CN108929369A - Piperazine -2,5- diketone of 3R- indole methyl -6R- acidic amino acid modification, synthesis, activity and application - Google Patents

Piperazine -2,5- diketone of 3R- indole methyl -6R- acidic amino acid modification, synthesis, activity and application Download PDF

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CN108929369A
CN108929369A CN201710363811.1A CN201710363811A CN108929369A CN 108929369 A CN108929369 A CN 108929369A CN 201710363811 A CN201710363811 A CN 201710363811A CN 108929369 A CN108929369 A CN 108929369A
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amino
piperazine
methyl
boc
indoles
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CN108929369B (en
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赵明
彭师奇
王玉记
吴建辉
张筱宜
丛林
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Capital Medical University
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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Abstract

The invention discloses (3R, 6R) -3- of following formula (the positive caproyl amino normal-butyl of AA- amino) -6- (indoles -3- methyl)-piperazine-2,5-dione (AA is L-Asp residue and L-Glu residue in formula).It discloses their preparation method, disclose their anti-tumor activity, and disclose their activity of resisting tumor metastasis, thus the invention discloses them to prepare the application in anti-tumor drug and medicine for anti transfer of tumor.

Description

Piperazine -2,5- diketone of 3R- indole methyl -6R- acidic amino acid modification, synthesis, Activity and application
Technical field
The present invention relates to (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (indoles -3- methyl)-piperazines - 2,5- diketone.It is related to their preparation method, is related to their anti-tumor activity, and is related to their anti-tumor metastasis work Property, thus anti-tumor drug is being prepared the present invention relates to them, the application in medicine for anti transfer of tumor.The invention belongs to biologies to cure Medicine field.
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 R, the fourth amino of the diketopiperazine of R- configuration.It was visited by 3 years Rope, the discovery acylated R of acidic side chains (L-Asp and L-Glu) acylated aminocaproic acid, the fourth of the diketopiperazine of R- configuration Amino can not only make the minimum effective dose of anti-tumor metastasis be down to 0.5 μm of ol/kg, but also can make antitumor minimum effective agent Amount is down to 0.5 μm of ol/kg.It disappears because the toxic side effect of drug can be reduced with dosage, effective dose reduces by 10 Showing this structural modification again has technical effect outstanding.According to these discoveries, the present invention is inventors herein proposed.
Summary of the invention
First content of the invention is to provide (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino)-of following formula 6- (indoles -3- methyl)-piperazine-2,5-dione (AA is L-Asp residue and L-Glu residue in formula).
Second content of the invention is to provide (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (Yin Diindyl -3- methyl)-piperazine -2,5- diketone (AA is L-Asp residue and L-Glu residue in formula) synthetic method, this method includes：
(1) D-Boc-Lys (Cbz) and D-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 containing 5% sodium bicarbonate aqueous solution saturation ethyl acetate middle ring symphysis at (3R, 6R) -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, 6R) -3- (amino normal-butyl) -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (2)；
(5) Amino-n-hexanoic acid methyl esters and Boc-AA [AA is L-Asp (OMe) residue and L-Glu (OMe) residue] are condensed Boc-AA- Amino-n-hexanoic acid methyl esters (3a, b) [AA is L-Asp (OMe) residue and L-Glu (OMe) residue]；
(6) compound 3a, b piptonychia ester obtain Boc-AA (OMe)-Amino-n-hexanoic acid (4a, b), and (AA is L-Asp residue and L- Glu residue)；
(7) compound 2 and compound 4a, b is condensed (3R, 6R) -3-, and (the positive caproyl amino of Boc-AA (OMe)-amino is just Butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (5a, b) (AA is L-Asp residue and L-Glu residue)；
(8) compound 5a, b piptonychia ester obtain (3R, 6R) -3- (the positive caproyl amino normal-butyl of Boc-AA- amino) -6- (indoles -3- methyl)-piperazine-2,5-dione (6a, b) (AA is L-Asp residue and L-Glu residue)；
(9) compound 6a, b take off Boc in the ethyl acetate solution of hydrogen chloride and obtain (3R, 6R) -3- (positive hexanoyl of AA- amino Base amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (7a, b) (AA is L-Asp residue and L-Glu residue).
Third content of the invention is evaluation (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (Yin Diindyl -3- methyl)-piperazine-2,5-dione (AA is L-Asp residue and L-Glu residue in formula) inhibition C57BL/6 mouse anti-lung cancer turn Move activity.
4th content of the invention is evaluation (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (Yin Diindyl -3- methyl) the suppression of-piperazine-2,5-dione (AA is L-Asp residue and L-Glu residue in formula) to S180 mice tumors grew System application.
Detailed description of the invention
Fig. 1 (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (indoles -3- methyl)-piperazine -2,5- two AA is L-Asp (OMe) residue in the synthetic route .3a and 4a of ketone (6a, b), and AA is L-Glu (OMe) residue in 3b and 4b；I) two Carbodicyclo hexylimide (DCC), I-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), tetrahydrofuran (THF)；Ii) chlorine Change the ethyl acetate solution of hydrogen；Iii) ethyl acetate, 5% sodium bicarbonate；Iv) dimethylformamide (DMF), Pd/C, H2；V) two Carbodicyclo hexylimide (DCC), I-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), N,N-dimethylformamide (DMF)；Vi) 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)-D-Trp-OBzl
7.7g (20mmol) D-Boc-Lys (Cbz) is suspended in 100mL anhydrous tetrahydro furan (THF), under ice bath according to It is secondary to add 2.7g (20mmol) 1- hydroxy benzo triazole (HOBt) and 5.0g (25mmol) dicyclohexyl carbon two sub- into suspension Amine (DCC), then stirs 30min.Later, add 8.0g (25mmol) D-Trp-OBzl.N- methyl is added dropwise in compound of reaction Morpholine (NMM) adjusts pH to 9.Reaction mixture first stirs 1h under ice bath, then 12h is stirred at room temperature.Compound of reaction filtering, filter Liquid is concentrated under reduced pressure, and residue 150mL ethyl acetate solution dissolves.Obtained ethyl acetate solution successively uses 5%KHSO4It is water-soluble Liquid is washed 3 times, and saturation NaCl aqueous solution is washed 3 times.Ethyl acetate layer anhydrous Na2SO4Dry 12h, filtering, filtrate decompression are concentrated into It is dry.Obtained yellow syrup object is purified by silica gel column chromatography (CH2Cl2/CH3OH,100:1) 12.0g (88%) title compound is obtained Object is colorless solid.ESI-MS(m/e):657[M+H]+。
Embodiment 2 prepares D-Lys (Cbz)-D-Trp-OBzl
The acetic acid of 3.8g (5mmol) D-Boc-Lys (Cbz)-D-Trp-OBzl and 52mL hydrogen chloride under ice bath and stirring Ethyl ester solution (4M) is slowly mixed together.Obtained solution stirs 5h in ice bath.Later, reaction mixture is concentrated under reduced pressure.Residue It is dissolved with 50mL anhydrous ethyl acetate, obtained solution is concentrated under reduced pressure.The operation is in triplicate.Residue anhydrous ether is abundant It washes, obtains 3.41g (93%) title compound, be yellow powder.ESI-MS(m/e):557[M+H]+。
Embodiment 3 prepares (3R, 6R) -3- (benzyloxycarbonyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- two Ketone (1)
3.45g (6.2mmol) D-Boc-Lys (Cbz)-D-Trp-OBzl 150mL ethyl acetate is dissolved.What is obtained is molten After liquid is washed three times with the sodium bicarbonate aqueous solution that concentration is 5%, 12h, which is stirred at room temperature, in ethyl acetate solution keeps colorless solid abundant It is precipitated.Filter out 1.8g (51%) title compound.ESI-MS(m/e):449[M+H]+。
Embodiment 4 prepares (3R, 6R) -3- (amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (2)
Past 1.9g (4.2mmol) (3R, 6R) -3- (benzyloxycarbonyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2, Add 200mgPd/C in 5- diketone (1) and the solution of the anhydrous n,N-Dimethylformamide of 20mL (DMF), is passed through H2, it is stirred at room temperature anti- Answer 48h.Pd/C is filtered off, filtrate decompression is concentrated to give 1.2g (92%) title compound, is colourless powder.ESI-MS(m/e)：315 [M+H]+Embodiment 5 prepares Amino-n-hexanoic acid methyl esters
Into 40mL methanol be added dropwise 5.6mL thionyl chloride, activate 30min after, be added 2.62g (20mmol) amino just oneself 12h is stirred at room temperature in acid.Dry methanol is added in reaction solution decompressing and extracting with water pump under 37 DEG C of tepidarium stirrings of compound of reaction Water pump decompressing and extracting is used after dissolution, is repeated 3 times；Anhydrous ether is added to be suspended, lower decompressing and extracting is stirred in 37 DEG C of tepidariums, repeats 3 It is secondary, obtain 2.72g (95%) title compound.ESI-MS(m/e):145[M+H]+
Embodiment 6 prepares Boc-Asp (OMe)-Amino-n-hexanoic acid methyl esters (3a)
Using the method for embodiment 1 from 1330mg (5.0mmol) Boc-Aps (OMe) and 720mg (5.0mmol) amino just Methyl caproate obtains 1320mg (91%) title compound, is colorless solid.ESI-MS(m/e):375[M+H]+。
Embodiment 7 prepares Boc-Glu (OMe)-Amino-n-hexanoic acid methyl esters (3b)
Using the method for embodiment 1 from 1300mg (5.0mmol) Boc-Glu (OMe) and 720mg (5.0mmol) amino just Methyl caproate obtains 1520mg (78%) title compound, is colorless solid.ESI-MS(m/e):389[M+H]+。
Embodiment 8 prepares Boc-Asp (OMe) Amino-n-hexanoic acid (4a)
By 1.11g (3.0mmol) Boc-Asp (OMe)-Amino-n-hexanoic acid methyl esters (3a) 20mL CH3OH dissolution.It obtains Solution NaOH aqueous solution (2M) be added under ice bath stirring adjust pH value to 12, ice bath stirring reacts 6h.Under ice bath stirring, instead Liquid is answered to be saturated KHSO4Solution adjusts pH value to 7, obtains solution reduced pressure.Residue 5%KHSO4Aqueous solution adjusts pH value To 2.Obtained solution is extracted with ethyl acetate 3 times, then ethyl acetate solution is washed till neutrality with saturation NaCl aqueous solution.Acetic acid Methacrylate layer anhydrous Na2SO4Dry 12h, filtering, filtrate decompression are concentrated to dryness.1.32g title compound is obtained, is yellowish sugar colour Slurry.ESI-MS(m/e):361[M+H]+。
Embodiment 9 prepares Boc-Glu (OMe)-Amino-n-hexanoic acid (4b)
It is obtained using the method for embodiment 8 from 1.15g (3.0mmol) Boc-Glu (OMe)-Amino-n-hexanoic acid methyl esters (3b) 1.38g title compound is faint yellow syrup.ESI-MS(m/e):375[M+H]+。
Embodiment 10 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Boc-Asp (OMe)-amino) -6- (indoles - 3- methyl)-piperazine-2,5-dione (5a)
Using the method for embodiment 1 from Boc-Asp (OMe)-Amino-n-hexanoic acid (4a) of the faint yellow syrup of 1320mg and 940mg (3.0mmol) (3R, 6R) -3- amino normal-butyl -6- (indoles -3- methyl)-piperazine-2,5-dione (2) obtains 700mg (36%) title compound is colorless solid.ESI-MS(m/e):655[M+H]+；1H NMR(300MHz,DMSO-d6):δ/ppm =10.882 (s, 1H), 8.050 (d, J=1.8Hz, 1H), 7.940 (d, J=1.8Hz, 1H), 7.795 (m, 1H), 7.573 (m, 2H), 7.296 (d, J=8.1Hz, 1H), 7.032 (m, 3H), 6.924 (t, J=7.2Hz, 3H), 4.258 (m, 1H), 4.108 (m,1H),3.571(m,3H),3.496(m,1H),3.246(dd,J1=14.1Hz, J2=3.9Hz, 1H), 3.004 (m, 3H), 2.736 (m, 3H), 1.988 (t, J=7.5Hz, 1H), 1.420 (m, 13H), 1.166 (m, 2H), 0.959 (m, 3H), 0.565 (m,3H)。
Embodiment 11 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Boc-Glu (OMe)-amino) -6- (indoles - 3- methyl)-piperazine-2,5-dione (5b)
Using the method for embodiment 1 from Boc-Glu (OMe)-Amino-n-hexanoic acid (4b) of the faint yellow syrup of 1380mg and 940mg (3.0mmol) (3R, 6R) -3- amino normal-butyl -6- (indoles -3- methyl)-piperazine-2,5-dione (2) obtains 440mg (22%) title compound is colorless solid.ESI-MS(m/e):669[M+H]+；1H NMR(300MHz,DMSO-d6):δ/ppm =10.874 (s, 1H), 8.035 (m, 2H), 7.934 (s, 1H), 7.796 (m, 1H), 7.564 (m, 2H), 7.302 (m, 1H), 7.040 (m, 2H), 6.941 (t, J=7.5Hz, 1H), 6.836 (d, J=8.4Hz, 1H), 4.114 (m, 1H), 3.886 (m, 1H),3.581(s,3H),3.504(m,1H),3.255(dd,J1=14.4Hz, J2=3.9Hz, 1H), 3.032 (m, 3H), 2.758 (m, 2H), 2.297 (t, J=7.5Hz, 2H), 2.007 (t, J=7.2Hz, 2H), 1.850 (m, 1H), 1.730 (m, 1H),1.378(m,13H),1.217(m,2H),0.972(m,3H),0.603(m,3H)。
Embodiment 12 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Boc-Asp- amino) -6- (indoles -3- first Base)-piperazine-2,5-dione (6a)
Using the method for embodiment 11 by 0.65g (1.0mmol) (3R, 6R) -3- (Boc-Asp (the OMe)-positive hexanoyl of amino Base amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (5a) saponification obtain the faint yellow syrup of 0.80g be title Compound.ESI-MS(m/e):641[M+H]+。
Embodiment 13 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Boc-Glu- amino) -6- (indoles -3- first Base)-piperazine-2,5-dione (6b)
Using the method for embodiment 11 by 0.67g (1.0mmol) (3R, 6R) -3- (Boc-Glu (the OMe)-positive hexanoyl of amino Base amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (5b) saponification obtain the faint yellow syrup of 0.87g be title Compound.ESI-MS(m/e):655[M+H]+。
Embodiment 14 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Asp- amino) -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (7a)
According to the method for embodiment 3 from (3R, 6R) -3- (positive caproyl ammonia of Boc-Asp- amino of the faint yellow syrup of 800mg Base normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone (6a) obtains 80mg (15%) title compound, and it is colourless solid Body.ESI-MS(m/e):543[M+H]+；Mp:161–163℃；(C=0.1, H2O)；1H NMR (300MHz,DMSO-d6):δ/ppm=10.995 (s, 1H), 8.274 (m, 1H), 8.065 (m, 1H), 7.963 (s, 1H), 7.644 (m, 1H), 7.576 (d, J=7.8Hz, 1H), 7.312 (d, J=7.5Hz, 1H), 7.044 (m, 3H), 6.927 (m, 1H),4.115(m,1H),3.424(m,2H),3.043(m,4H),2.750(m,2H),2.405(m,1H),2.205(m,1H), 2.016(m,2H),1.432(m,4H),1.239(m,3H),0.972(m,3H),0.590(m,3H)。
Embodiment 15 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Glu- amino) -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (7b)
According to the method for embodiment 3 from (3R, 6R) -3- (positive caproyl ammonia of Boc-Glu- amino of the faint yellow syrup of 870mg Base normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone (6b) obtains 440mg (87%) title compound, and it is colourless solid Body.ESI-MS(m/e):557[M+H]+；Mp:141–143℃；(C=0.1, H2O)；1H NMR (300MHz,DMSO-d6):δ/ppm=10.968 (s, 1H), 8.074 (m, 2H), 7.962 (s, 1H), 7.626 (t, J= 5.1Hz, 1H), 7.571 (d, J=7.8Hz, 1H), 7.298 (m, 1H), 7.028 (m, 2H), 6.932 (m, 1H), 4.108 (m, 1H), 3.495 (m, 1H), 3.296 (m, 1H), 3.223 (d, J=3.9Hz, 1H), 3.029 (m, 4H), 2.741 (m, 2H), 2.241 (t, J=7.2Hz, 2H), 2.008 (t, J=7.2Hz, 2H), 1.772 (m, 2H), 1.427 (m, 4H), 1.217 (m, 3H),0.957(m,3H),0.586(m,3H)。
Embodiment 16 prepares (3R, 6R) -3- (Boc- aminocaProyl fourth amino) -6- (indoles -3- methyl)-piperazine -2, 5- diketone (8)
Using the method for embodiment 1 from 0.97g (4.2mmol) Boc- aminocaproic acid and 1.9g (3.5mmol) (3R, 6R)- 3- fourth amino -6- (indoles -3- methyl)-piperazine -2,5- diketone (2) obtains 0.641g (21%) title compound, is colourless solid Body.ESI-MS(m/e):528[M+H]+；1H NMR(300MHz,DMSO-d6):δ/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)。
Embodiment 17 prepares (3R, 6R) -3- (aminocaProyl fourth amino) -6- (indoles -3- methyl)-piperazine -2,5- two Ketone (9)
Using the method for embodiment 3 from 2.21g (4mmol) (3R, 6R) -3- (Boc- aminocaProyl fourth amino) -6- (Yin Diindyl -3- methyl)-piperazine -2,5- diketone (7) obtains 1.45g (82%) title compound, and it is colourless powder.ESI-MS(m/e): 428[M+H]+；1H NMR(300MHz,DMSO-d6):δ/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)。
Embodiment 18 measures compound 7a, the activity of resisting tumor metastasis of b
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.
10min is impregnated with 75% ethyl alcohol, knurl is removed in disinfection on superclean bench.Select well-grown tumor group It is woven in sterilized petri dishes and shreds, be placed in the tissue homogenizer of glass manufacture.It is again 1 to 3 (g than physiological saline volume by tumor mass Than mL) ratio heating degree be 4 DEG C of physiological saline, be lightly ground and cell suspension be made.Cell suspension crosses 200 mesh cell sieve systems Single cell suspension.With the cell density of physiological saline tune single cell suspension to 1.5 × 107A/mL.The dyeing of placenta indigo plant makes living thin Born of the same parents count>95%.Left hand fixes inbred strais C57BL/6 male mice, is disappeared with 75% Mice Hepatocytes Injured by Ethanol right fore skin of axillary fossa Poison.The right hand holds 1mL asepsis injector and tumor cell suspension, every injection 0.2mL is subcutaneously injected in mouse armpit.It is small after inoculation 10 days Mouse grows the tumour of diameter 4-5mm, is grouped Mice Inoculated at random by the gross tumor volume measured.Every group of 12 mouse.Inoculation is swollen 11st day mouse of tumor or the normal saline solution (dosage be 20 μm ol/kg/ days) for taking orally generally acknowledged anti tumor translocation peptide RGDS Or the normal saline solution (dosage be 0.5 μm ol/kg/ days) or the physiology salt of oral administration of compound 9 of oral administration of compound 7a, b are water-soluble Liquid (dosage be 5 μm ol/kg/ days) or oral normal saline (dosage is 10mL/kg/ days) give 1 medicine, successive administration 12 daily It, measures and records gross tumor volume every three days.The next day measurement knurl of last time administration is long-pending, at etherization cervical dislocation Extremely, it takes the tumour of mouse to weigh, take the lung of mouse and calculates the burrknot number of tumour lung transfer.It is united with t inspection to data Meter analysis.It the results are shown in Table 1.Neoplasm lung metastasis is not only effectively inhibited in 0.5 μm of ol/kg dosages for Compound 7a, b, but also living Property with their high 40 times RGDS of dose ratio and their high 10 times compounds 9 of dose ratio there is no significant difference.These data Show that the present invention has significant technical effect.
The activity of resisting tumor metastasis of table 1 compound 7a, b
A) with physiological saline ratio p<0.01, compare p with RGDS and compound 9>0.05；N=11
Embodiment 19 measures compound 7a, the neoplasm growth activity of b
Adriamycin, compound 9 and compound 7a, b are used into physiological saline solution before measurement, are administered for S180 mouse. It is taken in gnotobasis and is inoculated in male ICR mouse 10 days eugonic S180 ascitic tumor fluids, with normal saline dilution at (1: 2) liquid is sufficiently mixed, and by 0.2% Trypan Blue of tumor cell suspension Fresh, white blood cell count(WBC) is pressed after mixing Method counts, and dye blue person is dead cell, and tinter is not living cells.By viable count/4 in cell concentration=4 block plaids × 104× extension rate=cell number/mL calculates cell density, by cell survival rate=viable count/(viable count+dead cell Number) × 100% calculating cell survival rate.It is 2.0 × 10 that density, which is made, with homogenate method in tumor liquid by survival rate greater than 90%7A/ The cell suspension of mL.The cell suspension inoculation is subcutaneous (0.2mL/ is only) in mouse right axillary, manufactures S180 tumor-bearing mice.Inoculation is for 24 hours The normal saline solution (dosage is 2 μm of ol/kg/ days g) or daily oral of adriamycin is injected intraperitoneally in S180 tumor-bearing mice daily afterwards The normal saline solution (dosage be 5 μm ol/kg/ days) of compound 9 or the daily normal saline solution (agent of oral administration of compound 7a, b Amount for 0.5 μm ol/kg/ days).It is administered once a day, successive administration 12 days.The next day measurement knurl product of last time administration, second Ehterization cervical dislocation is put to death, and is then fixed mouse right axillary tumor location with tweezers, is cut off skin blunt separation tumour and claim Weight.Curative effect is indicated with knurl weight (mean value ± SD g), and data are examined with t and variance analysis.It the results are shown in Table 2.In 0.5 μm of ol/kg agent Lower compound 7a is measured, b not only effectively inhibits tumour growth, but also their high 10 times compounds 9 do not have activity with dose ratio Significant difference.These statistics indicate that, the present invention has significant technical effect.
The influence of table 2 compound 7a, b to S180 mice tumors grew
A) with physiological saline ratio p<0.01, compare p with compound 9>0.05；N=12.

Claims (4)

1. (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (indoles -3- methyl)-piperazine -2,5- two of following formula Ketone,
AA is L-Asp residue and L-Glu residue in formula.
Claim 2. (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (indoles -3- methyl)-piperazine -2,5- The preparation method of diketone, this method include：
(1) D-Boc-Lys (Cbz) and D-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 containing 5% sodium bicarbonate aqueous solution saturation ethyl acetate middle ring symphysis at (3R, 6R) -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, 6R) -3- (amino normal-butyl) -6- (indoles -3- methyl)-piperazine - 2,5- diketone (2)；
(5) Amino-n-hexanoic acid methyl esters and Boc-AA are condensed to obtain Boc-AA- Amino-n-hexanoic acid methyl esters (3a, b), and AA is L-Asp (OMe) Residue and L-Glu (OMe) residue；
(6) compound 3a, b piptonychia ester obtain Boc-AA (OMe)-Amino-n-hexanoic acid (4a, b), and AA is L-Asp residue and L-Glu Residue；
(7) compound 2 and compound 4a, b are condensed (3R, 6R) -3- (positive positive fourth of caproyl amino of Boc-AA (OMe)-amino Base) -6- (indoles -3- methyl)-piperazine -2,5- diketone (5a, b), AA is L-Asp residue and L-Glu residue；
(8) compound 5a, b piptonychia ester obtain (3R, 6R) -3- (the positive caproyl amino normal-butyl of Boc-AA- amino) -6- (indoles - 3- methyl)-piperazine -2,5- diketone (6a, b), AA is L-Asp residue and L-Glu residue；
(9) compound 6a, b take off Boc in the ethyl acetate solution of hydrogen chloride and obtain (3R, 6R) -3- (positive caproyl ammonia of AA- amino Base normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone (7a, b), AA is L-Asp residue and L-Glu residue.
3. (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (indoles -3- methyl)-piperazine-of claim 1 2,5- diketone is preparing the application in medicine for anti transfer of tumor.
4. (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (indoles -3- methyl)-piperazine-of claim 1 2,5- diketone application in preparation of anti-tumor drugs.
CN201710363811.1A 2017-05-22 2017-05-22 3R-indolylmethyl-6R-acidic amino acid modified piperazine-2, 5-dione, and synthesis, activity and application thereof Expired - Fee Related CN108929369B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105254709A (en) * 2014-07-10 2016-01-20 首都医科大学 Imidazopyridine-6-formyl-Met-AA-OBzl, synthesis, activity and applications thereof
CN105294660A (en) * 2014-06-10 2016-02-03 首都医科大学 3R, 6S-3, 6-disubstituted piperazine-2, 5-diketone, preparation therefor and application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105294660A (en) * 2014-06-10 2016-02-03 首都医科大学 3R, 6S-3, 6-disubstituted piperazine-2, 5-diketone, preparation therefor and application thereof
CN105254709A (en) * 2014-07-10 2016-01-20 首都医科大学 Imidazopyridine-6-formyl-Met-AA-OBzl, synthesis, activity and applications thereof

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