Application of 4-[2-(methylamino) ethyoxyl] phenol in preparation of medicine for preventing and treating inflammatory diseases

Abstract

The invention discloses an application of 4-[2-(methylamino) ethyoxyl] phenol in preparation of a medicine for preventing and treating inflammatory diseases. As a novel candidate drug for treating inflammation and inflammation-related diseases, the compound 4-[2-(methylamino) ethyoxyl] phenol provided by the invention has a broad-spectrum anti-inflammatory effect, is novel in target spot and clear in action mechanism, has the effect superior to that of an existing treatment drug, has higher targeting property and safety and lower side effect risk, and can be applied to preparation of medicines for treating inflammation and inflammation-related diseases. Good application prospects and industrialization potential are realized.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to the use of 4-[2-(methylamino)ethoxy]phenol in the preparation of medicaments for the prevention and treatment of inflammatory diseases. Background Technology

[0002] Inflammation is the body's protective response to pathogens, damage, or immune abnormalities. However, excessive or persistent inflammation can lead to tissue damage and various chronic diseases, including intestinal inflammation (such as ulcerative colitis and Crohn's disease), arthritis, atherosclerosis, and neuroinflammation. Existing anti-inflammatory drugs, such as glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs), mainly control disease progression by inhibiting abnormal immune responses and reducing inflammation. However, they generally suffer from drawbacks such as unstable efficacy, numerous adverse reactions, poor tolerability, inability to comprehensively improve inflammation-related symptoms, high risks associated with long-term use, or high cost. Especially in chronic inflammatory states, existing drugs often struggle to balance efficacy and safety. Previous studies have shown that 4-hydroxybenzoic acid (p-HBA) at low doses can effectively alleviate the inflammatory response in mice with dextran sulfate sodium (DSS)-induced colitis, demonstrating good anti-inflammatory potential. However, further experiments revealed that while p-hydroxybenzoic acid can significantly reduce symptoms in various inflammatory models, it can cause some degree of liver damage under gavage administration. Therefore, there is an urgent need to develop a compound with an optimized structure, higher safety and better anti-inflammatory activity, in order to improve the inflammatory response without increasing toxic side effects and broaden its application prospects in a variety of inflammatory diseases.

[0003] This invention aims to provide a novel compound with a well-defined mechanism of action and low risk of side effects for the treatment of inflammation-related diseases. The compound, 4-[2-(methylamino)ethoxy]phenol (MEP), exhibits good anti-inflammatory effects in various inflammation models, particularly showing significant efficacy in intestinal inflammation models. Furthermore, it also has potential applications in respiratory, neurological, and immune inflammation models. Summary of the Invention

[0004] This invention aims to at least solve one of the aforementioned technical problems existing in the prior art. Therefore, the object of this invention is to provide the use of 4-[2-(methylamino)ethoxy]phenol (CAS No.: 178161-83-6) in the preparation of medicaments for the prevention and treatment of inflammation. This invention is the first to discover that the compound 4-[2-(methylamino)ethoxy]phenol has a broad-spectrum and significant anti-inflammatory effect, effectively reducing inflammatory responses induced by lipopolysaccharide (LPS) or the cytokine TNFα in epithelial cells, immune cells, and endothelial cells, inhibiting the expression of inflammatory factors, and reducing immune cell infiltration and inhibiting the expression of inflammatory factors in in vitro and in vivo models of inflammatory bowel disease, thereby restoring CDH1 expression loss caused by inflammation and protecting intestinal adhesion structures. Furthermore, 4-[2-(methylamino)ethoxy]phenol exhibits agonistic activity and selective affinity for ERβ, avoiding the hormone-related side effects that may be caused by estrogen-like drugs stimulating ERα, and has higher targeting, safety, and lower risk of side effects. Therefore, the compound 4-[2-(methylamino)ethoxy]phenol provided by this invention is a novel candidate drug for treating inflammation and inflammation-related diseases. It has a broad-spectrum anti-inflammatory effect, a novel target, a clear mechanism of action, and better efficacy than existing therapeutic drugs. It also has higher targeting, safety, and lower risk of side effects, and has good application prospects and industrialization potential.

[0005] It is worth noting that existing technologies indicate that epithelial barrier disruption, monocyte / macrophage activation, and endothelial inflammation are common inflammatory mechanisms in various systemic diseases. Therefore, the validation of this application using epithelial cell inflammation models, monocyte / macrophage line immune inflammation models, and human umbilical vein endothelial cell line endothelial inflammation models can effectively support the application of compound 4-[2-(methylamino)ethoxy]phenol in cardiovascular diseases. [1, 2] Metabolic diseases [3] and intestinal inflammation such as colitis [4, 5] Inflammation of the nervous system (such as neurological inflammation and inflammatory processes related to degenerative diseases of the central nervous system) [6] Autoimmune diseases (such as rheumatoid arthritis) [7] Systemic lupus erythematosus [8] Other gastrointestinal inflammations [9] Respiratory tract inflammation (such as airway epithelial inflammation)

[10] ,asthma

[11] or COPD-related inflammatory mechanisms

[12] Skin inflammation

[13] (such as damage to the epidermal barrier and local chronic inflammation), urinary tract infections (such as urinary tract infections)

[14] Inflammation of the reproductive system (such as endometriosis-related inflammatory processes)

[15] ) and inflammation of the musculoskeletal system (such as tendinitis)

[16] The therapeutic effect in ).

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: In a first aspect of the invention, there is provided the use of a compound in the preparation of a medicament for the prevention and / or treatment of inflammatory diseases, said compound having the following structure: .

[0007] In this invention, inflammation refers to a complex and dynamic defensive physiological and pathological response of cells or tissues to various damaging stimuli (including but not limited to physical, chemical, biological, or psychological stimuli). The core characteristics of this process are the activation of the immune system, the recruitment of immune cells, and the release of inflammatory mediators, with the aim of clearing damaging factors, repairing damaged tissues, and restoring homeostasis.

[0008] In some embodiments of the present invention, the inflammation includes epithelial cell inflammation; specifically, epithelial cell inflammation refers to an inflammatory response occurring in epithelial tissue and its adjacent subepithelial stroma and lamina propria, mainly affecting the epithelium covering the body surface, lining cavities, or organ lumens. Its pathological features may include changes in the structure and function of the epithelial barrier (such as impaired tight junctions and increased permeability), elevated levels of local inflammatory mediators, and infiltration of inflammatory cells. In this process, the epithelium can act as a barrier and immune regulatory interface, and can also participate in inflammation amplification and immune cell recruitment by secreting cytokines and chemokines.

[0009] In some embodiments of the present invention, the epithelial cell inflammation includes, but is not limited to, skin inflammation, respiratory tract inflammation, digestive tract inflammation, urinary system inflammation, and reproductive system inflammation.

[0010] In some embodiments of the present invention, the skin inflammation includes, but is not limited to, atopic dermatitis, psoriasis, ichthyosis, acne (e.g., rosacea), seborrheic dermatitis, cutaneous discoid lupus erythematosus, chronic simple lichen simplex, and contact dermatitis.

[0011] In some embodiments of the present invention, the respiratory tract inflammation includes, but is not limited to, asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, acute bronchitis, bronchiectasis, cystic fibrosis, eosinophilic bronchitis, pneumonia, allergic rhinitis, and idiopathic pulmonary fibrosis; the pneumonia includes, but is not limited to, infectious pneumonia, such as bacterial pneumonia and viral pneumonia; and non-infectious pneumonia, such as allergic pneumonia, aspiration pneumonia, and interstitial pneumonia.

[0012] In some embodiments of the present invention, the gastrointestinal inflammation includes, but is not limited to, gastritis, colitis, and inflammatory bowel disease; the inflammatory bowel disease includes Crohn's disease and ulcerative colitis; the gastritis includes chronic gastritis, erosive gastritis, drug-induced gastritis (e.g., caused by nonsteroidal anti-inflammatory drugs), and autoimmune gastritis.

[0013] In some embodiments of the present invention, the urinary tract inflammation includes, but is not limited to, urinary tract infections and non-infectious urinary tract inflammations; the urinary tract infections include, but are not limited to, acute or chronic cystitis, pyelonephritis, complicated or uncomplicated urinary tract infections, urethritis, and urinary tract infections associated with catheter placement; the non-infectious urinary tract inflammations include, but are not limited to, prostatitis, interstitial cystitis / bladder pain syndrome, drug-induced or radiation-induced cystitis, and urinary tract inflammatory diseases mediated by autoimmune reactions or aseptic inflammation.

[0014] In some embodiments of the present invention, the reproductive system inflammation includes, but is not limited to, endometriosis-related inflammation, pelvic inflammatory disease, endometritis, cervicitis, vaginitis, salpingitis, and oophoritis; the endometriosis-related inflammation includes local chronic inflammation of ectopic endometrial tissue, peritoneal / pelvic microenvironment inflammation, immune cell recruitment and activation mediated by inflammatory factors and chemokines, and angiogenesis-related inflammatory responses; the pelvic inflammatory disease includes acute pelvic inflammatory disease and chronic pelvic inflammatory disease; the vaginitis includes bacterial vaginosis-related inflammation, candidal vaginitis, and trichomonal vaginitis; the cervicitis includes non-infectious cervicitis; the endometritis includes chronic endometritis and postpartum / post-abortion endometritis; and the adnexitis includes chronic salpingitis and oophoritis.

[0015] In some embodiments of the present invention, the inflammation includes immune inflammation; immune inflammation refers to a broad type of inflammatory response mediated by monocytes / macrophages. The monocyte / macrophage-mediated inflammatory response includes initiation, amplification, and effector phases, including but not limited to activation of inflammatory signaling pathways, production and release of inflammatory factors, and alterations in inflammation-related phenotypes. Applicable types of inflammation include, but are not limited to, inflammatory responses caused by infection, tissue damage, metabolic abnormalities, or immune imbalance; acute or chronic inflammatory states accompanied by immune cell activation and release of inflammatory factors; and inflammatory-related diseases or pathological processes occurring in different tissues or organs but sharing a common immune inflammatory mechanism. Immune inflammation includes, but is not limited to, pathogen-activated immune responses and aseptic injury inflammation.

[0016] In some embodiments of the present invention, the immune inflammation includes, but is not limited to, autoimmune inflammation, nervous system inflammation, metabolic and circulatory system-related inflammation, and musculoskeletal system-related inflammation.

[0017] In some embodiments of the present invention, the autoimmune inflammation includes, but is not limited to, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and gouty arthritis.

[0018] In some embodiments of the present invention, the neurological inflammation includes, but is not limited to, multiple sclerosis and Alzheimer's disease.

[0019] In some embodiments of the present invention, the metabolic and circulatory system-related inflammation includes, but is not limited to, diabetic vascular disease, thrombosis, and non-alcoholic steatohepatitis.

[0020] In some embodiments of the present invention, the musculoskeletal-related inflammation includes, but is not limited to, osteoarthritis, rheumatoid arthritis-related joint inflammation, tendinitis, Achilles tendinitis, synovitis, muscle inflammation (such as polymyositis, dermatomyositis), and local tissue inflammation caused by sports injury, trauma, or degenerative changes.

[0021] In some embodiments of the present invention, the inflammation includes endothelial cell inflammation; endothelial cell inflammation refers to the transformation of endothelial cells lining blood vessels and non-vascular tissues from a homeostatic anti-inflammatory, anticoagulant, and barrier-permeability-maintaining phenotype to a pro-inflammatory, procoagulant, and activated state accompanied by increased vascular permeability after stimulation by cytokines, oxidative stress, pathogens, metabolic disorders, mechanical stress, or toxic substances. At the molecular level, this manifests as upregulation of adhesion molecules, increased secretion of inflammatory mediators, and activation of inflammation-related signaling pathways, thereby mediating immune cell adhesion, infiltration, and activation, leading to amplification of local inflammation and systemic inflammatory responses. Besides vascular endothelium, similar inflammatory activation can also occur in lymphatic endothelium, synovial endothelium, blood-brain barrier and blood-testis barrier endothelium, mesentery, and reproductive tract endothelium.

[0022] In some embodiments of the present invention, the endothelial cell inflammation includes, but is not limited to, cardiovascular-related inflammation.

[0023] In some embodiments of the present invention, the cardiovascular-related inflammation includes, but is not limited to, atherosclerosis, sepsis, hypertensive vascular disease, vasculitis, and myocarditis.

[0024] In some embodiments of the present invention, the compound 4-[2-(methylamino)ethoxy]phenol exerts its anti-inflammatory effect by activating estrogen receptor β (ERβ).

[0025] Once activated, ERβ can compete for transcriptional cofactors or block their nuclear translocation by directly or indirectly interacting with NF-κB subunits (such as the p65 subunit), thereby weakening the binding ability of p65 to the κB binding site in the promoter region of target genes and inhibiting the transcriptional activation of core pro-inflammatory factors such as TNF-α and IL-1β.

[17] On the other hand, ERβ activation can also reduce the maturation and release of core pro-inflammatory factors such as IL-1β and IL-18 by downregulating the expression, assembly, and activation of the NLRP3 inflammasome.

[18] ERβ activation can alter the activity and phosphorylation state of key signaling molecules such as MAPK.

[19] This reshapes the transcriptional lineage of downstream target genes, inducing the expression of anti-inflammatory genes and inhibiting the expression of some pro-inflammatory genes. Therefore, in some embodiments of the present invention, the applicant believes that ERβ activation can synergistically affect key signaling pathways such as NF-κB, NLRP3, and MAPK by: blocking the nuclear transcriptional activity of NF-κB / p65, inhibiting the expression and activation of the NLRP3 inflammasome, and reshaping the MAPK cascade and its downstream inflammatory transcriptional network, thereby achieving multi-target, multi-level anti-inflammatory regulation. This provides a molecular mechanism basis for the application of the composition described in the present invention in the prevention and treatment of inflammation-related diseases.

[0026] In some embodiments of the present invention, the inflammation includes types of inflammation that can be treated by activating ERβ, including but not limited to the skin inflammations described above.

[20] Respiratory tract inflammation

[21] Gastrointestinal inflammation

[22] Immune inflammation

[23] Nervous system inflammation

[24] Cardiovascular system-related inflammation

[24] Inflammation of the musculoskeletal system and inflammation of the reproductive system

[26] Urinary tract inflammation

[27] and metabolism

[28] Related inflammation.

[0027] In some embodiments of the present invention, the medicament includes pharmaceutically acceptable excipients.

[0028] In one embodiment of the present invention, the pharmaceutically acceptable excipients include at least one of the following: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, binding agents, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, encapsulating agents, humectants, absorbents, diluents, flocculants and anti-flocculation agents, filter aids, release inhibitors, and carriers.

[0029] In some embodiments of the present invention, the dosage form of the drug includes a gastrointestinal dosage form or a non-gastrointestinal dosage form.

[0030] In some embodiments of the present invention, the gastrointestinal dosage form includes at least one of powder, tablet, granule, capsule, sustained-release, solution, dry suspension, effervescent tablet, emulsion, suspension, syrup, drops, and chewable tablet.

[0031] In some embodiments of the present invention, the non-gastrointestinal dosage form includes at least one of injection dosage form, respiratory dosage form, skin dosage form, mucosal dosage form, and cavity dosage form.

[0032] In some embodiments of the present invention, the route of administration of the drug includes at least one of intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, sublingual administration, nasal administration, nebulized administration, or transdermal administration.

[0033] In some embodiments of the invention, the compound 4-[2-(methylamino)ethoxy]phenol is administered at a therapeutically effective amount that is effective in the subject without unacceptable toxicity. Those skilled in the art can adjust the dosing regimen to suit different subjects based on preclinical trial results and conventional pharmacokinetic and toxicological principles.

[0034] In some embodiments of the present invention, the subject includes a mammal; preferably, the subject includes a human.

[0035] In a second aspect of the invention, a treatment method for inflammation is provided, the method comprising administering an effective dose of a compound to a subject in need, the compound having the following structure: .

[0036] In some embodiments of the present invention, the inflammation includes the types of inflammation described above.

[0037] In some embodiments of the present invention, the compound 4-[2-(methylamino)ethoxy]phenol is administered at a therapeutically effective dose that is effective in the subject without unacceptable toxicity. Those skilled in the art can adjust the dosing regimen to suit different subjects based on preclinical trial results and in accordance with conventional pharmacokinetic and toxicological principles.

[0038] In some embodiments of the invention, the subjects of the drug include mammals; preferably, the subjects include humans.

[0039] The beneficial effects of this invention are: This invention is the first to discover that compound 4-[2-(methylamino)ethoxy]phenol possesses a broad-spectrum and significant anti-inflammatory effect. It effectively reduces inflammatory responses induced by lipopolysaccharide (LPS) or the cytokine TNFα in epithelial cells, immune cells, and endothelial cells, inhibits the expression of inflammatory factors, and restores CDH1 expression loss caused by inflammation in in vitro and in vivo models of inflammatory bowel disease, thereby protecting intestinal adhesion structures. Furthermore, 4-[2-(methylamino)ethoxy]phenol exhibits agonistic activity and selective affinity for ERβ, avoiding the hormone-related side effects that may be caused by estrogen-based drugs activating ERα, thus demonstrating higher targeting, safety, and lower side effect risk. Therefore, the compound 4-[2-(methylamino)ethoxy]phenol provided by this invention, as a novel candidate drug for treating inflammation and inflammation-related diseases, possesses a broad-spectrum anti-inflammatory effect. Its target is novel, its mechanism of action is clear, and its efficacy is superior to existing therapeutic drugs, exhibiting higher targeting, safety, and lower side effect risk, demonstrating promising application prospects and industrialization potential. Attached Figure Description

[0040] Figure 1 This study demonstrates the therapeutic effect of 4-[2-(methylamino)ethoxy]phenol on an HT-29 epithelial cell inflammation model.

[0041] Figure 2 This study demonstrates the therapeutic effect of 4-[2-(methylamino)ethoxy]phenol on a Caco2 epithelial cell inflammation model.

[0042] Figure 3 This study demonstrates the therapeutic effect of 4-[2-(methylamino)ethoxy]phenol on an immune inflammatory model of the THP-1 mononuclear / macrophage cell line.

[0043] Figure 4 This study demonstrates the therapeutic effect of 4-[2-(methylamino)ethoxy]phenol on an endothelial inflammation model of the HUVEC human umbilical vein endothelial cell line.

[0044] Figure 5 This shows the aggregation and number of Tg(Lyz:EGFP) intestinal macrophages in zebrafish from different treatment groups.

[0045] Figure 6 This shows the aggregation and number of Tg(mpx:EGFP) gut neutrophils in zebrafish under different treatment groups.

[0046] Figure 7 show Figure 5 and Figure 6 The statistical results; among which Figure 7 The A in the text is displayed. Figure 5 Statistical results Figure 7 B in the display Figure 6 The statistical results.

[0047] Figure 8 The results of hematoxylin-eosin staining of zebrafish intestines in different treatment groups are shown.

[0048] Figure 9 This shows the qPCR detection results of zebrafish in different treatment groups.

[0049] Figure 10 This demonstrates the regulatory effect of 4-[2-(methylamino)ethoxy]phenol on estrogen receptors. Detailed Implementation

[0050] The present invention will be further described in detail below through specific embodiments. Unless otherwise specified, the raw materials, reagents, or apparatus used in the embodiments and comparative examples are all available from conventional commercial sources or can be obtained by existing technical methods. Unless otherwise specified, the test or experimental methods are conventional methods in the art.

[0051] Example 1: The intervention effect of compound 4-[2-(methylamino)ethoxy]phenol on LPS-induced HT-29 and Caco2 epithelial cell inflammation models Sample preparation: Colorectal cancer epithelial cell lines HT-29 and Caco2 were prepared and starved in serum-free medium for 6 hours. Inflammatory bowel disease was induced by induction with 1 μg / mL LPS (Lipopolysaccharide) for 24 hours. During the last 12 hours of LPS induction, cells were administered 0 μM, 25 μM, 50 μM, or 100 μM 4-[2-(methylamino)ethoxy]phenol or an equivalent dose of mesalazine (MS), respectively. HT-29 and Caco2 colon cells not treated with LPS served as the normal control group.

[0052] RNA extraction and reverse transcription: Total RNA was extracted from HT-29 and Caco2 cells using the Direct-zol™ RNA miniprep kit (catalog number R2052) according to the manufacturer's instructions. Then, 5 μL of TransScript® All-in-One First-Strand cDNA Synthesis SuperMix for qPCR (one-step gDNA removal) (TransGen Biotech, catalog number AT341-01), 1 μL of gDNA remover, and 1 μg of RNA were mixed, and enzyme-free water was added to a final volume of 20 μL for reverse transcription to synthesize cDNA. The reverse transcription program was 42 °C for 15 minutes, followed by inactivation of the reverse transcriptase at 85 °C for 5 seconds, and finally cooling to 4 °C.

[0053] qPCR detection: The relative expression levels of IL1β, CXCL8, and CDH1 genes were detected using qPCR. The primers used are shown in Table 1 below. 10 μL of premixed solution containing SYBR Green (PerfectStart Green qPCR SuperMix, Transgen, catalog number AQ601) was mixed with 2 μL of cDNA, 0.5 μL of forward primer (10 μM), 0.5 μL of reverse primer (10 μM), and enzyme-free water to form a 20 μL system. This system was then loaded onto an Applied Biosystems QuantStudio™ 6 Flex real-time quantitative PCR system for amplification and detection.

[0054] Table 1: Primer sequences of Example 1

[0055] Calculate the relative expression of target genes: Using GAPDH as an internal reference gene, calculate the relative expression levels of target genes (IL1β, CXCL8, and CDH1) relative to the internal reference gene. The cycle threshold Ct value obtained from PCR amplification is used to calculate the relative expression level of each sample. Specifically, for each test sample, the Ct values ​​of the target gene and the internal reference gene are measured separately, and their ΔCt (ΔCt = Ct) is calculated. 目标基因 – Ct 内参基因 Using the average ΔCt of the control group cells that did not receive stimulation or drug treatment as the calibration value, the ΔΔCt of each treated sample was calculated (ΔΔCt = ΔCt). 样本 -ΔCt 对照组平均值 Finally, the relative expression level was calculated using 2. -ΔΔCt The method calculates that the relative expression level of the target gene in the treated sample compared to the normal control group is 2. -ΔΔCt This method can be used to compare the upregulation or downregulation of target gene expression under different treatment conditions. Statistical significance was calculated using conventional ANOVA, with significance values ​​marked as *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001.

[0056] Experimental results are as follows Figure 1 , Figure 2 As shown, compared to the normal control group, the inflammatory factors in the inflammatory bowel disease model group... IL1B , CXCL8 The expression level of adhesion factor increased significantly. CDH1The expression level of 4-[2-(methylamino)ethoxy]phenol decreased significantly, indicating impaired intestinal epithelial barrier function and successful model establishment. Compared with the untreated inflammatory colitis model group, the inflammatory factors in the 4-[2-(methylamino)ethoxy]phenol treatment group decreased significantly, and the expression of adhesion factors was restored, suggesting that 4-[2-(methylamino)ethoxy]phenol can inhibit the transcription of typical pro-inflammatory cytokines, improve the downregulation of epithelial adhesion molecules caused by inflammation, and help repair or maintain the integrity of the intestinal epithelial barrier.

[0057] Furthermore, compared to the positive control group treated with mesalazine (MS), under the same experimental conditions, the 4-[2-(methylamino)ethoxy]phenol treatment group showed better inhibition. IL1B , CXCL8 Overexpression and recovery CDH1 Both showed more significant improvement in expression, suggesting that 4-[2-(methylamino)ethoxy]phenol has better overall anti-inflammatory and epithelial barrier protection effects than MS.

[0058] Example 2: The intervention effect of compound 4-[2-(methylamino)ethoxy]phenol on LPS-induced THP-1 monocyte / macrophage cell line immune inflammation model Sample preparation: THP-1 monocytes were prepared and induced to differentiate into macrophages for 24 hours with 100 nM PMA (phorbol 12-myristate 13-acetate). They were then cultured in normal medium (RPMI-1640 medium supplemented with 10% fetal bovine serum, 1% penicillin and streptomycin antibiotics, and 0.05 mM β-mercaptoethanol) for 24 hours. An immune inflammation model was then induced for 18 hours using 1 μg / mL LPS. During the last 12 hours of LPS induction, cells were administered 0 μM, 25 μM, 50 μM, or 100 μM 4-[2-(methylamino)ethoxy]phenol, or 1 μM dexamethasone, respectively. THP-1 cells not treated with LPS served as the normal control group.

[0059] The RNA extraction and reverse transcription steps, qPCR detection steps, and steps for calculating the relative expression of the target gene are the same as in Example 1. The primers used in this example are shown in Table 2 below.

[0060] Table 2: Primer sequences of Example 2

[0061] Experimental results are as follows Figure 3As shown, compared with the normal control group, the expression levels of inflammatory factors in the immune inflammation model group were significantly increased, indicating successful model establishment. Compared with the untreated immune inflammation model group, the inflammatory factors in the 4-[2-(methylamino)ethoxy]phenol treatment group were significantly decreased, showing that 4-[2-(methylamino)ethoxy]phenol has a good anti-inflammatory effect on immune inflammation. While the overall anti-inflammatory efficacy of 4-[2-(methylamino)ethoxy]phenol is lower than that of dexamethasone, it exhibits certain advantages in terms of safety with long-term use. Therefore, its potential for low hormone dependence and fewer systemic side effects makes 4-[2-(methylamino)ethoxy]phenol more suitable for adjunctive intervention in chronic or immune-related inflammation.

[0062] Example 3: The intervention effect of compound 4-[2-(methylamino)ethoxy]phenol on TNF-α-induced endothelial inflammation model of HUVEC human umbilical vein endothelial cell line. Sample preparation: Human umbilical vein endothelial cells (HUVECs) were prepared and starved in serum-free medium for 2 hours. Endothelial inflammation was induced by induction with 10 ng / mL TNF-α for 16 hours. For the last 12 hours after TNF-α induction, cells were administered 0 μM, 25 μM, 50 μM, or 100 μM 4-[2-(methylamino)ethoxy]phenol or 1 μM dexamethasone. HUVECs without TNF-α were used as the normal control group.

[0063] The RNA extraction and reverse transcription steps, qPCR detection steps, and steps for calculating the relative expression of the target gene are the same as in Example 1. This example uses qPCR detection. GAPDH, CXCL8 and TNFA The relative expression levels of the genes and the primer sequences used are shown in Table 2.

[0064] Experimental results are as follows Figure 4 As shown, compared with the normal control group, the expression levels of inflammatory factors in the endothelial inflammation model group were significantly increased, indicating successful model establishment. Compared with the untreated endothelial inflammation model group, the inflammatory factors in the 4-[2-(methylamino)ethoxy]phenol treatment group were significantly decreased, showing that 4-[2-(methylamino)ethoxy]phenol has a good anti-inflammatory effect on endothelial inflammation.

[0065] While the overall anti-inflammatory efficacy of 4-[2-(methylamino)ethoxy]phenol is lower than that of dexamethasone, it exhibits certain advantages in terms of safety with long-term use. Therefore, its potential for low hormone dependence and fewer systemic side effects makes 4-[2-(methylamino)ethoxy]phenol more suitable for adjunctive intervention in chronic or immune-related inflammation.

[0066] Example 4: The intervention effect of compound 4-[2-(methylamino)ethoxy]phenol on a DSS-induced zebrafish inflammatory bowel disease model. Animal strains: Tg(mpx:EGFP) zebrafish and Tg(Lyz:EGFP) zebrafish, where Tg(mpx:EGFP) represents zebrafish with neutrophil-labeled EGFP and Tg(Lyz:EGFP) represents zebrafish with macrophage-labeled EGFP.

[0067] Modeling treatment: Fertilized eggs from two transgenic zebrafish species were treated with 0.5% (w / v) DSS (sodium dextran sulfate) for 72 hours on the third day after fertilization to establish an inflammatory bowel disease model. They were then treated for 48 hours with 31.25 μg / mL, 62.5 μg / mL, 125 μg / mL 4-[2-(methylamino)ethoxy]phenol, or 50 μg / mL mesalazine (positive control, MS). The normal control group received no treatment.

[0068] Detection: 1. The number and distribution of neutrophils and macrophages in the zebrafish intestine were observed under a fluorescence microscope. The specific steps were as follows: After treatment with 4-[2-(methylamino)ethoxy]phenol or mesalazine for 48 hours, the zebrafish were anesthetized with tricaine and fixed with low-melting-point agarose. The intestinal Z-stack was collected in the GFP channel using a fluorescence microscope. A Python script was used to perform batch segmentation and automatic counting (blind method) with a uniform threshold. The number of neutrophils and macrophages in each zebrafish and their spatial distribution around the intestinal lumen were counted.

[0069] Experimental results are as follows Figures 5-7 As shown, compared to the normal control group, the number of macrophages aggregated in the intestine of the inflammatory bowel disease model group (0.5% (w / v) DSS treatment) was significantly higher. Figure 5 ) and the number of neutrophil aggregates ( Figure 6 The number of intestinal macrophages significantly increased, indicating successful modeling. Compared to the untreated inflammatory bowel disease model group, the number of intestinal macrophages aggregated in the three doses of 4-[2-(methylamino)ethoxy]phenol (MEP) treatment groups and the mesalazine (MS) treatment groups was significantly higher. Figure 5 ) and the number of neutrophil aggregates ( Figure 6The levels of inflammatory cells decreased significantly, and the infiltration area of ​​inflammatory cells was significantly reduced, suggesting that 4-[2-(methylamino)ethoxy]phenol can effectively inhibit the abnormal recruitment and aggregation of myeloid immune cells in the inflammatory bowel disease model, thereby alleviating the local inflammatory response of the intestinal wall. Quantitative analysis showed that 4-[2-(methylamino)ethoxy]phenol exhibited a dose-dependent effect, and low-dose 4-[2-(methylamino)ethoxy]phenol could significantly improve the level of inflammatory cell aggregation (…). Figure 7 Statistical results showed that 4-[2-(methylamino)ethoxy]phenol's effect in inhibiting the aggregation of myeloid immune cells was comparable to that of MS, suggesting that 4-[2-(methylamino)ethoxy]phenol has a good therapeutic effect on inflammatory bowel disease. Figure 7 ).

[0070] 2. Hematoxylin / eosin (H&E) staining was performed to observe the damage to intestinal epithelial cells. The specific steps are as follows: 2.1 After 48 hours of treatment with 4-[2-(methylamino)ethoxy]phenol or MS, several juvenile fish from each group were taken and fixed in 4% paraformaldehyde fixative for 24 hours.

[0071] 2.2 Dehydration and wax impregnation: Place the dehydration box into the dehydrator and dehydrate it sequentially with alcohol in a gradient manner, as follows: 75% ethanol for 4 hours, 85% ethanol for 2 hours, 90% ethanol for 2 hours, 95% ethanol for 1 hour, anhydrous ethanol I for 30 minutes, and anhydrous ethanol II for 30 minutes; the clearing process is as follows: benzene for 5-10 minutes, xylene I for 5-10 minutes, and xylene II for 5-10 minutes; the wax impregnation process is as follows: molten paraffin I at 65℃ for 1 hour, molten paraffin II at 65℃ for 1 hour, and molten paraffin III at 65℃ for 1 hour.

[0072] 2.3 Paraffin embedding: The tissue impregnated with paraffin is embedded in an embedding machine and cooled on a -20℃ freezing stage. After the paraffin solidifies, the paraffin block is removed from the embedding frame and trimmed.

[0073] 2.4 Paraffin sectioning: Place the trimmed wax block on a paraffin microtome and section it to a thickness of 4 μm; float the section on a 40 ℃ warm water spreader to flatten the tissue, pick up the tissue with a glass slide, and bake the section in a 60 ℃ oven; after the water-dried wax melts, remove it and store it at room temperature for later use.

[0074] 2.5 Dewaxing paraffin sections to water: The sections were placed in environmentally friendly dewaxing solution I for 20 minutes, environmentally friendly dewaxing solution II for 20 minutes, anhydrous ethanol I for 5 minutes, anhydrous ethanol II for 5 minutes, 75% ethanol for 5 minutes, and then rinsed with tap water.

[0075] 2.6 Pretreatment: The sections were immersed in high-resolution constant staining pretreatment solution (Servicebio, catalog number G1076) for 1 minute.

[0076] 2.7 Hematoxylin staining: Immerse the sections in hematoxylin staining solution for 3-5 minutes, wash with tap water, differentiate with differentiation solution, wash with tap water, re-blue with blue solution, and rinse with running water.

[0077] 2.8 Eosin staining: Dehydrate the sections in 95% ethanol for 1 minute, then stain them in eosin staining solution for 15 seconds.

[0078] 2.9 Dehydration and mounting: Place the sections in anhydrous ethanol I for 2 minutes, anhydrous ethanol II for 2 minutes, anhydrous ethanol III for 2 minutes, n-butanol I for 2 minutes, and n-butanol II for 2 minutes in sequence.

[0079] 2.10 Use a 20x microscope to observe the damage to intestinal epithelial cells.

[0080] Experimental results are as follows Figure 8 As shown, compared to the normal control group, the intestinal epithelial tissue thickness was significantly reduced in the inflammatory bowel disease model group, with disrupted intestinal epithelial structure, fewer goblet cells, disordered and absent folds, and increased immune cell infiltration. Compared to the untreated inflammatory bowel disease model group, all concentrations of 4-[2-(methylamino)ethoxy]phenol treatment groups showed significant recovery in intestinal thickness, restored intestinal epithelial structure, increased goblet cells, restored folds, and reduced immune cell infiltration, suggesting that 4-[2-(methylamino)ethoxy]phenol has a good mucosal protective and repair-promoting effect on inflammatory bowel disease. The positive control drug mesalazine (MS) group also showed similar recovery in mucosal thickness and reduction in inflammatory infiltration.

[0081] 3. qPCR was used to detect the relative expression levels of IL1β, CXCL8, TNFα, and CDH1 genes. The steps were as follows: Total RNA was extracted from zebrafish homogenates using an animal tissue / cell total RNA extraction kit (Wuhan Saiwei Biotechnology, G3640-50T). Then, 5 μL of TransScript® All-in-One First-Strand cDNA Synthesis SuperMix for qPCR (one-step gDNA removal) (TransGen Biotech, catalog number AT341-01), 1 μL of gDNA remover, and 1 μg of RNA were mixed, and enzyme-free water was added to a final volume of 20 μL. cDNA was synthesized by reverse transcription. The reverse transcription program was 42 ℃ for 15 minutes, followed by 85 ℃ for 5 seconds to inactivate the reverse transcriptase, and finally cooling to 4 ℃. 10 μL of premixed solution containing SYBR Green (PerfectStart Green qPCR SuperMix, TransGen Biotech, catalog number AQ601) was mixed with 2 μL of cDNA, 0.5 μL of forward primer (10 μM), 0.5 μL of reverse primer (10 μM), and enzyme-free water to form a 20 μL system. This mixture was then loaded onto an Applied Biosystems QuantStudio™ 6 Flex real-time quantitative PCR system for amplification and detection. il1b, cxcl8, tnfa and cdh1 The primer sequences used are shown in Table 3. actb1 As an internal reference, the steps for calculating the relative expression of the target gene are the same as in Example 1, except that the internal reference gene is replaced with... actb1 .

[0082] Table 3: Primer sequences of Example 4

[0083] Experimental results are as follows Figure 9 As shown, compared to the normal control group, the inflammatory factors in the inflammatory bowel disease model group... IL1B , CXCL8 and TNFA The expression level of adhesion factor increased significantly. CDH1 The expression level of 4-[2-(methylamino)ethoxy]phenol decreased significantly, indicating successful model establishment. Compared with the untreated inflammatory bowel disease model group, the inflammatory factors in the 4-[2-(methylamino)ethoxy]phenol treatment group decreased significantly, and CDH1 adhesion factor expression was restored, suggesting increased intestinal epithelial barrier integrity and repair of mucosal damage. Compared with the positive control group, each dose of 4-[2-(methylamino)ethoxy]phenol showed comparable or even better effects.

[0084] Example 5: Molecular mechanism of action of the anti-inflammatory effect of compound 4-[2-(methylamino)ethoxy]phenol To investigate the potential anti-inflammatory mechanism of compound 4-[2-(methylamino)ethoxy]phenol, estrogen response element (ERE) fluorescent reporter gene plasmid and ERα and ERβ expression plasmids were co-transfected into HEK293T cells to detect the effect of this compound on ERE-driven luciferase activity. The specific experimental steps are as follows: Sample and plasmid preparation: 1. Cell line: HEK293T cells were seeded in 24-well plates at a density of 5 × 10⁶ cells per well. 3 The cells were cultured in DMEM + 10% charcoal-stripped FBS for 72 hours at 37 °C and 5% CO2.

[0085] 2. Plasmid: The fluorescent reporter plasmid pGL3-basic-ERE-Firefly is a plasmid vector containing an estrogen response element (ERE) and a firefly luciferase reporter gene. This vector uses the pGL3-basic plasmid (Promega, catalog number E1751, containing Firefly) as its backbone, inserting a 2X multiple-copy estrogen response element at its 5' MluI and 3' HindIII restriction endonuclease recognition sites. The sequence is 5'-GTCCAAAGTCAGGTCACAGTGACCTGATCAAAGTTAATGTAACCTCA. The double-stranded deoxyribonucleic acid (DNA) fragment GTCCAAAGTCAGGTCACAGTGACCTGATCAAAGTTAATGTAACCTCA-3' (SEQ ID NO: 21). The estrogen receptor protein (ERα or ERβ) expression plasmid uses a pcDNA3.1(+) (Invitrogen, catalog number V79020) backbone, with the ERα or ERβ protein expression sequence inserted into its 5' HindIII and 3' EcoRI restriction endonuclease recognition sites. The ERα and ERβ proteins involved in this invention have amino acid sequences that are identical to those of human proteins. ESR1 The encoded protein (GeneBank: NP_000116.2) and ESR2The amino acid sequence of the encoded protein (GeneBank: NP_001428.1) is identical. The nucleic acid sequence encoding the aforementioned ERα or ERβ protein can be a variant obtained by synonymous codon substitution of the natural coding sequence. Without altering the encoded amino acid sequence, optimization can be performed based on the codon usage preferences of the host system to improve expression efficiency in the heterologous expression system. The aforementioned synonymous codon substitution is an implementation method that can be achieved by those skilled in the art using conventional techniques. In the experiment, the plasmid was transformed into DH5α competent *E. coli*, positive single clones were picked and amplified (cultured in LB liquid medium containing 10 g / L tryptone, 5 g / L yeast extract, 10 g / L sodium chloride, and 100 mg / L penicillin). Subsequently, a high-purity plasmid was obtained using an endotoxin-free plasmid large-scale extraction kit (Tiangen, catalog number DP117) for subsequent transfection experiments.

[0086] 3. Co-transfection: Using the Lipofectamine 3000 transfection kit (Invitrogen, catalog number L3000001), Lipo3000 was diluted 25-fold with Opti-MEM medium (Gibco, catalog number 31985062) according to the instructions. P300 was diluted 50-fold, and after mixing with the plasmid, it was mixed with an equal volume of diluted Lipo3000. After incubating at room temperature for 15 minutes, 0.25 μg of fluorescent reporter plasmid pGL3-basic-ERE-Firefly and 0.5 μg of ERα or ERβ expression vector were co-transfected into each well of cells. Cells transfected only with fluorescent reporter plasmid pGL3-basic-ERE-Firefly served as the control group.

[0087] 4. Drug administration: 8 hours after transfection, compound 4-[2-(methylamino)ethoxy]phenol was added at concentration gradients (1 nM, 3 nM, 10 nM, 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM, 30 μM, 100 μM, 300 μM, 1 mM, 3 mM), and incubation continued for 48 hours.

[0088] 5. Luciferase assay: Discard the supernatant, lyse cells containing the reporter gene ERE-Luc with passive lysate buffer (120 μL per well), shake at room temperature for 15 minutes, centrifuge at 12000 rpm for 5 minutes, collect the supernatant, and then mix the supernatant with firefly luciferase working solution at a 1:1 volume ratio according to the instructions. Use the PerkinElmer EnVision™ multi-label microplate reader to read the ERE fluorescent reporter gene signal (Firefly signal).

[0089] 6. Protein Concentration Assay: Add 1 μL of supernatant and 19 μL of dPBS (Dulbecco's Phosphate Buffered Saline) to each well of a clear 96-well plate to dilute the protein sample; then add 200 μL of BCA working solution (Coolaber, catalog number SK1070) to each well, incubate at 37 ℃ in the dark for 30 minutes, cool to room temperature, and read the absorbance at 562 nm. Perform serial dilutions with 0.5 mg / mL bovine serum albumin standard solution, measure the absorbance at 562 nm to plot a linear regression curve, and then calculate the protein concentration in the supernatant based on the linear regression curve and the dilution factor of the supernatant.

[0090] 7. Data Processing and Statistics: The relative fluorescence unit (RLU) for each well was calculated as Firefly / protein concentration, and normalized to 1 using the vehicle control. A four-parameter logistic regression model (4PL) was used to perform nonlinear regression on the dose-response curve to obtain the EC50. 50 With a 95% confidence interval (GraphPad Prism). The vector control is achieved by transfecting only empty liposomes, without the receptor expression plasmid and luciferase expression plasmid.

[0091] Experimental results are as follows Figure 10 As shown in Table 4 below, compared with the control group, the ERE fluorescence activity of the compound-treated group was significantly increased, and the EC... 50 The levels were significantly higher than ERα, suggesting that 4-[2-(methylamino)ethoxy]phenol can activate ERβ receptors, enhance ERβ-mediated transcriptional activity, and exhibit selectivity for ERβ. This indicates that 4-[2-(methylamino)ethoxy]phenol may exert its anti-inflammatory effects by regulating estrogen receptor-related pathways.

[0092] Table 4: ECG activation of ERα and ERβ receptors by 4-[2-(methylamino)ethoxy]phenol 50 value

[0093] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

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Claims

1. Use of a compound in the preparation of a medicament for the prevention and / or treatment of inflammatory diseases, said compound having the following structure: 。 2. The use according to claim 1, characterized in that, The inflammation includes epithelial cell inflammation; the epithelial cell inflammation includes skin inflammation, respiratory tract inflammation, digestive tract inflammation, urinary system inflammation, and reproductive system inflammation.

3. The use according to claim 1, characterized in that, The inflammation includes immune-mediated inflammation; the immune-mediated inflammation includes autoimmune inflammation, nervous system inflammation, metabolic and circulatory system-related inflammation, and musculoskeletal system-related inflammation.

4. The use according to claim 2, characterized in that, The skin inflammations include atopic dermatitis, psoriasis, ichthyosis, acne, seborrheic dermatitis, cutaneous discoid lupus erythematosus, chronic simple lichen simplex, and contact dermatitis; the respiratory tract inflammations include asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, acute bronchitis, bronchiectasis, cystic fibrosis, eosinophilic bronchitis, pneumonia, allergic rhinitis, and idiopathic pulmonary fibrosis; the digestive tract inflammations include gastritis, colitis, and inflammatory bowel disease; the urinary tract inflammations include acute or chronic cystitis, pyelonephritis, complicated or uncomplicated urinary tract infections, urethritis, urinary tract infections associated with indwelling catheters, prostatitis, interstitial cystitis / bladder pain syndrome, drug-induced or radiation-induced cystitis, and urinary tract inflammatory diseases mediated by autoimmune reactions or aseptic inflammation; the reproductive system inflammations include endometriosis-related inflammation, pelvic inflammatory disease, endometritis, cervicitis, vaginitis, salpingitis, and oophoritis.

5. The use according to claim 4, characterized in that, The inflammatory bowel disease mentioned includes Crohn's disease and ulcerative colitis.

6. The use according to claim 3, characterized in that, The autoimmune inflammations mentioned include rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and gouty arthritis.

7. The use according to claim 3, characterized in that, The neurological inflammations include multiple sclerosis and Alzheimer's disease; the metabolic and circulatory system-related inflammations include, but are not limited to, diabetic vascular disease, thrombosis, and non-alcoholic steatohepatitis; the musculoskeletal system-related inflammations include osteoarthritis, rheumatoid arthritis-related joint inflammation, tendinitis, Achilles tendinitis, synovitis, muscle inflammation, and local tissue inflammation caused by sports injuries, trauma, or degenerative changes.

8. The use according to claim 1, characterized in that, The inflammation includes endothelial cell inflammation; the endothelial cell inflammation includes cardiovascular-related inflammation.

9. The use according to claim 8, characterized in that, The cardiovascular-related inflammations include atherosclerosis, sepsis, hypertensive vascular disease, vasculitis, and myocarditis.

10. The use according to claim 1, characterized in that, The drug comprises pharmaceutically acceptable excipients, which include at least one of the following: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and anti-flocculators, filter aids, release inhibitors, and carriers.

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