CN108976210A - Piperazine -2,5- diketone of 3S- indole methyl -6R- ArAA modification, synthesis, activity and application - Google Patents

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

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CN108976210A
CN108976210A CN201710405372.6A CN201710405372A CN108976210A CN 108976210 A CN108976210 A CN 108976210A CN 201710405372 A CN201710405372 A CN 201710405372A CN 108976210 A CN108976210 A CN 108976210A
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piperazine
methyl
indoles
amino
butyl
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CN108976210B (en
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赵明
彭师奇
吴建辉
王玉记
胡西
胡明芳
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Capital Medical University
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    • 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
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Abstract

Piperazine -2,5- diketone of 3S- indole methyl -6R- ArAA modification, synthesis, activity and application.The invention discloses (3S, 6R) -3- of following formula (AA- aminocaProyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (AA is L-Phe residue and L-Tyr 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 3S- indole methyl -6R- ArAA modification, synthesis, Activity and application
Technical field
The present invention relates to (3S, 6R) -3- (AA- aminocaProyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine -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, and It is related to their anti-inflammatory activity activity, thus is preparing anti-tumor drug the present invention relates to them, medicine for anti transfer of tumor and anti- Application in scorching 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 diketone piperazine of R- configuration again Piperazine can inhibit the tumour of C57BL/6 mouse to Lung metastases under 5 μm of ol/kg dosage.But minimum effective dose is 5 μm of ol/ kg.In order to reduce minimum effective dose, inventor expands various modifications to R, the fourth amino of the diketopiperazine of S- configuration.By It explores within 3 years, the discovery acylated R of ArAA (L-Phe and L-Tyr) acylated aminocaproic acid, the diketopiperazine of S- configuration Fourth amino can not only make the minimum effective dose of anti-tumor metastasis be down to 0.5 μm of ol/kg, and can make it is antitumor and it is anti-inflammatory most Low 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, effectively 10 times of dosage reduction, which shows this structural modification, technical effect outstanding.According to these discoveries, this hair is inventors herein proposed It is bright.
Summary of the invention
First content of the invention is to provide (3S, 6R) -3- (AA- aminocaProyl amino normal-butyl) -6- of following formula (indoles -3- methyl)-piperazine-2,5-dione (AA is L-Phe residue and L-Tyr residue in formula).
Second content of the invention is to provide (3S, 6R) -3- (AA- aminocaProyl amino normal-butyl) -6- (indoles - 3- methyl)-piperazine -2,5- diketone (AA be L-Phe residue and L-Tyr residue) synthetic method, this method comprises:
(1) L-Boc-Lys (Cbz) and D-Trp-OBzl are condensed to obtain Boc-Lys (Cbz)-D-Trp-OBzl；
(2) Boc-Lys (Cbz)-D-Trp-OBzl de- Boc in the ethyl acetate solution of hydrogen chloride obtains Lys (Cbz)-D- Trp-OBzl；
(3) the ethyl acetate solution middle ring symphysis that Lys (Cbz)-D-Trp-OBzl is saturated in 5% sodium bicarbonate aqueous solution at (3S, 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 (3S, 6R) -3- amino normal-butyl -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (2)；
(5) compound 2 and Boc- Amino-n-hexanoic acid are condensed (3S, 6R) -3- (positive positive fourth of caproyl amino of Boc- amino Base) -6- (indoles -3- methyl)-piperazine-2,5-dione (3)；
(6) the de- Boc in the ethyl acetate solution of hydrogen chloride of compound 3 obtains (3S, 6R) -3- (positive caproyl ammonia of amino Base normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (4)；
(7) compound 4 and Boc-AA (AA is L-Phe residue and L-Tyr residue) are condensed (3S, 6R) -3- (Boc-AA- AminocaProyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (5a, b).
(8) compound 5a, b take off Boc in the ethyl acetate solution of hydrogen chloride and obtain (3S, 6R) -3- (AA- aminohexanoyl Base amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (6a, b) (AA is L-Phe residue and L-Tyr residue).
Third content of the invention is evaluation (3S, 6R) -3- (AA- aminocaProyl amino normal-butyl) -6- (indoles - 3- methyl)-piperazine-2,5-dione (AA is L-Phe residue and L-Tyr residue) inhibition C57BL/6 mouse anti-lung cancer transfer work Property.
4th content of the invention is evaluation (3S, 6R) -3- (AA- aminocaProyl amino normal-butyl) -6- (indoles - 3- methyl)-piperazine-2,5-dione (AA be L-Phe residue and L-Tyr residue) is to the inhibiting effect of ICR mouse inflammation.
5th content of the invention is evaluation (3S, 6R) -3- (AA- aminocaProyl amino normal-butyl) -6- (indoles - 3- methyl) the inhibition application of-piperazine-2,5-dione (AA is L-Phe residue and L-Tyr residue) to S180 mice tumors grew.
Detailed description of the invention
Fig. 1 (3S, 6R) -3- (AA- aminocaProyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione AA is L-Phe residue in synthetic route the 5a and 6a of (6a-b)；AA is L-Tyr residue in 5b and 6b；I) dicyclohexyl carbon two Imines (DCC), I-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), tetrahydrofuran (THF)；Ii) the acetic acid of hydrogen chloride Ethyl ester solution；Iii) ethyl acetate, 5% sodium bicarbonate；Iv) dimethylformamide (DMF), Pd/C, H2。
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)-D-Trp-OBzl
4.56g (10mmol) L-Boc-Lys (Cbz) is suspended in 100mL anhydrous tetrahydro furan (THF), under ice bath Successively add 1.35g (10mmol) 1- hydroxy benzo triazole (HOBt) and 2.47g (12mmol) dicyclohexyl carbon into suspension Diimine (DCC), then stirs 30min.Later, add 3.31g (10mmol) D-Trp-OBzl.N- is added dropwise in compound of reaction Methyl morpholine (NMM) adjusts pH to 9.Reaction mixture first stirs 1h under ice bath, then 12h is stirred at room temperature.Reaction mixture mistake Filter, filtrate decompression concentration, residue 150mL ethyl acetate solution dissolve.Obtained ethyl acetate solution successively uses 5% KHSO4Aqueous solution is washed 3 times, and saturation NaCl aqueous solution is washed 3 times.Ethyl acetate layer anhydrous Na2SO4Dry 12h, filtering, filtrate subtract Pressure is concentrated to dryness.Obtained yellow syrup object is purified by silica gel column chromatography (CH2Cl2/CH3OH, 100:1) obtain 4.95 g (87%) title compound is colorless solid.ESI-MS(m/e):657[M+H]+。
Embodiment 2 prepares Lys (Cbz)-D-Trp-OBzl
The acetic acid second of 3.28g (5mmol) Boc-Lys (Cbz)-D-Trp-OBzl and 52mL hydrogen chloride under ice bath and stirring Ester solution is slowly mixed together.Obtained solution stirs 5h in ice bath.Later, reaction mixture is concentrated under reduced pressure.Residue 50mL Anhydrous ethyl acetate dissolution, obtained solution are concentrated under reduced pressure.The operation is in triplicate.Residue is sufficiently washed with anhydrous ether, is obtained It is colourless powder to 2.36g (85%) title compound.ESI-MS(m/e):557[M+H]+。
Embodiment 3 prepares (3S, 6R) -3- (benzyloxycarbonyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- Diketone (1)
2.22g (4mmol) L-Lys (Cbz)-D-Trp-OBzl 100ml ethyl acetate is dissolved, extremely with triethylamine tune pH 9,80 DEG C are stirred 100 hours.Filter out colorless solid.Filtrate decompression concentration, residue silica gel column chromatography purify (CH2Cl2/ CH3OH, 100/1).It there are 1.32g (65%) title compound.ESI-MS(m/e):449[M+H]+。
Embodiment 4 prepares (3S, 6R) -3- amino normal-butyl -6- (indoles -3- methyl)-piperazine-2,5-dione (2)
Toward 1.30g (2.9mmol) (3S, 6R) -3- (benzyloxycarbonyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine - In 2,5- diketone (1) and the solution of the anhydrous n,N-Dimethylformamide of 20mL (DMF) plus 200mg Pd/C, room temperature lead to H248h。 Pd/C is filtered off, filtrate decompression is concentrated to give 0.51g (56%) title compound, is colourless powder.ESI-MS (m/e): 315 [M+H ]+。
Embodiment 5 prepares Boc- Amino-n-hexanoic acid
Add 2.83g (Boc) into the solution of 1.311g (10mmol) Amino-n-hexanoic acid and 30mL distilled water2O and 30mL bis- The solution of six ring of oxygen, 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, it is during which continuous Decompression pumping.Reaction mixture KHSO4Aqueous solution adjusts pH to 7, is concentrated under reduced pressure.Remaining solution continues to use KHSO4It adjusts PH to 2 is extracted with 100mL ethyl acetate again.Ethyl acetate layer anhydrous Na SO4Dry 8h.Filtering, filtrate decompression concentration, obtains 2.18g (94%) title compound.ESI-MS(m/e):232[M+H]+。
Embodiment 6 prepares (3S, 6R) -3- (the positive caproyl amino normal-butyl of Boc- amino) -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (3)
Using embodiment 1 method from 0.97g (4.2mmol) Boc- Amino-n-hexanoic acid and 1.9g (3.5mmol) (3S, 6R) -3- amino normal-butyl -6- (indoles -3- methyl)-piperazine -2,5- diketone (2) obtains 2.21g (71%) title compound, is Colorless solid.ESI-MS (m/z): 528 [M+H]+.1H-NMR(300MHz,DMSO-d6): δ/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).
Embodiment 7 prepares (3S, 6R) -3- (the positive caproyl amino normal-butyl of amino) -6- (indoles -3- methyl)-piperazine - 2,5- diketone (4)
Using the method for embodiment 2 from 0.3g (0.5mmol) (3S, 6R) -3- (positive positive fourth of caproyl amino of Boc- amino Base) -6- (indoles -3- methyl)-piperazine -2,5- diketone (3) obtains 0.14g (58%) title compound, and it is colourless powder. 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):δ/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)。
Embodiment 8 prepares (3S, 6R) -3- (Boc-Phe- aminocaProyl fourth amino) -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (5a)
Using the method for embodiment 1 from 0.125g (0.5mmol) Boc-Phe and 0.258g (0.6mmol) (3S, 6R) -3- It is titled that (aminocaProyl fourth amino) -6- (indoles -3- methyl)-piperazine-2,5-dione (4) obtains 0.145g (45.60%) Object is closed, is colorless solid.ESI-MS (m/z): 697 [M+Na]+；1H NMR(300MHz,DMSO-d6): δ/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).
Embodiment 9 prepares (3S, 6R) -3- (Boc-Tyr- aminocaProyl fourth amino) -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (5b)
Using the method for embodiment 1 from 0.509g (1.8mmol) Boc-Tyr and 0.7g (1.5mmol) (3S, 6R) -3- (ammonia Base caproyl fourth amino) -6- (indoles -3- methyl)-piperazine-2,5-dione (4) obtains 0.343g (32.92%) title compound Object is colorless solid.ESI-MS (m/z): 713 [M+Na]+；1H NMR(300MHz,DMSO-d6): δ/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).
Embodiment 10 prepares (3S, 6R) -3- (Phe- aminocaProyl fourth amino) -6- (indoles -3- methyl)-piperazine -2, 5- diketone (6a)
According to the method for embodiment 2 from 0.675g (1mmol) (3S, 6R) -3- (Boc-Phe- aminocaProyl fourth amino) - 6- (indoles -3- methyl)-piperazine -2,5- diketone (5a) obtains 0.354mg (61.67%) title compound, is 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):δ/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).
Embodiment 11 prepares (3S, 6R) -3- (Tyr- aminocaProyl fourth amino) -6- (indoles -3- methyl)-piperazine -2, 5- diketone (6b)
According to the method for embodiment 2 from 0.827g (1.2mmol) (3S, 6R) -3- (Boc-Tyr- aminocaProyl fourth ammonia Base) -6- (indoles -3- methyl)-piperazine -2,5- diketone (5b) obtains 0.302g (42%) title compound, and it is 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):δ/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)。
Embodiment 12 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 after inoculation 10 days Mice Inoculated is grouped by the tumour of 4-5mm at random by the gross tumor volume measured.Every group of 12 mouse.The 11st day of inoculated tumour Mouse or the normal saline solution (dosage be 20 μm ol/kg/ days) or oral chemical combination for taking orally generally acknowledged anti tumor translocation peptide RGDS The normal saline solution (dosage be 0.5 μm ol/kg/ days) of object 6a, b or the normal saline solution (dosage 5 of oral administration of compound 4 μm ol/kg/ days) or oral normal saline (dosage is 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 4 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=12
Embodiment 13 measures compound 6a, the neoplasm growth activity of b
Adriamycin, compound 4 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 4 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 activity is gone back with their high 10 times compounds 4 of dose ratio By force.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 4 than p < 0.05；N=12.
Embodiment 14 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 (42 ± 3g 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 is 1.11 mmol/kg), (dosage is 0.5 μm of ol/ for 4 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 4 or oral administration of compound 6a, c.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 agent Amount does not have significant difference than their high 10 times compounds 4.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 4 than p>0.05；N=12.

Claims (5)

1. (3S, 6R) -3- (AA- aminocaProyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- two of following formula Ketone, AA is L-Phe residue and L-Tyr residue in formula,
2. (3S, 6R) -3- (AA- aminocaProyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2 of claim 1, The preparation method of 5- diketone, this method comprises:
(1) L-Boc-Lys (Cbz) and D-Trp-OBzl are condensed to obtain Boc-Lys (Cbz)-D-Trp-OBzl；
(2) Boc-Lys (Cbz)-D-Trp-OBzl de- Boc in the ethyl acetate solution of hydrogen chloride obtains Lys (Cbz)-D-Trp- OBzl；
(3) the ethyl acetate solution middle ring symphysis that Lys (Cbz)-D-Trp-OBzl is saturated in 5% sodium bicarbonate aqueous solution at (3S, 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 (3S, 6R) -3- amino normal-butyl -6- (indoles -3- methyl)-piperazine -2, 5- diketone (2)；
(5) compound 2 and Boc- Amino-n-hexanoic acid are condensed (3S, 6R) -3- (the positive caproyl amino normal-butyl of Boc- amino) -6- (indoles -3- methyl)-piperazine-2,5-dione (3)；
(6) compound 3 takes off Boc in the ethyl acetate solution of hydrogen chloride and obtains (3S, 6R) -3- (the positive caproyl amino of amino is just Butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (4)；
(7) compound 4 and Boc-AA (AA is L-Phe residue and L-Tyr residue) are condensed (3S, 6R) -3- (Boc-AA- amino Caproyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (5a, b)；
(8) compound 5a, b take off Boc in the ethyl acetate solution of hydrogen chloride and obtain (3S, 6R) -3- (AA- aminocaProyl ammonia Base normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (6a, b).
3. (3S, 6R) -3- (AA- aminocaProyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2 of claim 1, 5- diketone is preparing the application in medicine for anti transfer of tumor.
4. (3S, 6R) -3- (AA- aminocaProyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2 of claim 1, 5- diketone application in preparation of anti-tumor drugs.
5. (3S, 6R) -3- (AA- aminocaProyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2 of claim 1, The application in preparing anti-inflammatory drugs of 5- diketone.
CN201710405372.6A 2017-05-31 2017-05-31 3S-indolylmethyl-6R-aromatic amino acid modified piperazine-2, 5-dione, and synthesis, activity and application thereof Expired - Fee Related CN108976210B (en)

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JPS61112060A (en) * 1984-11-02 1986-05-30 Fujisawa Pharmaceut Co Ltd Piperazine compound
WO2006132594A1 (en) * 2005-06-10 2006-12-14 Viogard Ab Novel dipodazine compounds and applications
CN102234278A (en) * 2010-04-26 2011-11-09 首都医科大学 (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives, and synthesis method and application thereof
CN105218526A (en) * 2014-06-10 2016-01-06 首都医科大学 (3S, 6S)-3,6 disubstituted piperazine-2,5-diketone, its preparation and therapeutic action
CN105272968A (en) * 2014-06-10 2016-01-27 首都医科大学 (3S,6R)-3,6-disubstitutedpiperazine-2,5-dione, and preparation and application 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

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* Cited by examiner, † Cited by third party
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JPS61112060A (en) * 1984-11-02 1986-05-30 Fujisawa Pharmaceut Co Ltd Piperazine compound
WO2006132594A1 (en) * 2005-06-10 2006-12-14 Viogard Ab Novel dipodazine compounds and applications
CN102234278A (en) * 2010-04-26 2011-11-09 首都医科大学 (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives, and synthesis method and application thereof
CN105218526A (en) * 2014-06-10 2016-01-06 首都医科大学 (3S, 6S)-3,6 disubstituted piperazine-2,5-diketone, its preparation and therapeutic action
CN105272968A (en) * 2014-06-10 2016-01-27 首都医科大学 (3S,6R)-3,6-disubstitutedpiperazine-2,5-dione, and preparation and application 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

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