CN108976210B - 3S-indolylmethyl-6R-aromatic amino acid modified piperazine-2, 5-dione, and synthesis, activity and application thereof - Google Patents
3S-indolylmethyl-6R-aromatic amino acid modified piperazine-2, 5-dione, and synthesis, activity and application thereof Download PDFInfo
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Abstract
The invention discloses (3S,6R) -3- (AA-aminocaproylamino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (AA in the formula is L-Phe residue and L-Tyr residue) with the following formula, discloses a preparation method thereof, discloses anti-tumor activity thereof, discloses anti-tumor metastasis activity thereof, and discloses anti-inflammatory activity thereof, so that the invention discloses application thereof in preparing anti-tumor drugs, anti-tumor metastasis drugs and anti-inflammatory drugs.
Description
Technical Field
The present invention relates to (3S,6R) -3- (AA-aminocaproylamino-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
The inventor discloses that S, S-, R, R-, S-and S-diketopiperazines can inhibit the migration and invasion of HCC L M3 (highly metastatic human hepatoma cells) at the concentration of 0.5 mu M, and later discloses that R, R-diketopiperazines can inhibit the tumor metastasis of C57B L/6 mice to the lung at the dose of 5 mu mol/kg, but the lowest effective dose is 5 mu mol/kg., the inventor develops various types of butylamino groups of R, S-diketopiperazines, and the inventor discovers that the modified aromatic amino acid (L-Phe) and the amino acid acylated amino acid of Tyr-L-Tyr can reduce the effective dose of the acylated amino acid of the modified diketopiperazine to 0.5 mu mol/kg, so that the anti-tumor metastasis effect of the modified diketopiperazine can be reduced to 0 mu mol/kg, and the anti-metastasis effect of the acylated amino acid modified by 5 mu mol/Tyr-L-amino acid can be reduced to 0 mu mol/kg.
Disclosure of Invention
The first aspect of the present invention is to provide (3S,6R) -3- (AA-aminocaproylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione of the formula (wherein AA is a L-Phe residue and a L-Tyr residue).
The second aspect of the present invention provides a method for synthesizing (3S,6R) -3- (AA-aminocaproylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (AA is L-Phe residue and L-Tyr residue), which comprises:
(1) L-Boc-L ys (Cbz) and D-Trp-OBzl are condensed to obtain Boc-L ys (Cbz) -D-Trp-OBzl;
(2) Boc-L ys (Cbz) -D-Trp-OBzl is subjected to Boc removal in ethyl acetate solution of hydrogen chloride to obtain L ys (Cbz) -D-Trp-OBzl;
(3) l ys (Cbz) -D-Trp-OBzl cyclizing in 5% sodium bicarbonate water solution saturated ethyl acetate solution to generate (3S,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 (3S,6R) -3-amino-n-butyl-6- (indole-3-methyl) -piperazine-2, 5-dione (2);
(5) condensing the compound 2 and Boc-amino n-hexanoic acid to obtain (3S,6R) -3- (Boc-amino n-hexanoylamino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (3);
(6) removing Boc from the compound 3 in an ethyl acetate solution of hydrogen chloride to obtain (3S,6R) -3- (amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (4);
(7) the compound 4 is condensed with Boc-AA (AA is L-Phe residue and L-Tyr residue) to obtain (3S,6R) -3- (Boc-AA-aminocaproylamino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (5a, b).
(8) The compound 5a, b was depbocylated in hydrogen chloride in ethyl acetate to give (3S,6R) -3- (AA-aminocaproylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (6a, b) (AA L-Phe residue and L-Tyr residue).
The third aspect of the present invention is to evaluate the anti-lung cancer metastasis activity of (3S,6R) -3- (AA-aminocaproylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (AA is L-Phe residue and L-Tyr residue) in C57B L/6 mice.
The fourth aspect of the present invention was to evaluate the inhibitory effect of (3S,6R) -3- (AA-aminocaproylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (AA is L-Phe residue and L-Tyr residue) on ICR mouse inflammation.
The fifth aspect of the present invention is to evaluate the use of (3S,6R) -3- (AA-aminocaproylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (AA L-Phe residue and L-Tyr residue) for inhibiting tumor growth in S180 mice.
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FIG. 1(3S,6R) -3- (AA-aminocaproylamino-N-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (6a-b) synthetic route AA in 5a and 6a is L-Phe residue, AA in 5b and 6b is L-Tyr residue, i) Dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), Tetrahydrofuran (THF), ii) hydrogen chloride in ethyl acetate, iii) ethyl acetate, 5% sodium bicarbonate iv) Dimethylformamide (DMF), Pd/C, H2。
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-L ys (Cbz) -D-Trp-OBzl
Suspending 4.56g (10mmol) L-Boc-L ys (Cbz) in 100m L anhydrous Tetrahydrofuran (THF), adding 1.35g (10mmol) 1-hydroxybenzotriazole (HOBt) and 2.47g (12mmol) Dicyclohexylcarbodiimide (DCC) to the suspension in turn under ice bath, stirring for 30min, adding 3.31g (10mmol) D-Trp-OBzl, adding N-methylmorpholine (NMM) dropwise to adjust pH to 9, stirring the reaction mixture for 1h under ice bath, stirring for 12h at room temperature, filtering the reaction mixture, concentrating the filtrate under reduced pressure, dissolving the residue in 150m L ethyl acetate solution, and sequentially using 5% KHSO to obtain ethyl acetate solution4The 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) 4.95 g (87%) of the title compound are obtained as a colorless solid. ESI-MS (M/e):657[ M + H]+。
EXAMPLE 2 preparation of L ys (Cbz) -D-Trp-OBzl
Slowly mix 3.28g (5mmol) of Boc-L ys (Cbz) -D-Trp-OBzl with stirring in an ethyl acetate solution of 52M L hydrogen chloride after stirring the resulting solution in an ice bath for 5H, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in 50M L anhydrous ethyl acetate, the resulting solution was concentrated under reduced pressure, this operation was repeated three times, the residue was thoroughly washed with anhydrous diethyl ether to give 2.36g (85%) of the title compound as a colorless powder, ESI-MS (M/e):557[ M + H ]: 557]+。
EXAMPLE 3 preparation of (3S,6R) -3- (benzyloxycarbonylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (1)
2.22g (4mmol) L-L ys (Cbz) -D-Trp-OBzl are dissolved in 100ml ethyl acetate, the pH is adjusted to 9 with triethylamine, stirring is carried out at 80 DEGStirring for 100 hours. The colorless solid was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column Chromatography (CH)2Cl2/CH3OH, 100/1). A total of 1.32g (65%) of the title compound are obtained. ESI-MS (M/e):449[ M + H ]]+。
EXAMPLE 4 preparation of (3S,6R) -3-amino-n-butyl-6- (indole-3-methyl) -piperazine-2, 5-dione (2)
Add 200mg Pd/C to a solution of 1.30g (2.9mmol) of (3S,6R) -3- (benzyloxycarbonylamino N-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (1) in 20m L anhydrous N, N-Dimethylformamide (DMF) and let H in at room temperature2And (5) 48 h. Pd/C was filtered off, and the filtrate was concentrated under reduced pressure to give 0.51g (56%) of the title compound as a colorless powder. ESI-MS (m/e): 315[ M + H ]]+。
EXAMPLE 5 preparation of Boc-amino-n-hexanoic acid
Add 2.83g (Boc) to a solution of 1.311g (10mmol) amino-n-hexanoic acid and 30m L distilled water2O and 30m L dioxane, adjusting pH of the obtained reaction solution to 9 with 2N NaOH aqueous solution, stirring at room temperature for 24h, continuously pumping air under reduced pressure, and reacting the mixture with KHSO4Adjusting pH of the aqueous solution to 7, and concentrating under reduced pressure. The remaining solution was further treated with KHSO4Adjusting pH to 2, extracting with 100m L ethyl acetate, and extracting with anhydrous NaSO4Drying for 8 h. Filtration and concentration of the filtrate under reduced pressure gave 2.18g (94%) of the title compound. ESI-MS (M/e):232[ M + H]+。
EXAMPLE 6 preparation of (3S,6R) -3- (Boc-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (3)
From 0.97g (4.2mmol) Boc-amino-n-hexanoic acid and 1.9g (3.5mmol) (3S,6R) -3-amino-n-butyl-6- (indole-3-methyl) -piperazine-2, 5-dione (2) 2.21g (71%) of the title compound were obtained as colorless solid using the method of example 1. ESI-MS (m/z): 528[ M + H ]]+.1H-NMR(300MHz,DMSO-d6):/ppm＝10.878(s,1H),8.044(s,1H), 7.848(s,1H),7.681(m,1H),7.564(d,J＝7.8Hz,1H),7.313(d,J＝7.8Hz,1H),7.056(m,2H), 6.943(m,1H),6.766(m,1H),4.063(m,1H),3.251(m,1H),2.969(m,6H),1.993(t,J＝7.5Hz, 2H),1.291(m,21H)。
EXAMPLE 7 preparation of (3S,6R) -3- (amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (4)
From 0.3g (0.5mmol) (3S,6R) -3- (Boc-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (3) 0.14g (58%) of the title compound was obtained as colorless powder by the method of example 2. ESI-MS (m/z): 428[ M + H]+；Mp:129-131℃；
＝-45.8(C＝0.1,CH3OH)；IR(cm-1):3213,3054,2928，2861, 1660,1547,1455,1324,1259,1099,743；1HNMR(300MHz,DMSO-d6):/ppm＝10.887(s,1 H),8.007(s,1H),7.820(s,1H),7.681(t,J＝3.6Hz,1H),7.560(d,J＝7.8Hz,1H),7.312(d,J＝ 7.8Hz,1H),7.036(m,2H),6.942(t,J1＝4.5Hz,1H),4.065(m,1H),3.040(m,2H),3.002(m,1 H),2.939(m,1H),2.012(t,J＝4.5Hz,2H),1.474(m,7H),1.263(m,7H)。
EXAMPLE 8 preparation of (3S,6R) -3- (Boc-Phe-aminocaproyl butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (5a)
From 0.125g (0.5mmol) of Boc-Phe and 0.258g (0.6mmol) of (3S,6R) -3- (aminocaproyl butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (4) by the method of example 1, 0.145g (45.60%) of the title compound was obtained as a colorless solid. ESI-MS (m/z): 697[ M + Na ]]+；1H NMR(300MHz,DMSO-d6):/ppm＝10.914(s,1H),8.055(s,1 H),7.857(s,2H),7.578(m,1H),7.513(d,J＝7.5Hz,1H),7.175(m,6H),7.039(m,2H),7.039(m, 2H),6.967(m,2H),4.067(s,1H),2.924(m,9H),3.109(d,5H),2.963(m,4H),1.995(dd,J1＝7.2 Hz,J2＝7.5Hz,2H),1.092(m,21H)。
EXAMPLE 9 preparation of (3S,6R) -3- (Boc-Tyr-aminocaproyl butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (5b)
From 0.509g (1.8mmol) of Boc-Tyr and 0.7g (1.5mmol) of (3S,6R) -3- (aminocaproyl butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (4) by the method of example 1 was obtained 0.343g (32.92%) of the title compound as a colorless solid. ESI-MS (m/z): 713[ M + Na ]]+；1H NMR(300MHz,DMSO-d6):/ppm＝10.898(s,1H),9.146(s.1 H),8.035(s,1H),7.850(s,1H),7.775(s,1H),7.677(dd,J1＝5.4Hz,J2＝5.1Hz,1H),7.572(d,J ＝7.8Hz,1H),7.319(d,J＝7.8Hz,1H),6.994(m,5H),6.725(d,J＝8.4Hz,1H),6.641(d,J＝8.4 Hz,1H),4.048(m,2H),3.258(dd,J1＝4.5Hz,J2＝3.9Hz,1H),3.176(d,J＝5.1Hz,1H),2.998 (m,5H),2.766(dd,J1＝9.0Hz,J2＝4.5Hz,1H),2.636(d,J＝7.8Hz,1H),2.003(dd,J1＝7.2Hz, J2＝7.2Hz,2H),1.254(m,21H)。
EXAMPLE 10 preparation of (3S,6R) -3- (Phe-aminocaproyl butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (6a)
From 0.675g (1mmol) of (3S,6R) -3- (Boc-Phe-aminocaproyl butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (5a) according to the method of example 2, 0.354mg (61.67%) of the title compound was obtained as a colorless solid. ESI-MS (m/z): 575[ M + H ]]+；Mp:149-153℃；
＝-13.6(C＝0.1,CH3OH)；IR(cm-1):3222,3060,2928,2860, 1659,1548,1455,1323,1258,1099,742；1H NMR(300MHz，DMSO-d6):/ppm＝10.966(d,J ＝1.8Hz,1H),8.465(dd,J1＝5.4Hz,J2＝5.7Hz,1H),8.348(s,3H),8.071(d,J＝2.1Hz,1H), 7.864(s,J＝8.1,1H),7.761(dd,J1＝5.7Hz,J2＝5.4Hz,1H),7.570(d,J＝2.1Hz,1H),7.270(m, 6H),7.040(m,2H),6.943(m,1H),4.071(d,J＝1.8Hz,1H),3.957(d,J＝1.5Hz,1H),3.045(m, 9H),1.192(dd,J1＝7.2Hz,J2＝7.5Hz,1H),1.127(m,12H)。
EXAMPLE 11 preparation of (3S,6R) -3- (Tyr-aminocaproyl butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (6b)
From 0.827g (1.2mmol) (3S,6R) -3- (Boc-Tyr-aminocaproyl butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (5b) according to the method of example 2, 0.302g (42%) of the title compound was obtained as a colorless solid. ESI-MS (m/z): 591[ M + H]+；Mp 124-125℃；
＝-9.4(C＝0.1,CH3OH)；IR(cm-1):3271,3076,2927,2858,1660, 1514,1435,1324,1239,1100,742；1H NMR(300MHz,DMSO-d6):/ppm＝10.898(d,J＝1.8Hz, 1H),9.160(s,1H),8.047(s,J＝2.1Hz,1H),7.857(s,1H),7.740(dd,J1＝5.7Hz,J2＝6.0Hz, 1H),7.683(dd,J1＝5.4Hz,J2＝5.7Hz,2H),7.573(d,J＝7.8Hz,1H),7.320(d,J＝7.8Hz,1H), 6.981(m,5H),6.674(d,J＝2.7Hz,2H),4.076(d,J＝2.1Hz,1H),3.043(m,9H),2.780(dd,J1＝5.1Hz,J2＝5.4Hz,1H),2.004(dd,J1＝7.5Hz,J2＝7.5Hz,2H),1.365(m,12H)。
EXAMPLE 12 determination of the anti-tumor metastasis Activity of Compounds 6a, b
The assay model was inoculated with L ewis mouse lung carcinoma cells (LL C, purchased from ATCC) in DMEM medium (containing 10% inactivated fetal calf serum, 1 × 10)5U/L penicillin and 100 mg/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 saline7Per/m L placenta blue staining, viable cells were counted>95 percent, taking inbred line C57B L/6 male mice (SPF grade, weight 20 +/-2 g), fixing the mice with the left hand, using 75 percent ethanol to disinfect the axillary skin of the right forelimb of the mice, using a 1m L sterile injector to inject LL C tumor cell suspension to the axillary part of the mice with the right hand, injecting 0.2m L into each mouse, after the mice are inoculated for 10 days, growing tumors with the diameter of about 4-5mm, namely, a tumor source, inoculating L ewis lung cancer tumor-bearing mice for 10 days to be anesthetized, removing cervical vertebrae, soaking the mice for 10min with 75 percent ethanol, sterilizing, stripping tumor bodies on a super-clean working table, selecting well-grown tumor tissues to be sheared in a sterile flat dish, placing the mice in a tissue homogenizer made of glass, adding 4 ℃ physiological saline according to the ratio of the tumor mass to the physiological saline volume of 1 to 3(g to m L), lightly grinding the physiological saline to prepare the cell suspension, passing the cell suspension through a 200-mesh cell sieve, and adjusting the density of the single cell to 1.5.5910.57Per m L placenta blue stainingColor, counting of viable cells>The left-handed fixed inbred C57B L/6 male mice, the right forelimb axillary skin of the mice were disinfected with 75% ethanol, the right-handed 1m L sterile syringes were injected subcutaneously into the mouse axillary, each injection was 0.2m L, the mice developed tumors of 4-5mm diameter after 10 days of inoculation, the inoculated mice were randomly grouped into groups of 12 mice per group, the tumor-inoculated day 11 mice were either orally administered a normal saline solution of the recognized anti-tumor metastasis peptide RGDS (dose of 20 μmol/kg/day) or orally administered a normal saline solution of compound 6a, b (dose of 0.5 μmol/kg/day) or a normal saline solution of compound 4 (dose of 5 μmol/kg/day) or orally administered a normal saline solution of compound 4 (dose of 10m L/kg/day), 1 drug was administered daily for 12 days continuously, the tumor volume was measured and recorded every last day the tumor volume was measured every other day, the mice were anesthetized with ether, the mice were taken for significant tumor metastasis inhibition of lung cancer, the tumor metastasis was not only the results of the tumor growth was taken, the test results showed that the tumor growth was significantly different from the tumor growth of the tumor cells, the tumor cells were not only the tumor cells, but the tumor cells were taken as the tumor cells, the tumor cells were analyzed, the tumor cells were taken, the tumor cells were.
TABLE 1 antitumor metastatic Activity of Compounds 6a, b
a) P <0.01 to saline, p >0.05 to RGDS and compound 4; n-12
EXAMPLE 13 determination of the anti-tumor growth Activity of Compounds 6a, b
Doxorubicin, compound 4 and compounds 6a, b were all dissolved in saline prior to assay for administration to S180 mice. Taking S180 ascites tumor liquid which is inoculated in male ICR mice and grows vigorously for 10 days in a sterile environment, diluting the S180 ascites tumor liquid into liquid (1:2) by using normal saline, fully mixing the liquid, dyeing the tumor cell suspension by using freshly prepared 0.2% trypan blue, uniformly mixing the liquid and the liquid, counting the liquid according to a white cell counting method, wherein the blue-dyed cells are dead cells, and the non-dyed cells are live cellsCell concentration 4. large check viable cell number/4 × 104× the dilution factor is cell number/m L, the cell survival rate is calculated according to the cell survival rate is live cell number/(live cell number + dead cell number) × 100%, and the tumor liquid with the survival rate of more than 90% is made into the density of 2.0 × 10 by a homogenization method7The present invention relates to a method for inhibiting tumor growth, which comprises the steps of inoculating a cell suspension of L/m subcutaneously (0.2m L/mouse) in the right axilla of a mouse, producing S180 tumor-bearing mice, injecting S180 tumor-bearing mice intraperitoneally daily with a physiological saline solution of doxorubicin (at a dose of 2 μmol/kg/day g) or daily orally administered with a physiological saline solution of compound 4 (at a dose of 5 μmol/kg/day) or daily orally administered with a physiological saline solution of compound 6a, b (at a dose of 0.5 μmol/kg/day), administering once daily, continuously for 12 days, measuring the tumor volume the day after the last administration, deaning the cervical vertebrae with ether, then fixing the tumor growth site in the right axilla of the mice with forceps, cutting and weighing the skin blunt dissecting the tumors, expressing the therapeutic effect with the tumor weight (mean SD ± g), examining and analyzing the data with variance, see table 2, the effect of compound 6a, b at a dose of 0.5 μmol/kg is not only effective in inhibiting tumor growth, but the activity is 10 times higher than the data of these compounds, and the present invention is also shown to be significantly effective.
TABLE 2 Effect of Compounds 6a, b on tumor growth in S180 mice
a) P <0.01 to saline, p <0.05 to compound 4; n is 12.
EXAMPLE 14 determination of the anti-inflammatory Activity of Compounds 6a, b
Since the xylene-induced ear swelling of mice is recognized as an acute inflammation model, the present invention measured the therapeutic effects of compounds 6a, b on the xylene-induced ear swelling model of mice, since aspirin is a positive drug for treating acute inflammation, the present invention selected aspirin as a positive control, ICR male mice (body weight 42 ± 3g) were allowed to rest for 2 days in an environment at a temperature of 22 ℃, freely drink water and eat, after which they were randomly divided into a saline group (dose of 0.2m L/mouse), an aspirin group (dose of 1.11 mmol/kg), a compound 4 group (dose of 5 μmol/kg) and a compound 6a, b group (dose of 0.5 μmol/kg), 12 mice in each group, the mice were subjected to the measurement either oral saline, or oral aspirin, or oral compound 4, or oral compound 6a, c. after administration for 30min, the mice were evenly smeared with 30 μ L xylene at the left auricle of the mice, 2h received ether anesthesia, neck was cut off, the mice were left ear swelling after administration of compound 4, or oral compound 6a, the two ear discs were taken with the same weight as the ear swelling inhibition effect of the two ear discs, i.10 mm, the two discs were not only the weight of the same as the test, the dose of the mice was found that the dose of the invention, the dose of the disc was found to be effective for the same, the same as the dose of the mouse, the dose of the same as the dose of the mouse, i.5 μ ear swelling.
TABLE 3 Effect of Compounds 6a, b on xylene swelling of mouse ears
a) P <0.01 to saline, p >0.05 to compound 4; n is 12.
Claims (5)
1. (3S,6R) -3- (AA-aminocaproylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione of the formula, wherein AA is a residue of L-Phe and a residue of L-Tyr,
2. a process for the preparation of (3S,6R) -3- (AA-aminocaproylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1, which comprises:
(1) L-Boc-L ys (Cbz) and D-Trp-OBzl are condensed to obtain Boc-L ys (Cbz) -D-Trp-OBzl;
(2) Boc-L ys (Cbz) -D-Trp-OBzl is subjected to Boc removal in ethyl acetate solution of hydrogen chloride to obtain L ys (Cbz) -D-Trp-OBzl;
(3) l ys (Cbz) -D-Trp-OBzl cyclizing in 5% sodium bicarbonate water solution saturated ethyl acetate solution to generate (3S,6R) -3- (benzyloxycarbonylamino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione;
(4) hydrogenolysis of (3S,6R) -3- (benzyloxycarbonylamino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione to debenzyloxycarbonyl (3S,6R) -3-amino n-butyl-6- (indole-3-methyl) -piperazine-2, 5-dione;
(5) condensing (3S,6R) -3-amino n-butyl-6- (indole-3-methyl) -piperazine-2, 5-dione and Boc-amino n-hexanoic acid to obtain (3S,6R) -3- (Boc-amino n-hexanoyl amino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione;
(6) de-Boc (3S,6R) -3- (Boc-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione in a solution of hydrogen chloride in ethyl acetate to give (3S,6R) -3- (amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione;
(7) condensing (3S,6R) -3- (amino n-hexanoylamino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione with Boc-AA to obtain (3S,6R) -3- (Boc-AA-aminocaproylamino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione;
(8) boc removal of (3S,6R) -3- (Boc-AA-aminocaproylamino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione in a solution of hydrogen chloride in ethyl acetate gives (3S,6R) -3- (AA-aminocaproylamino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione.
3. Use of (3S,6R) -3- (AA-aminocaproylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1 for the preparation of a medicament against tumor metastases.
4. Use of (3S,6R) -3- (AA-aminocaproylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1 for the preparation of an antitumor medicament.
5. Use of (3S,6R) -3- (AA-aminocaproylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1 for the preparation of an anti-inflammatory medicament.
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