Application of limonin compound or medicinal derivative thereof in preparation of medicine for preventing or treating inflammation

Abstract

The invention relates to the field of natural products, and relates to application of limonin compounds or medicinal derivatives thereof in preparation of medicines for preventing or treating inflammation. The inventor of the invention finds for the first time that the compound I or the compound II extracted and separated from the mallotus oblongifolius can significantly inhibit the content of inflammatory factors of immune cells at an extremely low concentration, and can be used for preparing medicines for preventing or treating inflammation. Besides, the compound I or II can significantly reduce the expression level of LPS-induced inflammatory factors TNF-alpha, IL-1alpha, IL-1beta, IL-6 and IL-18 at a low concentration, and does not affect the survival of immune cells, which proves that the compound I or II can inhibit the expression of inflammatory factors and has a strong anti-inflammatory effect.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of natural products, and relates to application of limonoids or a pharmaceutical derivative thereof in preparation of a medicine for preventing or treating inflammation. BACKGROUND

[0002] Inflammation, as a core defense mechanism of the body against injury or infection, its chronic process may trigger tissue fibrosis, autoimmune diseases and even malignant tumors, and has become a major challenge in the field of global health. In the field of anti-inflammatory drug research and development, significant progress has been made in the past two decades: from traditional therapies such as non-steroidal anti-inflammatory drugs (NSAIDs) to biological agents and small molecule inhibitors targeting cytokine pathways such as TNF-α, IL-1α and IL-6, and multi-target intervention strategies have gradually become a new paradigm for treatment. It is worth noting that natural products have always been an important source of drug development due to their multi-component synergistic effect, broad spectrum of regulatory potential and lower toxicity and side effects. Data shows that among the 89 anti-inflammatory drugs currently in clinical use, 65% are small molecule drugs, and 72% of them are directly derived from plant extracts or microbial metabolites. This phenomenon highlights the irreplaceability of natural products in the development of new anti-inflammatory active molecules, and provides a key direction for the prevention and treatment of inflammation-related diseases in the future.

[0003] Trichilia connaroides belongs to the family Meliaceae and the genus Trichilia, and is mainly distributed in tropical regions of Guangdong, Guangxi and Yunnan in China. Studies have shown that the plant is rich in limonoids, a class of complex triterpenoid derivatives with highly oxidized carbon skeletons and often modified with furan or lactone rings, exhibiting significant chemical diversity. Currently, more than a hundred such components have been isolated from the roots, stems, barks, leaves and fruits of Trichilia connaroides, and they have a wide range of biological activities, including cytotoxicity, anti-inflammatory, antibacterial and insect antifeeding effects. The structural specificity and functional diversity of these compounds make them have important development value in the fields of medicine and agriculture. Different limonoids have many differences in biological activities.

[0004] The present application found that among the four new limonoids extracted from Trichilia connaroides, two of them have strong inhibitory effect on the release of multiple inflammatory factors. SUMMARY

[0005] The present application aims to provide the application of limonoids or a pharmaceutical derivative thereof in preparation of a medicine for preventing or treating inflammation. The compounds provided by the present application have significant inhibitory effect on the synthesis and release of inflammatory factors in immune cells, and can be used as anti-inflammatory drugs for the treatment of inflammation-related diseases.

[0006] The technical scheme of the present application is as follows:

[0007] This invention provides the use of limonene compounds or their pharmaceutical derivatives in the preparation of medicaments for the prevention or treatment of inflammation, wherein the medicament uses limonene compounds or their pharmaceutical derivatives as the active pharmaceutical ingredient, and the limonene compounds are selected from compounds I with structural formula I or compounds II with structural formula II.

[0008]

[0009] Furthermore, in the application described, the pharmaceutical derivative is a pharmaceutically acceptable salt, ester, or stereoisomer of compound I or compound II.

[0010] Furthermore, in the aforementioned applications, the percentage content of the active pharmaceutical ingredient in the total mass of the drug is from 0.1% to 99.9%.

[0011] Furthermore, in the aforementioned applications, the active pharmaceutical ingredient can be combined with a pharmaceutically acceptable carrier to formulate a drug formulation that is easy to administer. The pharmaceutically acceptable carrier includes, but is not limited to, diluents, absorption enhancers, surfactants, preservatives, lubricants, binders, disintegrants, solvents, or coating materials. The dosage form of the drug formulation can be specifically selected according to the route of administration, for example: oral or injectable formulations for systemic administration; or topical or inhaled formulations for local administration.

[0012] Furthermore, in the aforementioned applications, the active pharmaceutical ingredient can be used alone or in combination with other drugs. The main purposes of combination therapy include enhancing therapeutic effects, reducing the dosage of a single drug, reducing the occurrence of adverse reactions, or delaying the development of drug resistance.

[0013] The present invention has the following beneficial effects:

[0014] The inventors of this invention have discovered for the first time that compound I or compound II, extracted and isolated from partridge flowers, can significantly inhibit the content of inflammatory factors in immune cells at extremely low concentrations, and can be used to prepare drugs for the prevention or treatment of inflammation.

[0015] As shown in Example 2, compound I significantly inhibited LPS-induced inflammatory cytokine expression at extremely low concentrations (2.5 nM and 10 nM treatments), reducing LPS-induced IL-6 and IL-1β levels secreted into the culture medium by THP-1 cells in a concentration-gradient manner. This demonstrates that compound I possesses extremely strong anti-inflammatory activity. Compound II also significantly inhibited LPS-induced inflammatory cytokine expression at extremely low concentrations (1 nM and 10 nM treatments), reducing LPS-induced IL-6 and IL-1β levels secreted into the culture medium by THP-1 cells in a concentration-gradient manner. This also demonstrates that compound II possesses extremely strong anti-inflammatory activity.

[0016] As can be seen from Example 3, compounds I or II significantly reduced the expression levels of LPS-induced inflammatory factors TNF-α, IL-1α, IL-1β, IL-6 and IL-18 at low concentrations without affecting immune cell survival, demonstrating that compounds I or II can inhibit the expression of inflammatory factors and have strong anti-inflammatory effects. Attached Figure Description

[0017] Figure 1 The structures of the four limonoid compounds in this invention are shown.

[0018] Figure 2 This invention illustrates the effects of four limonene compounds on the RNA levels of inflammatory factors in immune cells. Specifically, A represents the effect of the four limonene compounds on the RNA levels of human interleukin-1α (IL-1α) in immune cells THP-1; B represents the effect of the four limonene compounds on the RNA levels of human interleukin-1β (IL-1β) in immune cells THP-1. Figure 2 The vertical axis represents the RNA level of inflammatory factors in immune cells, and the horizontal axis represents the treatment conditions (* represents p<0.05, ** represents p<0.01, *** represents p<0.001). The leftmost bar in the figure represents the control group (DMSO) without compound I and LPS (lipopolysaccharide). The LPS treatment concentration in the figure is 10 μg / mL.

[0019] Figure 3 The effect of limonene compounds I and II on THP-1 cell viability. ns indicates no significant difference. The leftmost bar in the figure represents the control group without compound I or II.

[0020] Figure 4 The results show the effects of limonene compound I on the protein content of inflammatory factors secreted by immune cells THP-1. In this study, A represents the effect of compound I on the protein content of human interleukin-6 (IL-6) secreted by immune cells THP-1; B represents the effect of compound I on the protein content of human interleukin-1β (IL-1β) secreted by immune cells THP-1. Figure 4 The vertical axis represents the protein content of inflammatory factors secreted by immune cells, and the horizontal axis represents the treatment conditions (** represents p<0.01, *** represents p<0.001). The leftmost bar in the figure represents the control group without compound I and LPS.

[0021] Figure 5This image shows the results of measuring the protein content of inflammatory factors secreted by immune cells THP-1, using limonene compound II. In this image, A represents the effect of compound II on the protein content of human interleukin-6 (IL-6) secreted by immune cells THP-1; B represents the effect of compound II on the protein content of human interleukin-1β (IL-1β) secreted by immune cells THP-1. Figure 5 The vertical axis represents the protein content of inflammatory factors secreted by immune cells, and the horizontal axis represents the treatment conditions (** represents p<0.01, *** represents p<0.001). The leftmost bar in the figure represents the control group without compound II and LPS.

[0022] Figure 6 The effect of compound I of the present invention on the RNA content of inflammatory factors in immune cells and its half-maximal inhibitory concentration (IC50) 50 The results were calculated as follows: A represents the effect of compound I on the RNA content of IL-6 in THP-1 immune cells; B represents the effect of compound I on the RNA content of IL-1β in THP-1 immune cells; C represents the effect of compound I on the RNA content of IL-1α in THP-1 immune cells; D represents the effect of compound I on the RNA content of TNF-α in THP-1 immune cells; and E represents the effect of compound I on the RNA content of human interleukin-18 (IL-18) in THP-1 immune cells. Figure 6 The vertical axis represents the RNA content of inflammatory factors in immune cells, and the horizontal axis represents the treatment conditions. ns indicates no significant difference, * represents p<0.05, ** represents p<0.01, *** represents p<0.001, and **** represents p<0.0001. The leftmost bar in the figure represents the control group without compound I and LPS.

[0023] Figure 7 The effect of compound II of this invention on the RNA content of inflammatory factors in immune cells and its half-maximal inhibitory concentration (IC50) 50 The results were calculated as follows: A represents the effect of compound II on the RNA content of IL-6 in THP-1 immune cells; B represents the effect of compound II on the RNA content of IL-1β in THP-1 immune cells; C represents the effect of compound II on the RNA content of IL-1α in THP-1 immune cells; D represents the effect of compound II on the RNA content of TNF-α in THP-1 immune cells; and E represents the effect of compound II on the RNA content of human interleukin-18 (IL-18) in THP-1 immune cells. Figure 7The vertical axis represents the RNA content of inflammatory factors in immune cells, and the horizontal axis represents the treatment conditions. ns indicates no significant difference, * represents p<0.05, ** represents p<0.01, *** represents p<0.001, and **** represents p<0.0001. The leftmost bar in the figure represents the control group without compound II and LPS. Detailed Implementation

[0024] This invention isolates and purifies sesquiterpenoid compounds I-IV from partridge flowers. The methods for isolating compounds I, II, III, and IV are based on Chinese patents: CN202510828220.1 and CN202411239773.5.

[0025] The structural formulas of compounds I, II, III, and IV are shown in formulas I, II, III, and IV, respectively:

[0026]

[0027] The human immune cells used in the following experiments are human immune cells THP-1, purchased from the ATCC cell bank, catalog number TIB-202.

[0028] Unless otherwise specified, all reagents used in the embodiments of this invention can be purchased commercially. RPMI 1640 medium, LPS, and fetal bovine serum were purchased from Gibco. The ELISA kits used to detect immune factors in the cell culture medium were purchased from Shanghai Duma Biotechnology Co., Ltd., with catalog numbers DM4670 (human interleukin-6 ELISA kit) and DM4708 (human interleukin-1β ELISA kit).

[0029] The cell lines were cultured in RPMI 1640 medium containing 10% fetal bovine serum at 37°C, 5% CO2 and 90% humidity.

[0030] The RT-qPCR primer sequences involved in the examples are as follows:

[0031] TNF-α:

[0032] Forward: SEQ ID NO.1 5′-CCTCTCTCTAATCAGCCCTCTG-3′,

[0033] Reverse: SEQ ID NO.2 5′-GAGGACCTGGGAGTAGATGAG-3′;

[0034] IL-1α:

[0035] Forward: SEQ ID NO.3 5′-AGATGCCTGAGATACCCAAAACC-3′,

[0036] Reverse: SEQ ID NO.4 5′-CCAAGCACACCCAGTAGTCT-3′;

[0037] IL-18:

[0038] Forward: SEQ ID NO.5 5′-TCTTCATTGACCAAGGAAATCGG-3′,

[0039] Reverse: SEQ ID NO.6 5′-TCCGGGGTGCATTATCTCTAC-3′;

[0040] IL-6:

[0041] Forward: SEQ ID NO.7 5′-TAGTCCTTCCTACCCCAATTTCC-3′,

[0042] Reverse: SEQ ID NO.8 5′-TTGGTCCTTAGCCACTCCTTC-3′;

[0043] IL-1β:

[0044] Forward: SEQ ID NO.9 5′-TGGACCTTCCAGGATGAGGACA-3′,

[0045] Reverse: SEQ ID NO.10 5′-GTTCATCTCGGAGCCTGTAGTG-3′;

[0046] 18S:

[0047] Forward: SEQ ID NO.11 5′-CCTGAGAAACGGCTACCACATC-3′,

[0048] Reverse: SEQ ID NO.12 5′-GCCTCGAAAGAGTCCTGTATTG-3′.

[0049] The primers were synthesized by Beijing Qingke Biotechnology Co., Ltd.

[0050] Example 1: Determination of the anti-inflammatory activity of four limonene compounds

[0051] Will Figure 1Compounds I, II, III, and IV were dissolved in DMSO (dimethyl sulfoxide) and then prepared into solutions with a concentration of 5 or 80 nM (compounds I and II were prepared to a final concentration of 5 nM, and compounds III and IV were prepared to a final concentration of 80 nM). These solutions were used as test solutions. To detect the anti-inflammatory activity of compounds I, II, III, and IV, the following experiment was performed: THP-1 immune cells were treated with lipopolysaccharide (LPS) for 24 h, then the THP-1 cells were transformed into inflammatory cells. Compounds I or II were added and treated for 12 h. RNA was extracted, and then RT-qPCR was performed to detect the levels of 18S, IL-1α, and IL-1β. 18S was used as an internal control for statistical analysis.

[0052] Experimental results: Figure 2 A and Figure 2 B shows that compounds I and II at a concentration of 5 nM significantly reduced the expression levels of LPS-induced inflammatory cytokines IL-1α and IL-1β, demonstrating that compounds I or II can inhibit the expression of inflammatory cytokines and have strong anti-inflammatory effects. However, compounds III or IV at a concentration of 80 nM failed to reduce the expression levels of LPS-induced inflammatory cytokines IL-1α and IL-1β; instead, they further promoted the expression levels of IL-1α and IL-1β, indicating that compounds III or IV lack anti-inflammatory activity. This demonstrates that limonene compounds with the same or similar core structures do not necessarily have the same activity.

[0053] Example 2: Detection of cell proliferation of immune cells by limonene compounds I and II

[0054] To determine whether compounds I or II themselves cause cell damage and death, a CCK-8 assay kit was used to detect cell viability. The CCK-8 method was also used to assess cell growth inhibition. The CCK-8 assay, short for Cell Counting Kit-8, is a commonly used method for detecting cell proliferation and cytotoxicity. The principle of the CCK-8 assay is based on the fact that compound WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonic acid phenyl)-2H-tetrazole monosodium salt), in the presence of the electron carrier 1-Methoxy PMS (menaquinone phosphate), can be reduced by intracellular mitochondrial dehydrogenases to produce a highly water-soluble orange-yellow formazan product. The amount of formazan produced is directly proportional to the number of viable cells, and the color intensity reflects cellular metabolic activity. The number of viable cells can be indirectly reflected by measuring the absorbance at 450 nm using a microplate reader. Therefore, CCK-8 can be used to assess cell proliferation, cytotoxicity, or the cellular effects of drugs.

[0055] The specific steps for CCK-8 testing are as follows: When performing CCK-8 testing, use 3×10 5 THP-1 cells were seeded in 90 μL of culture medium into five replicate wells of a 96-well plate. After 24 hours of culture, the cells were treated with different concentrations of compound I and LPS. After 48 hours of treatment, 10 μL of CCK-8 reagent was added to each well, and the 96-well plate was incubated at 37°C for 1 hour. The absorbance was measured at 450 nm using a microplate reader. The average OD value of each well was calculated, and changes in cell proliferation or viability were analyzed by comparing it with the control group (without compound I or LPS). The percentage of absorbance value of the experimental group relative to the absorbance value of the control group represents the cell viability or cell proliferation level; the control group was assumed to be 100%.

[0056] Experimental results: Figure 3 The results showed that compounds I or II (40 nM, 20 nM, 10 nM) did not inhibit the viability of THP-1 cells. This indicates that compounds II or II are well-tolerated and do not inhibit the growth of immune cells. ns represents no statistically significant difference.

[0057] Example 3: Effects of limonene compounds I and II on extracellular inflammatory factors

[0058] To further investigate the anti-inflammatory activity of compounds I or II, an ELISA kit was used to test whether compounds II or II affected the levels of IL-6 and IL-1β secreted by THP-1 immune cells. The specific experimental procedure was as follows: THP-1 cells were treated with LPS for 24 hours, followed by treatment with compounds I or II for 12 hours. The cell suspension was collected, centrifuged, the precipitate was discarded, and the supernatant was collected. The levels of IL-6 and IL-1β secreted by THP-1 cells were measured according to the ELISA kit instructions. Figure 4 and Figure 5 The vertical axis represents the expression level of inflammatory factors, and the horizontal axis represents the treatment conditions. ** represents p<0.01, and *** represents p<0.001.

[0059] Experimental results:

[0060] Figure 4 The results showed that compound I significantly inhibited LPS-induced expression of inflammatory factors at extremely low concentrations (2.5 nM and 10 nM treatments), and reduced the levels of IL-6 and IL-1β secreted into the culture medium by LPS-induced THP-1 cells in a concentration gradient-dependent manner. This demonstrates that compound I possesses extremely strong anti-inflammatory activity.

[0061] Figure 5The results showed that compound II significantly inhibited LPS-induced expression of inflammatory factors at extremely low concentrations (1 nM and 10 nM treatments), and reduced the levels of IL-6 and IL-1β secreted into the culture medium by LPS-induced THP-1 cells in a concentration gradient-dependent manner. This demonstrates that compound II possesses extremely strong anti-inflammatory activity.

[0062] Example 3: IC50 of limonene compounds I and II on the inhibition of inflammatory factor expression 50 calculate

[0063] TNF-α is a core driver and key regulator of inflammatory responses, primarily produced by activated immune cells. Through mechanisms such as activating vascular endothelial cells, recruiting and activating leukocytes, and inducing the release of other pro-inflammatory mediators, it powerfully initiates and amplifies local and systemic inflammatory responses, playing a crucial role in the body's resistance to infection and damage repair. However, excessive or persistent production can disrupt the balance between pro-inflammatory and anti-inflammatory responses, leading to tissue damage and becoming a core culprit in the pathological damage of various chronic inflammatory diseases (such as rheumatoid arthritis and inflammatory bowel disease). This also makes it a revolutionary target for anti-inflammatory therapy. IL-6 is a marker of early inflammation in inflammatory responses. IL-6 is associated with various autoimmune diseases; for example, serum IL-6 levels are typically high in patients with rheumatoid arthritis, psoriasis, and systemic lupus erythematosus. IL-1β plays an important role in the pathogenesis of acute and chronic inflammation and is closely related to the pathological processes of diabetes, rheumatoid arthritis, and periodontitis. IL-1α is a key pro-inflammatory cytokine, playing a pioneering and core driver role in the initiation and amplification of inflammatory responses. Sustained action of IL-1α can exacerbate inflammation and lead to pathological damage. IL-18 is a pleiotropic pro-inflammatory cytokine; its overactivation in chronic inflammation (such as rheumatoid arthritis and inflammatory bowel disease) or autoimmune diseases can lead to tissue damage. Therefore, TNF-α, IL-1α, IL-1β, IL-6, and IL-18 are important inflammatory targets.

[0064] To further investigate the IC50 of compound I's anti-inflammatory activity 50 The following experiment was conducted: After treating THP-1 immune cells with lipopolysaccharide (LPS) for 24 hours, the THP-1 cells were transformed into inflammatory cells that released inflammatory factors. Compound I was added and treated for 12 hours. RNA was extracted and then RT-qPCR was performed to detect the levels of 18S, TNF-α, IL-1β, IL-1α, IL-6, and IL-18. 18S was used as an internal control for statistical analysis.

[0065] Experimental results:

[0066] Figure 6A showed that LPS treatment of THP-1 cells induced an increase in the mRNA expression level of the inflammatory cytokine IL-6. Compound I significantly reduced the LPS-induced mRNA level of the inflammatory cytokine IL-6 and inhibited the IC50 of IL-6. 50 It is 3.99 nM.

[0067] Figure 6 B showed that LPS treatment of THP-1 cells induced an increase in the mRNA expression level of the inflammatory cytokine IL-1β, and compound I significantly reduced the LPS-induced mRNA content of the inflammatory cytokine IL-1β. Compound I inhibited the IC50 of IL-1β. 50 It is 1.21 nM.

[0068] Figure 6 C showed that LPS treatment of THP-1 cells induced an increase in the mRNA expression level of the inflammatory cytokine IL-1α, and compound I significantly reduced the LPS-induced mRNA content of the inflammatory cytokine IL-1α. Compound I inhibited the IC50 of IL-1α. 50 It is 5.08 nM.

[0069] Figure 6 D showed that LPS treatment of THP-1 cells induced an increase in the mRNA expression level of the inflammatory cytokine TNF-α. Compound I significantly reduced the LPS-induced mRNA content of the inflammatory cytokine TNF-α and inhibited the IC50 of TNF-α. 50 It is 4.53 nM.

[0070] Figure 6 E showed that LPS treatment of THP-1 cells induced an increase in the mRNA expression level of the inflammatory cytokine IL-18, and compound I significantly reduced the LPS-induced mRNA content of the inflammatory cytokine IL-18. Compound I inhibited the IC50 of IL-18. 50 It is 3.27 nM.

[0071] To further investigate the anti-inflammatory activity of compound II, IC50 was used. 50 The following experiment was conducted: After treating THP-1 immune cells with lipopolysaccharide (LPS) for 24 hours, the THP-1 cells were transformed into inflammatory cells that released inflammatory factors. Compound II was added and treated for 12 hours. RNA was extracted and then RT-qPCR was performed to detect the levels of 18S, TNF-α, IL-1β, IL-1α, IL-6, and IL-18. 18S was used as an internal control for statistical analysis.

[0072] Experimental results:

[0073] Figure 7A showed that LPS treatment of THP-1 cells induced an increase in the mRNA expression level of the inflammatory cytokine IL-6, while compound II significantly reduced the LPS-induced IL-6 mRNA level and inhibited the IC50 of IL-6. 50 It is 3.38 nM.

[0074] Figure 7 B showed that LPS treatment of THP-1 cells induced an increase in the mRNA expression level of the inflammatory cytokine IL-1β, while compound II significantly reduced the LPS-induced mRNA level of IL-1β and inhibited the IC50 of IL-1β. 50 It is 18.41 nM.

[0075] Figure 7 C showed that LPS treatment of THP-1 cells induced an increase in the mRNA expression level of the inflammatory cytokine IL-1α, while compound II significantly reduced the LPS-induced mRNA level of IL-1α and inhibited the IC50 of IL-1α. 50 It is 9.68 nM.

[0076] Figure 7 D showed that LPS treatment of THP-1 cells induced an increase in the mRNA expression level of the inflammatory cytokine TNF-α, while compound II significantly reduced the LPS-induced mRNA content of the inflammatory cytokine TNF-α and inhibited the IC50 of TNF-α. 50 It is 10.43 nM.

[0077] Figure 7 E showed that LPS treatment of THP-1 cells induced an increase in the mRNA expression level of the inflammatory cytokine IL-18, while compound II significantly reduced the LPS-induced mRNA level of IL-18 and inhibited the IC50 of IL-18. 50 It is 9.95 nM.

[0078] In summary, compounds I or II can significantly reduce the expression levels of LPS-induced inflammatory factors TNF-α, IL-1α, IL-1β, IL-6 and IL-18 at low concentrations without affecting immune cell survival, demonstrating that compounds I or II can inhibit the expression of inflammatory factors and have strong anti-inflammatory effects.

[0079] In summary, compounds I or II have extremely strong anti-inflammatory effects and can effectively inhibit the expression and release of inflammatory factors TNF-α, IL-1α, IL-1β, IL-6 and IL-18 at very low concentrations.

[0080] It should be noted that the embodiments described above are only for explaining the present invention and do not constitute any limitation on the present invention. The present invention has been described with reference to typical embodiments, but it should be understood that the words used therein are descriptive and explanatory terms, not limiting terms. Modifications can be made to the present invention within the scope of the claims, and revisions can be made to the present invention without departing from the scope and spirit of the present invention. Although the present invention described herein relates to specific methods, materials, and embodiments, it does not mean that the present invention is limited to the specific examples disclosed herein; on the contrary, the present invention extends to all other methods and applications having the same function.

Claims

1. The use of limonene compounds or their pharmaceutical derivatives in the preparation of drugs for the prevention or treatment of inflammation, characterized in that, The drug uses limonene compounds or their pharmaceutical derivatives as the active pharmaceutical ingredient, wherein the limonene compounds are selected from compound I with structural formula I or compound II with structural formula II.

2. The application according to claim 1, characterized in that, The pharmaceutical derivative is a pharmaceutically acceptable salt, ester, or stereoisomer of compound I or compound II.

3. The application according to claim 1, characterized in that, The percentage content of the active pharmaceutical ingredient in the total mass of the drug is from 0.1% to 99.9%.

4. The application according to claim 1, characterized in that, The active pharmaceutical ingredient is combined with a pharmaceutically acceptable carrier to form a pharmaceutical formulation that is easy to administer.

5. The application according to claim 4, characterized in that, The pharmaceutically acceptable carrier is selected from any one or more of the following carriers: diluent, absorption enhancer, surfactant, preservative, lubricant, binder, disintegrant, solvent or coating material.

6. The application according to claim 4, characterized in that, The dosage form of the pharmaceutical preparation is an oral or injectable preparation for systemic administration, or a topical or inhaled preparation for local administration.

7. The application according to claim 1, characterized in that, The active pharmaceutical ingredient may be used alone or in combination with other drugs.

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