Anti-inflammatory small molecule compound as well as synthesis method and application thereof

Abstract

The invention relates to an anti-inflammatory small molecule compound as well as a synthesis method and application thereof. The structural formula of the anti-inflammatory small molecule compound is shown in the specification. The anti-inflammatory small molecule compound has a remarkable treatment effect on inflammatory diseases (such as acute colitis), has a remarkable anti-inflammatory effect, has good druggability, has no obvious toxicity on mice at the animal level, has a certain protection effect on kidneys, and is good in safety and free of toxic and side effects. The compound can be used for preparing medicines for treating inflammatory diseases (such as acute colitis). # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and relates to small molecule pharmaceutical compounds, in particular to a novel anti-inflammatory small molecule compound and a synthesis method and application thereof. Background Art

[0002] Inflammatory bowel disease (IBD) is an idiopathic intestinal inflammatory disease involving the ileum, rectum, and colon, including ulcerative colitis (UC) and Crohn's disease (CD). Its pathogenesis involves immune system dysregulation, intestinal microbiota imbalance, genetic susceptibility, and environmental factors. The overreaction of the immune system to intestinal microorganisms or food components can lead to chronic inflammation, while acute colitis can be caused by infection, drugs, ischemia, or radiotherapy, and the mechanism is usually related to overactivation of the immune response and damaged intestinal barrier. Ulcerative colitis (UC) is a chronic, recurrent, immune-induced gastrointestinal disease that increases the risk of colon cancer in patients and has become a public health issue. The exact cause of UC remains unclear. However, the overactivation of the mucosal immune system, especially the innate immunity, accompanied by a large number of immune cell recruitment and secretion of cellular inflammatory factors, such as interleukin (IL)-1β, interleukin (IL)-6, and tumor necrosis factor (TNF)-α in the colon, further promotes the onset and exacerbation of colitis.

[0003] At present, the drugs for treating inflammatory bowel disease (IBD) mainly include anti-inflammatory drugs (such as 5-aminosalicylic acid (5-ASA) drugs) and steroid drugs (such as prednisone and beclomethasone). Although they are effective in treating mild to moderate inflammatory bowel disease (IBD), they also have some disadvantages. 5-ASA drugs have limited effects in some patients, especially in the treatment of Crohn's disease, and long-term use may cause side effects such as liver and kidney damage. Although steroid drugs can quickly relieve acute inflammation, their long-term use may bring serious side effects such as osteoporosis, diabetes, weight gain, gastrointestinal bleeding and immunosuppression. Therefore, they are not suitable for long-term dependence and cannot fundamentally change the course of the disease.

[0004] Therefore, it is necessary to develop more safe and effective anti-inflammatory drugs for the treatment of inflammatory bowel disease. Summary of the invention

[0005] Based on this, the purpose of the present invention is to provide a novel anti-inflammatory small molecule compound to treat inflammatory diseases, such as colitis.

[0006] The technical solution for achieving the above-mentioned invention object is as follows.

[0007] In a first aspect, the present invention provides a compound ZYZ311 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the structural formula of the compound ZYZ311 is as follows:

[0008]

[0009] In a second aspect, the present invention provides use of compound ZYZ311 or a pharmaceutically acceptable salt or a stereoisomer thereof in the preparation of an anti-inflammatory drug.

[0010] In a third aspect, the present invention provides use of compound ZYZ311 or a pharmaceutically acceptable salt or a stereoisomer thereof in the preparation of a medicament for preventing and / or treating inflammatory diseases.

[0011] Among them, the inflammatory disease is preferably inflammatory bowel disease, more preferably colitis, and more preferably acute colitis or ulcerative colitis.

[0012] In a fourth aspect, the present invention provides a method for preparing a compound ZYZ311, comprising the following steps:

[0013] (1) reacting carvacrol with ethyl chloroacetate to obtain 2-(5-isopropyl-2-methylphenoxy)ethyl ester;

[0014] (2) 2-(5-isopropyl-2-methylphenoxy)ethyl ester reacts with hydrazine hydrate to obtain 2-(5-isopropyl-2-methylphenoxy)acetohydrazide;

[0015] (3) reacting 2-(5-isopropyl-2-methylphenoxy)acetohydrazide with 4-pyridinecarboxaldehyde to obtain a compound having a structure represented by formula (I);

[0016] The reaction formula is as follows:

[0017]

[0018] The present invention has the following beneficial effects:

[0019] The invention synthesizes a novel anti-inflammatory small molecule compound by a simple and efficient method. The compound has a significant therapeutic effect on inflammatory diseases (such as acute colitis). The compound can inhibit the expression of nitric oxide (NO) and inflammatory factors (such as interleukin 6 (IL-6) and tumor necrosis factor (TNF-α)) in the supernatant of inflammatory cells, and reduce the protein expression of inflammation-related proteins p-NF-κB / NF-κB, COX-2, IL-6, and TNF-α; it can improve the colon length and histological score of acute colitis mice, inhibit the release of inflammatory factors such as IL-1β, IL-6, and TNF-α, reduce the expression of orphan receptor F4 / 80 (a mature mouse macrophage marker) involved in cell adhesion, upregulate the expression of tight junction protein ZO-1 involved in proliferation, differentiation, metastasis and material transport, and inhibit the expression of myeloperoxidase (MPO, also known as peroxidase, a marker of neutrophil activation), and has a significant anti-inflammatory effect.

[0020] In addition, the anti-inflammatory small molecule compound of the present invention has good drugability, has no obvious toxicity to mice at the animal level, has a certain protective effect on the kidneys, has good safety, and can be used to prepare drugs for treating inflammatory diseases (such as acute colitis). BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Schematic diagram of mass spectrum for molecular weight characterization of compound ZYZ311.

[0022] Figure 2 Schematic diagram of the H NMR spectrum for the structure confirmation of compound ZYZ311.

[0023] Figure 3 Schematic diagram of the carbon NMR spectrum for the structure confirmation of compound ZYZ311.

[0024] Figure 4 Schematic diagram of compound ZYZ311 inhibiting the expression of nitric oxide (NO) and inflammatory factor IL-6 in the supernatant of the LPS-induced Raw264.7 cell inflammation model.

[0025] Figure 5 Schematic diagram of protein immunoblotting experiments showing that compound ZYZ311 inhibits the protein expression of inflammatory-related proteins p-NF-κB / NF-κB, COX-2, and IL-6 in the LPS-induced Raw264.7 cell inflammation model.

[0026] Figure 6 Schematic diagram of the drugability study analysis curve of compound ZYZ311.

[0027] Figure 7 This is a graph showing the results of animal toxicity experiments on compound ZYZ311.

[0028] Figure 8 Schematic diagram of mouse body weight and kidney weight / mouse body weight in the acute colitis model of C57BL / 6 mice induced by dextran sulfate sodium salt (DSS).

[0029] Fig. 9 Schematic diagram showing that compound ZYZ311 improves colon length in C57BL / 6 mice in the acute colitis model induced by dextran sulfate sodium salt (DSS).

[0030] Fig.10 Schematic diagram of the histological scoring of compound ZYZ311 in improving the acute colitis model induced by dextran sodium sulfate (DSS) in C57BL / 6 mice.

[0031] Fig.11 Schematic diagram of compound ZYZ311 reducing the expression of orphan receptor F4 / 80 (a marker of mature mouse macrophages) involved in cell adhesion in mice with acute colitis model induced by dextran sodium sulfate (DSS).

[0032] Fig.12 Schematic diagram of compound ZYZ311 increasing the expression level of tight junction protein ZO-1 involved in proliferation, differentiation, metastasis and material transport in mice with acute colitis model induced by dextran sulfate sodium salt (DSS).

[0033] Fig.13 Schematic diagram showing that compound ZYZ311 reduces the expression of myeloperoxidase (MPO, also known as peroxidase, a marker of neutrophil activation) in mice with acute colitis model induced by dextran sulfate sodium salt (DSS). DETAILED DESCRIPTION

[0034] In order to facilitate the understanding of the present invention, the present invention will be described more fully below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0035] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0036] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used in the present invention includes any and all combinations of one or more of the related listed items.

[0037] In addition, as used in the present invention, the term "or" is an inclusive "or" symbol and is equivalent to the term "and / or", unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for being based on other factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meanings of "a", "an", and "the" include plural referents. The meaning of "in..." includes "in..." and "on...".

[0038] In some embodiments of the present invention, a compound ZYZ311 or a pharmaceutically acceptable salt or a stereoisomer thereof is involved, and the structural formula of the compound ZYZ311 is as follows:

[0039]

[0040] The compound ZYZ311 of the present invention has a significant therapeutic effect on inflammatory diseases (such as acute colitis). It can inhibit the expression of nitric oxide (NO) and inflammatory factors (such as interleukin 6 (IL-6) and tumor necrosis factor (TNF-α)) in the supernatant of inflammatory cells, and reduce the protein expression of inflammation-related proteins p-NF-κB / NF-κB, COX-2, IL-6, and TNF-α; it can improve the colon length and histological score of mice with acute colitis, inhibit the release of inflammatory factors such as IL-1β, IL-6, TNF-α, etc., reduce the expression of orphan receptor F4 / 80 (a marker of mature mouse macrophages) involved in cell adhesion, upregulate the expression of tight junction protein ZO-1 involved in proliferation, differentiation, metastasis and material transport, and inhibit the expression of myeloperoxidase (MPO, also known as peroxidase, a marker of neutrophil activation), and has a significant anti-inflammatory effect. In addition, the compound ZYZ311 of the present invention has good drugability, has no obvious toxicity to mice at the animal level, has a certain protective effect on the kidneys, and has good safety.

[0041] Based on this, some embodiments of the present invention involve the use of compound ZYZ311 or a pharmaceutically acceptable salt or a stereoisomer thereof in the preparation of an anti-inflammatory drug.

[0042] Some embodiments of the present invention also involve the use of compound ZYZ311 or a pharmaceutically acceptable salt or a stereoisomer thereof in the preparation of a drug for preventing and / or treating inflammatory diseases.

[0043] In some embodiments, the inflammatory disease is inflammatory bowel disease.

[0044] In some embodiments, the inflammatory bowel disease is colitis.

[0045] In some embodiments, the colitis is acute colitis or ulcerative colitis.

[0046] In some embodiments of the present invention, there is also a method for preparing compound ZYZ311, comprising the following steps:

[0047] (1) reacting carvacrol with ethyl chloroacetate to obtain 2-(5-isopropyl-2-methylphenoxy)ethyl ester;

[0048] (2) 2-(5-isopropyl-2-methylphenoxy)ethyl ester reacts with hydrazine hydrate to obtain 2-(5-isopropyl-2-methylphenoxy)acetohydrazide;

[0049] (3) reacting 2-(5-isopropyl-2-methylphenoxy)acetohydrazide with 4-pyridinecarboxaldehyde to obtain a compound having a structure represented by formula (I);

[0050] The reaction formula is as follows:

[0051]

[0052] In some preferred embodiments, the reaction in step (1) is carried out under the action of a base, preferably potassium carbonate, and the molar ratio of the base to carvacrol is preferably 1-1.5:1.

[0053] In some preferred embodiments, the reaction in step (1) is carried out in an organic solvent, and the organic solvent is preferably acetone.

[0054] In some preferred embodiments, the reaction in step (1) is carried out under the protection of an inert gas.

[0055] In some preferred embodiments, the molar ratio of carvacrol to ethyl chloroacetate in step (1) is 1:1-1.5.

[0056] In some preferred embodiments, the reaction temperature in step (1) is 50° C.-70° C., and the reaction time is 2-6 hours, preferably 3-5 hours.

[0057] In some preferred embodiments, the reaction in step (2) is carried out in an organic solvent, and the organic solvent is preferably ethanol.

[0058] In some preferred embodiments, the reaction in step (2) is carried out under the protection of an inert gas.

[0059] In some preferred embodiments, the molar ratio of 2-(5-isopropyl-2-methylphenoxy)ethyl ester to hydrazine hydrate in step (2) is 1:1.2-1.5.

[0060] In some preferred embodiments, the reaction temperature in step (2) is 70° C.-90° C., and the reaction time is 2-4 hours.

[0061] In some preferred embodiments, the reaction in step (3) is carried out in an organic solvent, and the organic solvent is preferably ethanol.

[0062] In some preferred embodiments, the reaction in step (3) is carried out under the protection of an inert gas.

[0063] In some preferred embodiments, the molar ratio of 2-(5-isopropyl-2-methylphenoxy)acetohydrazide to 4-pyridinecarboxaldehyde in step (3) is 1:2-4.

[0064] In some preferred embodiments, the reaction temperature in step (3) is 70° C.-90° C., and the reaction time is 1-3 hours.

[0065] The present invention is further described in detail below with reference to specific embodiments.

[0066] Example 1 Synthesis of anti-inflammatory small molecule compounds

[0067]

[0068] Step 1: Use a pipette to measure carvacrol (2.75 mL, 20 mmol) and place it in a 50 mL round-bottom flask, add acetone (20 mL), stir to make it uniform, add potassium carbonate (3.0 g, 22 mmol), and then slowly add ethyl chloroacetate (2.4 mL, 22 mmol) dropwise under stirring, fill the reaction system with nitrogen, and then react at 60 ° C for 4 hours. Monitor the reaction progress by thin layer chromatography (TLC). After the reaction is completed, cool to room temperature, then concentrate the reaction mixture under reduced pressure and evaporate to dryness, extract with ethyl acetate, wash with water, collect the organic layer, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a light yellow oily liquid, that is, 2-(5-isopropyl-2-methylphenoxy)ethyl ester, which can be carried out to the next step without further purification.

[0069] Step 2: Weigh 2-(5-isopropyl-2-methylphenoxy)ethyl ester (3.54 g, 15 mmol) using an electronic analytical balance and place it in a 50 mL round-bottom flask, add ethanol (20 mL), stir to dissolve it, then slowly drop hydrazine hydrate (1 mL, 20 mmol) under stirring, fill the reaction system with nitrogen, and react the resulting reaction mixture at 80°C for 3 hours. Monitor the progress of the reaction by TLC, and after the reaction is completed, concentrate under reduced pressure to form a suspension, pour it into crushed ice, let it stand, and precipitate a large amount of precipitation. Filter the precipitate and wash it with cold water, dry it, and then recrystallize it with ethanol to obtain a white powder, which is 2-(5-isopropyl-2-methylphenoxy)acetohydrazide (3.33 g, 92%).

[0070] Step 3: Weigh 2-(5-isopropyl-2-methylphenoxy)acetohydrazide (222 mg, 1 mmol) using an electronic analytical balance, place in a 25 mL round-bottom flask, add ethanol (10 mL), stir to dissolve, then slowly drop 4-pyridinecarboxaldehyde (300 uL, 3 mmol) under stirring, fill the reaction system with nitrogen, and react the resulting reaction mixture at 80 ° C for 2 h. Monitor the reaction progress by TLC, after the reaction is completed, add 2-3 drops of acetic acid and mix, concentrate under reduced pressure to form a suspension, pour into crushed ice, let stand, precipitate a large amount of precipitate, filter the precipitate and wash with cold water, dry, and then recrystallize with ethanol to obtain an anti-inflammatory small molecule compound named ZYZ311, 280 mg, with a yield of 90%.

[0071] NMR Spectrum: 1 H NMR(500MHz, CDCl3)δ9.91(s,1H),8.65(s,2H),8.29(s,1H),7.66–7.38(m,2H),7.10(dd,J=14.4,7.7Hz,1H),6.9 1–6.76(m,1H),6.70(s,1H),5.18(s,1H),4.70(s,1H),2.29(s,3H),1.21(dd,J=15.3,6.9Hz,6H).13CNMR(126MHz , CDCl3)δ171.71,165.37,156.52,155.19,150.40,148.79,147.99,146.94,142.91,140.76,131.15,130.93,124 .76,123.89,121.50,121.02,120.29,119.37,110.77,110.48,67.72,66.22,34.06,24.14,24.09,16.09,15.99.

[0072] Its molecular weight is characterized by Figure 1The chemical structure is shown in Figure 2 and Figure 3 shown.

[0073] Example 2 Detection of the effect of ZYZ311 on the expression of nitric oxide (NO) and inflammatory factor IL-6 in the supernatant of the LPS-induced Raw264.7 cell inflammation model

[0074] Methods: Raw264.7 cells were cultured at 37°C and 5% CO2 to the logarithmic growth phase. When the cell density reached about 80-90%, the cells were pretreated with ZYZ311 (20, 40, 60, 80, 100, 120, 140, 160, 180, 200 μM) and carvacrol (200 μM) for 1 h, respectively. The cells were then stimulated with LPS for 24 h, the supernatant was collected, and the NO level in the supernatant was detected using Griess reagent. The secretion level of IL-6 inflammatory factor was detected by ELISA.

[0075] The results are as follows Figure 4 As shown, ZYZ311 could downregulate the secretion of nitric oxide (NO) and inflammatory factor IL-6 in the supernatant of the LPS-induced Raw264.7 cell inflammation model, while carvacrol had no significant effect at a concentration of 200 μM.

[0076] Example 3 Protein extraction and western blotting to investigate the effect of ZYZ311 on the expression of inflammation-related proteins in the LPS-induced Raw264.7 cell inflammation model

[0077] Methods: Raw264.7 cells were cultured at 37°C and 5% CO2 until the logarithmic growth phase. When the cell density reached about 80-90%, the cells were pretreated with ZYZ311 (120 μM) for 1 h, and then stimulated with LPS for different times (0, 0.5, 1, 2, 4, 6 h). The cells were collected and lysed on ice for 1 h in Ripa lysis. The lysate was then centrifuged at 4°C for 10 min (13000 rpm). The protein concentration in the supernatant was determined by BCA protein assay (Thermo, Waltham, MA). Equal amounts of protein were then separated by 12% or 10% SDS-PAGE and transferred to polyvinylidene fluoride (PVDF) membranes (Millipore, Bedford, MA) using a semi-dry transfer system (Bio-rad, Hercules, CA). Proteins were detected using specific antibodies for β-actin, pp65, p65, COX-2, and IL-6 overnight at 4°C, followed by incubation with HRP-conjugated secondary antibodies for 1 h at 37°C. All antibodies were diluted in PBST containing 1% BSA. Enhanced chemiluminescence reagent (Beyotime, Jiangsu, China) was used to detect HRP on immunoblots. Signals were analyzed using the ECL chemiluminescence detection system (Tanon, Nanjing, China).

[0078] The results are as follows Figure 5 As shown, ZYZ311 can inhibit the protein expression of inflammation-related proteins p-NF-κB / NF-κB, COX-2, and IL-6 in the LPS-induced Raw264.7 cell inflammation model.

[0079] Example 4 ADMET prediction of anti-inflammatory small molecule compound ZYZ311

[0080] Methods: Discovery Studio software was used to calculate the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties of the drug, namely, aqueous solubility at 25 degrees Celsius; blood brain barrier penetration (BBB); cytochrome P4502D6 inhibition (Cytochrome P4502D6inhibition), hepatotoxicity; human intestinal absorption (HIA), plasma protein binding. The ADMET properties of ZYZ311 were calculated by selecting Small Molecules|Calculate Molecular Properties|ADMET Descriptors in Discovery Studio and selecting the default settings for parameters.

[0081] The results are as follows Figure 6 As shown, the ADMET plot is a two-dimensional graph of ADMET_PSA_2D vs ADMET_AlogP98, which respectively represents the 95% and 99% confidence intervals of the blood-brain barrier permeability (BBB) ​​model, and the 95% and 99% confidence intervals of the human intestinal absorption (HIA) model. The experimental results show that ZYZ311 has good ADMET properties and good drugability.

[0082] Example 5 Animal toxicity test of ZYZ311

[0083] Methods: Twenty C57BL / 6J mice aged 6 weeks and weighing 22-26g in good condition were randomly selected and divided into a blank group and a drug-treated group (n=10). The maximum dose of 2g / kg / time was given by intragastric gavage and observed for 14 consecutive days. Figure 7 As shown, the experimental results showed that there was no death within 14 days after administration, and there was no abnormality in the mice's food intake, water intake, spontaneous activities, etc. The LD50 of ZYZ311 is >2g / kg.

[0084] Example 6 Establishment and histological analysis of the acute colitis model induced by dextran sulfate sodium salt (DSS) in C57BL / 6 mice

[0085] Methods: Acute colitis was induced by administering DSS in drinking water. The specific experimental steps are as follows:

[0086] 60 male C57BL / 6J mice were randomly assigned to a control group, a DSS-treated group, a ZYZ311-treated group (50, 100, 200 mg / kg) and a 5-ASA-treated group (40 mg / kg) (n=10). ZYZ311 and 5-ASA were dissolved in a 0.5% sodium carboxymethylcellulose (CMC-Na) aqueous solution to obtain a ZYZ311 solution with a concentration of 0.5 mg / mL, 1 mg / mL, 2 mg / mL and a 5-ASA solution with a concentration of 0.4 mg / mL, and then administered by gavage; the control group and the DSS-treated group were given the same dose of a 0.5% CMC-Na aqueous solution.

[0087] Six days after intragastric administration, the mice began to drink drinking water containing 3% (w / v) DSS for 6 days. The mice were gavaged once a day and their body weights were recorded.

[0088] After 6 days of DSS drinking water administration, mice were euthanized by cervical dislocation, and the colon and kidneys of each mouse were removed, and the colon length and kidney weight / mouse body weight were calculated. Parts of the colon were fixed in 10% buffered formalin and embedded in paraffin. The sections were stained with H&E according to standard protocols. The histological evaluation of H&E-stained colon sections was graded as follows: 0, no signs of inflammation; 1, low leukocyte infiltration; 2, moderate leukocyte infiltration; 3, high leukocyte infiltration, moderate fibrosis, high vascular density, colon wall thickening, moderate goblet cell loss, focal crypt loss; 4, transmural infiltration, extensive goblet cell loss, extensive fibrosis, and diffuse crypt loss.

[0089] like Figure 8 As shown, the body weight of mice in the model group dropped sharply on the 6th day, while the body weight of mice in the ZYZ311-treated group did not change significantly, demonstrating that ZYZ311 can alleviate the weight loss caused by colitis.

[0090] like Fig. 9 As shown, the colon in the DSS model group was significantly shorter than that in the normal control group, while ZYZ311 could effectively increase the length of the colon.

[0091] like Fig.10 As shown, ZYZ311 can effectively reduce inflammatory infiltration, crypt erosion and deformation, loss of glandular epithelial cells, and reduce histological scores.

[0092] Example 7 Immunohistochemistry detection

[0093] In this example, immunohistochemistry was used to detect the expression of orphan receptor F4 / 80 (a marker of mature mouse macrophages) involved in cell adhesion, tight junction protein ZO-1 involved in proliferation, differentiation, migration and material transport, and myeloperoxidase (MPO, also known as peroxidase, a marker of neutrophil activation).

[0094] Methods: The colon tissue treated in Example 6 was fixed in 4% paraformaldehyde, followed by dehydration, clearing, wax immersion and sectioning. The paraffin-embedded slides were deparaffinized, rehydrated and washed in 1% PBS-Tween. Then they were treated with 3% hydrogen peroxide and blocked with 10% goat serum for 1 hour at 37°C. The slides were incubated with the primary antibody in PBS containing 1% BSA (1:50) at 37°C for 1 hour. Biotinylated anti-rabbit secondary antibody was added and incubated at room temperature for 1 hour. Streptavidin-HRP was added, and after 40 minutes, the sections were stained with DAB substrate and counterstained with hematoxylin.

[0095] like Figure 11-13 As shown, ZYZ311 can reduce the expression of F4 / 80 and MPO and increase the expression of ZO-1.

[0096] The above results prove that the small molecule compound ZYZ311 of the present invention has a significant therapeutic effect on inflammatory diseases such as acute colitis, is safe and effective, and can be used to prepare drugs for treating acute colitis.

[0097] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. Compound ZYZ311 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, characterized in that: The structural formula of the compound ZYZ311 is as follows:

2. Use of the compound ZYZ311 or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 1 in the preparation of an anti-inflammatory drug.

3. Use of the compound ZYZ311 or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 1 in the preparation of a medicament for preventing and / or treating inflammatory diseases.

4. The use according to claim 3, characterized in that: The inflammatory disease is inflammatory bowel disease, preferably colitis.

5. The use according to claim 4, characterized in that: The colitis is acute colitis or ulcerative colitis.

6. The use according to any one of claims 2 to 5, characterized in that: The compound ZYZ311 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof can inhibit the expression of nitric oxide and inflammatory factors IL-6 and TNF-α in inflammatory cells; and / or, can inhibit the protein expression of inflammation-related proteins p-NF-κB / NF-κB, COX-2, IL-6 and TNF-α in inflammatory cells; and / or, capable of inhibiting the expression of orphan receptor F4 / 80 and myeloperoxidase; And / or, the expression of tight junction protein ZO-1 can be increased.

7. A method for preparing the compound ZYZ311 according to claim 1, characterized in that: The steps include: (1) reacting carvacrol with ethyl chloroacetate to obtain 2-(5-isopropyl-2-methylphenoxy)ethyl ester; (2) 2-(5-isopropyl-2-methylphenoxy)ethyl ester reacts with hydrazine hydrate to obtain 2-(5-isopropyl-2-methylphenoxy)acetohydrazide; (3) reacting 2-(5-isopropyl-2-methylphenoxy)acetohydrazide with 4-pyridinecarboxaldehyde to obtain a compound having a structure represented by formula (I); The reaction formula is as follows:

8. The method for preparing the compound ZYZ311 according to claim 7, characterized in that: The reaction in step (1) is carried out under the action of a base, wherein the base is preferably potassium carbonate, and the molar ratio of the base to carvacrol is preferably 1-1.5:1; And / or, the reaction in step (1) is carried out in an organic solvent, and the organic solvent is preferably acetone; And / or, the reaction in step (1) is carried out under the protection of an inert gas; And / or, the molar ratio of carvacrol to ethyl chloroacetate in step (1) is 1:1-1.5; And / or, the reaction temperature in step (1) is 50°C-70°C and the reaction time is 2-6 hours.

9. The method for preparing the compound ZYZ311 according to claim 7, characterized in that: The reaction in step (2) is carried out in an organic solvent, and the organic solvent is preferably ethanol; And / or, the reaction in step (2) is carried out under the protection of an inert gas; And / or, the molar ratio of 2-(5-isopropyl-2-methylphenoxy)ethyl ester to hydrazine hydrate in step (2) is 1:1.2-1.5; And / or, the reaction temperature in step (2) is 70°C-90°C and the reaction time is 2-4 hours.

10. The method for preparing the compound ZYZ311 according to any one of claims 7 to 9, characterized in that: The reaction in step (3) is carried out in an organic solvent, and the organic solvent is preferably ethanol; And / or, the reaction in step (3) is carried out under the protection of an inert gas; And / or, the molar ratio of 2-(5-isopropyl-2-methylphenoxy)acetohydrazide to 4-pyridinecarboxaldehyde in step (3) is 1:2-4; And / or, the reaction temperature in step (3) is 70°C-90°C, and the reaction time is 1 hour-3 hours.

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