CN109456311A - Piperazine -2,5- diketone of 3R- indole methyl -6R- ArAA modification, synthesis, activity and application - Google Patents

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

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CN109456311A
CN109456311A CN201710794235.6A CN201710794235A CN109456311A CN 109456311 A CN109456311 A CN 109456311A CN 201710794235 A CN201710794235 A CN 201710794235A CN 109456311 A CN109456311 A CN 109456311A
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amino
piperazine
methyl
boc
indoles
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CN109456311B (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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    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D403/14—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 three or more hetero rings

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-Phe residue and L-Trp residue in formula).It discloses their preparation method, disclose their anti-tumor activity, disclose their activity of resisting tumor metastasis, and their anti-inflammatory activity activity is disclosed, thus anti-tumor drug is being prepared the invention discloses them, the application in medicine for anti transfer of tumor and anti-inflammatory drug.

Description

Piperazine -2,5- diketone of 3R- indole methyl -6R- ArAA 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, is related to their activity of resisting tumor metastasis, with And be related to their anti-inflammatory activity activity, thus preparing anti-tumor drug the present invention relates to them, medicine for anti transfer of tumor and Application in anti-inflammatory drug.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 R, the fourth amino of the diketopiperazine of R- configuration.It was visited by 3 years Rope, the discovery acylated R of aromatic side chain amino acid (L-Phe, L-Tyr and L-Trp) acylated aminocaproic acid, the diketone piperazine of R- configuration The n-butyl amine base of piperazine 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 and anti- Scorching minimum effective dose is all down to 0.5 μm of ol/kg.It disappears because the toxic side effect of drug can be reduced with dosage, institute Showing this structural modification with 10 times of effective dose reduction has technical effect outstanding.According to these discoveries, inventor is proposed The present invention.
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- diketone (AA is L-Phe residue, L-Tyr residue and L-Trp 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-Phe residue and L-Trp residue in formula) synthetic method, this method comprises:
(1) D-Boc-Lys (Cbz) and D-Trp-OBzl are condensed to obtain Boc-Lys (Cbz)-Trp-OBzl；
(2) Boc-Lys (Cbz)-Trp-OBzl de- Boc in the ethyl acetate solution of hydrogen chloride obtains Lys (Cbz)-Trp- OBzl；
(3) Lys (Cbz)-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 Phe residue and Trp residue) be condensed Boc-AA- amino just oneself Sour methyl esters (3a-c)；
(6) compound 3a-c saponification removing methyl esters obtains Boc-AA- Amino-n-hexanoic acid (4a, b)；
(7) compound 2 and compound 4a, b are condensed (3R, 6R) -3- (positive positive fourth of caproyl amino of Boc-AA- amino Base) -6- (indoles -3- methyl)-piperazine-2,5-dione (5a, b) (AA is Phe residue and Trp residue)；
(8) compound 5a-c in the ethyl acetate solution of hydrogen chloride take off Boc obtain (3R, 6R) -3- (AA- amino just oneself Acyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (6a, b) (AA is Phe residue and Trp 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-Phe residue and L-Trp residue) inhibition C57BL/6 mouse anti-lung cancer transfer work Property.
4th 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 be L-Phe residue and L-Trp residue) is to the inhibiting effect of ICR mouse inflammation.
5th 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 be L-Phe residue and L-Trp residue) answers the inhibition of S180 mice tumors grew With.
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-Phe residue in the synthetic route .3a-6a of ketone (6a-c)；AA is L-Trp residue in 3b-6b；I) dicyclohexyl carbon two is sub- Amine (DCC), I-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), tetrahydrofuran (THF)；Ii) the acetic acid second of hydrogen chloride Ester solution；Iii) ethyl acetate, 5% sodium bicarbonate；Iv) dimethylformamide (DMF), Pd/C, H2；V) dicyclohexyl carbon two is sub- Amine (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 Boc-Lys (Cbz)-Trp-OBzl
7.7g (20mmol) Boc-Lys (Cbz) is suspended in 100mL anhydrous tetrahydro furan (THF), under ice bath successively Add 2.7g (20mmol) 1- hydroxy benzo triazole (HOBt) and 5.0g (25mmol) dicyclohexylcarbodiimide into suspension (DCC), 30min is then stirred.Later, add 8.0g (25mmol) Trp-OBzl.N-methylmorpholine is added dropwise in compound of reaction (NMM) pH to 9 is adjusted.Reaction mixture first stirs 1h under ice bath, then 12h is stirred at room temperature.Compound of reaction filtering, filtrate subtract Pressure concentration, residue 150mL ethyl acetate solution dissolve.Obtained ethyl acetate solution successively uses 5%KHSO4Aqueous solution is washed 3 times, saturation NaCl aqueous solution is washed 3 times.Ethyl acetate layer anhydrous Na2SO4Dry 12h, filtering, filtrate decompression are concentrated to dryness.? To yellow syrup object be purified by silica gel column chromatography (CH2Cl2/CH3OH, 100:1) 12.0g (88%) title compound is obtained, be Colorless solid.ESI-MS(m/e):657[M+H]+。
Embodiment 2 prepares Lys (Cbz)-Trp-OBzl
The ethyl acetate of 3.8g (5mmol) Boc-Lys (Cbz)-Trp-OBzl and 52mL hydrogen chloride under ice bath and stirring Solution (4M) is slowly mixed together.Obtained solution stirs 5h in ice bath.Later, reaction mixture is concentrated under reduced pressure.Residue is used The dissolution of 50mL anhydrous ethyl acetate, obtained solution are 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) Lys (Cbz)-Trp-OBzl 150mL ethyl acetate is dissolved.Obtained solution concentration For 5% sodium bicarbonate aqueous solution wash three times after, 12h, which is stirred at room temperature, in ethyl acetate solution is precipitated colorless solid sufficiently.Filter 1.8g (51%) title compound out.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)
Toward 1.9g (4.2mmol) (3R, 6R) -3- (benzyloxycarbonyl group fourth amino) -6- (indoles -3- methyl)-piperazine -2,5- two Add 200mgPd/C in ketone (1) and the solution of the anhydrous n,N-Dimethylformamide of 20mL (DMF), is passed through H2, reaction is stirred at room temperature 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-Phe- Amino-n-hexanoic acid methyl esters (3a)
Using the method for embodiment 1 from 1330mg (5.0mmol) Boc-Phe and 720mg (5.0mmol) Amino-n-hexanoic acid first Ester obtains 1320mg (91%) title compound, is colorless solid.ESI-MS(m/e):391[M+H]+。
Embodiment 7 prepares Boc-Trp- Amino-n-hexanoic acid methyl esters (3b)
Using the method for embodiment 1 from 1520mg (5.0mmol) Boc-Trp and 720mg (5.0mmol) Amino-n-hexanoic acid first Ester obtains 1960mg (91%) title compound, is colorless solid.ESI-MS(m/e):432[M+H]+。
Embodiment 8 prepares Boc-Phe- Amino-n-hexanoic acid (4a)
By 1.17g (3.0mmol) Boc-Phe- Amino-n-hexanoic acid methyl esters (3a) 20mL CH3OH dissolution.Obtained solution NaOH aqueous solution (2M) is added under ice bath stirring and adjusts pH value to 12, ice bath stirring reacts 6h.Under ice bath stirring, reaction solution is used It is saturated KHSO4Solution adjusts pH value to 7, obtains solution reduced pressure.Residue 5%KHSO4Aqueous solution adjusts pH value to 2.? To solution be extracted with ethyl acetate 3 times, then by ethyl acetate solution with saturation NaCl aqueous solution be washed till neutrality.Ethyl acetate layer Use anhydrous Na2SO4Dry 12h, filtering, filtrate decompression are concentrated to dryness.Obtain the title compound of the faint yellow syrup sample of 1.30g. ESI-MS(m/e):379[M+H]+。
The preparation preparation of embodiment 9 Boc-Trp- Amino-n-hexanoic acid (4b)
1.29g (3.0mmol) Boc-Trp- Amino-n-hexanoic acid methyl esters (3c) saponification is obtained using the method for embodiment 8 The faint yellow syrup of 1.5g is title compound.ESI-MS(m/e):421[M+H]+。
Embodiment 10 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Boc-Phe- amino) -6- (indoles -3- first Base)-piperazine-2,5-dione (5a)
Using the method for embodiment 1 from the Boc-Phe- Amino-n-hexanoic acid (4a) and 940mg of the faint yellow syrup of 1300mg (3.0mmol) (3R, 6R) -3- fourth amino -6- (indoles -3- methyl)-piperazine-2,5-dione (2) obtains 610mg (36%) title Compound is colorless solid.ESI-MS(m/e):575[M+H]+；1H NMR(300MHz,DMSO-d6): δ/ppm=10.879 (m, 1H), 8.052 (d, J=4.8Hz, 1H), 7.947 (d, J=4.8Hz, 1H), 7.846 (t, J=5.4Hz, 1H), 7.576 (m,2H),7.239(m,6H),7.035(m,2H),6.901(m,2H),4.109(m,2H),3.499(m,1H),3.248(dd, J1=4.2Hz, J2=14.4Hz, 1H), 3.027 (m, 3H), 2.899 (dd, J1=4.2Hz, J2=13.5Hz, 1H), 2.740 (m,2H),1.428(m,2H),1.338(m,10H),1.192(m,3H),0.953(m,3H),0.583(m,3H)。
Embodiment 11 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Boc-Trp- amino) -6- (indoles -3- first Base)-piperazine-2,5-dione (5c)
Using the method for embodiment 1 from the Boc-Trp- Amino-n-hexanoic acid (4b) and 940mg of the faint yellow syrup of 1500mg (3.0mmol) (3R, 6R) -3- fourth amino -6- (indoles -3- methyl)-piperazine-2,5-dione (2) obtains 360mg (17%) title Compound is colorless solid.ESI-MS(m/e):714[M+H]+；1H NMR(300MHz,DMSO-d6): δ/ppm=10.871 (s,1H),10.793(s,1H),8.034(s,1H),7.933(s,1H),7.825(m,1H),7.577(m,3H),7.312(m, 2H), 7.027 (m, 6H), 6.708 (d, J=7.8Hz, 1H), 4.114 (m, 2H), 3.503 (m, 1H), 3.250 (dd, J= 3.9Hz, J=14.4Hz, 1H), 3.029 (m, 4H), 2.894 (m, 1H), 2.762 (m, 2H), 2.003 (t, J=6.9Hz, 2H), 1.454(m,2H),1.315(s,10H),1.185(m,4H),0.974(m,3H),0.604(m,3H)。
Embodiment 12 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Phe- amino) -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (6a)
According to the method for embodiment 3 from 300mg (0.5mmol) (3R, 6R) -3- (positive caproyl amino of Boc-Phe- amino Normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone (5a) obtains 220mg (92%) title compound, and it is colourless solid Body.ESI-MS(m/e):574[M+H]+；Mp:127-128℃；=+59.154, (C=0.1, H2O)；1H NMR (300MHz,DMSO-d6): δ/ppm=10.890 (s, 1H), 8.051 (s, 1H), 7.947 (s, 1H), 7.784 (m, 1H), 7.580 (d, J=6.9Hz, 2H), 7.248 (m, 6H), 7.042 (m, 2H), 6.929 (m, 1H), 4.114 (m, 1H), 3.505 (m, 1H), 3.279 (d, J=14.1Hz, 1H), 3.032 (m, 3H), 2.893 (dd, J1=5.1Hz, J2=13.2Hz, 1H), 2.758 (m,2H),2.604(dd,J1=8.1Hz, J2=12.9Hz, 1H), 2.003 (t, J=6.6Hz, 2H), 1.703 (s, 2H), 1.437(m,2H),1.323(m,2H),1.167(m,1H),0.971(m,3H),0.585(m,3H)。
Embodiment 13 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Trp- amino) -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (6b)
According to the method for embodiment 3 from 300mg (0.4mmol) (3R, 6R) -3- (positive caproyl amino of Boc-Trp- amino Normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone (5b) obtains 230mg (93%) title compound, for no toner End.ESI-MS(m/e):614[M+H]+；Mp:145–147℃；=+53.584, (C=0.1, H2O)；1H NMR (300MHz,DMSO-d6): δ/ppm=10.899 (s, 1H), 10.848 (s, 1H), 8.073 (s, 1H), 7.958 (s, 1H), 7.824 (t, J=5.4Hz, 1H), 7.562 (m, 3H), 7.311 (m, 2H), 7.141 (m, 1H), 6.986 (m, 5H), 4.112 (m, 1H),3.497(m,1H),3.398(m,1H),3.249(dd,J1=3.9Hz, J2=14.4Hz, 1H), 3.168 (d, J= 5.4Hz, 1H), 3.023 (m, 4H), 2.724 (m, 2H), 1.996 (t, J=7.2Hz, 2H), 1.720 (s, 2H), 1.392 (m, 4H),1.172(m,2H),0.957(m,3H),0.556(m,3H)。
Embodiment 14 prepares Boc- aminocaproic acid
Add 5.23g (Boc) into the solution of 2.62g (20mmol) aminocaproic acid and 30mL distilled water2O and 30mL dioxy six The solution of ring, obtained reaction solution adjust pH to 9 with the NaOH aqueous solution that concentration is 2N.It is stirred at room temperature for 24 hours, during which constantly depressurizes Pumping.Compound of reaction KHSO4Aqueous solution adjusts pH to 7, and removal dioxane is concentrated under reduced pressure.Remaining solution continues to use KHSO4Adjust pH to 2.Remaining solution is extracted with 100mL ethyl acetate, is water NaSO with nothing4Dry 8h.Filtering, filtrate decompression Concentration, obtains 4.36g (94%) title compound.ESI-MS(m/e):232[M+H]+。
Embodiment 15 prepares (3R, 6R) -3- (Boc- aminocaProyl fourth amino) -6- (indoles -3- methyl)-piperazine -2, 5- diketone (7)
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 (20.6%) title compound, is colourless Solid.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 16 prepares (3R, 6R) -3- (aminocaProyl fourth amino) -6- (indoles -3- methyl)-piperazine -2,5- two Ketone (8)
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 17 measures compound 6a, 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.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 Mouse or the normal saline solution (dosage be 20 μm ol/kg/ days) or oral administration of compound for taking orally generally acknowledged anti tumor translocation peptide RGDS (dosage is 5 μ to the normal saline solution (dosage be 0.5 μm ol/kg/ days) or the normal saline solution of oral administration of compound 8 of 6a, b Mol/kg/ days) or oral normal saline (dosage be 10mL/kg/ days), daily to 1 medicine, successive administration 12 days, every three days Measure and record gross tumor volume.The next day measurement knurl product of last time administration, etherization cervical dislocation are put to death, and the swollen of mouse is taken Tumor weighing takes the lung of mouse and calculates the burrknot number of tumour lung transfer.It is examined with t for statistical analysis to data.As a result see Table 1.Not only effectively inhibit neoplasm lung metastasis in 0.5 μm of ol/kg dosages for Compound 6a, b, and activity and dose ratio they High 40 times of RGDS and their high 10 times compounds 8 of dose ratio do not have significant difference.These statistics indicate that, the present invention has aobvious The technical effect of work.
The activity of resisting tumor metastasis of table 1 compound 6a, b
And physiological saline ratio p<0.01, a) with RGDS and compound 4 than p>0.05；N=11
Embodiment 18 measures compound 6a, the neoplasm growth activity of b
Adriamycin, compound 8 and compound 6a, b are used into physiological saline solution before measurement, are administered for S180 mouse. Taken in gnotobasis and be 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 8 or the daily normal saline solution (agent of oral administration of compound 6a, 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 6a is measured, b not only effectively inhibits tumour growth, but also their high 10 times compounds 8 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 6a, b to S180 mice tumors grew
And physiological saline ratio p<0.01, a) with compound 8 than p>0.05；N=12.
Embodiment 19 measures compound 6a, the anti-inflammatory activity of b
Because mouse ear swelling caused by dimethylbenzene is acknowledged as acute inflammation model, the present invention causes in dimethylbenzene Mouse ear swelling model on measure compound 6a, the therapeutic effect of b.Because aspirin is the positive for treating acute inflammation Medicine, so the present invention selects aspirin for positive control drug.The ring that ICR male mice (20 ± 2g of weight) is 22 DEG C in temperature Border tranquillization 2 days, free water and feed.Later, physiological saline group (dosage is 0.2mL/), aspirin group are randomly divided into (dosage 1.11mmol/kg), (dosage is 0.5 μm of ol/ for 8 groups of compound (dosage is 5 μm of ol/kg) and compound 6a, b group Kg), every group of 12 mouse.Mouse is by place group or oral normal saline or oral aspirin or oral administration of compound when measurement 8 or oral administration of compound 6a, b.After 30min is administered, the left auricle toward mouse uniformly smears 30 μ L dimethylbenzene, and mouse receives after 2h Etherization, the neck that breaks are put to death, and are cut two ears of left and right, are taken round auricle in the same position of two ears with the punch of 7mm, weigh, Two ear swelling differences are found out as swelling.That is swelling=left ear disk weight-auris dextra disk weight.It the results are shown in Table 3.? 0.5 μm of ol/kg dosages for Compound 6a, b not only effectively inhibit mouse ear swelling caused by dimethylbenzene, but also activity and dosage There is no significant difference than their high 10 times compounds 8.These statistics indicate that, the present invention has significant technical effect.
The influence of mouse ear swelling caused by 3 compound 6a, b paraxylene of table
And physiological saline ratio p<0.01, a) with compound 8 than p>0.05；N=12.

Claims (5)

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-Phe residue and L-Trp 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 comprises:
(1) D-Boc-Lys (Cbz) and D-Trp-OBzl are condensed to obtain Boc-Lys (Cbz)-Trp-OBzl；
(2) Boc-Lys (Cbz)-Trp-OBzl de- Boc in the ethyl acetate solution of hydrogen chloride obtains Lys (Cbz)-Trp-OBzl；
(3) Lys (Cbz)-Trp-OBzl is in the saturation ethyl acetate middle ring symphysis containing 5% sodium bicarbonate aqueous solution 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 (AA is Phe residue and Trp residue) are condensed to obtain Boc-AA- Amino-n-hexanoic acid first Ester (3a-c)；
(6) compound 3a-c saponification removing methyl esters obtains Boc-AA- Amino-n-hexanoic acid (4a, b)；
(7) compound 2 and compound 4a, b are condensed (3R, 6R) -3- (the positive caproyl amino normal-butyl of Boc-AA- amino) -6- (indoles -3- methyl)-piperazine-2,5-dione (5a, b) (AA is Phe residue and Trp residue)；
(8) compound 5a-c de- Boc in the ethyl acetate solution of hydrogen chloride obtains (3R, 6R) -3- (positive caproyl of AA- amino Amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (6a, b) (AA is Phe residue and Trp 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.
5. (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (indoles -3- methyl)-piperazine-of claim 1 The application in preparing anti-inflammatory drugs of 2,5- diketone.
CN201710794235.6A 2017-09-06 2017-09-06 3R-indolylmethyl-6R-aromatic amino acid modified piperazine-2, 5-diketone and synthesis, activity and application thereof Active CN109456311B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105503833A (en) * 2014-10-20 2016-04-20 首都医科大学 Indole piperazine dione compound, and preparation and treatment effect thereof
CN106349148A (en) * 2015-07-13 2017-01-25 首都医科大学 Novel indoles compound having anti-tumor metastasis activity and anti-inflammatory activity, as well as synthesis and application of novel indoles compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105503833A (en) * 2014-10-20 2016-04-20 首都医科大学 Indole piperazine dione compound, and preparation and treatment effect thereof
CN106349148A (en) * 2015-07-13 2017-01-25 首都医科大学 Novel indoles compound having anti-tumor metastasis activity and anti-inflammatory activity, as well as synthesis and application of novel indoles compound

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