CN108929314A - Piperazine -2,5- diketone of 3R- indole methyl -6S- acidic amino acid modification, synthesis, activity and application - Google Patents

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

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CN108929314A
CN108929314A CN201710393397.9A CN201710393397A CN108929314A CN 108929314 A CN108929314 A CN 108929314A CN 201710393397 A CN201710393397 A CN 201710393397A CN 108929314 A CN108929314 A CN 108929314A
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amino
piperazine
methyl
indoles
butyl
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CN108929314B (en
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赵明
彭师奇
王玉记
吴建辉
张可欣
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Capital Medical University
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Capital Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The piperazine -2 of 3R- indole methyl -6S- acidic amino acid modification; 5- diketone; it is synthesized; activity and application; the invention discloses (the 3R of following formula; 6S) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (indoles -3- methyl)-piperazine -2,5- diketone (AA is L-Asp residue and L-Glu residue in formula).It discloses their preparation method, disclose their activity of resisting tumor metastasis, and disclose their anti-inflammatory activity, thus the invention discloses them to prepare the application in medicine for anti transfer of tumor and anti-inflammatory drug.

Description

Piperazine -2,5- diketone of 3R- indole methyl -6S- acidic amino acid modification, synthesis, Activity and application
Technical field
The present invention relates to (3R, 6S) -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, The application that thus the present invention relates to them 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 in 0.5 μM of concentration It 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. In order to reduce minimum effective dose, inventor expands various modifications to S, the amino normal-butyl of the diketopiperazine of R- configuration.Through It spends 3 years and explores, the discovery acylated S of L-Asp and L-Glu acylated Amino-n-hexanoic acid, the positive fourth of the amino 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 anti-inflammatory minimum effective dose It is 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 Showing this structural modification has 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, 6S) -3- (the positive caproyl amino normal-butyl of AA- amino)-of following formula 6- (indoles -3- methyl)-piperazine-2,5-dione (AA is L-Asp residue and L-Glu residue in formula).
Second content of the invention is to provide (3R, 6S) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (Yin Diindyl -3- methyl)-piperazine -2,5- diketone (AA is L-Asp residue and L-Glu residue in formula) synthetic method, this method includes：
(1) D-Boc-Lys (Cbz) and L-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 cyclization in the ethyl acetate solution that 5% sodium bicarbonate aqueous solution is saturated obtains (3R, 6S) -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, 6S) -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 (3R, 6S) -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 (3R, 6S) -3- (positive caproyl ammonia of amino Base normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (4)；
(7) compound 4 and Cbz-AA [AA is L-Asp (OBzl) residue and L-Glu (OBzl) residue in formula] are condensed (3R, 6S) -3- (the positive caproyl amino normal-butyl of Cbz-AA- amino) -6- (indoles -3- methyl)-piperazine-2,5-dione (5a, b)。
(8) the de- benzyloxycarbonyl group of compound 5a, b hydrogenolysis and benzyl obtain (3R, 6S) -3-, and (the positive caproyl amino of AA- amino is just Butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (6a, b) (AA is L-Asp residue and L-Glu residue in formula).
Third content of the invention is evaluation (3R, 6S) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (Yin Diindyl -3- methyl)-piperazine-2,5-dione (AA is L-Asp residue and L-Glu residue in formula) inhibition C57BL/6 mouse anti-lung cancer turn Move activity.
4th content of the invention is evaluation (3R, 6S) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (Yin Diindyl -3- methyl)-piperazine-2,5-dione (AA is L-Asp residue and L-Glu residue in formula) makees the inhibition of ICR mouse inflammation With.
Detailed description of the invention
Fig. 1 (3R, 6S) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (indoles -3- methyl)-piperazine -2,5- two AA is L-Asp (OBzl) residue in the synthetic route .5a of ketone (6a, b)；AA is L-Asp residue in 6a；AA is L-Glu in 5b (OBzl) residue；AA is L-Glu residue in 6b；I) dicyclohexylcarbodiimide (DCC), I-hydroxybenzotriazole (HOBt), N- Methyl morpholine (NMM)；Ii) the ethyl acetate solution of hydrogen chloride；Iii) ethyl acetate, 5% sodium bicarbonate aqueous solution；iv)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 D-Boc-Lys (Cbz)-L-Trp-OBzl
Add under ice bath into the solution of 1.90g (5.0mmol) D-Boc-Lys (Cbz) and 20mL dry tetrahydrofuran (THF) Enter 0.68g (5.0mmol) I-hydroxybenzotriazole (HOBt) and 1.24g (6.0mmol) dicyclohexylcarbodiimide (DCC) simultaneously Stirring 30 minutes, obtains reaction solution A.1.47g (5.0mmol) L-Trp-OBzl is dissolved in 20mL dry THF, N- methyl is added Morpholine (NMM) adjusts pH to 9 and obtains reaction solution B.Reaction solution B is added in reaction solution A, is reacted at room temperature 12 hours, TLC (dichloro Methane/methanol, 40/1) display reaction completion.Reaction mixture filtering, filtrate decompression concentration, residue 50mL ethyl acetate Dissolution.Obtained solution is successively with saturation NaHCO3Aqueous solution is washed (25mL × 3), and saturation NaCl aqueous solution washes (25 mL × 3), 5%KHSO4Aqueous solution is washed (25mL × 3), and saturation NaCl aqueous solution is washed (25mL × 3), is saturated NaHCO3Aqueous solution wash (25mL × 3) and saturation NaCl aqueous solution washes (25mL × 3).Ethyl acetate layer anhydrous Na2SO4It is 12 hours dry.Filter out Na2SO4, filter Liquid is concentrated under reduced pressure, and residue silica gel column chromatography is purified (methylene chloride/methanol, 40/1), and it is titled to obtain 2.94g (90%) Object is closed, is colorless solid.ESI-MS(m/z):657[M+H]+。
Embodiment 2 prepares D-Lys (Cbz)-L-Trp-OBzl
The second of 30mL hydrogen chloride is slowly added under ice bath to 2.62g (4.0mmol) D-Boc-Lys (Cbz)-L-Trp-OBzl Acetate solution (4M) simultaneously stirs 4 hours, and TLC (methylene chloride/methanol, 40/1) display reaction is completed.Reaction mixture decompression Concentration, residue add 30mL anhydrous ethyl acetate to dissolve, and obtained solution is concentrated under reduced pressure, and residue adds 30mL anhydrous acetic acid second Ester dissolution.The operation is in triplicate.Residue adds 30mL anhydrous ether to make to be suspended by Ultrasound Instrument, removes ether after standing, 2.07g (93%) title compound is obtained, is yellow powder.ESI-MS(m/z):557[M+H]+。
Embodiment 3 prepares (3R, 6S) -3- (benzyloxycarbonyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- two Ketone (1)
By the solution of 1.95g (3.5mmol) D-Lys (Cbz)-L-Trp-OBzl and 50mL ethyl acetate saturation NaHCO3 Aqueous solution is sufficiently washed after (25mL × 3), and ethyl acetate layer stirs 56 hours in 80 DEG C.TLC (methylene chloride/methanol, 20/1) Display reaction is completed.Reaction mixture room temperature is sufficiently placed, and filtering obtains 0.72g (46%) title compound, is colourless solid Body.ESI-MS (m/z):449[M+H]+。
Embodiment 4 prepares (3R, 6S) -3- (amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (2)
To 0.67g (1.5mmol) (3R, 6S) -3- (benzyloxycarbonyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine - In the solution of 2,5- diketone (1) and 10mL dimethylformamide (DMF) plus 0.07g Pd/C (10%), room temperature lead to H248 is small When, TLC (methylene chloride/methanol, 20/1) display reaction is completed.Pd/C is filtered out from reaction mixture, filtrate decompression is concentrated, 0.48g (95%) title compound is obtained, is colorless solid.ESI-MS(m/z):315[M+H]+。
Embodiment 5 prepares Boc- Amino-n-hexanoic acid
Stirring is lower to add 0.58g (2.6 mmol) into the solution of 0.26g (2.0mmol) Amino-n-hexanoic acid and 5mL distilled water (Boc)2The solution of O and 5mL dioxane.By the obtained solution aqueous solution tune pH to 9 of NaOH (2M) under ice bath.Ice bath After lower stirring 30 minutes, it is stirred at room temperature and is evacuated with water pump.PH is monitored during stirring and is allowed to remain 9, until TLC (methylene chloride/methanol, 3/1) display reaction is completed.Under ice bath, reaction mixture saturation KHSO4Aqueous solution adjusts pH to 7, It is concentrated under reduced pressure.Water phase saturation KHSO4Aqueous solution adjusts pH to 2, is sufficiently washed three times with 10mL ethyl acetate, is saturated with 10mL NaCl aqueous solution is washed makes pH value of solution 7 three times, uses anhydrous Na2SO4It is 12 hours dry.It is filtered to remove Na2SO4, filtrate decompression is dense Contracting, obtains 0.41g (89%) title compound, is colorless solid.ESI-MS(m/e): 232[M+H]+。
Embodiment 6 prepares (3R, 6S) -3- (the positive caproyl amino normal-butyl of Boc- amino) -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (3)
0.16g is added into 0.28g (1.2mmol) Boc- Amino-n-hexanoic acid and the solution of 5mL anhydrous DMF under ice bath (1.2mmol) HOBt and 0.29g (1.4mmol) DCC stirs 30 minutes, obtains reaction solution A.By 0.38g (1.2mmol) (3R, 6S) -3- (amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (2) is dissolved in 5mL anhydrous DMF, adds N- methyl Quinoline adjusts pH to 9, obtains reaction solution B.Reaction solution B is added in reaction solution A, is stirred at room temperature 12 hours, TLC (methylene chloride/ Methanol, 10/1) display reaction completion.Reaction mixture filtering, filtrate decompression concentration, residue silica gel column chromatography purify (two Chloromethanes/methanol, 50/1), 0.12g (19%) title compound is obtained, is colorless solid.ESI-MS(m/z):528[M+H ]+；1H NMR(300 MHz,DMSO-d6) δ/ppm=10.903 (s, 1H), 8.046 (d, J=1.8Hz, 1H), 7.851 (s, 1H), 7.686 (t, J=5.4Hz, 1H), 7.556 (d, J=7.8Hz, 1H), 7.314 (d, J=7.8Hz, 1H), 7.039 (m, 2H),6.943(td,J1=7.8Hz, J2=0.6Hz, 1H), 6.758 (t, J=5.4Hz, 1H), 4.068 (m, 1H), 3.252 (dd,J1=14.4Hz, J2=4.2Hz, 1H), 2.924 (m, 6H), 1.995 (t, J=7.2Hz, 2H), 1.292 (m, 21H).
Embodiment 7 prepares (3R, 6S) -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 0.11g (0.2mmol) (3R, 6S) -3- (positive positive fourth of caproyl amino of Boc- amino Base) -6- (indoles -3- methyl)-piperazine -2,5- diketone (3) obtains 0.08g (96%) title compound, and it is colorless solid. ESI-MS(m/z):428 [M+H]+；1H NMR(300MHz,DMSO-d6) δ/ppm=10.924 (s, 1H), 8.071 (s, 1H), 7.866 (s, 1H), 7.729 (t, J=5.4Hz, 1H), 7.568 (d, J=7.5Hz, 1H), 7.321 (d, J=7.5Hz, 1H), 7.044 (m, 2H), 6.949 (t, J=7.5Hz, 1H), 4.070 (m, 1H), 3.239 (dd, J1=14.4Hz, J2=3.6Hz, 1H), 2.991 (m, 4H), 2.694 (m, 2H), 2.021 (t, J=7.5Hz, 2H), 1.467 (m, 6H), 1.240 (m, 6H).
Embodiment 8 prepares (3R, 6S) -3- (the positive caproyl amino normal-butyl of Cbz-Asp (OBzl)-amino) -6- (indoles - 3- methyl)-piperazine-2,5-dione (5a)
Using embodiment 6 method from 0.06g (0.18mmol) Cbz-Asp (OBzl) and 0.08g (0.18mmol) (3R, 6S) -3- (the positive caproyl amino normal-butyl of amino) -6- (indoles -3- methyl)-piperazine-2,5-dione (4) obtains 0.03g (18%) title compound is colorless solid.ESI-MS(m/z):767[M+H]+；1H NMR(300MHz,DMSO-d6)δ/ppm =10.891 (s, 1H), 8.029 (d, J=1.8Hz, 1H), 7.900 (t, J=5.4Hz, 1H), 7.842 (s, 1H), 7.675 (t, J=5.4Hz, 1H), 7.548 (m, 2H), 7.354 (m, 10H), 7.044 (m, 2H), 6.947 (td, J1=7.8Hz, J2= 0.9Hz,1 H),5.082(s,2H),5.042(s,2H),3.345(m,1H),4.070(m,1H),3.255(dd,J1= 14.4Hz,J2=4.2 Hz, 1H), 2.994 (m, 6H), 2.707 (dd, J1=16.2Hz, J2=5.4Hz, 1H), 2.561 (dd, J1=16.2Hz, J2=5.4 Hz, 1H), 2.000 (t, J=7.2Hz, 2H), 1.449 (m, 6H), 1.207 (m, 6H).
Embodiment 9 prepares (3R, 6S) -3- (the positive caproyl amino normal-butyl of Cbz-Glu (OBzl)-amino) -6- (indoles - 3- methyl)-piperazine -2,5- diketone (5b)
Using embodiment 6 method from 0.07g (0.18mmol) Cbz-Glu (OBzl) and 0.08g (0.18mmol) (3R, 6S) -3- (the positive caproyl amino normal-butyl of amino) -6- (indoles -3- methyl)-piperazine-2,5-dione (4) obtains 0.02g (16%) title compound is colorless solid.ESI-MS(m/z):781[M+H]+；1H NMR(300MHz,DMSO-d6)δ/ppm =10.887 (s, 1H), 8.031 (s, 1H), 7.868 (m, 2H), 7.670 (t, J=5.4Hz, 1H), 7.569 (d, J= 7.8Hz,1H),7.354(m,11H), 7.042(m,2H),6.944(td,J1=7.8Hz, J2=1.2Hz, 1H), 5.077 (s, 2H),5.018(s,2H),4.070(m,1 H),3.975(m,1H),3.254(dd,J1=14.4Hz, J2=4.2Hz, 1H), 2.978 (m, 6H), 2.404 (t, J=7.8Hz, 2 H), 1.997 (t, J=7.2Hz, 2H), 1.909 (m, 1H), 1.791 (m, 1H),1.429(m,6H),1.232(m,6H)。
Embodiment 10 prepares (3R, 6S) -3- (the positive caproyl amino normal-butyl of Asp- amino) -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (6a)
According to the method for embodiment 4 from 0.02g (0.03mmol) (3R, 6S) -3- (Cbz-Asp (the OBzl)-positive hexanoyl of amino Base amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone (5a) obtains 0.02g (94%) title compound, and it is nothing Color solid.ESI-MS (m/z):541[M-H]-；Mp 153-154℃；(c=0.1, methanol)；IR(cm-1): 3244,3079,2929, 2860,1651,1556,1455,1385,1327,1098,1010,923,741；1H NMR (300MHz,DMSO-d6) δ/ppm=10.933 (s, 1H), 8.247 (t, J=5.4Hz, 1H), 8.077 (d, J=1.5Hz, 1H), 7.872 (s, 1H), 7.732 (t, J=5.4Hz, 1H), 7.564 (d, J=7.8Hz, 1H), 7.314 (d, J=7.8Hz, 1H), 7.037 (m, 2H), 6.942 (t, J=7.2 Hz, 1H), 4.064 (m, 1H), 3.629 (m, 1H), 3.226 (dd, J1= 14.4Hz,J2=4.2Hz, 1H), 3.032 (m, 6H), 2.408 (dd, J1=16.2Hz, J2=4.8Hz, 1H), 2.211 (dd, J1=16.2Hz, J2=4.8Hz, 1H), 2.003 (t, J=7.2Hz, 2H), 1.428 (m, 6H), 1.129 (m, 6H).
Embodiment 11 prepares (3R, 6S) -3- (the positive caproyl amino normal-butyl of Glu- amino) -6- (indoles -3- methyl)-piperazine Piperazine -2,5- diketone (6b)
According to the method for embodiment 4 from 0.02g (0.03mmol) (3R, 6S) -3- (Cbz-Glu (the OBzl)-positive hexanoyl of amino Base amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone (5b) obtains 0.02g (96%) title compound, and it is nothing Color solid.ESI-MS (m/z):557[M+H]+；Mp 131-133℃；(c=0.1, methanol)；IR(cm-1): 3243,3086,2930, 2862,1660,1549,1435,1397,1323,1259,1099,1010,924,742；1H NMR (300MHz,DMSO-d6) δ/ppm=10.922 (s, 1H), 8.048 (d, J=1.8Hz, 1H), 7.988 (t, J=5.4Hz, 1H), 7.858 (s, 1H), 7.703 (t, J=5.4Hz, 1H), 7.569 (d, J=7.8Hz, 1H), 7.319 (d, J=7.8Hz, 1H),7.042(m,2H),6.947(td, J1=7.8Hz, J2=0.9Hz, 1H), 4.069 (m, 1H), 3.271 (m, 2H), 3.008 (m, 6H), 2.246 (t, J=7.2Hz, 2 H), 2.009 (t, J=7.2Hz, 2H), 1.765 (m, 1H), 1.642 (m, 1H),1.438(m,6H),1.229(m,6H)。
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 4- after inoculation 10 days Mice Inoculated is grouped by the tumour of 5mm at random by the gross tumor volume measured.Every group of 12 mouse.The 11st day of inoculated tumour is small Mouse or the normal saline solution (dosage be 20 μm ol/kg/ days) or oral administration of compound for taking orally generally acknowledged anti tumor translocation peptide RGDS (dosage is 5 μ to the normal saline solution (dosage be 0.5 μm ol/kg/ days) or the normal saline solution of oral administration of compound 4 of 6a, b Mol/kg/ days) or oral normal saline (dosage be 10mL/kg/ days), daily to 1 medicine, successive administration 12 days.For the last time The next day etherization cervical dislocation of administration is put to death, and is taken the lung of mouse and is calculated the burrknot number of tumour lung transfer.With t inspection pair Data are for statistical analysis.It the results are shown in Table 1.Tumour lung is not only effectively inhibited in 0.5 μm of ol/kg dosages for Compound 6a, b to turn It moves, and activity does not have significant difference with their high 40 times RGDS of dose ratio and their high 10 times compounds 4 of dose ratio. These statistics indicate that, the present invention has significant technical effect.
The activity of resisting tumor metastasis of table 1 compound 6a, b
A) with physiological saline ratio p<0.01, compare p with RGDS and compound 4>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.ICR male mice (SPF grades, 20 ± 2g of weight) is 22 in temperature DEG C environment tranquillization 2 days, free water and feed.Later, physiological saline group (dosage is 0.2mL/), Ah Si are randomly divided into Woods group (dosage 1.11mmol/kg), (dosage is 0.5 μ for 4 groups of compound (dosage is 5 μm of ol/kg) and compound 6a, b group Mol/kg), every group of 12 mouse.Mouse is by place group or oral normal saline or oral aspirin, or oralization when measurement Close object 4 or oral administration of compound 6a, b.After 30min is administered, the left auricle toward mouse uniformly smears 30 μ L dimethylbenzene, mouse after 2h Receive etherization, the neck that breaks is put to death, and is cut two ears of left and right, is taken round auricle in the same position of two ears with the punch of 7mm, claims Weight, finds out two ear swelling differences as swelling.That is swelling=left ear disk weight-auris dextra disk weight.It the results are shown in Table 2. Mouse ear swelling caused by dimethylbenzene can be not only effectively inhibited in 0.5 μm of ol/kg dosages for Compound 6a, b, but also living Property with their high 2220 times aspirin of dose ratio and their high 10 times compounds 4 of dose ratio there is no significant difference.This Statistics indicate that, the present invention has significant technical effect a bit.
The influence of mouse ear swelling caused by 2 compound 6a, b paraxylene of table
A) with physiological saline ratio p<0.01, compare p with aspirin and compound 4>0.05；N=12.

Claims (4)

1. (3R, 6S) -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-Asp residue and L-Glu residue in formula.
2. (3R, 6S) -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 include：
(1) D-Boc-Lys (Cbz) and L-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 cyclization in the ethyl acetate solution that 5% sodium bicarbonate aqueous solution is saturated obtain (3R, 6S) -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, 6S) -3- (amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2, 5- diketone (2)；
(5) compound 2 and Boc- Amino-n-hexanoic acid are condensed (3R, 6S) -3- (the positive caproyl amino normal-butyl of Boc- amino) -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 (3R, 6S) -3- (positive positive fourth of caproyl amino of amino Base) -6- (indoles -3- methyl)-piperazine-2,5-dione (4)；
(7) compound 4 and Cbz-AA [AA is L-Asp (OBzl) residue and L-Glu (OBzl) residue in formula] be condensed (3R, 6S) -3- (the positive caproyl amino normal-butyl of Cbz-AA- amino) -6- (indoles -3- methyl)-piperazine-2,5-dione (5a, b).
(8) compound 5a, b hydrogenolysis take off benzyloxycarbonyl group and benzyl obtains (3R, 6S) -3- (positive positive fourth of caproyl amino of AA- amino Base) -6- (indoles -3- methyl)-piperazine -2,5- diketone (6a, b), AA is L-Asp residue and L-Glu residue.
3. (3R, 6S) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (indoles -3- methyl)-piperazine-of claim 1 2,5- diketone is preparing the application in medicine for anti transfer of tumor.
4. (3R, 6S) -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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US4743614A (en) * 1985-03-04 1988-05-10 Fujisawa Pharmaceutical Co., Ltd. Amino acid derivatives and processes for preparation thereof
EP0644181A1 (en) * 1992-06-03 1995-03-22 Fuji Photo Film Co., Ltd. Amino acid derivative and use thereof
WO2002008202A2 (en) * 2000-07-21 2002-01-31 Elan Pharmaceuticals, Inc. Alpha amino acid derivatives--inhibitors of leukocyte adhesion mediated by vla-4
CN105254709A (en) * 2014-07-10 2016-01-20 首都医科大学 Imidazopyridine-6-formyl-Met-AA-OBzl, synthesis, activity and applications 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
CN106349148A (en) * 2015-07-13 2017-01-25 首都医科大学 Novel indoles compound having anti-tumor metastasis activity and anti-inflammatory activity, as well as synthesis and application of novel indoles compound

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4743614A (en) * 1985-03-04 1988-05-10 Fujisawa Pharmaceutical Co., Ltd. Amino acid derivatives and processes for preparation thereof
EP0644181A1 (en) * 1992-06-03 1995-03-22 Fuji Photo Film Co., Ltd. Amino acid derivative and use thereof
WO2002008202A2 (en) * 2000-07-21 2002-01-31 Elan Pharmaceuticals, Inc. Alpha amino acid derivatives--inhibitors of leukocyte adhesion mediated by vla-4
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
CN105254709A (en) * 2014-07-10 2016-01-20 首都医科大学 Imidazopyridine-6-formyl-Met-AA-OBzl, synthesis, activity and applications thereof
CN106349148A (en) * 2015-07-13 2017-01-25 首都医科大学 Novel indoles compound having anti-tumor metastasis activity and anti-inflammatory activity, as well as synthesis and application of novel indoles compound

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