CN108929320B

CN108929320B - 3R-indolylmethyl-6R-oxazolidinone modified piperazine-2, 5-dione, synthesis, activity and application thereof

Info

Publication number: CN108929320B
Application number: CN201710363797.5A
Authority: CN
Inventors: 赵明; 彭师奇; 王玉记; 吴建辉; 张筱宜; 丛林
Original assignee: Capital Medical University
Current assignee: Capital Medical University
Priority date: 2017-05-22
Filing date: 2017-05-22
Publication date: 2020-10-16
Anticipated expiration: 2037-05-22
Also published as: CN108929320A

Abstract

The present invention discloses (3R,6R) -3- (5S-methyl-2-oxazolidinone-4S-formylamino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione of the formula. Discloses a preparation method thereof, discloses the antitumor activity thereof, discloses the anti-tumor metastasis activity thereof and discloses the anti-inflammatory activity thereof, and thus the invention discloses the application thereof in preparing antitumor drugs, anti-tumor metastasis drugs and anti-inflammatory drugs.

Description

3R-indolylmethyl-6R-oxazolidinone modified piperazine-2, 5-dione, synthesis, activity and application thereof

Technical Field

The present invention relates to (3R,6R) -3- (5S-methyl-2-oxazolidinone-4S-formylamino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione. To their preparation, to their antitumor activity, to their antitumor metastatic activity, and to their anti-inflammatory activity, and thus to their use in the preparation of antitumor, antitumor metastatic and anti-inflammatory drugs. The invention belongs to the field of biological medicine.

Background

Tumors seriously threaten the health of human beings. In addition to the poor prognosis of patients with tumors by themselves, metastasis associated with tumors further worsens the prognosis of patients. For example, more than 90% of patients with tumors die from metastases. Because the existing antitumor drugs have no effect of resisting tumor metastasis, the clinical curative effect of tumor chemotherapy is not ideal. The invention relates to a medicament for resisting tumor metastasis, which is an urgent clinical need. The inventors have previously disclosed that diketopiperazines of the four S, S-, R, R-, R, S-and S, R-configurations inhibit migration and invasion of HCCLM3 (highly metastatic human liver cancer cells) at a concentration of 0.5. mu.M. Later, the inventors further disclosed that R, R-configured diketopiperazines inhibited tumor metastasis to the lung in C57BL/6 mice at a dose of 5. mu. mol/kg. However, the lowest effective dose is 5. mu. mol/kg. To reduce the minimum effective dose, the inventors have developed various modifications to the butylamino group of the diketopiperazine in the R, R-configuration. After 3 years of investigation, it was found that acylation of the butylamino group of the R, R-configured diketopiperazine with 5S-methyl-2-oxazolidinone-4S-formylated amino-n-hexanoic acid not only reduced the minimum effective anti-tumor metastasis dose to 0.5. mu. mol/kg, but also reduced the minimum effective anti-tumor and anti-inflammatory doses to 0.5. mu. mol/kg. Because the toxic and side effects of the medicine can disappear along with the reduction of the dosage, the reduction of the effective dosage by 10 times shows that the structure modification has outstanding technical effect. Based on these findings, the inventors have proposed the present invention.

Disclosure of Invention

In a first aspect of the invention there is provided (3R,6R) -3- (5S-methyl-2-oxazolidinone-4S-formylamino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione of the formula.

In a second aspect, the present invention provides a process for the synthesis of (3R,6R) -3- (5S-methyl-2-oxazolidinone-4S-formylamino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione, which process comprises:

(1) D-Boc-Lys (Cbz) and D-Trp-OBzl are condensed to obtain D-Boc-Lys (Cbz) -D-Trp-OBzl;

(2) removing Boc from D-Boc-Lys (Cbz) -D-Trp-OBzl in ethyl acetate solution of hydrogen chloride to obtain D-Lys (Cbz) -D-Trp-OBzl;

(3) cyclizing D-Lys (Cbz) -D-Trp-OBzl in saturated ethyl acetate containing 5% sodium bicarbonate water solution to obtain (3R,6R) -3- (benzyloxycarbonylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (1);

(4) the compound 1 is subjected to hydrogenolysis to remove benzyloxycarbonyl to obtain (3R,6R) -3- (amino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (2);

(5) condensing the amino methyl hexanoate and Cbz-Thr to obtain Cbz-Thr-amino methyl hexanoate (3);

(6) the compound 3 is saponified to obtain a compound 4 and a compound 4 which are cyclized in situ to obtain 5S-methyl-2-oxazolidone-4S-formamido-n-hexanoic acid (5);

(7) the compound 2 and the compound 5 are condensed to obtain (3R,6R) -3- (5S-methyl-2-oxazolidone-4S-formamido n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-diketone (6).

In a third aspect of the present invention, (3R,6R) -3- (5S-methyl-2-oxazolidinone-4S-formylamino-n-hexylacylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione was evaluated for its ability to inhibit lung cancer metastasis in C57BL/6 mice.

A fourth aspect of the present invention is the evaluation of the inhibitory effect of (3R,6R) -3- (5S-methyl-2-oxazolidinone-4S-formylamino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione on inflammation in ICR mice.

A fifth aspect of the present invention is the evaluation of the use of (3R,6R) -3- (5S-methyl-2-oxazolidinone-4S-formylamino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione for inhibiting tumor growth in S180 mice.

Drawings

FIG. 1 is a synthetic route for (3R,6R) -3- (5S-methyl-2-oxazolidinone-4S-formylamino-n-hexylacylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (6); i) dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), Tetrahydrofuran (THF); ii) a solution of hydrogen chloride in ethyl acetate; iii) ethyl acetate, 5% sodium bicarbonate; iv) Dimethylformamide (DMF), Pd/C, H₂(ii) a v) Dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), N, N-Dimethylformamide (DMF); vi) methanol, NaOH (2M).

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 Boc-Lys (Cbz) -Trp-OBzl

7.7g (20mmol) of Boc-Lys (Cbz) was suspended in 100mL of anhydrous Tetrahydrofuran (THF), and 2.7g (20mmol) of 1-hydroxybenzotriazole (HOBt) and 5.0g (25mmol) of Dicyclohexylcarbodiimide (DCC) were added to the suspension in this order under ice bath, followed by stirring for 30 min. Thereafter, 8.0g (25mmol) of Trp-OBzl was added. The reaction mixture was adjusted to pH 9 by dropwise addition of N-methylmorpholine (NMM). The reaction mixture was stirred first for 1h on ice and then for 12h at room temperature. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 150mL of ethyl acetate solution. The ethyl acetate solution obtained was successively treated with 5% KHSO₄The aqueous solution was washed 3 times, and the saturated NaCl aqueous solution was washed 3 times. Anhydrous Na for ethyl acetate layer₂SO₄Drying for 12h, filtering, and concentrating the filtrate under reduced pressure to dryness. The resulting yellow syrup was purified by silica gel column Chromatography (CH)₂Cl₂/CH₃OH,100:1) 12.0g (88%) of the title compound are obtained as a colorless solid. ESI-MS (M/e):657[ M + H]⁺。

EXAMPLE 2 preparation of Lys (Cbz) -Trp-OBzl

3.8g (5mmol) Boc-Lys (Cbz) -Trp-OBzl was slowly mixed with 52mL of an ethyl acetate solution of hydrogen chloride (4M) with stirring in an ice bath. The resulting solution was stirred in an ice bath for 5 h. After that, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 50mL of anhydrous ethyl acetate, and the resulting solution was concentrated under reduced pressure. This operation was repeated three times. The residue was washed thoroughly with anhydrous ether to give 3.41g (93%) of the title compound as a yellow powder. ESI-MS (M/e):557[ M + H ]]⁺。

EXAMPLE 3 preparation of (3R,6R) -3- (benzyloxycarbonylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (1)

3.45g (6.2mmol) Lys (Cbz) -Trp-OBzl were dissolved in 150mL ethyl acetate. After the resulting solution was washed three times with a 5% aqueous solution of sodium hydrogencarbonate, the ethyl acetate solution was stirred at room temperature for 12 hours to sufficiently precipitate a colorless solid. 1.8g (51%) of the title compound are filtered off. ESI-MS (M/e):449[ M + H ]]⁺。

EXAMPLE 4 preparation of (3R,6R) -3- (amino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (2)

To a solution of 1.9g (4.2mmol) of (3R,6R) -3- (benzyloxycarbonyl butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (1) in 20mL of anhydrous N, N-Dimethylformamide (DMF) was added 200mg of Pd/C, and H was bubbled through₂The reaction was stirred at room temperature for 48 h. Pd/C was filtered off, and the filtrate was concentrated under reduced pressure to give 1.2g (92%) of the title compound as a colorless powder. ESI-MS (m/e): 315[ M + H ]]⁺.

EXAMPLE 5 preparation of amino-n-hexanoic acid methyl ester

5.6mL of thionyl chloride was added dropwise to 40mL of methanol, and after activation for 30min, 2.62g (20mmol) of aminohexanoic acid was added thereto and stirred at room temperature for 12 hours. Pumping the reaction solution under reduced pressure by using a water pump under stirring of the reaction compound in a 37 ℃ warm water bath, adding dry methanol for dissolving, then pumping the reaction solution under reduced pressure by using a water pump, and repeating the steps for 3 times; the suspension was suspended by adding anhydrous ether, and the mixture was dried under reduced pressure with stirring in a warm water bath at 37 ℃ and repeated 3 times to obtain 2.72g (95%) of the title compound. ESI-MS (M/e) 145[ M + H]⁺

EXAMPLE 6 preparation of Cbz-Thr-amino-n-hexanoic acid methyl ester (3)

1440mg (83%) of the title compound was obtained as a colorless solid from 1270mg (5.0mmol) of Boc-Thr and 720mg (5.0mmol) of methyl aminohexanoate by the method of example 1. ESI-MS (M/e):381[ M + H]⁺。

EXAMPLE 7 preparation of 5S-methyl-2-oxazolidinone-4S-formylamino-n-hexanoic acid (5)

1.14g (3.0mmol) Cbz-Thr-amino-n-hexanoic acid methyl ester (3) in 20mL CH₃OH is dissolved. And adding NaOH aqueous solution (2M) into the obtained solution under the stirring of ice bath to adjust the pH value to 12, and stirring and reacting for 6 hours in ice bath. Stirring in ice bath, and reacting with saturated KHSO₄The pH value of the solution is adjusted to 7, and the obtained solution is concentrated under reduced pressure. The residue was treated with 5% KHSO₄The aqueous solution adjusted the pH to 2. The resulting solution was extracted 3 times with ethyl acetate, and the ethyl acetate solution was washed with saturated aqueous NaCl solution to neutrality. Anhydrous Na for ethyl acetate layer₂SO₄Drying for 12h, filtering, and concentrating the filtrate under reduced pressure to dryness. 1.30g of the title compound were obtained as a pale yellow syrup. ESI-MS (M/e):257[ M + H]⁺。

EXAMPLE 8 preparation of (3R,6R) -3- (5S-methyl-2-oxazolidinone-4S-formylamino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (6)

From 1300mg of 5S-methyl-2-oxazolidinone-4S-formylamino-n-hexanoic acid (5) as pale yellow syrup and 940mg (3.0mmol) (3R,6R) -3-butylamino-6- (indole-3-methyl) -piperazine-2, 5-dione (2) by the method of example 1, 1120mg (67%) of the title compound are obtained as a colorless solid. ESI-MS (M/e) 555[ M + H ]]⁺；Mp:131–133℃；

(C＝0.1,H₂O)；IR(CM^-1)：3271.39,3084,2932,1747,1661,1548,1457,1384,1332,1231,1103,1065,973,743；¹H NMR(300MHz,DMSO-d₆):/ppm＝10.855(d,J＝1Hz,1H),8.099(t,J＝5Hz,1H),7.995(d,J＝2Hz,1H),7.909(d,J＝2Hz,1H),7.833(s,1H),7.586(d,J＝8Hz,1H),7.545(t,J＝5Hz,1H),7.307(d,J＝8Hz,1H),7.030(m,2H),6.937(m,1H),4.396(dq,J₁＝2Hz,J₂＝11.5Hz,1H),4.117(m,1H),3.794(dd,J₁＝1.0Hz,J₂＝5.0Hz,1H),3.515(m,1H),3.247(dd,J₁＝4.5Hz,J₂＝14.5Hz,1H),3.067(m,3H),2.790(m,2H),2.016(t,J＝7.5Hz,2H),1.451(m,4H),1.358(d,J＝6.0Hz,3H),1.217(m,2H),0.998(m,3H),0.630(m,3H)。

EXAMPLE 9 preparation of Boc-aminocaproic acid

Add 5.23g (Boc) to a solution of 2.62g (20mmol) aminocaproic acid and 30mL distilled water₂O and 30mL of dioxane, and the pH of the resulting reaction solution was adjusted to 9 with a 2N NaOH aqueous solution. Stirring at room temperature for 24h, and continuously reducing the pressure and exhausting gas in the period. KHSO for the reaction compound₄Adjusting the pH value of the aqueous solution to 7, and removing dioxane by decompression and concentration. The remaining solution was further treated with KHSO₄The pH was adjusted to 2. The remaining solution was extracted with 100mL ethyl acetate and anhydrous NaSO₄Drying for 8 h. Filtration and concentration of the filtrate under reduced pressure gave 4.36g (94%) of the title compound. ESI-MS (M/e):232[ M + H]⁺。

EXAMPLE 10 preparation of (3R,6R) -3- (Boc-aminocaproyl butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (7)

From 0.97g (4.2 mmo) using the method of example 1l) Boc-aminocaproic acid and 1.9g (3.5mmol) (3R,6R) -3-butylamino-6- (indole-3-methyl) -piperazine-2, 5-dione (2) gave 0.641g (20.6%) of the title compound as a colorless solid. ESI-MS (M/e):528[ M + H]⁺；¹H NMR(300MHz,DMSO-d₆):/ppm＝10.872(s,1H),8.035(d,J＝1.8Hz,1H),7.928(d,J＝1.8Hz,1H),7.560(m,2H),7.303(d,J＝5.7Hz,1H),7.034(m,2H),6.925(t,J＝7.5Hz,1H),6.763(t,J＝5.1Hz,1H),4.108(m,1H),3.499(m,1H),3.246(dd,J₁＝14.4Hz,J₂＝4.2Hz,1H),3.009(dd,J₁＝14.4Hz,J₂＝4.2Hz,1H),2.890(q,J＝6.6Hz,2H),2.750(q,J＝6.6Hz,2H),2.002(t,J＝7.2Hz,2H),1.465(m,2H),1.350(m,12H),1.205(m,3H),0.951(m,3H),0.553(m,3H)。

EXAMPLE 11 preparation of (3R,6R) -3- (aminocaproyl-butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (8)

From 2.21g (4mmol) (3R,6R) -3- (Boc-aminocaproyl butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (7) 1.45g (82%) of the title compound was obtained as colorless powder using the method of example 3. ESI-MS (M/e):428[ M + H]⁺；¹H NMR(300MHz,DMSO-d₆):/ppm＝11.003(s,1H),8.086(s,1H),7.999(s,1H),7.748(s,1H),7.578(s,J＝8.1Hz,1H),7.314(m,J＝8.1Hz,1H),7.023(m,2H),6.926(m,1H),4.117(m,1H),3.502(m,1H),3.269(m,1H),3.041(m,1H),2.736(m,4H),2.030(m,2H),1.542(m,4H),1.260(m,2H),0.981(m,3H),0.590(m,3H)。

EXAMPLE 12 determination of the anti-tumor metastasis Activity of Compound 6

The assay model was inoculated with Lewis mouse lung carcinoma cells (LLC, purchased from ATCC) in DMEM medium (containing 10% inactivated fetal bovine serum, 1 × 10)⁵U/L penicillin and 100mg/L streptomycin), passaging every two days according to an adherent cell culture method, enriching cells, digesting the cells when the cells are in a good growth state and in a logarithmic growth phase, and adjusting the cell density to 1 × 10 by using physiological saline⁷one/mL. Staining with placental blue to count viable cells>95 percent. Inbred C57BL/6 male mice (SPF grade, body weight 20. + -.2 g) were taken and left-handed mice fixed. The right anterior limb axillary skin of the mouse was disinfected with 75% ethanol. The right hand holds a 1mL sterile syringe to inject LLC tumor subcutaneously to the axilla of the mouseInjecting 0.2mL of tumor cell suspension into each mouse, inoculating the mice for 10 days, growing tumors with the diameter of about 4-5mm to obtain tumor sources, inoculating Lewis lung cancer tumor-bearing mice for 10 days to anaesthetize the mice by ether, removing cervical vertebrae, soaking the mice for 10min by using 75% ethanol, disinfecting, stripping tumor bodies on a clean bench, selecting well-grown tumor tissues, shearing the tumor tissues in a sterile flat dish, placing the sterile flat dish in a tissue homogenizer made of glass, adding physiological saline with the temperature of 4 ℃ according to the ratio of the tumor mass to the physiological saline with the volume of 1 to 3(g to mL), slightly grinding the mixture to prepare cell suspension, sieving the cell suspension with 200 meshes of cells to prepare single cell suspension, and regulating the cell density of the single cell suspension to 1.5 × 10 by using the physiological saline⁷one/mL. Staining with placental blue to count viable cells>95 percent. Left-handed inbred C57BL/6 male mice were fixed and their right anterior limb axillary skin was disinfected with 75% ethanol. The tumor cell suspension was injected subcutaneously into the mouse axilla with a 1mL sterile syringe in the right hand, 0.2mL each. 10 days after inoculation, the mice developed tumors of 4-5mm in diameter, and the inoculated mice were randomly grouped by the measured tumor volume. Each group had 12 mice. Mice on day 11 of tumor inoculation were orally administered either a normal saline solution of the putative antitumor metastatic peptide RGDS (dose of 20. mu. mol/kg/day) or compound 6 (dose of 0.5. mu. mol/kg/day) or compound 8 (dose of 5. mu. mol/kg/day) or compound 8 (dose of 10 mL/kg/day) 1 time daily for 12 consecutive days, and tumor volumes were measured and recorded every two days. The next day of the last administration, tumor volume was measured, cervical spine was removed by ether anesthesia and sacrificed, tumor of the mice was weighed, lung of the mice was taken and tumor nodules transferred from the lung of the tumor were counted. Statistical analysis of the data was performed using the t-test. The results are shown in Table 1. Compound 6 was not only effective in inhibiting tumor lung metastasis at 0.5 μmol/kg dose, but there was no significant difference in activity from RGDS at 40-fold higher doses and compound 8 at 10-fold higher doses. These data indicate that the present invention has significant technical effects.

TABLE 1 antitumor metastatic Activity of Compound 6

a) P <0.01 to saline, p >0.05 to RGDS and compound 8; n is 11

EXAMPLE 13 determination of the anti-tumor growth Activity of Compound 6

Dissolving adriamycin, compound 8 and compound 6 in normal saline before measurement, and administering to S180 mice, taking S180 ascites tumor liquid grown vigorously in male ICR mice in 10 days in sterile environment, diluting with normal saline to obtain (1:2) liquid, mixing well, staining tumor cell suspension with freshly prepared 0.2% trypan blue, counting according to white blood cell counting method, wherein the blue stained cells are dead cells, the non-stained cells are live cells, and the cell concentration is 4 check live cell number/4 × 10⁴× the cell density is calculated by diluting times of cell number/mL, the cell survival rate is calculated by the cell survival rate of × 100% live cell number/(live cell number + dead cell number), the tumor liquid with the survival rate of more than 90% is prepared into the density of 2.0 × 10 by a homogenization method⁷Cell suspension per mL. This cell suspension was inoculated subcutaneously (0.2 mL/mouse) in the right axilla of a mouse to prepare S180 tumor-bearing mice. 24h after inoculation, S180 tumor-bearing mice were intraperitoneally injected daily with a saline solution of doxorubicin (dose 2. mu. mol/kg/day g), or daily orally administered with a saline solution of Compound 8 (dose 5. mu. mol/kg/day), or daily orally administered with a saline solution of Compound 6 (dose 0.5. mu. mol/kg/day). The administration is once daily for 12 days. The day after the last dose, tumor volume was measured, cervical spine was removed under ether anesthesia and sacrificed, then the right axillary tumor growth site of the mouse was fixed with forceps, and the skin was excised and the tumor was blunt-stripped and weighed. Efficacy was expressed as tumor weight (mean ± SD g), and data were analyzed by t-test and variance. The results are shown in Table 2. Compound 6 was not only effective at 0.5 μmol/kg dose in inhibiting tumor growth, but also had no significant difference in activity from compound 8, which was 10-fold higher in dose. These data indicate that the present invention has significant technical effects.

TABLE 2 Effect of Compound 6 on tumor growth in S180 mice

a) P <0.01 to saline, p >0.05 to compound 8; n is 12.

EXAMPLE 14 determination of anti-inflammatory Activity of Compound 6

Since xylene-induced ear swelling in mice is recognized as an acute inflammation model, the present invention measures the therapeutic effect of compound 6 on a xylene-induced ear swelling model in mice. Because aspirin is a positive drug for treating acute inflammation, aspirin is selected as a positive control in the present invention. ICR male mice (body weight 20 ± 2g) were allowed to rest for 2 days at 22 ℃ with free access to water and food. Thereafter, 12 mice were randomly divided into a saline group (dose of 0.2 mL/mouse), an aspirin group (dose of 1.11mmol/kg), a compound 8 group (dose of 5. mu. mol/kg) and a compound 6 group (dose of 0.5. mu. mol/kg), each group. Mice were tested either orally with normal saline, orally with aspirin, orally with compound 8, or orally with compound 6, as indicated. After 30min of administration, the left auricle of the mouse was evenly smeared with 30 μ L of xylene, and after 2h, the mouse was subjected to ether anesthesia, the neck was cut off, the left and right ears were cut off, round ears were taken at the same positions of the two ears by a 7mm punch, and the difference in swelling between the two ears was weighed and found to be the swelling degree. Namely the swelling degree is equal to the weight of the left ear disk to the weight of the right ear disk. The results are shown in Table 2. Compound 6 was not only effective in inhibiting xylene-induced ear swelling in mice at the 0.5 μmol/kg dose, but the activity was not significantly different from aspirin, which was 2220-fold higher in dose, and compound 8, which was 10-fold higher in dose. These data indicate that the present invention has significant technical effects.

TABLE 3 Effect of Compound 6 on xylene-induced ear swelling in mice

a) P <0.01 to saline; n is 12.

Claims

1. (3R,6R) -3- (5S-methyl-2-oxazolidinone-4S-formylamino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione of the formula,

2. a process for the preparation of (3R,6R) -3- (5S-methyl-2-oxazolidinone-4S-formylamino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione as claimed in claim 1, which comprises:

(3) dissolving D-Lys (Cbz) -D-Trp-OBzl in ethyl acetate, washing the obtained solution with 5% sodium bicarbonate aqueous solution, and cyclizing to obtain (3R,6R) -3- (benzyloxycarbonylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione;

(4) hydrogenolysis of (3R,6R) -3- (benzyloxycarbonylamino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione to debenzyloxycarbonyl (3R,6R) -3- (amino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione;

(5) condensing amino methyl hexanoate and Cbz-Thr to obtain Cbz-Thr-amino methyl hexanoate;

(6) carrying out saponification reaction on Cbz-Thr-amino methyl hexanoate to obtain 5S-methyl-2-oxazolidinone-4S-formylamino methyl hexanoate;

(7) condensing (3R,6R) -3- (amino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione and 5S-methyl-2-oxazolidinone-4S-formylamino n-hexanoic acid to obtain (3R,6R) -3- (5S-methyl-2-oxazolidinone-4S-formylamino n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione.

3. Use of (3R,6R) -3- (5S-methyl-2-oxazolidinone-4S-formylamino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1 for the preparation of a medicament against lung cancer metastasis.

4. Use of (3R,6R) -3- (5S-methyl-2-oxazolidinone-4S-formylamino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1 for the preparation of a medicament against ascites tumors.

5. Use of (3R,6R) -3- (5S-methyl-2-oxazolidinone-4S-formylamino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1 for the preparation of an anti-inflammatory drug.