports indicate that pirfenidone, at the same therapeutic dosing time (starting on day 14 post-modeling), requires a dose of 200-400 mg / kg to produce a significant therapeutic effect.

[0137] This indicates that QX77, at a dose of only 20 mg / kg, achieved or even surpassed the effects of pirfenidone at a dose of 300 mg / kg in improving lung-to-body ratio, hydroxyproline content, and collagen deposition. The onset dose of QX77 is more than 10 times lower than that of pirfenidone, demonstrating a significant dose advantage.

[0138] HE staining results showed that while pirfenidone partially alleviated alveolar septal thickening, it had limited effect on the formation of silicotic nodules and central necrosis; whereas QX77 reduced the number and size of silicotic nodules. Quantitative analysis with Sirius red staining showed that QX77 had a higher inhibition rate on collagen deposition than pirfenidone.

[0139] Immunoblot analysis of γ-H2AX showed that the pirfenidone group had a weak inhibitory effect on DNA damage, while the QX77 group downregulated γ-H2AX levels. qRT-PCR analysis of the AT1 cell markers Hopx and Age showed that these markers were reduced in the model group, and the pirfenidone group could not effectively reverse this reduction, while the QX77 group was able to restore the expression levels of Hopx and Age.

[0140] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0141] Although embodiments of this application have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting this application. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of this application.

Claims

1. Use of a compound of formula (I), formula (II) or formula (III) or a tautomer, stereoisomer, solvate or pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of pneumoconiosis; (I)； (II); (III).

2. The use according to claim 1, characterized in that, The pneumoconiosis is selected from at least one of silicosis, coal worker's pneumoconiosis, asbestosis, welder's pneumoconiosis and cement pneumoconiosis; Preferably, the pneumoconiosis is silicosis; Optionally, the silicosis is a pathological injury induced by long-term inhalation of dust containing free silica.

3. The use according to claim 2, characterized in that, The treatment for silicosis includes one or more of the following: reducing the area of ​​silicotic nodules in lung tissue; reducing the hydroxyproline content in lung tissue; alleviating alveolar septal thickening and / or collagen deposition; reducing DNA damage to lung tissue cells; and promoting the repair and regeneration of alveolar epithelial cells.

4. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I), formula (II) or formula (III) or its tautomers, stereoisomers, solvates or pharmaceutically acceptable salts as an active ingredient, and optionally one or more pharmaceutically acceptable carriers, excipients or diluents; (I)； (II); (III).

5. Use of the pharmaceutical composition of claim 4 in the preparation of a medicament for the prevention and / or treatment of pneumoconiosis; Optionally, the pneumoconiosis is selected from at least one of silicosis, coal worker's pneumoconiosis, asbestosis, welder's pneumoconiosis and cement pneumoconiosis; Preferably, the pneumoconiosis is silicosis; Optionally, the silicosis is a pathological injury induced by long-term inhalation of dust containing free silica; Optionally, the treatment of silicosis includes one or more of the following: reducing the area of ​​silicotic nodules in lung tissue; reducing the hydroxyproline content in lung tissue; alleviating alveolar septal thickening and / or collagen deposition; alleviating DNA damage to lung tissue cells; and promoting the repair and regeneration of alveolar epithelial cells.

6. The use according to claim 1 or 5, characterized in that, The dosage forms of the drug include oral formulations, injectable formulations, or inhaled formulations.

7. The use according to claim 6, characterized in that, The inhaled preparations include nebulized inhalers, dry powder inhalers, or aerosols.

8. A combination drug or pillbox, characterized in that, include: The first active ingredient is a compound of formula (I), formula (II) or formula (III) or a tautomer, stereoisomer, solvate or pharmaceutically acceptable salt thereof; And optionally a second active ingredient, the second active ingredient being selected from one or more other drugs for relieving symptoms of pneumoconiosis; (I)； (II); (III).

9. The combined drug or cassette according to claim 8, characterized in that, The second active ingredient is selected from antitussive and bronchodilator drugs, bronchodilators, glucocorticoids, anti-infective drugs, or pulmonary lavage fluid.

10. Use of the combined medicament or medicament according to claim 8 or 9 in the preparation of a medicament for the prevention and / or treatment of pneumoconiosis; Optionally, the pneumoconiosis is selected from at least one of silicosis, coal worker's pneumoconiosis, asbestosis, welder's pneumoconiosis and cement pneumoconiosis; Preferably, the pneumoconiosis is silicosis; Optionally, the silicosis is a pathological injury induced by long-term inhalation of dust containing free silica; Optionally, the treatment of silicosis includes one or more of the following: reducing the area of ​​silicotic nodules in lung tissue; reducing the hydroxyproline content in lung tissue; alleviating alveolar septal thickening and / or collagen deposition; alleviating DNA damage to lung tissue cells; and promoting the repair and regeneration of alveolar epithelial cells.

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