CN108976209A - Piperazine -2,5- diketone of 3S- indole methyl -6R- heterocyclic amino acid containing N modification, synthesis, activity and application - Google Patents
Piperazine -2,5- diketone of 3S- indole methyl -6R- heterocyclic amino acid containing N modification, synthesis, activity and application Download PDFInfo
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Abstract
The invention discloses (3S, 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-His residue and L-Trp residue in formula).It discloses their preparation method, disclose their activity of resisting tumor metastasis, and disclose their anti-inflammatory activity activity, thus the invention discloses them to prepare the application in medicine for anti transfer of tumor and anti-inflammatory drug.
Description
Technical field
The present invention relates to (3S, 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 activity of resisting tumor metastasis, and is related to their anti-inflammatory activity work
Property, thus the present invention relates to them to prepare the application in medicine for anti transfer of tumor and anti-inflammatory drug.The invention belongs to biologies to cure
Medicine field.
Background technique
Tumour seriously threatens the health of the mankind.Other than itself is severe to the prognosis of tumor patient, tumor complicated turns
Move the prognosis for further deteriorating patient.For example, being all to die of transfer more than 90% or more tumor patient.Due to existing antineoplastic
Object does not have inhibiting effect on tumor metastasis, so the clinical efficacy of chemotherapy of tumors is undesirable.The drug of invention anti-tumor metastasis is clinical
Urgent need.Before this, inventor once discloses S, S-, R, R-, R, S- and S, and the diketopiperazine of tetra- kinds of configurations of R- is dense at 0.5 μM
Degree can inhibit HCCLM3 (high-transfer human liver cancer cell) migration and invasion.Later inventor discloses R, the 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 N heterocyclic side chain amino acid (L-His and L-Trp) acylated Amino-n-hexanoic acid, the diketone of S- configuration
The fourth amino 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 anti-inflammatory 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, effective agent
10 times of amount 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- (the positive caproyl amino normal-butyl of AA- amino)-of following formula
6- (indoles -3- methyl)-piperazine-2,5-dione (AA is L-His residue and L-Trp residue in formula).
Second content of the invention is to provide (3S, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (Yin
Diindyl -3- methyl)-piperazine -2,5- diketone (AA is L-His residue and L-Trp residue in formula) 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-His residue and L-Trp residue) are condensed (3S, 6R) -3- (Boc-AA-
The positive caproyl amino normal-butyl of amino) -6- (indoles -3- methyl)-piperazine-2,5-dione (5a, b);
(8) compound 5a, b in the ethyl acetate solution of hydrogen chloride take off Boc obtain (3S, 6R) -3- (AA- amino just oneself
Acyl amino normal-butyl) (AA is that L-His residue and L-Trp are residual to -6- (indoles -3- methyl)-piperazine-2,5-dione (6a, b)
Base).
Third content of the invention is evaluation (3S, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (Yin
Diindyl -3- methyl)-piperazine-2,5-dione (AA is L-His residue and L-Trp residue in formula) inhibition C57BL/6 mouse anti-lung cancer turn
Move activity.
4th content of the invention is evaluation (3S, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (Yin
Diindyl -3- methyl)-piperazine-2,5-dione (AA is L-His residue and L-Trp residue in formula) makees the inhibition of ICR mouse inflammation
With.
Detailed description of the invention
Fig. 1 (3S, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (indoles -3- methyl)-piperazine -2,5- two
AA is L-His residue in the synthetic route .5a and 6a of ketone (6a-b);AA is L-Trp residue in 5b and 6b;I) dicyclohexyl carbon two
Imines (DCC), 1- 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.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℃;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- (the positive caproyl amino normal-butyl of Boc-His- amino) -6- (indoles -3- first
Base)-piperazine-2,5-dione (5a)
Using the method for embodiment 1 from 3.092g (12mmol) Boc-His and 4.683g (10mmol) (3S, 6R) -3- (ammonia
The positive caproyl amino normal-butyl of base) to obtain 1.713g (26%) titled for -6- (indoles -3- methyl)-piperazine-2,5-dione (4)
Object is closed, is colorless solid.ESI-MS (m/z): 665 [M+H]+;1H NMR(300MHz,DMSO-d6): δ/ppm=11.004 (s,
1H), 8293 (s, 1H), 8.085 (s, 1H), 7.915 (s, 1H), 7.876 (m, 1H), 7.793 (m, 1H), 7.567 (d, J=
7.8Hz, 1H), 7.319 (d, J=8.1Hz, 1H), 7.041 (m, 3H), 6.938 (m, 2H), 4.178 (m, 1H), 4.074 (m,
1H),3.251(dd,J1=14.1Hz, J2=3.6Hz, 1H), 2.982 (m, 7H), 2.769 (m, 1H), 2.004 (t, J=
6.9Hz,1H),1.336(m,21 H)。
Embodiment 9 prepares (3S, 6R) -3- (the positive caproyl amino normal-butyl of Boc-Trp- amino) -6- (indoles -3- first
Base)-piperazine-2,5-dione (5b)
Using the method for embodiment 1 from 0.509g (1.8mmol) Boc-Trp and 0.7g (1.5mmol) (3S, 6R) -3- (ammonia
The positive caproyl amino normal-butyl of base) to obtain 0.365g (42%) titled for -6- (indoles -3- methyl)-piperazine-2,5-dione (4)
Object is closed, is colorless solid.ESI-MS (m/z): 736 [M+Na]+;1H NMR(300MHz,DMSO-d6): δ/ppm=10.896
(s,1H),10.789(s,1 H),8.035(s,1H),7.847(s,1H),7.814(m,1H),7.675(m,1H),7.567(d,
J=7.8Hz, 2H), 7.315 (d, J=7.8Hz, 2H), 7.026 (m, 6H), 6.686 (d, J=8.4Hz, 1H), 4.097 (m,
2H),3.253(dd,J1=14.4 Hz, J2=4.5,1H), 3.172 (d, J=2.1Hz, 1H), 2.991 (m, 8H), 1.994 (t,
J=7.2Hz, 2H), 1.238 (m, 21H).
Embodiment 10 prepares (3S, 6R) -3- (the positive caproyl amino normal-butyl of His- amino) -6- (indoles -3- methyl)-piperazine
Piperazine -2,5- diketone (6a)
According to the method for embodiment 2 from 1.075g (2.5mmol) (3S, 6R) -3- (positive caproyl amino of Boc-His- amino
Normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone (5a) obtains 0.495mg (54%) title compound, and it is colourless solid
Body.ESI-MS (m/z): 565 [M+H]+;Mp 157-160℃;IR(cm-1):
3217, 3082,2926,2858,1651,1556,1434,1324,1258,1093,742;1H NMR(300MHz, DMSO-
d6): δ/ppm=10.966 (s, 1H), 9.082 (s, 1H), 8.716 (m, 1H), 8.561 (s, 2H), 8.074 (s, 1H),
7.870 (s, 1H), 7.809 (m, 2H), 7.567 (d, J=7.8Hz, 1H), 7.510 (s, 1H), 7.319 (d, J=8.1Hz,
2H), 7.060 (m, 2H), 6.963 (t, J=6.9Hz, 1H), 4.220 (m, 1H), 4.078 (s, 1H), 3.065 (m, 9H),
2.013 (t, J=7.5Hz, 2H), 1.258 (m, 12H).
Embodiment 11 prepares (3S, 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 2 from 0.859g (1.2mmol) (3S, 6R) -3- (positive caproyl amino of Boc-Trp- amino
Normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone (5b) obtains 0.302g (41%) title compound, and it is colourless solid
Body.ESI-MS (m/z): 614 [M+H]+;Mp 128-132℃;
3271, 3076,2927,2858,1666,1650,1531,1455,1434,1324,12342,1099,742;1H NMR
(300MHz, DMSO-d6): δ/ppm=10.901 (s, 1H), 10.826 (s, 1H), 8.052 (s, 1H), 7.859 (s, 1H),
7.800 (m, 1H), 7.686 (m, 1H), 7.565 (m, 2H), 7.340 (d, J=3.0Hz, 1H), 7.313 (d, J=3.0Hz,
1H),7.142(s,1 H),7.031(m,3H),6.971(m,2H),4.079(m,1H),3.427(m,1H),3.255(dd,J1
=14.4Hz, J2=4.2 Hz, 1H), 3.183 (s, 1H), 2.959 (m, 7H), 2.735 (dd, J1=14.1Hz, J2=8.1Hz,
1H) 2.001 (t, J=7.2 Hz, 2H), 1.314 (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 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, 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 2.?
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 2 compound 6a, b paraxylene of table
And physiological saline ratio p<0.01, a) with compound 4 than p>0.05;N=12.
Claims (4)
1. (3S, 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-His residue and L-Trp residue in formula.
2. (3S, 6R) -3- (the positive caproyl amino normal-butyl of AA- 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-AA (AA is L-His residue and L-Trp residue) are condensed (3S, 6R) -3- (Boc-AA- amino
Positive 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- (positive caproyl of AA- amino
Amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone (6a, b), AA is L-His residue and L-Trp residue.
3. (3S, 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. (3S, 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.
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Citations (5)
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 |
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Patent Citations (5)
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)
Title |
---|
芦金荣等: "《化学药物》", 31 August 2006, 东南大学出版社 * |
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