CN108947975A - Piperazine -2,5- diketone of 3S- indolylethyl -6S- fatty acid/amino acid modification, synthesis, activity and application - Google Patents

Piperazine -2,5- diketone of 3S- indolylethyl -6S- fatty acid/amino acid modification, synthesis, activity and application Download PDF

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CN108947975A
CN108947975A CN201710350163.6A CN201710350163A CN108947975A CN 108947975 A CN108947975 A CN 108947975A CN 201710350163 A CN201710350163 A CN 201710350163A CN 108947975 A CN108947975 A CN 108947975A
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amino
piperazine
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ethyl
indoles
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CN108947975B (en
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赵明
彭师奇
吴建辉
王玉记
桂林
张筱宜
李姗姗
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Capital Medical University
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    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic 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
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Abstract

The invention discloses (the 3S of following formula, 6S) -3- (the positive hexanoyl amino normal-butyl of AA- amino) -6- (indoles -3- ethyl)-piperazine-2,5-dione (AA is L-Ala residue, Gly residue, L-Met residue, L-IIe residue, L-Pro residue, L-Val residue and L-Leu residue in formula).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 3S- indolylethyl -6S- fatty acid/amino acid modification, synthesis, Activity and application
Technical field
The present invention relates to (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of AA- amino) -6- (indoles -3- ethyl)-piperazine -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, and It is related to their anti-inflammatory activity activity, thus is preparing anti-tumor drug the present invention relates to them, medicine for anti transfer of tumor and anti- Application in scorching 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 S, the fourth amino of the diketopiperazine of S- configuration.It was visited by 3 years Rope, the amino that discovery uses aliphatic side chains amino acid (L-Ala, Gly, L-Met, L-IIe, L-Pro, L-Val and L-Leu) acylated is just Caproic acid is acylated S, and the amino normal-butyl of the diketopiperazine of S- configuration not only can make the minimum effective dose of anti-tumor metastasis be down to 0.5 μm ol/kg, and antitumor and anti-inflammatory minimum effective dose can be made all to be down to 0.5 μm of ol/kg.Effective dose reduces by 10 times of tables Bright, 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 (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of AA- amino) -6- of following formula (AA is L-Ala residue, Gly residue, L-Met residue, L-IIe residue, L- to (indoles -3- ethyl)-piperazine-2,5-dione in formula Pro residue, L-Val residue and L-Leu residue).
Second content of the invention is to provide (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of AA- amino) -6- (indoles - 3- ethyl) (AA is L-Ala residue, Gly residue, L-Met residue, L-IIe residue, L-Pro residual to-piperazine-2,5-dione in formula Base, L-Val residue and L-Leu residue) synthetic method, this method comprises:
(1) L-Boc-Lys (Cbz) and L-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 5% sodium bicarbonate aqueous solution middle ring symphysis at (3S, 6S) -3- (benzyloxy carbonyl ammonia Base normal-butyl) -6- (indoles -3- ethyl)-piperazine-2,5-dione (1);
(4) the de- benzyloxycarbonyl group of 1 hydrogenolysis of compound obtains (3S, 6S) -3- (fourth amino) -6- (indoles -3- ethyl)-piperazine - 2,5- diketone (2);
(5) compound 2 and Boc- Amino-n-hexanoic acid are condensed (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Boc- amino) - 6- (indoles -3- ethyl)-piperazine-2,5-dione (3);
(6) the de- Boc in the ethyl acetate solution of hydrogen chloride of compound 3 obtains (3S, 6S) -3- (positive hexanoyl amino of amino Normal-butyl) -6- (indoles -3- ethyl)-piperazine-2,5-dione (4);
(7) compound 4 and Boc-AA (AA is L-Phe residue, L-Tyr residue and L-Trp residue) are condensed (3S, 6S)- 3- (the positive hexanoyl amino normal-butyl of Boc-AA- amino) -6- (indoles -3- ethyl)-piperazine-2,5-dione (5a-g).
(8) compound 5a-g in the ethyl acetate solution of hydrogen chloride take off Boc obtain (3S, 6S) -3- (AA- amino just oneself Acylamino- normal-butyl) -6- (indoles -3- ethyl)-piperazine-2,5-dione (6a-g).
Third content of the invention is evaluation (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of AA- amino) -6- (indoles - 3- ethyl) (AA is L-Ala residue, Gly residue, L-Met residue, L-IIe residue, L-Pro residual to-piperazine-2,5-dione in formula Base, L-Val residue and L-Leu residue) inhibit C57BL/6 mouse anti-lung cancer transfer activity.
4th content of the invention is evaluation (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of AA- amino) -6- (indoles - 3- ethyl) (AA is L-Ala residue, Gly residue, L-Met residue, L-IIe residue, L-Pro residual to-piperazine-2,5-dione in formula Base, L-Val residue and L-Leu residue) to the inhibiting effect of ICR mouse inflammation.
5th content of the invention is evaluation (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of AA- amino) -6- (indoles - 3- ethyl) (AA is L-Ala residue, Gly residue, L-Met residue, L-IIe residue, L-Pro residual to-piperazine-2,5-dione in formula Base, L-Val residue and L-Leu residue) inhibition application to S180 mice tumors grew.
Detailed description of the invention
Fig. 1 (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of AA- amino) -6- (indoles -3- ethyl)-piperazine-2,5-dione AA is L-Ala residue in the synthetic route .5a and 6a of (6a-c);AA is Gly residue in 5b and 6b;AA is L-Met in 5c and 6c Residue;AA is L-IIe residue in 5d and 6d;AA is L-Pro residue in 5e and 6e;AA is L-Val residue in 5f and 6f;5g and 6g Middle AA is L-Leu residue;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) dimethyl formyl Amine (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)-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) 12.1g (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 is slowly mixed together.Obtained solution stirs 5h in ice bath.Later, reaction mixture is concentrated under reduced pressure.Residue with 50mL without The dissolution of water ethyl acetate, obtained solution are concentrated under reduced pressure.The operation is in triplicate.Residue is sufficiently washed with anhydrous ether, is obtained 3.45g (92%) title compound is yellow powder.ESI-MS(m/e):557[M+H]+
Embodiment 3 prepares (3S, 6S) -3- (benzyloxycarbonyl group fourth amino) -6- (indoles -3- ethyl)-piperazine-2,5-dione (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 1.9g (55%) title compound out.ESI-MS(m/e):449[M+H]+
Embodiment 4 prepares (3S, 6S) -3- fourth amino -6- (indoles -3- ethyl)-piperazine-2,5-dione (2)
Toward 1.9g (4.2mmol) (3S, 6S) -3- (benzyloxycarbonyl group fourth amino) -6- (indoles -3- ethyl)-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 1.1g (83%) title compound, is white powder.ESI-MS (m/e): 315 [M+ H]+
Embodiment 5 prepares Boc- Amino-n-hexanoic acid
Add 5.23g (Boc) into the solution of 2.62g (20mmol) Amino-n-hexanoic acid and 30mL distilled water2O and 30mL dioxy The solution of six rings, obtained reaction solution adjust pH to 9 with the NaOH aqueous solution that concentration is 2N.It is stirred at room temperature for 24 hours, during which constantly subtracts Pressure pumping.Compound of reaction KHSO4Aqueous solution adjusts pH to 7, and removal dioxane is concentrated under reduced pressure.Remaining solution continues to use KHSO4Adjust pH to 2.Remaining solution is extracted with 100mL ethyl acetate, is water NaSO with nothing4Dry 8h.Filtering, filtrate decompression Concentration, obtains 4.36g (94%) title compound.ESI-MS(m/e):232[M+H]+
Embodiment 6 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Boc- amino) -6- (indoles -3- ethyl)-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, 6S) -3- ammonia amino normal-butyl -6- (indoles -3- ethyl)-piperazine -2,5- diketone (2) obtains 2.21g (71%) title compound, For colorless solid.ESI-MS(m/e):528[M+H]+.1H-NMR(300MHz,DMSO-d6): δ/ppm=10.865 (s, 1H), 8.018 (s, 1H), 7.918 (s, 3H), 7.586 (m, 2H), 7.313 (d, J=8.1Hz, 1H), 7.042 (m, 2H), 6.952 (m, 1H),6.744(s,1H),4.109(m,1H),3.640(m,1H),3.228(m,1H),3.031(m,1H),2.891(m,2H), 2.745 (m, 2H), 2.004 (t, J=7.2Hz, 2H), 1.575 (m, 2H), 1.431 (m, 10H), 1.118 (m, 3H), 0.970 (m,3H),0.612(m,3H)。
Embodiment 7 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of amino) -6- (indoles -3- ethyl)-piperazine -2,5- Diketone (4)
Using the method for embodiment 3 from 2.21g (4mmol) (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Boc- amino) - 6- (indoles -3- ethyl)-piperazine -2,5- diketone (3) obtains 1.45g (82%) title compound, is colourless powder.ESI-MS (m/z):428[M+H]+.1H NMR(300MHz,DMSO-d6): δ/ppm=10.947 (s, 1H), 8.056 (s, 1H), 7.936 (s, 3H), 7.664 (s, 1H), 7.598 (d, J=7.8Hz, 1H), 7.314 (d, J=8.1Hz, 1H), 7.045 (m, 2H), 6.906(m,1H),4.116(m,1H),3.507(m,1H),3.267(m,2H),3.059(m,1H),2.773(m,4H),2.067 (t, J=7.2Hz, 2H), 1.574-1.463 (m, 4H), 1.290 (m, 2H), 0.986 (m, 3H), 0.601 (m, 3H).
Embodiment 8 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Boc-Ala- amino) -6- (indoles -3- ethyl) - Piperazine-2,5-dione (5a)
Using the method for embodiment 1 from 679mg (3.6mmol) Boc-Phe and 1280mg (3mmol) (3S, 6S) -3- (ammonia The positive hexanoyl amino normal-butyl of base) -6- (indoles -3- ethyl)-piperazine-2,5-dione (4) obtains 820mg (45%) title compound Object is colorless solid.ESI-MS(m/z):599[M+H]+.1H NMR(300MHz,DMSO-d6): δ/ppm=10.884 (s, 1H), 8.037 (s, 1H), 7.936 (s, 1H), 7.749 (m, 1H), 7.588 (m, 2H), 7.314 (d, J=7.8Hz, 1H), 7.045 (m, 2H), 6.952 (m, 1H), 6.783 (d, J=8.4Hz, 1H), 4.111 (m, 1H), 3.941 (m, 1H), 3.769 (m, 1H), 3.535 (m, 2H), 3.219 (m, 1H), 3.042 (m, 3H), 2.768 (m, 2H), 2.028 (t, J=7.2Hz, 2H), 1.583-1.486(m,3H),1.437(m,13H),1.225(m,3H),0.991(m,3H),0.877(m,6H),0.609(m, 3H)。
Embodiment 9 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Boc-Gly- amino) -6- (indoles -3- ethyl) - Piperazine-2,5-dione (5b)
Using the method for embodiment 1 from 629mg (3.6mmol) Boc-Gly and 1280mg (3mmol) (3S, 6S) -3- (ammonia The positive hexanoyl amino normal-butyl of base) -6- (indoles -3- ethyl)-piperazine -2,5- diketone obtains 780mg (44%) title compound, be Colorless solid.ESI-MS(m/z):585[M+H]+.1H NMR(300MHz,DMSO-d6): δ/ppm=10.879 (s, 1H), 8.048 (m, 1H), 7.939 (m, 1H), 7.722 (m, 1H), 7.585 (m, 2H), 7.309 (d, J=8.1Hz, 1H), 7.038 (m, 2H),6.923(m,2H),4.107(m,1H),3.488(m,3H),3.214(m,1H),3.036(m,3H),2.891(m,2H), 2.027 (t, J=7.2Hz, 2H), 1.507 (m, 2H), 1.434 (m, 10H), 1.199 (m, 3H), 0.981 (m, 3H), 0.590 (m,3H)。
Embodiment 10 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Boc-Met- amino) -6- (indoles -3- ethyl) - Piperazine-2,5-dione (5c)
Using the method for embodiment 1 from 750mg (3.6mmol) Boc-Met and 1280mg (3mmol) (3S, 6S) -3- (ammonia The positive hexanoyl amino normal-butyl of base) -6- (indoles -3- ethyl)-piperazine-2,5-dione (4) obtains 650mg (33%) title compound Object is colorless solid.ESI-MS(m/z):659[M+H]+.1H NMR(300MHz,DMSO-d6): δ/ppm=10.877 (s, 1H), 8.036 (s, 1H), 7.931 (s, 1H), 7.587 (m, 2H), 7.315 (d, J=7.8Hz, 1H), 7.045 (m, 2H), 6.929(m,1H),6.73(m,1H),4.114(m,1H),3.502(m,1H),3.231(m,1H),3.043(m,1H),2.894 (m, 2H), 2.006 (t, J=7.2Hz, 2H), 1.481 (m, 13H), 1.267 (m, 2H), 0.981 (m, 3H), 0.613 (m, 3H).
Embodiment 11 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Boc-Ile- amino) -6- (indoles -3- ethyl) - Piperazine-2,5-dione (5d)
Using the method for embodiment 1 from 831mg (3.6mmol) Boc-IIe and 1280mg (3mmol) (3S, 6S) -3- (ammonia The positive hexanoyl amino normal-butyl of base) -6- (indoles -3- ethyl)-piperazine-2,5-dione (4) obtains 955mg (52%) title compound Object is colorless solid.ESI-MS(m/z):641[M+H]+.1H NMR(300MHz,DMSO-d6): δ/ppm=10.947 (s, 1H),8.519(m,1H),8.223(m,1H),8.047(s,1H),7.944(s,2H),7.658(m,1H),7.591(m,2H), 7.321(m,1H),6.929(m,1H),4.113(m,1H),3.927(m,1H),3.6275(m,1H),3.277(m,1H), 3.055(m,3H),2.773(m,2H),2.031(m,2H),1.810(s,1H),1.2.97(m,15H),1.138(m,3H), 0.981(m,2H),0.907(m,4H),0.843(m,6H),0.621(m,3H)。
Embodiment 12 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Boc-Pro- amino) -6- (indoles -3- ethyl) - Piperazine-2,5-dione (5e)
Using the method for embodiment 1 from from 770mg (3.6mmol) Boc-Pro and 1280mg (3mmol) (3S, 6S) -3- It is titled that (the positive hexanoyl amino normal-butyl of amino) -6- (indoles -3- ethyl)-piperazine-2,5-dione (4) obtains 1125mg (60%) Object is closed, is colorless solid.ESI-MS(m/z):625[M+H]+.1H NMR (300MHz, DMSO-d6): δ/ppm=10.897 (s, 1H),8.057(m,1H),7.945(m,1H),7.814(m,1H),7.587(m,2H),7.311(m,1H),7.040(m,2H), 6.927(m,1H),4.118(m,1H),4.001(m,1H),3.497(m,1H),3.179(m,2H),3.179(m,1H),3.023 (m,4H),2.756(m,2H),2.088(m,3H),1.738(m,4H),1.461(m,3H),1.392-.325(m,13H), 1.214(m,3H),0.936(m,3H),0.563(m,3H)。
Embodiment 13 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Boc-Val- amino) -6- (indoles -3- ethyl) - Piperazine-2,5-dione (5f)
Using the method for embodiment 1 from from 780mg (3.6mmol) Boc-Val and 1280mg (3mmol) (3S, 6S) -3- It is titled that (the positive hexanoyl amino normal-butyl of amino) -6- (indoles -3- ethyl)-piperazine-2,5-dione (4) obtains 870mg (46%) Object is closed, is colorless solid.ESI-MS(m/z):627[M+H]+.1H NMR(300MHz,DMSO-d6): δ/ppm=10.876 (s, 1H), 8.037 (m, 1H), 7.940 (m, 1H), 7.814 (m, 1H), 7.590 (m, 2H), 7.315 (d, J=7.8Hz, 1H), 7.045(m,2H),6.927(m,1H),6.817(m,1H),4.118(s,1H),3.927(m,1H),3.642(s,1H),3.233 (m,2H),3.079(m,3H),2.750(m,2H),2.590(m,5H),2.005(m,2H),1.896(m,1H),1.464(m, 3H),1.379(m,10H),1.238(m,3H),0.970(m,3H),0.822(m,6H),0.611(m,3H)。
Embodiment 14 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Boc-Leu- amino) -6- (indoles -3- ethyl) - Piperazine-2,5-dione (5g)
Using the method for embodiment 1 from from 766mg (3.6mmol) Boc-Leu and 1280mg (3mmol) (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of amino) -6- (indoles -3- ethyl)-piperazine -2,5- diketone (4) 915mg (46%) title compound, For colorless solid.ESI-MS(m/z):641[M+H]+.1H NMR(300MHz,DMSO-d6): δ/ppm=10.884 (s, 1H), 8.037 (s, 1H), 7.936 (s, 1H), 7.749 (m, 1H), 7.588 (m, 2H), 7.314 (d, J=7.8Hz, 1H), 7.045 (m, 2H),6.928(m,1H),6.783(m,1H),4.111(m,1H),3.927(m,1H),3.768(m,1H),3.532(m,1H), 3.219 (m, 1H), 3.029 (m, 3H), 2.768 (m, 2H), 2.005 (t, J=7.2Hz, 2H), 1.3 (m, 3H), 1.373 (m, 13H),1.225(m,3H),0.971(m,3H),0.856(m,6H),0.624(m,3H)。
Embodiment 15 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Ala- amino) -6- (indoles -3- ethyl)-piperazine Piperazine -2,5- diketone (6a)
Using the method for embodiment 3 from 600mg (1mmol) (3S, 6S) -3- (positive positive fourth of hexanoyl amino of Boc-Ala- amino Base) -6- (indoles -3- ethyl)-piperazine -2,5- diketone (5a) obtains 335mg (71%) title compound, and it is colorless solid. ESI-MS(m/z):499[M+H]+.Mp 159-160℃;[α]D 25=-26.9 (c=0.1, methanol);IR(KBr,cm-1): 3226,3007,2931,1651,1548,1455,1327,1259,1098,1009,742;1H NMR(300MHz,DMSO-d6): δ/ppm=10.945 (s, 1H), 8.477 (s, 1H), 8.303 (s, 3H), 8.061 (s, 1H), 7.949 (s, 1H), 7.657 (s, 1H), 7.590 (d, J=7.5Hz, 1H), 7.319 (d, J=8.1Hz, 1H), 7.045 (m, 2H), 6.951 (m, 1H), 4.114 (m,1H),3.797(m,1H),3.502(m,1H),3.277(m,1H),3.136-2.989(m,3H),2.766(m,2H), 2.028 (t, J=7.5Hz, 2H), 1.477 (m, 7H), 1.256 (m, 1H), 0.973 (m, 3H), 0.609 (m, 3H).
Embodiment 16 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Gly- amino) -6- (indoles -3- ethyl)-piperazine Piperazine -2,5- diketone (6b)
Using the method for embodiment 3, from 350mg (0.7mmol) (3S, 6S) -3-, (the positive hexanoyl amino of Boc-Gly- amino is just Butyl) -6- (indoles -3- ethyl)-piperazine -2,5- diketone (5b) obtains 214mg (73%) title compound, and it is colorless solid. ESI-MS(m/z):485[M+H]+.Mp 159-161℃;[α]D 25=-34.4 (c=0.1, methanol);IR(KBr,cm-1): 3218,3077,2928,2861,1659,1556,1455,1328,1262,1094,1010,918,742;1H NMR(300MHz, DMSO-d6): δ/ppm=10.927 (s, 1H), 8.393 (s, 1H), 8.052 (s, 3H), 7.947 (s, 1H), 7.640 (s, 1H), 7.590 (d, J=7.8Hz, 1H), 7.318 (d, J=8.1Hz, 1H), 7.027 (m, 2H), 6.927 (m, 1H), 4.114 (m, 1H), 3.502 (m, 3H), 3.276 (m, 1H), 3.075 (m, 3H), 2.769 (m, 2H), 2.027 (t, J=7.2Hz, 2H), 1.502-1.397(m,4H),1.154(m,2H),0.989(m,3H),0.613(m,3H)。
Embodiment 17 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Met- amino) -6- (indoles -3- ethyl)-piperazine Piperazine -2,5- diketone (6c)
Using the method for embodiment 3, from 650mg (1.2mmol) (3S, 6S) -3-, (the positive hexanoyl amino of Boc-Met- amino is just Butyl) -6- (indoles -3- ethyl)-piperazine -2,5- diketone (5c) obtains 490mg (90%) title compound, and it is colorless solid. ESI-MS(m/z):541[M+H]+.Mp 171-173℃;[α]D 25=-33.8 (c=0.1, methanol);IR(KBr,cm-1): 3307,3053,2934,1650,1455,1330,1097,742;1H NMR(300MHz,DMSO-d6): δ/ppm=10.947 (s, 1H), 8.519 (m, 1H), 8.223 (s, 3H), 8.047 (s, 1H), 7.944 (s, 1H), 7.658 (m, 1H), 7.591 (d, J= 7.8Hz, 1H), 7.321 (d, J=7.8Hz, 1H), 7.046 (m, 2H), 6.929 (m, 1H), 4.113 (m, 1H), 3.927 (m, 2H), 3.277-3.164 (m, 2H), 3.055-2.995 (m, 2H), 2.773 (m, 2H), 2.031 (t, J=6.9Hz, 2H), 1.810(s,1H),1.508-1.408(m,5H),1.342(m,2H),1.138(m,1H),0.981(m,3H),0.907-0.843 (m,6H),0.621(m,3H)。
Embodiment 18 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Ile- amino) -6- (indoles -3- ethyl)-piperazine Piperazine -2,5- diketone (6d)
Using the method for embodiment 3, from 650mg (1.2mmol) (3S, 6S) -3-, (the positive hexanoyl amino of Boc-Ile- amino is just Butyl) -6- (indoles -3- ethyl)-piperazine -2,5- diketone (5d) obtains 490mg (90%) title compound, and it is colorless solid. ESI-MS(m/z):541[M+H]+.Mp 171-173℃;[α]D 25=-33.8 (c=0.1, methanol);IR(KBr,cm-1): 3307,3053,2934,1650,1455,1330,1097,742;1H NMR(300MHz,DMSO-d6): δ/ppm=10.947 (s, 1H), 8.519 (m, 1H), 8.223 (s, 3H), 8.047 (s, 1H), 7.944 (s, 1H), 7.658 (m, 1H), 7.591 (d, J= 7.8Hz, 1H), 7.321 (d, J=7.8Hz, 1H), 7.046 (m, 2H), 6.929 (m, 1H), 4.113 (m, 1H), 3.927 (m, 2H), 3.277-3.164 (m, 2H), 3.055-2.995 (m, 2H), 2.773 (m, 2H), 2.031 (t, J=6.9Hz, 2H), 1.810(s,1H),1.508-1.408(m,5H),1.342(m,2H),1.138(m,1H),0.981(m,3H),0.907-0.843 (m,6H),0.621(m,3H)。
Embodiment 19 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Pro- amino) -6- (indoles -3- ethyl)-piperazine Piperazine -2,5- diketone (6e)
Using the method for embodiment 3, from 628mg (1.2mmol) (3S, 6S) -3-, (the positive hexanoyl amino of Boc-Pro- amino is just Butyl) -6- (indoles -3- ethyl)-piperazine -2,5- diketone (5e) obtains 286mg (54%) title compound, and it is colorless solid. ESI-MS(m/z):525[M+H]+.Mp 134-136℃;[α]D 25=-15.2 (c=0.1, methanol);IR(KBr,cm-1): 3226,3078,2929,2929,1651,1551,1455,1327,1258,1096,1010,743.1H NMR(300MHz, DMSO-d6): δ/ppm=10.929 (s, 1H), 8.568 (m, 1H), 8.045 (m, 2H), 7.641 (m, 1H), 7.641 (d, J= 7.8Hz, 1H), 7.319 (d, J=7.8Hz, 1H), 7.024 (m, 2H), 6.951 (m, 1H), 4.116 (m, 2H), 3.730 (m, 1H),3.277-2.988(m,7H),2.751(m,2H),2.496(m,1H),2.054(m,2H),1.712(m,3H),1.503- 1.406(m,4H),1.257(m,2H),0.974(m,3H),0.613(m,3H)。
Embodiment 20 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Val- amino) -6- (indoles -3- ethyl)-piperazine Piperazine -2,5- diketone (6f)
Using the method for embodiment 3 from 630mg (1mmol) (3S, 6S) -3- (positive positive fourth of hexanoyl amino of Boc-Val- amino Base) -6- (indoles -3- ethyl)-piperazine -2,5- diketone (5f) obtains 338mg (66%) title compound, and it is colorless solid. ESI-MS(m/z):527[M+H]+.Mp 169-172℃;[α]D 25=-11.5 (c=0.1, methanol);IR(KBr,cm-1): 3219,3075,2929,1651,1556,1455,1328,1254,742;1H NMR(300MHz,DMSO-d6): δ/ppm= 10.952 (s, 1H), 8.559 (t, J=5.4Hz, 1H), 8.218 (s, 3H), 8.055 (m, 1H), 7.941 (m, 1H), 7.679 (d, J=5.4Hz, 1H), 7.618 (d, J=8.1Hz, 1H), 7.319 (d, J=8.1Hz, 1H), 7.073-7.021 (m, 2H), 6.998-6.902(m,1H),4.114(m,1H),3.557(m,2H),3.539-3.141(m,2H),3.079(m,2H),2.770 (m,2H),2.054(m,3H),1.507-1.383(m,4H),1.247(m,2H),0.947(m,9H),0.643(m,3H)。
Embodiment 21 prepares (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Leu- amino) -6- (indoles -3- ethyl)-piperazine Piperazine -2,5- diketone (6g)
Using the method for embodiment 3 from 650mg (1mmol) (3S, 6S) -3- (positive positive fourth of hexanoyl amino of Boc-Leu- amino Base) -6- (indoles -3- ethyl)-piperazine -2,5- diketone (5g) obtains 305mg (56%) title compound, and it is colorless solid. ESI-MS(m/z):541[M+H]+.Mp 132-135℃;[α]D 25=-26.4 (c=0.1, methanol);IR(KBr,cm-1): 3232,2931,2161,1650,1557,1456,1330,1097,742;1H NMR(300MHz,DMSO-d6): δ/ppm= 10.930(s,1H),8.575(m,1H),8.224(s,3H),8.043(s,1H),7.941(s,1H),7.640(m,1H), 7.591 (d, J=7.8Hz, 1H), 7.320 (d, J=8.1Hz, 1H), 7.048 (m, 2H), 6.929 (m, 1H), 4.114 (m, 1H), 3.927 (m, 1H), 3.502 (m, 1H), 3.276-3.008 (m, 4H), 2.776 (m, 2H), 2.030 (t, J=7.2Hz, 2H),1.661-1.409(m,7H),1.267(m,2H),1.054(m,3H),0.981-0.901(m,6H),0.624(m,3H)。
The activity of resisting tumor metastasis of the measurement of embodiment 22 compound 6a-g
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-g 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-g, and activity and dose ratio they High 40 times of RGDS and high 10 times of compound 4 do not have significant difference.These statistics indicate that, the present invention has significant technology to imitate Fruit.
The activity of resisting tumor metastasis of 1 compound 6a-g of table
And physiological saline ratio p<0.01, a) with RGDS and compound 4 than p>0.05;N=12
Embodiment 23 measures the neoplasm growth activity of compound 6a-g
Adriamycin, compound 4 and compound 6a-g 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 4 or the daily normal saline solution (agent of oral administration of compound 6a-g 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-g and not only effectively inhibits tumour growth, but also their high 10 times compounds 4 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-g of table to S180 mice tumors grew
And physiological saline ratio p<0.05, a) with compound 4 than p>0.05;And physiological saline ratio p < 0.01, b) with compound 4 Than p > 0.05;N=12.
The anti-inflammatory activity of the measurement of embodiment 24 compound 6a-g
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-g therapeutic effect.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 1.11mmol/kg), (dosage is 0.5 μm of ol/ for 4 groups of compound (dosage is 5 μm of ol/kg) and compound 6a-g 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-g.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.In 0.5 μm of ol/kg agent It measures lower compound 6a-g and not only effectively inhibits mouse ear swelling caused by dimethylbenzene, but also activity and dose ratio he they are high by 10 Compound 4 again 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-g paraxylene of table
And physiological saline ratio p<0.05, a) with compound 4 than p>0.05;B) with physiological saline and compound 4 than p < 0.01; N=12.

Claims (5)

1. (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of AA- amino) -6- (indoles -3- ethyl)-piperazine -2,5- two of following formula Ketone, AA is that L-Ala residue, Gly residue, L-Met residue, L-IIe residue, L-Pro residue, L-Val residue and L-Leu are residual in formula Base,
Claim 2. (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of AA- amino) -6- (indoles -3- ethyl)-piperazine -2,5- two The preparation method of ketone, this method comprises:
(1) L-Boc-Lys (Cbz) and L-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) the ethyl acetate solution middle ring symphysis that Lys (Cbz)-Trp-OBzl is saturated in 5% sodium bicarbonate aqueous solution at (3S, 6S) -3- (Benzyloxycarbonylamino normal-butyl) -6- (indoles -3- ethyl)-piperazine-2,5-dione (1);
(4) the de- benzyloxycarbonyl group of 1 hydrogenolysis of compound obtains (3S, 6S) -3- (fourth amino) -6- (indoles -3- ethyl)-piperazine -2,5- Diketone (2);
(5) compound 2 and Boc- Amino-n-hexanoic acid are condensed (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Boc- amino) -6- (indoles -3- ethyl)-piperazine-2,5-dione (3);
(6) the de- Boc in the ethyl acetate solution of hydrogen chloride of compound 3 obtains (3S, 6S) -3- (positive positive fourth of hexanoyl amino of amino Base) -6- (indoles -3- ethyl)-piperazine-2,5-dione (4);
(7) compound 4 and Boc-AA (AA be L-Ala residue, Gly residue, L-Met residue, L-IIe residue, L-Pro residue and L-Val residue) it is condensed (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of Boc-AA- amino) -6- (indoles -3- ethyl)-piperazine - 2,5- diketone (5a-g);
(8) compound 5a-g de- Boc in the ethyl acetate solution of hydrogen chloride obtains (3S, 6S) -3- (positive hexanoyl ammonia of AA- amino Base normal-butyl) -6- (indoles -3- ethyl)-piperazine-2,5-dione (6a-g).
3. (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of AA- amino) -6- (indoles -3- ethyl)-piperazine -2 of claim 1, 5- diketone is preparing the application in medicine for anti transfer of tumor.
4. (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of AA- amino) -6- (indoles -3- ethyl)-piperazine -2 of claim 1, 5- diketone application in preparation of anti-tumor drugs.
5. (3S, 6S) -3- (the positive hexanoyl amino normal-butyl of AA- amino) -6- (indoles -3- ethyl)-piperazine -2 of claim 1, The application in preparing anti-inflammatory drugs of 5- diketone.
CN201710350163.6A 2017-05-18 2017-05-18 3S-indolylethyl-6S-fatty amino acid modified piperazine-2, 5-diketone and synthesis, activity and application thereof Expired - Fee Related CN108947975B (en)

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Citations (4)

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JPS61112060A (en) * 1984-11-02 1986-05-30 Fujisawa Pharmaceut Co Ltd Piperazine compound
CN105272980A (en) * 2014-06-10 2016-01-27 首都医科大学 (3R,12aS)-3-(4-aminobutyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione, 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
CN105503833A (en) * 2014-10-20 2016-04-20 首都医科大学 Indole piperazine dione compound, and preparation and treatment effect thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61112060A (en) * 1984-11-02 1986-05-30 Fujisawa Pharmaceut Co Ltd Piperazine compound
CN105272980A (en) * 2014-06-10 2016-01-27 首都医科大学 (3R,12aS)-3-(4-aminobutyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione, 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
CN105503833A (en) * 2014-10-20 2016-04-20 首都医科大学 Indole piperazine dione compound, and preparation and treatment effect thereof

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