CN108976206A - Piperazine -2,5- diketone of 3S- indole methyl -6R-Glu modification, synthesis, activity and application - Google Patents

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

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CN108976206A
CN108976206A CN201710403537.6A CN201710403537A CN108976206A CN 108976206 A CN108976206 A CN 108976206A CN 201710403537 A CN201710403537 A CN 201710403537A CN 108976206 A CN108976206 A CN 108976206A
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amino
piperazine
methyl
butyl
indoles
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CN108976206B (en
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赵明
彭师奇
吴建辉
王玉记
胡明芳
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Capital Medical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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Abstract

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

Description

3S- indole methyl -6R-Glu modification piperazine -2,5- diketone, synthesis, activity and Using
Technical field
The present invention relates to (3S, 6R) -3- (the positive caproyl amino normal-butyl of Glu- amino) -6- (indoles -3- methyl)-piperazines Piperazine -2,5- diketone.It is related to its preparation method, is related to its activity of resisting tumor metastasis, and is related to its anti-inflammatory activity activity, Thus the present invention relates to it to prepare the application in medicine for anti transfer of tumor and anti-inflammatory drug.The invention belongs to biological medicine necks Domain.
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 L-Glu acylated Amino-n-hexanoic acid, the fourth amino of the diketopiperazine of S- configuration can not only make anti-swollen The minimum effective dose of tumor metastasis is down to 0.5 μm of ol/kg, and anti-inflammatory minimum effective dose can be made all to be down to 0.5 μm of ol/ kg.It disappears because the toxic side effect of drug can be reduced with dosage, effective dose reduces by 10 times and shows this knot Structure is modified with 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 (3S, 6R) -3- (the positive caproyl amino normal-butyl of Glu- amino)-of following formula 6- (indoles -3- methyl)-piperazine-2,5-dione.
Second content of the invention is to provide (3S, 6R) -3- (the positive caproyl amino normal-butyl of Glu- amino) -6- (Yin Diindyl -3- methyl)-piperazine -2,5- diketone 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-Glu (OBzl) are condensed (3S, 6R) -3- [Boc-Glu (the OBzl)-positive caproyl of amino Amino normal-butyl] -6- (indoles -3- methyl)-piperazine-2,5-dione (5)；
(8) Boc is taken off in the ethyl acetate solution of hydrogen chloride after the de- benzyloxycarbonyl group of 5 hydrogenolysis of compound obtain (3S, 6R) -3- (the positive caproyl amino normal-butyl of Glu- amino) -6- (indoles -3- methyl)-piperazine-2,5-dione (6).
Third content of the invention is evaluation (3S, 6R) -3- (the positive caproyl amino normal-butyl of Glu- amino) -6- (Yin Diindyl -3- methyl)-piperazine-2,5-dione inhibition C57BL/6 mouse anti-lung cancer transfer activity.
4th content of the invention is evaluation (3S, 6R) -3- (the positive caproyl amino normal-butyl of Glu- amino) -6- (Yin Diindyl -3- methyl)-piperazine-2,5-dione is to the inhibiting effect of ICR mouse inflammation.
Detailed description of the invention
Fig. 1 (3S, 6R) -3- (the positive caproyl amino normal-butyl of Glu- amino) -6- (indoles -3- methyl)-piperazine -2,5- two The synthetic route .i of ketone) dicyclohexylcarbodiimide (DCC), I-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), four Hydrogen furans (THF)；Ii) the ethyl acetate solution of hydrogen chloride；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.Compound of reaction is added dropwise N-methylmorpholine (NMM) adjusts pH to 9.Reaction mixture first stirs 1h under ice bath, then 12h is stirred at room temperature.Reaction mixture Filtering, 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- two Ketone (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℃； 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- [the positive caproyl amino normal-butyl of Boc-Glu (OBzl)-amino] -6- (indoles - 3- methyl)-piperazine-2,5-dione (5)
Using embodiment 1 method from 0.802g (2.4mmol) Boc-Glu (OBzl) and 0.919g (1.9mmol) (3S, 6R) -3- (the positive caproyl amino normal-butyl of amino) -6- (indoles -3- methyl)-piperazine-2,5-dione (4) obtains 0.600g (41%) title compound is colorless solid.ESI-MS (m/z): 769 [M+Na]+；1H NMR(300MHz,DMSO-d6):δ/ Ppm=10.907 (s, 1H), 8.065 (m, 1H), 7.867 (s, 1H), 7.798 (m, 1H), 7.694 (m, 1H), 7.569 (d, J =7.8Hz, 1H), 7.347 (s, 5H), 7.311 (d, J=4.5Hz, 1H), 7.062 (m, 2H), 6.945 (t, J=7.5Hz, 1H), 6.881 (d, J=8.1Hz, 1H), 5.081 (s, 2H), 4.074 (m, 1H), 3.893 (m, 1H), 3.255 (dd, J1= 14.4Hz,J2=4.2Hz, 1H), 2.999 (m, 6H), 2.359 (m, 2H), 1.993 (t, J=7.2Hz, 2H), 1.805 (m, 15H),1.371(m,6H)。
Embodiment 9 prepares (3S, 6R) -3- (the positive caproyl amino normal-butyl of Glu- amino) -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (6)
According to method 1.30g (1.7mmol) (3S, 6R) -3- [Boc-Glu (the OBzl)-positive caproyl of amino of embodiment 4 Amino normal-butyl] the first debenzylation of -6- (indoles -3- methyl)-piperazine -2,5- diketone (5), Boc is taken off according still further to the method for embodiment 2 0.487g (51%) title compound is obtained, is colourless powder.ESI-MS(m/z):557[M+H]+；Mp 138-139℃； IR(cm-1):3234,3081,2930,2861,1661,1549,1435,1323, 1258,1099,742；1H NMR(300MHz,DMSO-d6): δ/ppm=10.934 (s, 1H), 8.049 (m, 2H), 7.870 (s, 1H), 7.718 (m, 1H), 7.569 (d, J=8.1,1H), 7.319 (d, J=8.1Hz, 1H), 7.045 (m, 2H), 6.945 (t, J=6.0Hz, 1H), 4.074 (m, 1H), 3.273 (m, 2H), 2.992 (m, 6H), 2.246 (m, 2H), 2.010 (t, J= 7.2Hz,2H),1.777(m, 1H),1.659(m,1H),1.415(m,6H),1.158(m,6H)。
The activity of resisting tumor metastasis of the measurement compound 6 of embodiment 10
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 (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 4 of object 6 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.Neoplasm lung metastasis is not only effectively inhibited in 0.5 μm of ol/kg dosages for Compound 6, but also they are high for activity and dose ratio Their high 10 times compounds 4 of 40 times of RGDS and dose ratio do not have significant difference.These statistics indicate that, the present invention has significantly Technical effect.
The activity of resisting tumor metastasis of 1 compound 6 of table
And physiological saline ratio p<0.01, a) with RGDS and compound 4 than p>0.05；N=12
The anti-inflammatory activity of the measurement compound 6 of embodiment 11
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 (42 ± 3g 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 1.11 mmol/kg), 4 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 4, 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, find out two ear swellings Difference is as swelling.That is swelling=left ear disk weight-auris dextra disk weight.It the results are shown in Table 2.In 0.5 μm of ol/kg dosage Lower compound 6 not only effectively inhibits mouse ear swelling caused by dimethylbenzene, and activity and dose ratio it high 2220 times Ah Taking charge of a woods and its high 10 times compound 4 of dose ratio does not have significant difference.These statistics indicate that, the present invention has significant technology Effect.
The influence of mouse ear swelling caused by 2 compound of table, 6 paraxylene
And physiological saline ratio p<0.01, a) with aspirin and compound 4 than p>0.05；N=12.

Claims (4)

1. (3S, 6R) -3- (the positive caproyl amino normal-butyl of Glu- amino) -6- (indoles -3- methyl)-piperazine -2,5- of following formula Diketone,
2. (3S, 6R) -3- (the positive caproyl amino normal-butyl of Glu- amino) -6- (indoles -3- methyl)-piperazine-of claim 1 The preparation method of 2,5- 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-Glu (OBzl) are condensed (3S, 6R) -3- [positive caproyl amino of Boc-Glu (OBzl)-amino Normal-butyl] -6- (indoles -3- methyl)-piperazine-2,5-dione (5)；
(8) Boc is taken off in the ethyl acetate solution of hydrogen chloride after the de- benzyloxycarbonyl group of 5 hydrogenolysis of compound obtain (3S, 6R) -3- (the positive caproyl amino normal-butyl of Glu- amino) -6- (indoles -3- methyl)-piperazine-2,5-dione (6).
3. (3S, 6R) -3- (the positive caproyl amino normal-butyl of Glu- amino) -6- (indoles -3- methyl)-piperazine-of claim 1 2,5- diketone is preparing the application in medicine for anti transfer of tumor.
4. (3S, 6R) -3- (the positive caproyl amino normal-butyl of Glu- amino) -6- (indoles -3- methyl)-piperazine-of claim 1 The application in preparing anti-inflammatory drugs of 2,5- diketone.
CN201710403537.6A 2017-06-01 2017-06-01 3S-indolylmethyl-6R-Glu modified piperazine-2, 5-dione, and synthesis, activity and application thereof Expired - Fee Related CN108976206B (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0181152A1 (en) * 1984-11-02 1986-05-14 Fujisawa Pharmaceutical Co., Ltd. Piperazine compound as PAF-antagonist
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
CN104098549A (en) * 2014-08-01 2014-10-15 华东理工大学 Piperazinedione derivative 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

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0181152A1 (en) * 1984-11-02 1986-05-14 Fujisawa Pharmaceutical Co., Ltd. Piperazine compound as PAF-antagonist
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
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
CN104098549A (en) * 2014-08-01 2014-10-15 华东理工大学 Piperazinedione derivative and preparation and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
芦金荣等: "《化学药物》", 31 August 2006, 东南大学出版社 *

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