阅读说明：本技术 二氧六环修饰的四氢咔啉-3-甲酰-The-HGE、其制备、抗炎活性和应用 (Dioxane-modified tetrahydrocarboline-3-formyl-The-HGE, preparation thereof, anti-inflammatory activity thereof and application thereof ) 是由 赵明 彭师奇 郤思远 于 2019-12-02 设计创作，主要内容包括：本发明公开了下式的3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu,公开了它的制备方法,公开了它的抗炎症活性。因而公开了它在制备抗炎药物中的应用。(The invention discloses 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Glu with The following formula, a preparation method thereof and anti-inflammatory activity thereof. Thus discloses the application of the compound in preparing anti-inflammatory drugs.)

1.3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Glu of The following formula,

2. a method of synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-His-Gly-Glu of claim 1, comprising:

2.1. synthesizing 3S-1,2,3, 4-tetrahydro-beta-carboline-3-benzyl carboxylate;

2.2. synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-benzyl carboxylate;

2.3. synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid;

2.4. adopting dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst to synthesize 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-OBzl in a liquid phase manner;

2.5. synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The;

2.6. adopting dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst to synthesize HCl, His-Gly-Glu (OBzl) -OBzl in a liquid phase manner;

2.7. synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Glu (OBzl) -OBzl by using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst;

2.8. synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Glu.

3. Use of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-His-Gly-Glu according to claim 1 in The preparation of an anti-inflammatory medicament.

Technical Field

The invention relates to a 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Glu compound, a preparation method thereof and anti-inflammatory activity thereof. The invention thus relates to the use of the compounds in anti-inflammatory drugs.

Background

The 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid is a pharmacophore with multiple biological activities, and the theanine is also the pharmacophore with multiple biological activities. In a related invention, The inventor discloses that 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid and theanine are fused to form 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The with The left formula, and The 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The has The function of resisting tumors. The inventor realizes that The 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Glu generated by introducing uremic toxin tripeptide His-Gly-Glu at The carboxyl terminal of The 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Glu has stronger antitumor effect. Further studies led the inventors to find that they also have anti-inflammatory effects.

Inflammation is the cause of many diseases. Among a range of diseases triggered by inflammation, fibrosis is one of the most important diseases. For example, inflammation of the central nervous system can trigger brain fibrosis. Cancer metastasis is another fatal disease triggered by inflammation. The proportion of deaths due to metastasis in dead cancer patients is up to 90%. Chronic inflammation of the brain may be associated with the onset of various metabolic diseases, such as obesity and diabetes. In connection with the brain, inflammation can cause a variety of common mental disorders. Coronary inflammation or chronic inflammation of blood vessels is associated with atherosclerotic cardiovascular disease. Another fatal problem of chronic inflammation is associated with the pathogenesis of a variety of tumors. For example, chronic inflammation is associated with the onset of colon cancer. Although the molecular mechanism is not clear, a large number of relationships between inflammation and affective disorders have been reported. Inflammation has long been recognized as a mechanism for triggering and sustaining depression, chronic pain, and long-term extreme fatigue. Inflammation plays a central role, for example, in behavioral and emotional changes in patients with liver disease. Inflammation can trigger premature birth and parturition. Perinatal inflammation can compromise the physiology and behavior of the mature brain. Systemic inflammation can affect neurological development. By affecting the immune system, chronic inflammation in the long term can damage the host. Physical aging is the strongest risk factor for most chronic diseases, causing several chronic diseases to be combined into a whole. Inflammation is a trigger for a combination of several chronic diseases. Senile tuberculosis is associated with a basal inflammatory state. In addition, inflammation is also associated with dementia. As such, the development of a drug for preventing and treating inflammation without toxic and side effects has been increasingly appreciated. Despite the great efforts that have been made, no substantial progress has been made.

The inventor realizes that 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Glu with anti-inflammatory effect contributes to research and development of anti-inflammatory drugs. Based on this knowledge, the inventors have proposed the present invention.

Disclosure of Invention

The first aspect of The present invention provides 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-His-Gly-Glu of The formula.

The second content of The invention is to provide a preparation method of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Glu, which comprises The following steps:

1) synthesizing (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-benzyl carboxylate;

2) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-benzyl carboxylate;

3) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid;

4) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-OBzl by adopting a liquid phase condensation method with Dicyclohexylcarbodiimide (DCC) as a condensing agent and 1-hydroxybenzotriazole (HOBt) as a catalyst;

5) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The;

6) synthesizing HCl, His-Gly-Glu (OBzl) -OBzl by adopting a liquid phase condensation method with DCC as a condensing agent and HOBt as a catalyst;

7) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Glu (OBzl) -OBzl by adopting a liquid phase condensation method with DCC as a condensing agent and HOBt as a catalyst;

8) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Glu;

the third aspect of The present invention is to evaluate The anti-inflammatory effect of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-His-Gly-Glu.

Drawings

FIG. 1. synthetic route of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Glu: i) trifluoroacetic acid, 1, 3-dihydroxyacetone; ii) concentrated sulfuric acid, acetone; iii) Palladium on carbon (Pd), H₂(ii) a iv) Dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM); v) a solution of hydrogen chloride in ethyl acetate (4M).

Detailed Description

To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.

EXAMPLE 1 preparation of benzyl (3S) -1, 1-dihydroxymethyl-tetrahydro- β -carboline-3-carboxylate (1)

2g (7.2mmol) of L-tryptophan benzyl ester was added to 10mL of dichloromethane, and the mixture was sufficiently stirred to dissolve it. Under ice-bath conditions, 1mL of trifluoroacetic acid was slowly added dropwise to the solution. Then, 0.78g (8.6mmol) of 1, 3-dihydroxyacetone was added to the solution and reacted at room temperature for 7 hours. TLC showed disappearance of L-tryptophan benzyl ester (dichloromethane/methanol: 30: 1). Ice bath conditionsNext, 50mL of saturated NaHCO was added to the solution₃The solution was stirred well, then a dichloromethane layer was left, followed by saturated NaHCO₃The solution (30 mL. times.3) was washed with saturated NaCl solution (30 mL. times.3), and the dichloromethane layer was dried over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave 2.03g (77%) of the title compound as a yellow powder. ESI-MS (M/e):367[ M + H]⁺。

EXAMPLE 2 preparation of benzyl 3S-1- (1, 1-dimethyl-1, 3-dioxan-6-spiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylate (2)

To 5mL of anhydrous acetone was added 0.2g (0.55mmol) of benzyl (3S) -1, 1-dimethylol-tetrahydro- β -carboline-3-carboxylate (1). 100. mu.L of concentrated sulfuric acid was added thereto under ice-bath conditions, followed by stirring at room temperature for 3 hours. TLC showed the disappearance of compound 1 (petroleum ether/ethyl acetate, 4: 1). Under ice-bath conditions, saturated NaHCO was used₃Adjusting pH of the reaction solution to 7, concentrating the obtained solution under reduced pressure to remove acetone, extracting and washing the residual solution with ethyl acetate for 3 times, and washing the ethyl acetate layer with saturated NaCl solution to neutrality. The ethyl acetate layer was dried over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave a tan solid which was separated by column chromatography (petroleum ether/ethyl acetate, 4:1) to give 0.08g (35.8%) of the title compound as a white solid. ESI-MS (M/e):407[ M + H]⁺。

EXAMPLE 3 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxan-6-spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid (3)

To 10mL of methanol were added 0.20g (0.5mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylic acid benzyl ester (2) and 0.02g of Pd/C. Stirring and passage of 12h hydrogen, TLC showed disappearance of Compound 2 (petroleum ether/ethyl acetate, 4: 1). The palladium-carbon (Pd/C) was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was triturated with ether to give 0.14g (90%) of the title compound as a colourless solid. ESI-MS (M/e) 317[ M + H ]]⁺。

EXAMPLE 4 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxan-6-spiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-OBzl (4)

To 20mL of tetrahydrofuran was added 0.19g (0.6mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-Spiro) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylic acid (3), 0.15g (0.72mmol) of N, N' -Dicyclohexylcarbodiimide (DCC) and 0.09g (0.72mmol) of 1-hydroxybenzotriazole (HOBt). Stir for 30 minutes in an ice bath. Then, 0.20g (0.66mmol) of HCl. The-OBzl was added to The reaction mixture. Subsequently, N-methylmorpholine (NMM) was added dropwise to the reaction mixture to adjust the pH of the reaction mixture to 9. After stirring at room temperature for 6 hours, TLC showed the disappearance of compound 3 (dichloromethane/methanol, 30/1). Dicyclohexylurea (DCU) was filtered off, the filtrate was concentrated under reduced pressure, the residue obtained was dissolved in 30mL of ethyl acetate, and the solution was filtered again to remove DCU. The filtrate was sequentially treated with 5% NaHCO₃Aqueous extraction (15 mL. times.3), saturated aqueous NaCl solution (15 mL. times.3), 5% KHSO₄Aqueous wash (15 mL. times.3), saturated aqueous NaCl wash (15 mL. times.3), 5% NaHCO₃The mixture was washed with an aqueous solution (15 mL. times.3) and with a saturated aqueous NaCl solution (15 mL. times.3), and dried over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave a yellow powder which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1) to give 0.27g (80%) of the title compound as a colourless powder. ESI-MS (M/e):563[ M + H]⁺；¹H-NMR(300MHz,DMSO-d₆):δ/ppm＝10.94(s,1H),8.28(t,J＝7.2Hz,1H),7.79(s,1H),7.37(m,6H),7.07(m,1H),7.02(m,1H),5.16(s,1H),5.12(s,1H),4.40(m,1H),4.21(m,1H),3.99(m,1H),3.75(m,1H),3.61(m,2H),3.02(m,2H),2.12(m,2H),1.82(m,2H),1.65(s,3H),1.42(s,3H),1.22(m,2H),1.01(m,3H)。

EXAMPLE 5 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxan-6-spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The (5)

To 10mL of methanol were added 0.28g (0.5mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-OBzl (4) and 0.02g of palladium on carbon (Pd/C). Stirring and passage of 12h hydrogen, TLC showed disappearance of compound 4 (dichloromethane/methanol, 30/1). Pd/C was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was triturated with ether to give 0.21g (90%) of the title compound as a yellow solid. ESI-MS (M/e):473[ M + H]⁺，¹H-NMR(300MHz,DMSO-d₆):δ/ppm＝10.98(s,1H),8.18(d,J＝7.5Hz,1H),7.79(s,1H),7.40(dt,J₁＝4.8Hz,J₂＝8.1Hz,2H),7.02(td,J₁＝8.1Hz,J₂＝4.8Hz,2H),4.40(m,1H),4.28(m,1H),4.12(m,1H),4.02(m,1H),3.81(m,1H),3.61(m,1H),3.02(m,2H),2.14(m,2H),1.82(m,2H),1.65(s,3H),1.41(s,3H),1.22(m,2H),1.03(m,3H)。

EXAMPLE 6 preparation of Boc-Gly-Glu (OBzl) -OBzl

Using the method of example 4, 1.93g (80%) of the title compound was obtained as a colorless solid from 0.88g (5mmol) of Boc-Gly and 2.00g (5.5mmol) of Hcl. Glu (OBzl) -OBzl.

EXAMPLE 7 preparation of HCl.Gly-Glu (OBzl) -OBzl

1.45g (3mmol) of Boc-Gly-Glu (OBzl) -OBzl was dissolved in 20mL of hydrogen chloride in ethyl acetate (4M) and reacted for 4 hours in ice bath. TLC monitoring indicated complete reaction (dichloromethane/methanol system, 30/1). The reaction mixture was concentrated under reduced pressure, the residue was dissolved in anhydrous ethyl acetate, and the resulting solution was concentrated under reduced pressure. This operation was repeated 3 times. The resulting white powdery substance was sufficiently washed with dehydrated ether to obtain 1.14g (90%) of the title compound as a colorless solid.

EXAMPLE 8 preparation of Boc-His (Boc) -Gly-Glu (OBzl) -OBzl

From 1.77g (5mmol) of Boc-His (Boc) and 2.52g (6mmol) of HCl.Gly-Glu (OBzl) -OBzl, 2.56g (67%) of the title compound were obtained as colorless solid using the method of example 4. ESI-MS (M/e):722[ M + H]⁺。

Example 9 preparation of HCl. His-Gly-Glu (OBzl) -OBzl

From 1.44g (2mmol) Boc-His (Boc) -Gly-Glu (OBzl) -OBzl, 1.03g (92%) of the title compound was obtained as a colorless solid using the method of example 7.

EXAMPLE 10 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxan-6-spiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-His-Gly-Glu (OBzl) -OBzl (6)

To 30mL of anhydrous tetrahydrofuran were added 0.47g (1mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The (5), 0.25g (1.2mmol) of DCC and 0.16g (1.2mmol) of HOBt, and The mixture was stirred for 30 minutes in an ice bath. Then, 0.62g (1.1mmol) of HCl. His-Gly-Glu (OBzl) -OBzl was added to the reaction mixture. N-methylmorpholine (NMM) was added dropwise to adjust the pH of the reaction mixture to 9. The reaction was carried out at room temperature for 8 hours. TLC shows Compound 5 bThe solvent was removed (dichloromethane/methanol, 15/1), Dicyclohexylurea (DCU) was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in 100mL of ethyl acetate and the solution was filtered to remove DCU. The filtrate was sequentially treated with 5% NaHCO₃Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), 5% KHSO₄Aqueous wash (30 mL. times.3), saturated aqueous NaCl wash (30 mL. times.3), 5% NaHCO₃The mixture was washed with an aqueous solution (30 mL. times.3) and with a saturated aqueous NaCl solution (30 mL. times.3), and dried over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave a yellow powder which was purified by silica gel column chromatography (dichloromethane/methanol, 15/1) to give 0.71g (70%) of the title compound as a yellow powder. ESI-MS (M/e):977[ M + H]⁺；¹H-NMR(300MHz,DMSO-d₆):δ/ppm＝10.99(s,1H),8.35(m,1H),8.27(m,1H),8,16(m,1H),7.79(m,1H),7.49(m,2H),7.35(m,12H),7.00(m,2H),5.13(s,2H),5.06(s,2H),4.41(m,2H),4.21(m,1H),4.02(m,1H),3.81(m,1H),3.65(m,2H),3.04(m,3H),2.92(m,2H),2.44(m,2H),2.09(m,2H),1.95(m,2H),1.85(m,2H),1.72(m,2H),1.62(s,3H),1.39(s,3H),1.23(m,2H),0.97(t,J＝7.2Hz,3H)。

EXAMPLE 11 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxan-6-spiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-His-Gly-Glu (7)

To 10mL of methanol were added 0.048g (0.05mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-His-Gly-Glu (OBzl) -OBzl preparation (6) and 0.005g of Pd/C, and stirred and charged with 12h of hydrogen, and TLC showed disappearance of Compound 6 (ethyl acetate: water: glacial acetic acid, 4:1: 1). The palladium-carbon (Pd/C) was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was triturated with ether to give 0.033g (85%) of the title compound as a colourless solid. ESI-MS (M/e):795[ M-H]^-，¹H-NMR(300MHz,DMSO-d₆):δ/ppm＝10.96(s,1H),8.34(m,1H),8.29(m,1H),8,15(m,1H),8.02(m,1H),7.79(m,1H),7.54(s,1H),7.39(m,1H),7.04(m,1H),6.98(m,1H),6.83(s,1H),4.44(m,3H),4.24(m,2H),4.12(m,2H),4.02(m,1H),3.03(m,3H),2.93(m,2H),2.27(m,2H),2.07(m,2H),1.93(m,2H),1.84(m,2H),1.62(s,3H),1.39(s,3H),1.20(m,2H),0.97(t,J＝7.2Hz,3H)；¹³C-NMR(125MHz,DMSO-d₆):δ/ppm＝173.64,171.83,171.80,171.67,169.31,135.22,120.62,119.33,118.23,111.76,109.32,98.15,64.75,53.92,51.57,42.55,33.80,32.24,30.79,29.60,22.97,22.91,15.17。

EXAMPLE 12 evaluation of anti-inflammatory Activity of Compound 7

Experimental animals:

ICR mice, male, 20 + -2 g, purchased from Experimental animals technology, Inc., Viton, Beijing.

Administration dose and administration mode:

the oral dosage of The compound 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Glu (compound 7) is 0.23 mu mol/kg, The oral dosage of positive control aspirin is 1.1mmol/kg, and The negative control is normal saline.

The experimental method comprises the following steps: the ICR induced ear swelling model was used for the experiment.

And (3) experimental operation:

the newly arrived mice were allowed to rest for one day and then randomly grouped, 12 mice per group. And (3) performing intragastric administration on the mice by adopting a sequential method, wherein 6 mice are taken in each group at intervals of 5min, the administration is performed according to a specified dose, after half an hour, the mice are sequentially fixed according to the intragastric sequence, the right ears of the mice are exposed, 30 mu L of dimethylbenzene is uniformly smeared at the edge of the auricle of the right ear of each mouse by using a liquid transfer gun, and the model is built after the dimethylbenzene is naturally volatilized. After coating xylene, the mice had restlessness and red and swollen right ears. Two hours after the model building, the mouse is anesthetized by ether, the mouse is killed by removing the neck, ears at two sides of the mouse are cut along the root part, the edges of the ears are overlapped together, two round ear sheets with the same area and the same size of the two ears are punched by an electric ear swelling ear punching device (model: YLS025A) with the diameter of 7mm, and the two round ear sheets are respectively weighed, wherein the ear swelling degree is the difference value of the two ear weights.

The experimental results are as follows:

swelling degree of ear (right ear weight-left ear weight)

Swelling degree of earmg, followed by statistical comparisons between groups by t-test.

The results are shown in Table 1:

TABLE 1 Activity of Compound 7 for inhibiting tumor Lung metastasis

Note: n is 10, and the test is carried out by t; a) p <0.05 compared to saline group and P >0.05 compared to RGDS group.

The result shows that the ear swelling degree (11.22 +/-3.43 mg) of the mice treated by oral compound 7 under the dosage of 0.23 mu mol/kg has significant difference (14.86 +/-3.26 mg, P <0.05) with the normal saline of the negative control group, and has no significant difference (11.75 +/-4.40 mg, P >0.05) with the aspirin of the positive control group, so that the compound 7 has the activity of inhibiting the mouse inflammation equivalent to that of 1100 mu mol/kg aspirin when the oral dose is as low as 0.23 mu mol/kg, and the invention has prominent technical effect.