CN108929315A - Piperazine -2,5- diketone of 3R- indole methyl -6S- methionine modification, synthesis, activity and application - Google Patents

Piperazine -2,5- diketone of 3R- indole methyl -6S- methionine modification, synthesis, activity and application Download PDF

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CN108929315A
CN108929315A CN201710405787.3A CN201710405787A CN108929315A CN 108929315 A CN108929315 A CN 108929315A CN 201710405787 A CN201710405787 A CN 201710405787A CN 108929315 A CN108929315 A CN 108929315A
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amino
piperazine
boc
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met
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CN108929315B (en
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赵明
彭师奇
王玉记
吴建辉
张可欣
康贵峰
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Capital Medical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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Abstract

The invention discloses (3R, 6S) -3- of following formula (the positive caproyl amino normal-butyl of Met- amino) -6- (indoles -3- methyl)-piperazine-2,5-diones.Its preparation method is disclosed, its activity of resisting tumor metastasis is disclosed, thus the invention discloses it to prepare the application in medicine for anti transfer of tumor.

Description

Piperazine -2,5- diketone of 3R- indole methyl -6S- methionine modification, synthesizes, living Property and application
Technical field
The present invention relates to (3R, 6S) -3- (the positive caproyl amino normal-butyl of Met- amino) -6- (indoles -3- methyl)-piperazines Piperazine -2,5- diketone.It is related to its preparation method, is related to its activity of resisting tumor metastasis, thus the present invention relates to it antitumor Application in diversion medicaments.The invention belongs to biomedicine fields.
Background technique
Tumour seriously threatens the health of the mankind.Other than itself is severe to the prognosis of tumor patient, tumor complicated turns Move the prognosis for further deteriorating patient.For example, being all to die of transfer more than 90% or more tumor patient.Due to existing antineoplastic Object does not have inhibiting effect on tumor metastasis, so the clinical efficacy of chemotherapy of tumors is undesirable.The drug of invention anti-tumor metastasis is clinical Urgent need.Before this, inventor once discloses S, S-, R, R-, R, S- and S, and the diketopiperazine of tetra- kinds of configurations of R- is dense at 0.5 μM Degree can inhibit HCCLM3 (high-transfer human liver cancer cell) migration and invasion.Later inventor discloses R, the diketopiperazine of R- configuration again The tumour of C57BL/6 mouse be can inhibit under 5 μm of ol/kg dosage to Lung metastases.But minimum effective dose is 5 μm of ol/kg.For Reduction minimum effective dose, inventor expand various modifications to S, the amino normal-butyl of the diketopiperazine of R- configuration.By 3 Year is explored, and the discovery acylated S of the acylated Amino-n-hexanoic acid of methionine, the amino normal-butyl of the diketopiperazine of R- configuration can make to resist The minimum effective dose of metastases is down to 0.5 μm of ol/kg.Disappear because the toxic side effect of drug can be reduced with dosage It loses, so 10 times of effective dose reduction shows this structural modification and has technical effect outstanding.According to these discoveries, inventor Propose the present invention.
Summary of the invention
First content of the invention is to provide (3R, 6S) -3- (the positive caproyl amino normal-butyl of Met- amino)-of following formula 6- (indoles -3- methyl)-piperazine-2,5-dione.
Second content of the invention is to provide (3R, 6S) -3- (the positive caproyl amino normal-butyl of Met- amino) -6- (Yin Diindyl -3- methyl)-piperazine -2,5- diketone synthetic method, this method includes：
(1) D-Boc-Lys (Cbz) and L-Trp-OBzl are condensed to obtain D-Boc-Lys (Cbz)-D-Trp-OBzl；
(2) D-Boc-Lys (Cbz)-D-Trp-OBzl de- Boc in the ethyl acetate solution of hydrogen chloride obtains D-Lys (Cbz)-D-Trp-OBzl；
(3) D-Lys (Cbz)-D-Trp-OBzl cyclization in the ethyl acetate solution that 5% sodium bicarbonate aqueous solution is saturated obtains (3R, 6S) -3- (benzyloxycarbonyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (1)；
(4) the de- benzyloxycarbonyl group of 1 hydrogenolysis of compound obtains (3R, 6S) -3- (amino normal-butyl) -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (2)；
(5) Amino-n-hexanoic acid methyl esters and Boc-Met are condensed to obtain Boc-Met- Amino-n-hexanoic acid methyl esters (3)；
(6) saponification of compound 3 removing methyl esters obtains Boc-Met- Amino-n-hexanoic acid (4)；
(7) compound 2 and compound 4 are condensed (3R, 6S) -3- (the positive caproyl amino normal-butyl of Boc-Met- amino) - 6- (indoles -3- methyl)-piperazine-2,5-dione (5).
(8) the de- Boc in the ethyl acetate solution of hydrogen chloride of compound 5 obtains (3R, 6S) -3- (positive caproyl of Met- amino Amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (6).
Third content of the invention is evaluation (3R, 6S) -3- (the positive caproyl amino normal-butyl of Met- amino) -6- (Yin Diindyl -3- methyl)-piperazine-2,5-dione inhibition C57BL/6 mouse anti-lung cancer transfer activity.
Detailed description of the invention
Fig. 1 (3R, 6S) -3- (the positive caproyl amino normal-butyl of Met- amino) -6- (indoles -3- methyl)-piperazine -2,5- two The synthetic route .i of ketone (6)) dicyclohexylcarbodiimide (DCC), I-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM)； Ii) the ethyl acetate solution of hydrogen chloride；Iii) ethyl acetate, 5% sodium bicarbonate aqueous solution；iv)Pd/C,H2；V) methanol, NaOH (2M)。
Specific embodiment
In order to which the present invention is further explained, a series of embodiments are given below.These embodiments be entirely it is illustrative, it Only be used to the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 prepares D-Boc-Lys (Cbz)-L-Trp-OBzl
Add under ice bath into the solution of 1.90g (5.0mmol) D-Boc-Lys (Cbz) and 20mL dry tetrahydrofuran (THF) Enter 0.68g (5.0mmol) I-hydroxybenzotriazole (HOBt) and 1.24g (6.0mmol) dicyclohexylcarbodiimide (DCC) and stirs It mixes 30 minutes, obtains reaction solution A.1.47g (5.0mmol) L-Trp-OBzl is dissolved in 20mL dry THF, N-methylmorpholine is added (NMM) it adjusts pH to 9 and obtains reaction solution B.Reaction solution B is added in reaction solution A, is reacted at room temperature 12 hours, TLC (methylene chloride/ Methanol, 40/1) display reaction completion.Reaction mixture filtering, filtrate decompression concentration, residue 50mL ethyl acetate dissolve. Obtained solution is successively with saturation NaHCO3Aqueous solution is washed (25mL × 3), and saturation NaCl aqueous solution washes (25mL × 3), 5%KHSO4 Aqueous solution is washed (25mL × 3), and saturation NaCl aqueous solution is washed (25mL × 3), is saturated NaHCO3Aqueous solution is washed (25mL × 3) and is saturated NaCl aqueous solution washes (25mL × 3).Ethyl acetate layer anhydrous Na2SO4It is 12 hours dry.Filter out Na2SO4, filtrate decompression it is dense Contracting, residue silica gel column chromatography are purified (methylene chloride/methanol, 40/1), and 2.94g (90%) title compound is obtained, and are nothing Color solid.ESI-MS(m/z):657[M+H]+。
Embodiment 2 prepares D-Lys (Cbz)-L-Trp-OBzl
The second of 30mL hydrogen chloride is slowly added under ice bath to 2.62g (4.0mmol) D-Boc-Lys (Cbz)-L-Trp-OBzl Acetate solution (4M) simultaneously stirs 4 hours, and TLC (methylene chloride/methanol, 40/1) display reaction is completed.Reaction mixture decompression Concentration, residue add 30mL anhydrous ethyl acetate to dissolve, and obtained solution is concentrated under reduced pressure, and residue adds 30mL anhydrous ethyl acetate Dissolution.The operation is in triplicate.Residue adds 30mL anhydrous ether to make to be suspended by Ultrasound Instrument, removes ether after standing, obtains It is yellow powder to 2.07g (93%) title compound.ESI-MS(m/z):557[M+H]+。
Embodiment 3 prepares (3R, 6S) -3- (benzyloxycarbonyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- two Ketone (1)
By the solution of 1.95g (3.5mmol) D-Lys (Cbz)-L-Trp-OBzl and 50mL ethyl acetate saturation NaHCO3 Aqueous solution is sufficiently washed after (25mL × 3), and ethyl acetate layer stirs 56 hours in 80 DEG C.TLC (methylene chloride/methanol, 20/1) Display reaction is completed.Reaction mixture room temperature is sufficiently placed, and filtering obtains 0.72g (46%) title compound, is colourless solid Body.ESI-MS(m/z):449[M+H]+。
Embodiment 4 prepares (3R, 6S) -3- (amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (2)
To 0.67g (1.5mmol) (3R, 6S) -3- (benzyloxycarbonyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine - In the solution of 2,5- diketone (1) and 10mL dimethylformamide (DMF) plus 0.07g Pd/C (10%), room temperature lead to H248 hours, TLC (methylene chloride/methanol, 20/1) display reaction is completed.Pd/C is filtered out from reaction mixture, filtrate decompression concentration obtains 0.48g (95%) title compound is colorless solid.ESI-MS(m/z):315[M+H]+。
Embodiment 5 prepares Amino-n-hexanoic acid methyl esters
5.2mL thionyl chloride is added dropwise under ice bath into 52mL methanol, stirs 30 minutes, adds 0.26g toward grain (2.0mmol) Amino-n-hexanoic acid.Reaction mixture is stirred at room temperature 24 hours.TLC (methylene chloride/methanol, 3/1) display has been reacted At.Reaction mixture is concentrated under reduced pressure, and residue adds 30mL methanol to dissolve, and obtained solution is concentrated under reduced pressure again.The operation repeats three It is secondary.30mL anhydrous ether is added in residue makes sufficiently to be suspended by Ultrasound Instrument, removes ether, it is titled to obtain 0.27g (94%) Object is closed, is colourless powder.ESI-MS(m/e):145[M+H]+。
Embodiment 6 prepares Boc-Met- Amino-n-hexanoic acid methyl esters (3)
Using the method for embodiment 1 from 0.37g (1.5mmol) Boc-Met and 0.22g (1.5mmol) Amino-n-hexanoic acid first Ester obtains 0.51g (90%) title compound, is colorless solid.ESI-MS(m/z):411[M+H]+。
Embodiment 7 prepares Boc-Met- Amino-n-hexanoic acid (4)
0.45g (1.2mmol) Boc-Met- Amino-n-hexanoic acid methyl esters (3) 8mL methanol is dissolved, uses NaOH under ice bath (2M) aqueous solution adjusts pH to 12, is stirred at room temperature 4 hours, and TLC (methylene chloride/methanol, 20/1) display reaction is completed.Under ice bath Reaction mixture saturation KHSO4Aqueous solution adjusts pH to 7, is concentrated under reduced pressure, water phase saturation KHSO4Aqueous solution adjusts pH to 2, It is sufficiently extracted three times with 10mL ethyl acetate.Ethyl acetate layer is saturated NaCl aqueous solution and is washed with 10mL makes pH value of solution 7 three times, uses Anhydrous Na2SO4It is 12 hours dry.It is filtered to remove Na2SO4, filtrate decompression concentration, obtain 0.41g (94%) title compound, be Colorless solid.ESI-MS(m/z):397[M+H]+。
Embodiment 8 prepares (3R, 6S) -3- (the positive caproyl amino normal-butyl of Boc-Met- amino) -6- (indoles -3- first Base)-piperazine-2,5-dione (5)
It is added under ice bath into 0.36g (1.0mmol) Boc-Met- Amino-n-hexanoic acid (4) and the solution of 5mL anhydrous DMF 0.14g (1.0mmol) HOBt and 0.25g (1.2mmol) DCC stirs 30 minutes, obtains reaction solution A.By 0.31g (1.0mmol) (3R, 6S) -3- (amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (2) is dissolved in 5mL anhydrous DMF, adds N- first Base morpholine adjusts pH to 9, obtains reaction solution B.Reaction solution B is added in reaction solution A, is stirred at room temperature 12 hours, TLC (dichloromethane Alkane/methanol, 10/1) display reaction completion.Reaction mixture filtering, filtrate decompression concentration, residue are purified with silica gel column chromatography (methylene chloride/methanol, 50/1) obtains 0.12g (18%) title compound, is colorless solid.ESI-MS(m/z):693[M+ H]+；1H NMR(300MHz,DMSO-d6) δ/ppm=10.887 (s, 1H), 8.031 (d, J=2.1Hz, 1H), 7.884 (s, 1H), 7.755 (t, J=5.4Hz, 1H), 7.674 (t, J=5.4Hz, 1H), 7.569 (d, J=7.8Hz, 1H), 7.317 (d, J =7.8Hz, 1H), 7.045 (m, 2H), 6.947 (td, J1=8.1Hz, J2=0.9Hz, 1H), 4.071 (m, 1H), 4.000 (m, 1H),3.287(dd,J1=14.4Hz, J2=4.2Hz, 1H), 3.008 (m, 6H), 2.412 (m, 2H), 2.028 (s, 3H), 1.994(m,4H),1.777(m,2H),1.377(m,15H),1.181(m,6H)。
Embodiment 9 prepares (3R, 6S) -3- (the positive caproyl amino normal-butyl of Met- amino) -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (6)
According to the method for embodiment 2 from 0.07g (0.1mmol) (3R, 6S) -3- (positive caproyl amino of Boc-Met- amino Normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone (5) obtains 0.05g (91%) title compound, and it is colorless solid. ESI-MS(m/z):559[M+H]+；Mp 146-148℃；(c=0.1, methanol)；IR(cm-1):3223,3078, 2924,2851,1654,1543,1443,1326,1237,1096,740；1H NMR(300MHz,DMSO-d6) δ/ppm= 10.922 (s, 1H), 8.500 (t, J=5.4Hz, 1H), 8.234 (s, 2H), 8.042 (d, J=1.9Hz, 1H), 7.847 (s, 1H), 7.720 (t, J=5.4Hz, 1H), 7.568 (d, J=7.8Hz, 1H), 7.320 (d, J=7.8Hz, 1H), 7.043 (m, 2H),6.947(td,J1=8.1Hz, J2=0.9Hz, 1H), 4.073 (m, 1H), 3.791 (m, 1H), 3.255 (dd, J1= 14.4Hz,J2=4.2Hz, 1H), 3.059 (m, 6H), 2.481 (m, 2H), 2.058 (s, 3H), 1.994 (m, 4H), 1.438 (m, 6H),1.229(m,6H)。
Embodiment 10 prepares Boc- Amino-n-hexanoic acid
Stirring is lower to add 0.58g (2.6mmol) into the solution of 0.26g (2.0mmol) Amino-n-hexanoic acid and 5mL distilled water (Boc)2The solution of O and 5mL dioxane.By the obtained solution aqueous solution tune pH to 9 of NaOH (2M) under ice bath.Under ice bath After stirring 30 minutes, it is stirred at room temperature and is evacuated with water pump.PH is monitored during stirring and is allowed to remain 9, until TLC (two Chloromethanes/methanol, 3/1) display reaction completion.Under ice bath, reaction mixture saturation KHSO4Aqueous solution adjusts pH to 7, decompression Concentration.Water phase saturation KHSO4Aqueous solution adjusts pH to 2, is sufficiently washed three times with 10mL ethyl acetate, is saturated NaCl water with 10mL Solution is washed makes pH value of solution 7 three times, uses anhydrous Na2SO4It is 12 hours dry.It is filtered to remove Na2SO4, filtrate decompression concentration, obtain 0.41g (89%) title compound is colorless solid.ESI-MS(m/e):232[M+H]+。
Embodiment 11 prepares (3R, 6S) -3- (the positive caproyl amino normal-butyl of Boc- amino) -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (7)
Using embodiment 8 method from 0.28g (1.2mmol) Boc- Amino-n-hexanoic acid and 0.38g (1.2mmol) (3R, 6S) -3- (amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone (2) obtains 0.12g (19%) title compound, For colorless solid.ESI-MS(m/z):528[M+H]+；1H NMR(300MHz,DMSO-d6) δ/ppm=10.903 (s, 1H), 8.046 (d, J=1.8Hz, 1H), 7.851 (s, 1H), 7.686 (t, J=5.4Hz, 1H), 7.556 (d, J=7.8Hz, 1H), 7.314 (d, J=7.8Hz, 1H), 7.039 (m, 2H), 6.943 (td, J1=7.8Hz, J2=0.6Hz, 1H), 6.758 (t, J= 5.4Hz,1H),4.068(m,1H),3.252(dd,J1=14.4Hz, J2=4.2Hz, 1H), 2.924 (m, 6H), 1.995 (t, J =7.2Hz, 2H), 1.292 (m, 21H).
Embodiment 12 prepares (3R, 6S) -3- (the positive caproyl amino normal-butyl of amino) -6- (indoles -3- methyl)-piperazine - 2,5- diketone (8)
Using the method for embodiment 2 from 0.11g (0.2mmol) (3R, 6S) -3- (positive positive fourth of caproyl amino of Boc- amino Base) -6- (indoles -3- methyl)-piperazine -2,5- diketone (7) obtains 0.08g (96%) title compound, and it is colorless solid.ESI- MS(m/z):428[M+H]+；1H NMR(300MHz,DMSO-d6) δ/ppm=10.924 (s, 1H), 8.071 (s, 1H), 7.866 (s, 1H), 7.729 (t, J=5.4Hz, 1H), 7.568 (d, J=7.5Hz, 1H), 7.321 (d, J=7.5Hz, 1H), 7.044 (m, 2H), 6.949 (t, J=7.5Hz, 1H), 4.070 (m, 1H), 3.239 (dd, J1=14.4Hz, J2=3.6Hz, 1H), 2.991 (m, 4H), 2.694 (m, 2H), 2.021 (t, J=7.5Hz, 2H), 1.467 (m, 6H), 1.240 (m, 6H).
The activity of resisting tumor metastasis of the measurement compound 6 of embodiment 13
Lewis murine lung cancer cell (LLC the is purchased from ATCC) inoculation of this rating model, selects DMEM culture medium (to contain 10% Fetal calf serum through inactivating, 1 × 105U/L penicillin and 100mg/L streptomysin), it was passed according to attached cell cultural method every two days In generation, is primary, enrichment of cell.Vitellophag when cell growth state is good and is in logarithmic growth phase, is adjusted thin with physiological saline Born of the same parents' density is to 1 × 107A/mL.The dyeing of placenta indigo plant, makes viable count>95%.Take inbred strais C57BL/6 male mice (SPF Grade, 20 ± 2g of weight), the fixed mouse of left hand.It is sterilized with 75% Mice Hepatocytes Injured by Ethanol right fore skin of axillary fossa.It is sterile that the right hand holds 1mL LLC tumor cell suspension is subcutaneously injected toward mouse armpit in syringe, and every mouse injects 0.2mL.After mouse inoculation 10 days, grow The tumour of diameter about 4-5mm is knurl source.The Lewis lung cancer tumor-bearing mice etherization of inoculation 10 days, cervical dislocation are put to death.With 75% ethyl alcohol impregnates 10min, and knurl is removed in disinfection on superclean bench.Select well-grown tumor tissues sterile flat It shreds, is placed in the tissue homogenizer of glass manufacture in ware.The ratio for being again 1 to 3 (g ratio mL) than physiological saline volume in tumor mass The physiological saline that heating degree is 4 DEG C, is lightly ground and cell suspension is made.Cell suspension crosses 200 mesh cell sieve single cell suspensions. With the cell density of physiological saline tune single cell suspension to 1.5 × 107A/mL.The dyeing of placenta indigo plant, makes viable count>95%. Left hand fixes inbred strais C57BL/6 male mice, is sterilized with 75% Mice Hepatocytes Injured by Ethanol right fore skin of axillary fossa.The right hand holds 1mL Tumor cell suspension, every injection 0.2mL is subcutaneously injected in mouse armpit in asepsis injector.Mouse grows diameter 4- after inoculation 10 days Mice Inoculated is grouped by the tumour of 5mm at random by the gross tumor volume measured.Every group of 12 mouse.The 11st day of inoculated tumour is small (dosage is 20 μm of ol/ to the normal saline solution of mouse or oral generally acknowledged anti tumor translocation peptide Arg-Gly-Asp-Ser (RGDS) Kg/ days) or the normal saline solution (dosage be 5 μm ol/kg/ days) or the physiology salt of oral administration of compound 6 of oral administration of compound 8 it is water-soluble Liquid (dosage be 0.5 μm ol/kg/ days) or oral normal saline (dosage is 10mL/kg/ days) give 1 medicine, successive administration daily 12 days.The next day etherization cervical dislocation of last time administration is put to death, and is taken the lung of mouse and is calculated the burrknot of tumour lung transfer Number.It is examined with t for statistical analysis to data.It the results are shown in Table 1.Do not press down only effectively in 0.5 μm of ol/kg dosages for Compound 6 Neoplasm lung metastasis processed, and activity and its high 40 times RGDS of dose ratio and its high 10 times compound 8 of dose ratio are no significant Sex differernce.These statistics indicate that, the present invention has significant technical effect.
The activity of resisting tumor metastasis of 1 compound 6 of table
A) with physiological saline ratio p<0.01, compare p with RGDS and compound 8>0.05；N=12.

Claims (3)

1. (3R, 6S) -3- (the positive caproyl amino normal-butyl of Met- amino) -6- (indoles -3- methyl)-piperazine -2,5- of following formula Diketone,
2. (3R, 6S) -3- (the positive caproyl amino normal-butyl of Met- amino) -6- (indoles -3- methyl)-piperazine-of claim 1 The preparation method of 2,5- diketone, this method include：
(1) D-Boc-Lys (Cbz) and L-Trp-OBzl are condensed to obtain D-Boc-Lys (Cbz)-D-Trp-OBzl；
(2) D-Boc-Lys (Cbz)-D-Trp-OBzl de- Boc in the ethyl acetate solution of hydrogen chloride obtains D-Lys (Cbz)-D- Trp-OBzl；
(3) D-Lys (Cbz)-D-Trp-OBzl cyclization in the ethyl acetate solution that 5% sodium bicarbonate aqueous solution is saturated obtain (3R, 6S) -3- (benzyloxycarbonyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (1)；
(4) the de- benzyloxycarbonyl group of 1 hydrogenolysis of compound obtains (3R, 6S) -3- (amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2, 5- diketone (2)；
(5) Amino-n-hexanoic acid methyl esters and Boc-Met are condensed to obtain Boc-Met- Amino-n-hexanoic acid methyl esters (3)；
(6) saponification of compound 3 removing methyl esters obtains Boc-Met- Amino-n-hexanoic acid (4)；
(7) compound 2 and compound 4 are condensed (3R, 6S) -3- (the positive caproyl amino normal-butyl of Boc-Met- amino) -6- (Yin Diindyl -3- methyl)-piperazine-2,5-dione (5)；
(8) the de- Boc in the ethyl acetate solution of hydrogen chloride of compound 5 obtains (3R, 6S) -3- (positive caproyl amino of Met- amino Normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (6).
3. (3R, 6S) -3- (the positive caproyl amino normal-butyl of Met- amino) -6- (indoles -3- methyl)-piperazine-of claim 1 2,5- diketone is preparing the application in medicine for anti transfer of tumor.
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