CN108929320A - Piperazine -2,5- diketone of 3R- indole methyl -6R- oxazolidone modification, synthesis, activity and application - Google Patents

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

Info

Publication number
CN108929320A
CN108929320A CN201710363797.5A CN201710363797A CN108929320A CN 108929320 A CN108929320 A CN 108929320A CN 201710363797 A CN201710363797 A CN 201710363797A CN 108929320 A CN108929320 A CN 108929320A
Authority
CN
China
Prior art keywords
methyl
piperazine
indoles
amino
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201710363797.5A
Other languages
Chinese (zh)
Other versions
CN108929320B (en
Inventor
赵明
彭师奇
王玉记
吴建辉
张筱宜
丛林
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Capital Medical University
Original Assignee
Capital Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Capital Medical University filed Critical Capital Medical University
Priority to CN201710363797.5A priority Critical patent/CN108929320B/en
Publication of CN108929320A publication Critical patent/CN108929320A/en
Application granted granted Critical
Publication of CN108929320B publication Critical patent/CN108929320B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention discloses (3R, 6R) -3- of following formula (the positive caproyl amino normal-butyl of 5S- methyl -2- oxazolidone -4S- Formylamino) -6- (indoles -3- methyl)-piperazine-2,5-diones.It discloses its preparation method, disclose its anti-tumor activity, disclose its activity of resisting tumor metastasis, and its anti-inflammatory activity activity is disclosed, thus anti-tumor drug is being prepared the invention discloses it, the application in medicine for anti transfer of tumor and anti-inflammatory drug.

Description

Piperazine -2,5- diketone of 3R- indole methyl -6R- oxazolidone modification, synthesizes, living Property and application
Technical field
The present invention relates to (3R, 6R) -3- (positive positive fourths of caproyl amino of 5S- methyl -2- oxazolidone -4S- Formylamino Base) -6- (indoles -3- methyl)-piperazine-2,5-dione.It is related to their preparation method, is related to their anti-tumor activity, relates to And their activity of resisting tumor metastasis, and it is related to their anti-inflammatory activity activity, thus that the present invention relates to them is anti-in preparation Tumour medicine, the application in medicine for anti transfer of tumor and 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 the formylated Amino-n-hexanoic acid of 5S- methyl -2- oxazolidone -4S-, the fourth ammonia of the diketopiperazine of R- configuration Base 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-inflammatory minimum to have Effect dosage is all down to 0.5 μm of ol/kg.It disappears because the toxic side effect of drug can be reduced with dosage, effective dose 10 times of reduction, which shows this structural modification, 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- (5S- methyl -2- oxazolidone -4S- formoxyl of following formula The positive caproyl amino normal-butyl of amino) -6- (indoles -3- methyl)-piperazine-2,5-dione.
Second content of the invention is to provide (3R, 6R) -3-, and (5S- methyl -2- oxazolidone -4S- Formylamino is just Caproyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone 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 Cbz-Thr are condensed to obtain Cbz-Thr- Amino-n-hexanoic acid methyl esters (3)；
(6) compound 3 reaches compound 4 and compound 4 cyclization obtains 5S- methyl -2- oxazolidone-on the spot by saponification 4S- Formylamino n-caproic acid (5)；
(7) compound 2 and compound 5 are condensed (3R, 6R) -3- (5S- methyl -2- oxazolidone -4S- Formylamino Positive caproyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (6).
Third content of the invention is that (5S- methyl -2- oxazolidone -4S- Formylamino is just by evaluation (3R, 6R) -3- Caproyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione inhibition C57BL/6 mouse anti-lung cancer transfer activity.
4th content of the invention is that (5S- methyl -2- oxazolidone -4S- Formylamino is just by evaluation (3R, 6R) -3- Caproyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione is to the inhibiting effect of ICR mouse inflammation.
5th content of the invention is that (5S- methyl -2- oxazolidone -4S- Formylamino is just by evaluation (3R, 6R) -3- Caproyl amino normal-butyl) inhibition application of -6- (indoles -3- the methyl)-piperazine-2,5-dione to S180 mice tumors grew.
Detailed description of the invention
Fig. 1 (3R, 6R) -3- (the positive caproyl amino normal-butyl of 5S- methyl -2- oxazolidone -4S- Formylamino) -6- The synthetic route of (indoles -3- methyl)-piperazine-2,5-dione (6)；I) dicyclohexylcarbodiimide (DCC), 1- hydroxy benzo three Azoles (HOBt), N-methylmorpholine (NMM), tetrahydrofuran (THF)；Ii) the ethyl acetate solution of hydrogen chloride；Iii) ethyl acetate, 5% sodium bicarbonate；Iv) dimethylformamide (DMF), Pd/C, H2；V) dicyclohexylcarbodiimide (DCC), 1- hydroxy benzo three Azoles (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, is 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 Cbz-Thr- Amino-n-hexanoic acid methyl esters (3)
Using the method for embodiment 1 from 1270mg (5.0mmol) Boc-Thr and 720mg (5.0mmol) Amino-n-hexanoic acid first Ester obtains 1440mg (83%) title compound, is colorless solid.ESI-MS(m/e):381[M+H]+。
Embodiment 7 prepares 5S- methyl -2- oxazolidone -4S- Formylamino n-caproic acid (5)
By 1.14g (3.0mmol) Cbz-Thr- Amino-n-hexanoic acid methyl esters (3) 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):257[M+H]+。
Embodiment 8 prepares (3R, 6R) -3-, and (the positive caproyl amino of 5S- methyl -2- oxazolidone -4S- Formylamino is just Butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (6)
Using the method for embodiment 1 from the 5S- methyl -2- oxazolidone -4S- Formylamino of the faint yellow syrup of 1300mg N-caproic acid (5) and 940mg (3.0mmol) (3R, 6R) -3- fourth amino -6- (indoles -3- methyl)-piperazine-2,5-dione (2) obtain It is colorless solid to 1120mg (67%) title compound.ESI-MS(m/e):555[M+H]+；Mp:131–133℃；(C=0.1, H2O)；IR(CM-1)：3271.39,3084,2932,1747,1661,1548,1457, 1384,1332,1231,1103,1065,973,743；1H NMR(300MHz,DMSO-d6):δ/ppm=10.855 (d, J= 1Hz, 1H), 8.099 (t, J=5Hz, 1H), 7.995 (d, J=2Hz, 1H), 7.909 (d, J=2Hz, 1H), 7.833 (s, 1H), 7.586 (d, J=8Hz, 1H), 7.545 (t, J=5Hz, 1H), 7.307 (d, J=8Hz, 1H), 7.030 (m, 2H), 6.937 (m, 1H),4.396(dq,J1=2Hz, J2=11.5Hz, 1H), 4.117 (m, 1H), 3.794 (dd, J1=1.0Hz, J2=5.0Hz, 1H),3.515(m,1H),3.247(dd,J1=4.5Hz, J2=14.5Hz, 1H), 3.067 (m, 3H), 2.790 (m, 2H), 2.016 (t, J=7.5Hz, 2H), 1.451 (m, 4H), 1.358 (d, J=6.0Hz, 3H), 1.217 (m, 2H), 0.998 (m, 3H),0.630(m,3H)。
Embodiment 9 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 10 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 11 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)。
The activity of resisting tumor metastasis of the measurement compound 6 of embodiment 12
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 6 for taking orally generally acknowledged anti tumor translocation peptide RGDS Normal saline solution (dosage be 0.5 μm ol/kg/ days) or the normal saline solution of oral administration of compound 8 (dosage is 5 μm of ol/ Kg/ days) or oral normal saline (dosage is 10mL/kg/ days), 1 medicine is given daily, successive administration 12 days, is measured every three days And record gross tumor volume.The next day measurement knurl product of last time administration, etherization cervical dislocation are put to death, and the tumour of mouse is taken to claim Weight takes the lung of mouse and calculates the burrknot number of tumour lung transfer.It is examined with t for statistical analysis to data.It the results are shown in Table 1. In 0.5 μm of ol/kg dosages for Compound 6 not only effectively inhibit neoplasm lung metastasis, and activity and dose ratio it high 40 times RGDS and its high 10 times compound 8 of dose ratio do not have significant difference.These statistics indicate that, the present invention has significant technology to imitate Fruit.
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=11
Embodiment 13 measures the neoplasm growth activity of compound 6
Adriamycin, compound 8 and compound 6 are all used into physiological saline solution before measurement, are administered for S180 mouse.In nothing It is taken in collarium border 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) method is pressed after mixing It counts, dye blue person is dead cell, and tinter is not living cells.By viable count/4 × 10 in cell concentration=4 block plaids4× Extension rate=cell number/mL calculates cell density, by cell survival rate=viable count/(viable count+dead cell number) × 100% calculates 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/mL's is thin Born of the same parents' suspension.The cell suspension inoculation is subcutaneous (0.2mL/ is only) in mouse right axillary, manufactures S180 tumor-bearing mice.S180 after inoculation for 24 hours Normal saline solution (dosage oral administration of compound 8 for 2 μm of ol/kg/ days g) or daily of adriamycin is injected intraperitoneally in tumor-bearing mice daily Normal saline solution (dosage be 5 μm ol/kg/ days) or the normal saline solution of daily oral administration of compound 6 (dosage is 0.5 μ Mol/kg/ days).It is administered once a day, successive administration 12 days.The next day measurement knurl product of last time administration, etherization are de- Cervical vertebra is put to death, and is then fixed mouse right axillary tumor location with tweezers, is cut off skin blunt separation tumour and weigh.Use knurl weight (mean value ± SD g) indicates curative effect, and data are examined with t and variance analysis.It the results are shown in Table 2.In 0.5 μm of ol/kg dosages for Compound 6 not only effectively inhibit tumour growth, but also activity does not have significant difference with its high 10 times compound 8 of dose ratio.These Statistics indicate that the present invention has significant technical effect.
Influence of 2 compound 6 of table to S180 mice tumors grew
A) with physiological saline ratio p<0.01, compare p with compound 8>0.05；N=12.
The anti-inflammatory activity of the measurement compound 6 of embodiment 14
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 6 therapeutic effect.Because aspirin is the positive drug for treating acute inflammation, institute Select aspirin as positive control drug using the present invention.ICR male mice (20 ± 2g of weight) is quiet in the environment that temperature is 22 DEG C Breath 2 days, free water and feed.Later, physiological saline group (dosage is 0.2mL/), aspirin group (dosage are randomly divided into For 1.11mmol/kg), 8 groups of compound (dosage is 5 μm of ol/kg) and 6 groups of compound (dosage is 0.5 μm of ol/kg), every group 12 Mouse.Mouse is by place group or oral normal saline or oral aspirin or oral administration of compound 8, or oralization when measurement Close object 6.After 30min is administered, the left auricle toward mouse uniformly smears 30 μ L dimethylbenzene, and mouse receives etherization after 2h, and break neck It puts to death, cuts two ears of left and right, take round auricle in the same position of two ears with the punch of 7mm, weigh, it is poor to find out two ear swellings Value is used as swelling.That is swelling=left ear disk weight-auris dextra disk weight.It the results are shown in Table 2.Under 0.5 μm of ol/kg dosage Compound 6 not only effectively inhibits mouse ear swelling caused by dimethylbenzene, but also activity and its high 2220 times Ah Si of dose ratio Woods and its high 10 times compound 8 of dose ratio do not have significant difference.These statistics indicate that, the present invention has significant technology to imitate Fruit.
The influence of mouse ear swelling caused by 3 compound of table, 6 paraxylene
A) with physiological saline ratio p<0.01；N=12.

Claims (5)

1. (3R, 6R) -3- (the positive caproyl amino normal-butyl of 5S- methyl -2- oxazolidone -4S- Formylamino) -6- of following formula (indoles -3- methyl)-piperazine -2,5- diketone,
Claim 2. (3R, 6R) -3- (the positive caproyl amino normal-butyl of 5S- methyl -2- oxazolidone -4S- Formylamino) - The preparation method of 6- (indoles -3- methyl)-piperazine -2,5- 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 Cbz-Thr are condensed to obtain Cbz-Thr- Amino-n-hexanoic acid methyl esters (3)；
(6) compound 3 obtains 5S- methyl -2- oxazolidone -4S- Formylamino n-caproic acid (4) by saponification；
(7) compound 2 and compound 4 be condensed (3R, 6R) -3- (5S- methyl -2- oxazolidone -4S- Formylamino just oneself Acyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (5)；
(8) compound 2 and Boc- aminocaproic acid are condensed (3R, 6R) -3- (Boc- aminocaProyl fourth amino) -6- (indoles -3- Methyl)-piperazine-2,5-dione (6)；
(9) the de- Boc in the ethyl acetate solution of hydrogen chloride of compound 7 obtains (3R, 6R) -3- (aminocaProyl fourth amino) - 6- (indoles -3- methyl)-piperazine-2,5-dione (7).
3. (3R, 6R) -3- (positive positive fourth of caproyl amino of 5S- methyl -2- oxazolidone -4S- Formylamino of claim 1 Base) -6- (indoles -3- methyl)-piperazine-2,5-dione preparing the application in medicine for anti transfer of tumor.
4. (3R, 6R) -3- (positive positive fourth of caproyl amino of 5S- methyl -2- oxazolidone -4S- Formylamino of claim 1 Base) -6- (indoles -3- methyl)-piperazine-2,5-dione application in preparation of anti-tumor drugs.
5. (3R, 6R) -3- (positive positive fourth of caproyl amino of 5S- methyl -2- oxazolidone -4S- Formylamino of claim 1 Base) -6- (indoles -3- methyl)-piperazine-2,5-dione application in preparing anti-inflammatory drugs.
CN201710363797.5A 2017-05-22 2017-05-22 3R-indolylmethyl-6R-oxazolidinone modified piperazine-2, 5-dione, synthesis, activity and application thereof Expired - Fee Related CN108929320B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710363797.5A CN108929320B (en) 2017-05-22 2017-05-22 3R-indolylmethyl-6R-oxazolidinone modified piperazine-2, 5-dione, synthesis, activity and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710363797.5A CN108929320B (en) 2017-05-22 2017-05-22 3R-indolylmethyl-6R-oxazolidinone modified piperazine-2, 5-dione, synthesis, activity and application thereof

Publications (2)

Publication Number Publication Date
CN108929320A true CN108929320A (en) 2018-12-04
CN108929320B CN108929320B (en) 2020-10-16

Family

ID=64449612

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710363797.5A Expired - Fee Related CN108929320B (en) 2017-05-22 2017-05-22 3R-indolylmethyl-6R-oxazolidinone modified piperazine-2, 5-dione, synthesis, activity and application thereof

Country Status (1)

Country Link
CN (1) CN108929320B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115466250A (en) * 2021-06-11 2022-12-13 首都医科大学 6-aminocaproyl tryptophan benzyl ester modified oxo oxazolidine, synthesis, activity and application thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1458844A (en) * 2000-08-04 2003-11-26 Dmi生物科学公司 Method of using diketopiperazines and composition containing them
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
CN104098549A (en) * 2014-08-01 2014-10-15 华东理工大学 Piperazinedione derivative and preparation 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

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1458844A (en) * 2000-08-04 2003-11-26 Dmi生物科学公司 Method of using diketopiperazines and composition containing them
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
CN104098549A (en) * 2014-08-01 2014-10-15 华东理工大学 Piperazinedione derivative and preparation and application thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115466250A (en) * 2021-06-11 2022-12-13 首都医科大学 6-aminocaproyl tryptophan benzyl ester modified oxo oxazolidine, synthesis, activity and application thereof

Also Published As

Publication number Publication date
CN108929320B (en) 2020-10-16

Similar Documents

Publication Publication Date Title
CN109111501A (en) The indoles alcohol derivative of fatty acid/amino acid modification, synthesis, activity and application
CN109081801A (en) The indoles alcohol derivative of acidic amino acid modification, synthesis, activity and application
CN109081803A (en) The indoles alcohol derivative of polar amino acid modification, synthesis, activity and application
CN108976159A (en) The indoles alcohol derivative of ArAA modification, synthesis, activity and application
CN108929320A (en) Piperazine -2,5- diketone of 3R- indole methyl -6R- oxazolidone modification, synthesis, activity and application
CN109134595B (en) Theanyl amino acid benzyl ester modified curcumin, and synthesis, activity and application thereof
CN108948137A (en) Piperazine -2,5- diketone of 3S- indolylethyl -6S- polar amino acid modification, synthesis, activity and application
CN108947978A (en) Piperazine -2,5- diketone of 3R- indole methyl -6R-Tyr modification, synthesis, activity and application
CN108976201A (en) Piperazine -2,5- diketone of 3R- indole methyl -6S- ArAA modification, synthesis, activity and application
CN108947979A (en) Piperazine -2,5- diketone of 3R- indole methyl -6R- polar amino acid modification, synthesis, activity and application
CN109456311A (en) Piperazine -2,5- diketone of 3R- indole methyl -6R- ArAA modification, synthesis, activity and application
CN108947977A (en) Piperazine -2,5- diketone of 3R- indole methyl -6R- amide side chains amino acid modification, synthesis, activity and application
CN108929313A (en) Piperazine -2,5- diketone of 3R- indole methyl -6R- fatty acid/amino acid modification, synthesis, activity and application
CN108976211A (en) Piperazine -2,5- diketone of 3S- indole methyl -6R- fatty acid/amino acid modification, synthesis, activity and application
CN108929369A (en) Piperazine -2,5- diketone of 3R- indole methyl -6R- acidic amino acid modification, synthesis, activity and application
CN108976204A (en) Piperazine -2,5- diketone of 3S- indole methyl -6R- aspartic acid modification, synthesis, activity and application
CN108947976A (en) Piperazine -2,5- diketone of 3S- indolylethyl -6S- ArAA modification, synthesis, activity and application
CN108976210A (en) Piperazine -2,5- diketone of 3S- indole methyl -6R- ArAA modification, synthesis, activity and application
CN112300245B (en) RGDS and theanine co-modified 5-fluorouracil, and synthesis, activity and application thereof
CN108976206A (en) Piperazine -2,5- diketone of 3S- indole methyl -6R-Glu modification, synthesis, activity and application
CN112390854B (en) 5-fluorouracil modified by theanine and RGDS together, and synthesis, activity and application thereof
CN108976208A (en) Piperazine -2,5- diketone of 3S- indole methyl -6R-Met modification, synthesis, activity and application
CN112300244B (en) 5-fluorouracil modified by theanine alone or together with RGDS, and synthesis, activity and application thereof
CN110577568B (en) Methyl indole and amide side chain amino acid modified diketopiperazine, synthesis, activity and application thereof
CN108976209A (en) Piperazine -2,5- diketone of 3S- indole methyl -6R- heterocyclic amino acid containing N modification, synthesis, activity and application

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20201016