CN108947979A - Piperazine -2,5- diketone of 3R- indole methyl -6R- polar amino acid modification, synthesis, activity and application - Google Patents

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

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CN108947979A
CN108947979A CN201710364631.5A CN201710364631A CN108947979A CN 108947979 A CN108947979 A CN 108947979A CN 201710364631 A CN201710364631 A CN 201710364631A CN 108947979 A CN108947979 A CN 108947979A
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amino
piperazine
boc
methyl
indoles
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CN108947979B (en
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赵明
彭师奇
王玉记
吴建辉
张筱宜
丛林
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Capital Medical University
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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 (3R, 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-Lys residue, L-Ser residue and L-Thr residue).It discloses their preparation method, disclose their anti-tumor activity, disclose their activity of resisting tumor metastasis, and their anti-inflammatory activity activity is disclosed, thus anti-tumor drug is being prepared the invention discloses them, the application in medicine for anti transfer of tumor and anti-inflammatory drug.

Description

Piperazine -2,5- diketone of 3R- indole methyl -6R- polar amino acid modification, synthesis, Activity and application
Technical field
The present invention relates to (3R, 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 anti-tumor activity, is related to their activity of resisting tumor metastasis, with And be related to their anti-inflammatory activity activity, thus preparing anti-tumor drug the present invention relates to them, medicine for anti transfer of tumor and Application in 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 polar amino acid (L-Lys, L-Ser and L-Thr) acylated aminocaproic acid, the diketopiperazine of R- configuration Fourth amino can not only make the minimum effective dose of anti-tumor metastasis be down to 0.5 μm of ol/kg, and can make it is antitumor and it is anti-inflammatory most Low effective dose is all down to 0.5 μm of ol/kg.It disappears because the toxic side effect of drug can be reduced with dosage, effectively 10 times of dosage reduction, which shows this structural modification, technical effect outstanding.According to these discoveries, this hair is inventors herein proposed It is bright.
Summary of the invention
First content of the invention is to provide (3R, 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-Lys residue, L-Ser residue and L-Thr residue).
Second content of the invention is to provide (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (Yin Diindyl -3- methyl)-piperazine -2,5- diketone (AA be L-Lys residue, L-Ser residue and L-Thr residue) synthetic method, this method Include:
(1) D-Boc-Lys (Cbz) and D-Trp-OBzl are condensed to obtain Boc-Lys (Cbz)-Trp-OBzl；
(2) Boc-Lys (Cbz)-Trp-OBzl de- Boc in the ethyl acetate solution of hydrogen chloride obtains Lys (Cbz)-Trp- OBzl；
(3) Lys (Cbz)-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 Boc-AA (AA is Lys (Boc) residue, Ser residue and Thr residue) are condensed Boc-AA- Amino-n-hexanoic acid methyl esters (3a-c)；
(6) compound 3a-c saponification removing methyl esters obtains Boc-AA- Amino-n-hexanoic acid (4a-c)；
(7) compound 2 and compound 4a-c are condensed (3R, 6R) -3- (positive positive fourth of caproyl amino of Boc-AA- amino Base) -6- (indoles -3- methyl)-piperazine-2,5-dione (5a-c)；
(8) compound 5a-c in the ethyl acetate solution of hydrogen chloride take off Boc obtain (3R, 6R) -3- (AA- amino just oneself Acyl amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (6a-c).
Third content of the invention is evaluation (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (Yin Diindyl -3- methyl)-piperazine-2,5-dione (AA be L-Lys residue, L-Ser residue and L-Thr residue) inhibits C57BL/6 mouse anti- Lung cancer metastasis activity.
4th content of the invention is evaluation (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (Yin Diindyl -3- methyl) the suppression of-piperazine-2,5-dione (AA is L-Lys residue, L-Ser residue and L-Thr residue) to ICR mouse inflammation Production is used.
5th content of the invention is evaluation (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (Yin Diindyl -3- methyl)-piperazine-2,5-dione (AA be L-Lys residue, L-Ser residue and L-Thr residue) is raw to S180 mouse tumor Long inhibition application.
Detailed description of the invention
Fig. 1 (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (indoles -3- methyl)-piperazine -2,5- two AA is L-Lys residue in the synthetic route .3a-6a of ketone (6a-e)；AA is Ser residue in 3b-6b；AA is that L-Thr is residual in 3c-6c Base；I) dicyclohexylcarbodiimide (DCC), I-hydroxybenzotriazole (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), I-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), N, N- diformazan Base formamide (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, be 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- Diketone (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 Boc-Lys (Boc)-Amino-n-hexanoic acid methyl esters (3a)
Using the method for embodiment 1 from 1730mg (5.0mmol) Boc-Lys (Boc) and 720mg (5.0mmol) amino just Methyl caproate obtains 1970mg (83%) title compound, is colorless solid.ESI-MS(m/e):474[M+H]+。
Embodiment 7 prepares Boc-Ser- Amino-n-hexanoic acid methyl esters (3b)
Using the method for embodiment 1 from 1030mg (5.0mmol) Boc-Ser and 720mg (5.0mmol) Amino-n-hexanoic acid first Ester obtains 1410mg (85%) title compound, is colorless solid.ESI-MS(m/e):333[M+H]+。
Embodiment 8 prepares Boc-Thr- Amino-n-hexanoic acid methyl esters (3c)
Using the method for embodiment 1 from 1100mg (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):347[M+H]+。
Embodiment 9 prepares Boc-Lys (Boc)-Amino-n-hexanoic acid (4a)
By 1.41g (3.0mmol) Boc-Lys (Boc)-Amino-n-hexanoic acid methyl esters (3a) 20mL CH3OH dissolution.It obtains Solution NaOH aqueous solution (2M) be added under ice bath stirring adjust pH value to 12, ice bath stirring reacts 6h.Under ice bath stirring, instead Liquid is answered to be saturated KHSO4Solution adjusts pH value to 7, obtains solution reduced pressure.Residue 5%KHSO4Aqueous solution adjusts pH value To 2.Obtained solution is extracted with ethyl acetate 3 times, then ethyl acetate solution is washed till neutrality with saturation NaCl aqueous solution.Acetic acid Methacrylate layer anhydrous Na2SO4Dry 12h, filtering, filtrate decompression are concentrated to dryness.Obtain the titled of the faint yellow syrup sample of 1.58g Close object.ESI-MS(m/e):460[M+H]+。
Embodiment 10 prepares Boc-Ser- Amino-n-hexanoic acid (4b)
0.99g (3.0mmol) Boc-Ser- Amino-n-hexanoic acid methyl esters (3b) saponification is obtained using the method for embodiment 9 The faint yellow syrup of 1.16g is title compound.ESI-MS(m/e):319[M+H]+。
The preparation preparation of embodiment 11 Boc-Thr- Amino-n-hexanoic acid (4c)
1.03g (3.0mmol) Boc-Thr- Amino-n-hexanoic acid methyl esters (3c) saponification is obtained using the method for embodiment 9 The faint yellow syrup of 1.20g is title compound.ESI-MS(m/e):333[M+H]+。
Embodiment 12 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Boc-Lys (Boc)-amino) -6- (indoles - 3- methyl)-piperazine-2,5-dione (5a)
Using the method for embodiment 1 from Boc-Lys (Boc)-Amino-n-hexanoic acid (4a) of the faint yellow syrup of 1580mg and 940mg (3.0mmol) (3R, 6R) -3- fourth amino -6- (indoles -3- methyl)-piperazine-2,5-dione (2) obtains 1060mg (47%) title compound is colorless solid.ESI-MS(m/e):756[M+H]+；1H NMR(300MHz,DMSO-d6):δ/ppm =10.871 (s, 1H), 8.026 (d, J=1.8Hz, 1H), 7.929 (d, J=1.8Hz, 1H), 7.725 (t, J=5.7Hz, 1H), 7.557 (m, 2H), 7.301 (d, J=8.1Hz, 1H), 7.040 (m, 2H), 6.929 (m, 1H), 6.720 (m, 1H), 4.112(m,1H),3.811(m,1H),3.504(m,1H),3.249(dd,J1=14.4Hz, J2=4.2Hz, 1H), 3.071 (m, 3H),2.874(m,2H),2.760(m,2H),2.001(m,2H),1.389(m,25H),1.193(m,6H),0.975(m,3H), 0.608(m,3H)。
Embodiment 13 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Boc-Ser- amino) -6- (indoles -3- first Base)-piperazine-2,5-dione (5b)
Using the method for embodiment 1 from the Boc-Ser- Amino-n-hexanoic acid (4b) and 940mg of the faint yellow syrup of 1160mg (3.0mmol) (3R, 6R) -3- fourth amino -6- (indoles -3- methyl)-piperazine-2,5-dione (2) obtains 480mg (26%) title Compound is colorless solid.ESI-MS(m/e):615[M+H]+；1H NMR(300MHz,DMSO-d6): δ/ppm=10.882 (s, 1H), 8.046 (s, 1H), 7.940 (s, 1H), 7.753 (s, 1H), 7.578 (m, 2H), 7.306 (d, J=7.8Hz, 1H), 7.044 (m, 2H), 6.930 (t, J=7.2Hz, 1H), 6.555 (d, J=8.1Hz, 2H), 4.793 (t, J=5.1Hz, 1H), 4.113(m,1H),3.925(m,1H),3.507(m,3H),3.270(m,1H),3.012(m,3H),2.755(m,2H),2.012 (m,3H),1.386(m,13H),1.192(m,3H),0.969(m,3H),0.594(m,3H)。
Embodiment 14 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Boc-Thr- amino) -6- (indoles -3- first Base)-piperazine-2,5-dione (5c)
Using the method for embodiment 1 from the Boc-Thr- Amino-n-hexanoic acid (4c) and 940mg of the faint yellow syrup of 1200mg (3.0mmol) (3R, 6R) -3- fourth amino -6- (indoles -3- methyl)-piperazine-2,5-dione (2) obtains 830mg (44%) title Compound is colorless solid.ESI-MS(m/e):629[M+H]+；1H NMR(500MHz,DMSO-d6): δ/ppm=10.873 (s,1H),8.035(s,1H),7.932(s,1H),7.739(m,1H),7.578(m,1H),7.303(m,1H),7.047(m, 2H), 6.931 (t, J=7.2Hz, 1H), 6.259 (m, 1H), 4.721 (m, 1H), 4.114 (m, 1H), 3.875 (m, 1H), 3.791 (m, 1H), 3.504 (m, 1H), 3.269 (m, 1H), 3.031 (m, 3H), 2.758 (m, 2H), 2.007 (t, J=7.2Hz, 2H),1.393(m,13H),1.227(m,3H),1.014(m,6H),0.603(m,3H)。
Embodiment 15 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Lys- amino) -6- (indoles -3- methyl) - Piperazine-2,5-dione (6a)
According to the method for embodiment 3 from 300mg (0.4mmol) (3R, 6R) -3- (Boc-Lys (the Boc)-positive caproyl of amino Amino normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone (5a) obtains 190mg (89%) title compound, and it is colourless Solid.ESI-MS(m/e):556[M+H]+；Mp:114–115℃；(C=0.1, H2O)；1H NMR (500MHz,DMSO-d6): δ/ppm=10.901 (s, 1H), 8.035 (m, 1H), 7.932 (m, 1H), 7.783 (t, J= 5.5Hz, 1H), 7.570 (d, J=7.5Hz, 2H), 7.295 (d, J=8Hz, 1H), 7.017 (m, 2H), 6.923 (m, 1H), 4.105 (m, 1H), 3.498 (m, 1H), 3.225 (m, 3H), 3.030 (m, 4H), 2.748 (m, 2H), 2.005 (t, J=7.5Hz, 2H),1.462(m,3H),1.342(m,6H),1.217(m,3H),0.972(m,3H),0.594(m,3H)。
Embodiment 16 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Ser- amino) -6- (indoles -3- methyl) - Piperazine-2,5-dione (6b)
According to the method for embodiment 3 from 300mg (0.5mmol) (3R, 6R) -3- (positive caproyl amino of Boc-Ser- amino Normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone (5b) obtains 210mg (87%) title compound, and it is colourless solid Body.ESI-MS(m/e):515[M+H]+；Mp:147–148℃； 1H NMR(300MHz, DMSO-d6): δ/ppm=10.935 (s, 1H), 8.458 (s, 1H), 8.157 (s, 3H), 8.059 (s, 1H), 7.947 (s, 1H), 7.648 (m, 1H), 7.547 (d, J=8.1Hz, 1H), 7.307 (d, J=7.8Hz, 1H), 7.045 (m, 2H), 6.942 (m, 1H),5.490(s,1H),4.115(s,1H),3.753(m,3H),3.503(m,1H),3.398(m,4H),3.111(m,5H), 2.762 (m, 2H), 2.028 (m, 2H), 1.453 (m, 4H), 1.241 (m, 2H), 1.097 (t, J=6.6Hz, 1H), 0.976 (m, 3H),0.602(m,3H)。
Embodiment 17 prepares (3R, 6R) -3- (the positive caproyl amino normal-butyl of Thr- amino) -6- (indoles -3- methyl) - Piperazine-2,5-dione (6c)
According to the method for embodiment 3 from 300mg (0.4mmol) (3R, 6R) -3- (positive caproyl amino of Boc-Thr- amino Normal-butyl) -6- (indoles -3- methyl)-piperazine -2,5- diketone (5c) obtains 230mg (94%) title compound, and it is colourless solid Body.ESI-MS(m/e):529[M+H]+；Mp:147–148℃； 1H NMR(500MHz, DMSO-d6): δ/ppm=10.903 (s, 1H), 8.468 (t, J=5.5Hz, 1H), 8.020 (d, J=2Hz, 1H), 7.921 (d, J=2Hz, 1H), 7.853 (s, 2H), 7.611 (t, J=5.5Hz, 1H), 7.568 (d, J=8Hz, 1H), 7.297 (d, J= 8.0Hz, 1H), 7.016 (m, 1H), 6.923 (m, 1H), 5.484 (s, 1H), 4.104 (m, 1H), 3.448 (d, J=7.0Hz, 1H), 3.235 (m, 1H), 3.145 (m, 1H), 3.048 (m, 2H), 2.757 (m, 2H), 2.019 (t, J=7.5Hz, 2H), 1.435 (m, 4H), 1.243 (m, 2H), 1.120 (d, J=6.5Hz, 3H), 0.989 (m, 3H), 0.626 (m, 3H).
Embodiment 18 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 (21%) title compound, is colourless solid Body.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 19 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]+；1HNMR(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 of embodiment 20 compound 6a-c
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 8 of 6a-c 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.Not only effectively inhibit neoplasm lung metastasis in 0.5 μm of ol/kg dosages for Compound 6a-c, and activity and dose ratio they High 40 times of RGDS and their high 10 times compounds 8 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 1 compound 6a-c of table
And physiological saline ratio p<0.01, a) with RGDS and compound 8 than p>0.05；N=11
Embodiment 21 measures the neoplasm growth activity of compound 6a-c
Adriamycin, compound 8 and compound 6a-c are used into physiological saline solution before measurement, are administered for S180 mouse. Taken in gnotobasis and be inoculated in male ICR mouse 10 days eugonic S180 ascitic tumor fluids, with normal saline dilution at (1: 2) liquid is sufficiently mixed, and by 0.2% Trypan Blue of tumor cell suspension Fresh, white blood cell count(WBC) is pressed after mixing Method counts, and dye blue person is dead cell, and tinter is not living cells.By viable count/4 in cell concentration=4 block plaids × 104× extension rate=cell number/mL calculates cell density, by cell survival rate=viable count/(viable count+dead cell Number) × 100% calculating cell survival rate.It is 2.0 × 10 that density, which is made, with homogenate method in tumor liquid by survival rate greater than 90%7A/ The cell suspension of mL.The cell suspension inoculation is subcutaneous (0.2mL/ is only) in mouse right axillary, manufactures S180 tumor-bearing mice.Inoculation is for 24 hours The normal saline solution (dosage is 2 μm of ol/kg/ days g) or daily oral of adriamycin is injected intraperitoneally in S180 tumor-bearing mice daily afterwards The normal saline solution (dosage be 5 μm ol/kg/ days) of compound 8 or the daily normal saline solution (agent of oral administration of compound 6a-c Amount for 0.5 μm ol/kg/ days).It is administered once a day, successive administration 12 days.The next day measurement knurl product of last time administration, second Ehterization cervical dislocation is put to death, and is then fixed mouse right axillary tumor location with tweezers, is cut off skin blunt separation tumour and claim Weight.Curative effect is indicated with knurl weight (mean value ± SD g), and data are examined with t and variance analysis.It the results are shown in Table 2.In 0.5 μm of ol/kg agent It measures lower compound 6a-e and not only effectively inhibits tumour growth, but also their high 10 times compounds 8 do not have activity with dose ratio Significant difference.These statistics indicate that, the present invention has significant technical effect.
Influence of the 2 compound 6a-c of table to S180 mice tumors grew
And physiological saline ratio p<0.01, a) with compound 8 than p>0.05；N=12.
The anti-inflammatory activity of the measurement of embodiment 22 compound 6a-c
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 6b therapeutic effect.Because aspirin is the positive drug for treating acute inflammation, So the present invention selects aspirin for positive control drug.The environment that ICR male mice (20 ± 2g of weight) is 22 DEG C in temperature Tranquillization 2 days, free water and feed.Later, physiological saline group (dosage is 0.2mL/), aspirin group (agent are randomly divided into Amount is 1.11mmol/kg), 8 groups of compound (dosage is 5 μm of ol/kg) and compound 6a-c group (dosage is 0.5 μm of ol/kg), often 12 mouse of group.Mouse is by place group or oral normal saline or oral aspirin or oral administration of compound 8 or mouth when measurement Take compound 6a-c.After 30min is administered, the left auricle toward mouse uniformly smears 30 μ L dimethylbenzene, and mouse receives ether fiber crops after 2h Liquor-saturated, 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, weighs, find out two Ear swelling 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 dosages for Compound 6a-c not only effectively inhibits mouse ear swelling caused by dimethylbenzene, but also they are high for activity and dose ratio 10 times of compound 8 does not have significant difference.These statistics indicate that, the present invention has significant technical effect.
The influence of mouse ear swelling caused by 3 compound 6a-c paraxylene of table
And physiological saline ratio p<0.01, a) with compound 8 than p>0.05；N=12.

Claims (5)

1. (3R, 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-Lys residue, L-Ser residue and L-Thr residue.
Claim 1 point 2. (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (indoles -3- methyl)-piperazine - The preparation method of 2,5- diketone, this method comprises:
(1) D-Boc-Lys (Cbz) and D-Trp-OBzl are condensed to obtain Boc-Lys (Cbz)-Trp-OBzl；
(2) Boc-Lys (Cbz)-Trp-OBzl de- Boc in the ethyl acetate solution of hydrogen chloride obtains Lys (Cbz)-Trp-OBzl；
(3) Lys (Cbz)-Trp-OBzl is in the saturation ethyl acetate middle ring symphysis containing 5% sodium bicarbonate aqueous solution 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 Boc-AA (AA is Lys (Boc) residue, Ser residue and Thr residue) are condensed to obtain Boc-AA- Amino-n-hexanoic acid methyl esters (3a-c)；
(6) compound 3a-c saponification removing methyl esters obtains Boc-AA- Amino-n-hexanoic acid (4a-c)；
(7) compound 2 and compound 4a-c are condensed (3R, 6R) -3- (the positive caproyl amino normal-butyl of Boc-AA- amino) -6- (indoles -3- methyl)-piperazine-2,5-dione (5a-c)；
(8) compound 5a-c de- Boc in the ethyl acetate solution of hydrogen chloride obtains (3R, 6R) -3- (positive caproyl of AA- amino Amino normal-butyl) -6- (indoles -3- methyl)-piperazine-2,5-dione (6a-c).
3. (3R, 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. (3R, 6R) -3- (the positive caproyl amino normal-butyl of AA- amino) -6- (indoles -3- methyl)-piperazine-of claim 1 2,5- diketone application in preparation of anti-tumor drugs.
5. (3R, 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.
CN201710364631.5A 2017-05-22 2017-05-22 3R-indolylmethyl-6R-polar amino acid modified piperazine-2, 5-dione, and synthesis, activity and application thereof Expired - Fee Related CN108947979B (en)

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