CN108948137B - 3S-indolylethyl-6S-polar amino acid modified piperazine-2, 5-diketone and synthesis, activity and application thereof - Google Patents

3S-indolylethyl-6S-polar amino acid modified piperazine-2, 5-diketone and synthesis, activity and application thereof Download PDF

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CN108948137B
CN108948137B CN201710350297.8A CN201710350297A CN108948137B CN 108948137 B CN108948137 B CN 108948137B CN 201710350297 A CN201710350297 A CN 201710350297A CN 108948137 B CN108948137 B CN 108948137B
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piperazine
amino
indole
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butyl
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CN108948137A (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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    • C—CHEMISTRY; METALLURGY
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
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Abstract

The invention discloses (3S,6S) -3- (AA-amino n-hexyl amido n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-diketone with the following formula (wherein AA is L-Asp residue, L-Arg residue, L-Gln residue, L-Glu residue, L-Lys residue, L-Asn residue, L-Ser residue and L-Thr residue). Discloses a preparation method thereof, discloses the antitumor activity thereof, discloses the anti-tumor metastasis activity thereof and discloses the anti-inflammatory activity thereof, so that the invention discloses the application thereof in preparing antitumor drugs, anti-tumor metastasis drugs and anti-inflammatory drugs.
Figure DDA0001297609530000011

Description

3S-indolylethyl-6S-polar amino acid modified piperazine-2, 5-diketone and synthesis, activity and application thereof
Technical Field
The invention relates to (3S,6S) -3- (AA-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione. To their preparation, to their antitumor activity, to their antitumor metastatic activity, and to their anti-inflammatory activity, and thus to their use in the preparation of antitumor, antitumor metastatic and anti-inflammatory drugs. The invention belongs to the field of biological medicine.
Background
Tumors seriously threaten the health of human beings. In addition to the poor prognosis of patients with tumors by themselves, metastasis associated with tumors further worsens the prognosis of patients. For example, more than 90% of patients with tumors die from metastases. Because the existing antitumor drugs have no effect of resisting tumor metastasis, the clinical curative effect of tumor chemotherapy is not ideal. The invention relates to a medicament for resisting tumor metastasis, which is an urgent clinical need. The inventors have previously disclosed that diketopiperazines of the four S, S-, R, R-, R, S-and S, R-configurations inhibit migration and invasion of HCCLM3 (highly metastatic human liver cancer cells) at a concentration of 0.5. mu.M. Later, the inventors further disclosed that R, R-configured diketopiperazines inhibited tumor metastasis to the lung in C57BL/6 mice at a dose of 5. mu. mol/kg. However, the lowest effective dose is 5. mu. mol/kg. To reduce the minimum effective dose, the inventors have developed various modifications to the butylamino group of the diketopiperazine in the S, S-configuration. After 3 years of exploration, the amino-n-hexanoic acid acylated with polar side chain amino acids (L-Asp, L-Arg, L-Gln, L-Glu, L-Lys, L-Asn, L-Ser and L-Thr) acylated the butylamino group of diketopiperazine in S, S-configuration, not only reduced the minimum effective dose for anti-tumor metastasis to 0.5. mu. mol/kg, but also reduced the minimum effective dose for both anti-tumor and anti-inflammatory to 0.5. mu. mol/kg. The effective dose is reduced by 10 times, which shows that the structure modification has outstanding technical effect. Based on these findings, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention is to provide (3S,6S) -3- (AA-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione of the formula (wherein AA is an L-Asp residue, an L-Arg residue, an L-Gln residue, an L-Glu residue, an L-Lys residue, an L-Asn residue, an L-Ser residue and an L-Thr residue).
Figure BDA0001297609510000011
The second aspect of the present invention provides a method for synthesizing (3S,6S) -3- (AA-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (wherein AA is L-Asp residue, L-Arg residue, L-Gln residue, L-Glu residue, L-Lys residue, L-Asn residue, L-Ser residue and L-Thr residue), which comprises:
(1) condensing L-Boc-Lys (Cbz) and L-Trp-OBzl to obtain Boc-Lys (Cbz) -Trp-OBzl;
(2) Boc-Lys (Cbz) -Trp-OBzl is subjected to Boc removal in an ethyl acetate solution of hydrogen chloride to obtain Lys (Cbz) -Trp-OBzl;
(3) lys (Cbz) -Trp-OBzl is cyclized in a saturated ethyl acetate solution of a 5% sodium bicarbonate water solution to generate (3S,6S) -3- (benzyloxycarbonylamino n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (1);
(4) hydrogenolysis of compound 1 to remove benzyloxycarbonyl to give (3S,6S) -3- (butylamino) -6- (indole-3-ethyl) -piperazine-2, 5-dione (2);
(5) condensing the compound 2 with Boc-amino n-hexanoic acid to obtain (3S,6S) -3- (Boc-amino n-hexanoylamino n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (3);
(6) the compound 3 is subjected to Boc removal in an ethyl acetate solution of hydrogen chloride to obtain (3S,6S) -3- (amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-diketone (4);
(7) and condensing the compound 4 with Boc-AA (AA is L-Asp residue, L-Arg residue, L-Gln residue, L-Glu residue, L-Lys residue, L-Asn residue, L-Ser residue and L-Thr residue) to obtain (3S,6S) -3- (Boc-AA-amino n-hexylamido n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-diketone (5 a-h).
(8) The compound 5a-h was depbocylated in hydrogen chloride in ethyl acetate to give (3S,6S) -3- (AA-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (6 a-h).
The third aspect of the present invention is to evaluate the anti-lung cancer metastasis activity of (3S,6S) -3- (AA-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (wherein AA is L-Asp residue, L-Arg residue, L-Gln residue, L-Glu residue, L-Lys residue, L-Asn residue, L-Ser residue and L-Thr residue) in C57BL/6 mice.
A fourth aspect of the present invention is to evaluate the inhibitory effect of (3S,6S) -3- (AA-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (wherein AA is L-Asp residue, L-Arg residue, L-Gln residue, L-Glu residue, L-Lys residue, L-Asn residue, L-Ser residue and L-Thr residue) on ICR mouse inflammation.
A fifth aspect of the present invention is to evaluate the use of (3S,6S) -3- (AA-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (wherein AA is L-Asp residue, L-Arg residue, L-Gln residue, L-Glu residue, L-Lys residue, L-Asn residue, L-Ser residue and L-Thr residue) for inhibiting tumor growth in S180 mice.
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FIG. 1 is a synthetic route for (3S,6S) -3- (AA-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (6a-c) AA in 5a and 6a is an L-Asp residue; 5b AA is L-Arg (NO)2) Residue 6b, AA is an L-Arg residue; AA in 5c and 6c is L-Gln residue; AA in 5d is a L-Glu (OBzl) residue, and AA in 6d is a L-Glu residue; AA in 5e is a L-Lys (Cbz) residue, AA in 6e is a L-Lys residue; AA in 5f and 6f is L-Asn residue; AA in 5g and 6g is L-Ser residue; AA in 5h and 6h is an L-Thr residue; i) dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), Tetrahydrofuran (THF); ii) a solution of hydrogen chloride in ethyl acetate; iii) ethyl acetate, 5% sodium bicarbonate; iv) Dimethylformamide (DMF), Pd/C, H2。
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 preparation of Boc-Lys (Cbz) -Trp-OBzl
7.7g (20mmol) of Boc-Lys (Cbz) was suspended in 100mL of anhydrous Tetrahydrofuran (THF), and 2.7g (20mmol) of 1-hydroxybenzotriazole (HOBt) and 5.0g (25mmol) of Dicyclohexylcarbodiimide (DCC) were added to the suspension in this order under ice bath, followed by stirring for 30 min. Thereafter, 8.0g (25mmol) of Trp-OBzl was added. The reaction mixture was adjusted to pH 9 by dropwise addition of N-methylmorpholine (NMM). The reaction mixture was stirred first for 1h on ice and then for 12h at room temperature. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 150mL of ethyl acetate solution. The ethyl acetate solution obtained was successively treated with 5% KHSO4Washing with aqueous solution for 3 times, and saturating with NaCl waterThe solution was washed 3 times. Anhydrous Na for ethyl acetate layer2SO4Drying for 12h, filtering, and concentrating the filtrate under reduced pressure to dryness. The resulting yellow syrup was purified by silica gel column Chromatography (CH)2Cl2/CH3OH,100:1) 12.1g (88%) of the title compound are obtained as a colorless solid. ESI-MS (M/e):657[ M + H]+。
EXAMPLE 2 preparation of Lys (Cbz) -Trp-OBzl
Slowly mix in an ice bath with 3.8g (5mmol) Boc-Lys (Cbz) -Trp-OBzl and 52mL of ethyl acetate hydrogen chloride with stirring. The resulting solution was stirred in an ice bath for 5 h. After that, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 50mL of anhydrous ethyl acetate, and the resulting solution was concentrated under reduced pressure. This operation was repeated three times. The residue was washed thoroughly with anhydrous ether to give 3.45g (92%) of the title compound as a yellow powder. ESI-MS (M/e):557[ M + H ]]+。
EXAMPLE 3 preparation of (3S,6S) -3- (benzyloxycarbonylamino-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (1)
3.45g (6.2mmol) Lys (Cbz) -Trp-OBzl were dissolved in 150mL ethyl acetate. After the resulting solution was washed three times with a 5% aqueous solution of sodium hydrogencarbonate, the ethyl acetate solution was stirred at room temperature for 12 hours to sufficiently precipitate a colorless solid. 1.9g (55%) of the title compound are filtered off. ESI-MS (M/e):449[ M + H ]]+。
EXAMPLE 4 preparation of (3S,6S) -3-amino-n-butyl-6- (indole-3-ethyl) -piperazine-2, 5-dione (2)
To a solution of 1.9g (4.2mmol) of (3S,6S) -3- (benzyloxycarbonyl butylamino) -6- (indole-3-ethyl) -piperazine-2, 5-dione (1) in 20mL of anhydrous N, N-Dimethylformamide (DMF) was added 200mg of Pd/C, and H was introduced2The reaction was stirred at room temperature for 48 h. Pd/C was filtered off, and the filtrate was concentrated under reduced pressure to give 1.1g (83%) of the title compound as a white powder. ESI-MS (m/e): 315[ M + H ]]+。
EXAMPLE 5 preparation of Boc-amino-n-hexanoic acid
Add 5.23g (Boc) to a solution of 2.62g (20mmol) amino-n-hexanoic acid in 30mL distilled water2O and 30mL of dioxane, and the pH of the resulting reaction solution was adjusted to 9 with a 2N NaOH aqueous solution. Stirring at room temperature for 24h, continuously reducing pressureAnd (6) exhausting. KHSO for the reaction compound4Adjusting the pH value of the aqueous solution to 7, and removing dioxane by decompression and concentration. The remaining solution was further treated with KHSO4The pH was adjusted to 2. The remaining solution was extracted with 100mL ethyl acetate and anhydrous NaSO4Drying for 8 h. Filtration and concentration of the filtrate under reduced pressure gave 4.36g (94%) of the title compound. ESI-MS (M/e):232[ M + H]+。
EXAMPLE 6 preparation of (3S,6S) -3- (Boc-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (3)
From 0.97g (4.2mmol) Boc-amino-n-hexanoic acid and 1.9g (3.5mmol) (3S,6S) -3-amino-n-butyl-6- (indole-3-ethyl) -piperazine-2, 5-dione (2) 2.21g (71%) of the title compound were obtained as colorless solid using the method of example 1. 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)。
EXAMPLE 7 preparation of (3S,6S) -3- (amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (4)
From 2.21g (4mmol) (3S,6S) -3- (Boc-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (3) 1.45g (82%) of the title compound was obtained as a colourless powder using the method of example 3. 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)。
EXAMPLE 8 preparation of (3S,6S) -3- [ Boc-Asp (OBzl) -amino-n-hexylamido-n-butyl ] -6- (indole-3-ethyl) -piperazine-2, 5-dione (5a)
From 965mg (3.6mmol) Boc-Asp (OBzl) and 1280mg (3mmol) (3S,6S) -3- (amino-n-hexanamido-n-butyl) using the method of example 1Butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (4) gave 1034mg (47%) of the title compound as a colourless solid. ESI-MS (M/z) 733[ M + H]+；1H NMR(300MHz,DMSO-d6):δ/ppm＝10.874(s,1H),8.034(m,1H),7.932(m,1H),7.785(m,1H),7.591(m,2H),7.360(m,6H),7.076(m,3H),6.953(m,1H),6.869(m,1H),5.084(m,2H),4.342(m,1H),4.311(m,2H),3.554(m,2H),3.276(m,3H),3.009(m,3H),2.765(m,3H),2.624(m,1H),2.508(m,1H),2.026(m,2H),1.478(m,3H),1.455(m,12H),1.215(m,3H),1.039(m,4H),1.460(m,3H)。
EXAMPLE 9 preparation of (3S,6S) -3- [ Boc-Arg (NO)2) -amino-n-hexanoylamino-n-butyl]-6- (indole-3-ethyl) -piperazine-2, 5-dione (5b)
From 876mg (3.6mmol) of Boc-Arg (NO) by the method of example 12) And 1280mg (3mmol) of (3S,6S) -3- (amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (4) to give 985mg (49%) of the title compound as a yellow solid. ESI-MS (M/z):670[ M + H]+.1H NMR(300MHz,DMSO-d6):δ/ppm＝10.871(s,1H),8.034(m,1H),7.932(m,3H),7.775(m,1H),7.590(m,1H),7.316(d,J＝7.8Hz,1H),7.048(m,1H),6.931(m,1H),6.805(m,1H),4.114(m,2H),3.848(m,1H),3.502(m,1H),3.282(m,5H),3.031(m,3H),2.770(m,2H),2.028(t,J＝6.9Hz,2H),1.581(m,6H),1.380(m,12H),1.256(m,3H),0.973(m,4H),0.609(m,3H)。
EXAMPLE 10 preparation of (3S,6S) -3- (Boc-Gln-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (5c)
From 885mg (3.6mmol) Boc-Gln and 1280mg (3mmol) (3S,6S) -3- (amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (4) using the method of example 1, 1120mg (64%) of the title compound was obtained as a colorless solid. ESI-MS (M/z):656[ M + H]+.1H-NMR(300MHz,DMSO-d6):δ/ppm＝10.872(s,1H),8.033(s,1H),7.938(s,1H),7.743(s,1H),7.591(m,2H),7.317(m,2H),7.047(m,2H),6.931(m,1H),6.759(m,2H),4.112(m,1H),3.927(m,1H),3.502(m,1H),3.268(m,2H),3.083(m,3H),2.769(m,2H),2.036(m,4H),1.729(m,2H),1.492(m,2H),1.444(m,12H),1.237(m,3H),0.952(m,3H),0.617(m,3H)。
EXAMPLE 11 preparation of (3S,6S) -3- [ Boc-Glu (OBzl) -amino-n-hexylamido-n-butyl ] -6- (indole-3-ethyl) -piperazine-2, 5-dione (5d)
Using the method of example 1, from 1007mg (3.6mmol) Boc-Glu (OBzl) and 1280mg (3mmol) (3S,6S) -3- (amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (4), 1235mg (55%) of the title compound was obtained as a colorless solid. ESI-MS (M/z):747[ M + H]+.1H NMR(300MHz,DMSO-d6):δ/ppm＝10.872(s,1H),8.033(m,1H),7.932(m,1H),7.785(m,1H),7.564(m,2H),7.400(m,4H),7.287(m,1H),7.039(m,2H),6.953(m,1H),6.869(m,1H),5.084(m,2H),4.113(m,1H),3.907(m,1H),3.642(m,2H),3.281(m,1H),3.000(m,3H),2.768(m,2H),2.387(m,2H),2.362(m,2H),1.904(m,1H),1.809(m,1H),1.508(m,3H),1.437(m,10H),1.460(m,3H),1.435(m,3H),1.184(m,1H),1.095(m,3H)。
EXAMPLE 12 preparation of (3S,6S) -3- [ Boc-Lys (Cbz) -amino-n-hexylamido-n-butyl ] -6- (indole-3-ethyl) -piperazine-2, 5-dione (5e)
From 1100mg (3.6mmol) Boc-Lys (Cbz) and 1280mg (3mmol) (3S,6S) -3- (amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (4) the procedure of example 1 was employed to give 1265mg (56%) of the title compound as a colorless solid. ESI-MS (M/z):641[ M + H]+.1H NMR(300MHz,DMSO-d6):δ/ppm＝10.880(s,1H),8.044(s,1H),7.939(s,1H),7.743(s,1H),7.743(s,1H),7.587(m,2H),7.316(m,7H),7.027(m,2H),6.929(m,1H),6.727(m,1H),5.004(s,1H),4.113(m,2H),3.642(m,2H),3.231(m,4H),3.024(m,5H),2.953(m,2H),2.004(t,J＝7.5Hz,2H),1.437(m,18H),1.392(m,4H),0.981(m,4H),0.621(m,3H)。
EXAMPLE 13 preparation of (3S,6S) -3- (Boc-Asn-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (5f)
From 832mg (mmol) Boc-Asn and 1280mg (3mmol) (3S,6S) -3- (amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (4) 980mg (49%) of the title compound was obtained as a colorless solid using the method of example 1. ESI-MS (M/z):642[ M + H]+.1H NMR(300MHz,DMSO-d6):δ/ppm＝10.882(s,1H),8.035(m,1H),7.934(m,1H),7.770(s,1H),7.591(m,2H),7.318(m,2H),7.045(m,2H),6.955(m,3H),6.843(s,1H),4.114(m,2H),3.506(m,1H),3.233(m,1H),3.034(m,4H),2.770(m,2H),2.425(m,1H),2.029(m,2H),1.591(m,2H),1.458(m,13H),1.239(m,3H),0.991(m,3H),0.605(m,3H)。
EXAMPLE 14 preparation of (3S,6S) -3- (Boc-Ser-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (5g)
From 738mg (3.6mmol) of Boc-Ser and 1280mg (3mmol) of (3S,6S) -3- (amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (4) by the method of example 1, 598mg (32%) of the title compound are obtained as a colorless solid. ESI-MS (M/z) 615[ M + H]+.1H NMR(300MHz,DMSO-d6):δ/ppm＝10.929(s,1H),8.035(s,1H),7.920(s,1H),7.760(m,1H),7.590(m,2H),7.319(d,J＝8.1Hz,1H),7.045(m,2H),6.927(m,1H),6.562(m,1H),4.817(m,1H),4.118(m,1H),3.927(m,1H),3.642(m,1H),3.280-3.091(m,1H),3.005(m,3H),2.750(m,2H),2.009(t,J＝7.5Hz,2H),1.482(m,2H),1.384(m,11H),1.233(m,3H),0.977(m,4H),0.618(m,3H)。
EXAMPLE 15 preparation of (3S,6S) -3- (Boc-Thr-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (5h)
From 430mg (3.6mmol) Boc-Thr and 1280mg (3mmol) (3S,6S) -3- (amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (4) 880mg (46%) of the title compound are obtained as colorless solid by the method of example 1. ESI-MS (M/z):629[ M + H]+.1H NMR(300MHz,DMSO-d6):δ/ppm＝10.869(s,1H),8.027(m,1H),8.134(m,1H),7.732(m,1H),7.592(m,2H),7.317(m,1H),7.048(m,2H),6.956(m,1H),6.266(m,1H),5.763(s,1H),4.113(m,1H),3.867(m,1H),3.807(s,2H),3.504(m,1H),3.268(m,1H),3.120(m,2H),2.771(m,2H),2.008(t,J＝7.2Hz,2H),1.490(m,1H),1.393(m,9H),1.242(m,2H),1.035(m,5H),0.620(m,2H)。
EXAMPLE 16 preparation of (3S,6S) -3- (Asp-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (6a)
From 980mg (1.3mmol) of (3S,6S) -3- [ Boc-Asp (OBzl) -amino-n-hexylamido-n-butyl-Asp following the procedure of example 3]-6- (indole-3-ethyl) -piperazine-2, 5-dione (5a) gave 698mg (82%) (3)S,6S) -3- [ Asp (OBzl) -amino-n-hexanoyl-butylamino]-6- (indole-3-ethyl) -piperazine-2, 5-dione as colorless solid. ESI-MS (M/z) 646[ M + H]+. From 450mg (0.7mmol) of (3S,6S) -3- [ Asp (OBzl) -amino-n-hexanoyl-butylamino]-6- (indole-3-ethyl) -piperazine-2, 5-dione gave 304mg (67%) of the title compound as a colorless solid. ESI-MS (M/z):543[ M + H]+.Mp152-154℃；[α]D 25-19.8(c ═ 0.1, methanol); IR (KBr, cm)-1):3207,3055,2930,1660,1556,1455,1385,1331,1231,1096,742；1H NMR(300MHz,DMSO-d6):δ/ppm＝10.952(s,1H),8.059(s,1H),7.627(m,2H),7.319(d,J＝7.8Hz,1H),7.027(m,2H),6.953(m,1H),4.114(m,1H),3.505(m,1H),3.279(m,1H),3.539-3.141(m,3H),3.079(m,2H),2.770(m,1H),2.030(m,1H),2.044(t,J＝7.2Hz,2H),1.507-1.383(m,4H),1.247(m,2H),0.947(m,3H),0.643(m,3H)。
EXAMPLE 17 preparation of (3S,6S) -3- (Arg-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (6b)
From 700mg (1mmol) of (3S,6S) -3- [ Boc-Arg (NO) according to the method of example 32) -amino-n-hexanoylamino-n-butyl]-6- (indole-3-ethyl) -piperazine-2, 5-dione (5b) gave 312mg (60%) (3S,6S) -3- [ Arg (NO)2) -amino-n-hexanoylamino-n-butyl]-6- (indole-3-ethyl) -piperazine-2, 5-dione as colorless solid. ESI-MS (M/z):630[ M + H]+. From 410mg of (3S,6S) -3- [ Arg (NO) according to the method of example 42) -amino-n-hexanoylamino-n-butyl]-6- (indole-3-ethyl) -piperazine-2, 5-dione gave 298mg (73%) of the title compound as a colorless solid. ESI-MS (M/z):584[ M + H]+.Mp167-169℃；[α]D 25-29.9(c ═ 0.1, methanol); IR (KBr, cm)-1):3226,2928,1651,1539,1454,1328,1259,1095,742；1H NMR(300MHz,DMSO-d6):δ/ppm＝10.952(s,1H),8.568(s,1H),8.235(s,3H),7.927(m,1H),7.319(d,J＝7.8Hz,1H),7.319(d,J＝8.1Hz,1H),7.027(m,2H),6.953(m,1H),4.114(m,1H),3.730(m,1H),3.279(m,1H),3.539-3.141(m,6H),3.079(m,2H),2.770(m,1H),2.044(t,J＝7.2Hz,2H),1.712(m,2H),1.507-1.383(m,6H),1.247(m,2H),0.947(m,3H),0.643(m,3H)。
EXAMPLE 18 preparation of (3S,6S) -3- (Gln-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (6c)
From 655mg (1mmol) (3S,6S) -3- (Boc-Gln-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (5c) was obtained 425mg (76%) of the title compound as a colorless solid according to the method of example 3. ESI-MS (M/z):556[ M + H]+.Mp:161-163℃；[α]D 25-153.5(c ═ 0.1, methanol); IR (KBr, cm)-1):3187,3074,2934,1659,1454,1330,1259,1095,742,1H-NMR(300MHz,DMSO-d6):δ/ppm＝10.949(m,1H),8.572(t,J＝5.4Hz,1H),8.289(s,3H),8.054(m,1H),7.948(m,1H),7.665(t,J＝5.4Hz,1H),7.590(d,J＝7.8Hz,1H),7.516(s,1H),7.321(d,J＝8.1Hz,1H),7.046-7.000(m,2H),6.996-6.901(m,2H),4.115(m,1H),3.927(m,1H),3.502(m,1H),3.264-3.076(m,4H),2.796(m,2H),2.202(m,2H),2.037(m,2H),1.928(m,2H),1.508-1.389(m,4H),1.269-1.219(m,2H),0.954(m,3H),0.646-0.526(m,3H)。
EXAMPLE 19 preparation of (3S,6S) -3- (Glu-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (6d)
From 1000mg (1.3mmol) of (3S,6S) -3- [ Boc-Glu (OBzl) -amino-n-hexanoylamido-n-butyl-according to the method of example 3]-6- (indole-3-ethyl) -piperazine-2, 5-dione (5d) gave 786mg (90%) (3S,6S) -3- [ Glu (OBzl) -amino-n-hexylamido-n-butyl-amide]-6- (indole-3-ethyl) -piperazine-2, 5-dione as colorless solid. ESI-MS (M/z):647[ M + H]+. From 500mg (0.77mmol) of (3S,6S) -3- [ Glu (OBzl) -amino-n-hexanoyl-butylamino according to the method of example 4]-6- (indole-3-ethyl) -piperazine-2, 5-dione gave 380mg (76%) of the title compound as a white solid. ESI-MS (M/z):557[ M + H ]]+.Mp:144-146℃；[α]D 25-23.4(c ═ 0.1, methanol); IR (KBr, cm)-1):3223,3079,2929,1660,1549,1455,1396,1259,1097,1010,742；1H NMR(300MHz,DMSO-d6):δ/ppm＝10.952(s,1H),8.559(s,1H),7.935(s,1H),7.607(m,2H),7.319(d,J＝7.8Hz,1H),7.045(m,2H),6.953(m,1H),5.083(s,5H),4.114(m,1H),3.505(m,1H),3.279(m,2H),3.539-3.141(m,3H),3.079(m,2H),2.770(m,2H),2.030(m,2H),2.054(m,2H),1.507-1.383(m,4H),1.247(m,2H),0.947(m,3H),0.643(m,3H)。
EXAMPLE 20 preparation of (3S,6S) -3- (Lys-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (6e)
From 755mg (1mmol) of (3S,6S) -3- [ Boc-Lys (Cbz) -amino-n-hexanoylamino-n-butyl according to the method of example 3]-6- (indole-3-ethyl) -piperazine-2, 5-dione (5e) to give 598mg (91%) (3S,6S) -3- [ Lys (Cbz) -amino-n-hexylamido-n-butyl]-6- (indole-3-ethyl) -piperazine-2, 5-dione as colorless solid. ESI-MS (M/z):655[ M + H]+. From 520mg (0.8mmol) of (3S,6S) -3- [ Lys (Cbz) -amino-n-hexanoylamido-n-butyl according to the method of example 4]-6- (indole-3-ethyl) -piperazine-2, 5-dione gave 425mg (84%) of the title compound as a solid without. ESI-MS (M/z):556[ M + H]+.Mp 159-162℃；[α]D 25-36.7(c ═ 0.1, methanol); IR (KBr, cm)-1):3214,3054,2929,2861,1651,1556,1455,1328,1254,1099,742；1H NMR(300MHz,DMSO-d6):δ/ppm＝10.952(s,1H),8.668(s,1H),8.310(s,3H),8.076(s,3H),7.960(s,1H),7.717(s,1H),7.319(d,J＝7.8Hz,1H),7.319(d,J＝7.8Hz,1H),7.027(m,2H),6.953(m,1H),4.114(m,1H),3.730(m,1H),3.279(m,1H),3.265(m,1H),3.170-3.005(m,3H),2.766(m,4H),2.062(t,J＝8.1Hz,2H),1.745(m,2H),1.593(m,2H),1.480(m,6H),1.247(m,2H),0.947(m,3H),0.643(m,3H)。
EXAMPLE 21 preparation of (3S,6S) -3- (Asn-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (6f)
From 710mg (1.1mmol) of (3S,6S) -3- (Boc-Asn-amino-n-hexanoyl-butylamino) -6- (indole-3-ethyl) -piperazine-2, 5-dione (5f) 412mg (68%) of the title compound are obtained as colorless solid according to the method of example 3. ESI-MS (M/z):542[ M + H]+.Mp 183-185℃；[α]D 25-23.9(c ═ 0.1, methanol); IR (KBr, cm)-1):3232,2931,2161,1650,1557,1456,1330,1096,744；1H NMR(300MHz,DMSO-d6):δ/ppm＝10.882(s,1H),8.045(s,1H),7.941(s,1H),7.856(m,1H),7.590(m,2H),7.382(s,1H),7.314(d,J＝8.1Hz,1H),7.046(m,2H),6.955(m,1H),6.843(s,1H),4.114(m,1H),3.506(m,1H),3.444(m,1H),3.280(m,1H),3.045(m,3H),2.768(m,2H),2.425-2.363(m,1H),2.159(m,1H),2.014(m,3H),1.492-1.367(m,4H),1.239(m,2H),0.991(m,3H),0.605(m,3H)。
EXAMPLE 22 preparation of (3S,6S) -3- (Ser-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (6g)
From 620mg (1mmol) (3S,6S) -3- (Boc-Ser-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (5g) 390mg (75%) of the title compound were obtained as colorless solid according to the method of example 3. ESI-MS (M/z) 515[ M + H]+.Mp 155-157℃；[α]D 25-15.3(c ═ 0.1, methanol); IR (KBr, cm)-1):3227,3080,2929,1651,1328,1261,1095,1062,743；1H NMR(300MHz,DMSO-d6):δ/ppm＝10.929(s,1H),8.514(t,J＝4.8Hz,1H),8.155(s,3H),8.046(m,1H),7.940(m,1H),7.658(m,2H),7.648(d,J＝8.1Hz,1H),7.047-7.024(m,2H),6.997-6.902(m,1H),5.482(s,1H),4.118(m,1H),3.927(m,3H),3.642(m,1H),3.280-3.091(m,1H),3.005(m,3H),2.750(m,2H),2.050(t,J＝7.2Hz,2H),1.526-1.378(m,4H),1.154(m,2H),0.977(m,3H),0.645-0.529(m,3H)。
EXAMPLE 23 preparation of (3S,6S) -3- (Thr-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (5h)
From 628mg (1mmol) (3S,6S) -3- (Boc-Thr-amino-n-hexylamido-n-butyl) -6- (indole-3-ethyl) -piperazine-2, 5-dione (5h) 405mg (64%) of the title compound was obtained as colorless solid according to the method of example 3. ESI-MS (M/z):529[ M + H]+.Mp 152-154℃；[α]D 25-17.2(c ═ 0.1, methanol); IR (KBr, cm)-1):3231,3080,2930,2860,1651,1556,1455,1097,1010,742；1H NMR(300MHz,DMSO-d6):δ/ppm＝10.928(m,1H),8.584(m,1H),8.134(s,3H),8.046(m,1H),7.940(m,1H),7.661(m,1H),7.625(d,J＝7.8Hz,1H),7.319(d,J＝8.1Hz,1H),7.047-7.000(m,2H),6.997-6.902(m,1H),5.561(s,1H),4.113(m,1H),3.867(m,1H),3.642(m,2H),3.228(m,1H),3.076(m,3H),3.005(m,2H),2.750(t,J＝7.2Hz,2H),1.531-1.383(m,4H),1.297-1.179(m,2H),1.123(m,3H),1.001-0.931(m,3H),0.647-0.529(m,3H)。
EXAMPLE 24 determination of the anti-tumor metastatic Activity of Compounds 6a-h
The assay model was inoculated with Lewis mouse lung carcinoma cells (LLC, purchased from ATCC) in DMEM medium (containing 10% inactivated fetal bovine serum, 1X 10)5U/L penicillin and 100mg/L streptomycin), and the cells are enriched by passage every two days according to an adherent cell culture method. Digesting the cells when the cells are in good growth state and in logarithmic growth phase, and adjusting the cell density to 1 × 10 with physiological saline7one/mL. Staining with placental blue to count viable cells>95 percent. Inbred C57BL/6 male mice (SPF grade, body weight 20. + -.2 g) were taken and left-handed mice fixed. The right anterior limb axillary skin of the mouse was disinfected with 75% ethanol. The LLC tumor cell suspension is injected subcutaneously into the axilla of a mouse with a 1mL sterile syringe held in the right hand, and 0.2mL is injected into each mouse. After the mice are inoculated for 10 days, tumors with the diameter of about 4-5mm grow out, namely the tumor source. The Lewis lung cancer tumor-bearing mice are inoculated for 10 days and anesthetized by ether, and then the cervical vertebrae are removed for killing. Soaking in 75% ethanol for 10min, sterilizing, and removing tumor on clean bench. Well-grown tumor tissue was selected, minced in a sterile plate, and placed in a tissue homogenizer made of glass. Adding physiological saline with the temperature of 4 ℃ according to the ratio of the tumor mass to the volume of the physiological saline of 1 to 3(g to mL), and lightly grinding to prepare the cell suspension. The cell suspension is screened by 200-mesh cells to prepare single cell suspension. Adjusting the cell density of the single cell suspension to 1.5X 10 with physiological saline7one/mL. Staining with placental blue to count viable cells>95 percent. Left-handed inbred C57BL/6 male mice were fixed and their right anterior limb axillary skin was disinfected with 75% ethanol. The tumor cell suspension was injected subcutaneously into the mouse axilla with a 1mL sterile syringe in the right hand, 0.2mL each. 10 days after inoculation, the mice developed tumors of 4-5mm in diameter, and the inoculated mice were randomly grouped by the measured tumor volume. Each group had 12 mice. Mice on day 11 of tumor inoculation were orally administered either a normal saline solution of the putative antitumor metastatic peptide RGDS (dose of 20. mu. mol/kg/day) or compounds 6a-h (dose of 0.5. mu. mol/kg/day) or compound 4 (dose of 5. mu. mol/kg/day) or compound 4 (dose of 10 mL/kg/day) 1 dose per day for 12 consecutive days, and tumor volumes were measured and recorded every two days. Measuring tumor volume the next day of the last administration, removing cervical vertebra by ether anesthesia, and collecting the swelling of mouseTumors were weighed, mice lungs were taken and tumor nodules were counted for tumor lung metastases. Statistical analysis of the data was performed using the t-test. The results are shown in Table 1. At a dose of 0.5 μmol/kg, compounds 6a-h were not only effective in inhibiting tumor lung metastasis, but also had no significant difference in activity from their doses of 40 RGDS and 10-fold higher compound 4. These data indicate that the present invention has significant technical effects.
TABLE 1 antitumor metastatic Activity of Compounds 6a-h
Figure BDA0001297609510000101
b) P <0.01 to saline, p >0.05 to RGDS and compound 4; n-12
EXAMPLE 25 determination of the anti-tumor growth Activity of Compounds 6a-h
Doxorubicin, compound 4 and compounds 6a-h were all dissolved in saline prior to assay for administration to S180 mice. Taking S180 ascites tumor liquid which is inoculated in a male ICR mouse and grows vigorously for 10 days in a sterile environment, diluting the S180 ascites tumor liquid into liquid (1:2) by using normal saline, fully mixing the liquid, dyeing the tumor cell suspension by using freshly prepared 0.2% trypan blue, uniformly mixing the liquid and the liquid, counting the liquid according to a white cell counting method, wherein the blue-dyed cell is a dead cell, and the non-dyed cell is a live cell. The cell concentration is 4-large-grid viable cell number/4 × 104The cell density was calculated as x dilution factor ═ cell number/mL, and the cell survival rate was calculated as live cell number/(live cell number + dead cell number) × 100%. Homogenizing tumor solution with survival rate of more than 90% to density of 2.0 × 107Cell suspension per mL. This cell suspension was inoculated subcutaneously (0.2 mL/mouse) in the right axilla of a mouse to prepare S180 tumor-bearing mice. 24h after inoculation, S180 tumor-bearing mice were intraperitoneally injected daily with a normal saline solution of doxorubicin (dose 2. mu. mol/kg/day g) or daily orally administered with a normal saline solution of Compound 4 (dose 5. mu. mol/kg/day) or daily orally administered with a normal saline solution of Compounds 6a-h (dose 0.5. mu. mol/kg/day). The administration is once daily for 12 days. The next day of the last administration, tumor volume was measured, cervical vertebrae were removed by ether anesthesia, and then the growing part of the right axillary tumor of the mouse was fixed with forcepsThe tumors were dissected blunt dissected and weighed. Efficacy was expressed as tumor weight (mean ± SD g), and data were analyzed by t-test and variance. The results are shown in Table 2. Compounds 6a-h were not only effective at 0.5 μmol/kg dose in inhibiting tumor growth, but also had no significant difference in activity from compound 4, which was 10-fold higher in dose than them. These data indicate that the present invention has significant technical effects.
TABLE 2 Effect of Compounds 6a-h on tumor growth in S180 mice
Figure BDA0001297609510000111
a) P <0.05 to saline, p >0.05 to compound 4; b) p <0.01 to saline, p >0.05 to compound 4; c) p is less than 0.01 compared with normal saline and normal saline; n is 12.
EXAMPLE 26 determination of the anti-inflammatory Activity of Compounds 6a-h
Since xylene-induced ear swelling in mice is recognized as an acute inflammation model, the present invention measures the therapeutic effect of compounds 6a-h on a xylene-induced ear swelling model in mice. Because aspirin is a positive drug for treating acute inflammation, aspirin is selected as a positive control in the present invention. ICR male mice (body weight 42 + -3 g) were allowed to rest for 2 days at 22 deg.C, with free access to water and food. Thereafter, the mice were randomly divided into a saline group (dose of 0.2 mL/mouse), an aspirin group (dose of 1.11mmol/kg), a compound 4 group (dose of 5. mu. mol/kg) and compound 6a-h groups (dose of 0.5. mu. mol/kg), and 12 mice were each group. The mice were tested either orally with normal saline, orally with aspirin, orally with compound 4, or orally with compound 6a-h, as indicated. After 30min of administration, the left auricle of the mouse was evenly smeared with 30 μ L of xylene, and after 2h, the mouse was subjected to ether anesthesia, the neck was cut off, the left and right ears were cut off, round ears were taken at the same positions of the two ears by a 7mm punch, and the difference in swelling between the two ears was weighed and found to be the swelling degree. Namely the swelling degree is equal to the weight of the left ear disk to the weight of the right ear disk. Compounds 6a-h were not only effective at 0.5 μmol/kg dose in inhibiting xylene-induced ear swelling in mice, but were not significantly different in activity from compound 4, which was 10-fold higher than their dose. These data indicate that the present invention has significant technical effects.
TABLE 3 Effect of Compounds 6a-h on xylene-induced ear swelling in mice
Figure BDA0001297609510000121
a) P <0.05 to saline, p >0.05 to compound 4; b) p <0.01 to saline and compound 4; n is 12.

Claims (5)

1. (3S,6S) -3- (AA-amino-n-hexylamido-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione of the formula, wherein AA is an L-Asp residue, an L-Arg residue, an L-Gln residue, an L-Glu residue, an L-Lys residue, an L-Asn residue, an L-Ser residue or an L-Thr residue,
Figure FDA0003063078090000011
2. a process for the preparation of (3S,6S) -3- (AA-amino-n-hexylamido-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione as claimed in claim 1, which comprises:
(1) condensing L-Boc-Lys (Cbz) and L-Trp-OBzl to obtain Boc-Lys (Cbz) -Trp-OBzl;
(2) Boc-Lys (Cbz) -Trp-OBzl is subjected to Boc removal in an ethyl acetate solution of hydrogen chloride to obtain Lys (Cbz) -Trp-OBzl;
(3) lys (cbz) -Trp-OBzl was dissolved in ethyl acetate, and the resulting solution was washed with a 5% aqueous solution of sodium hydrogencarbonate and cyclized to give (3S,6S) -3- (benzyloxycarbonylbutylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (1);
(4) the compound 1 is subjected to hydrogenolysis to remove benzyloxycarbonyl to obtain (3S,6S) -3- (amino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (2);
(5) condensing the compound 2 and Boc-amino n-hexanoic acid to obtain (3S,6S) -3- (Boc-amino n-hexanoylamino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (3);
(6) the compound 3 is subjected to Boc removal in an ethyl acetate solution of hydrogen chloride to obtain (3S,6S) -3- (amino-n-hexylamido-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-diketone (4);
(7) condensing the compound 4 with Boc-AA to obtain (3S,6S) -3- (Boc-AA-amino n-hexyl amido n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-diketone (5 a-h);
(8) compound 5a-h was Boc-removed in hydrogen chloride in ethyl acetate to give (3S,6S) -3- (AA-amino-n-hexylamido-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (6 a-h).
3. Use of (3S,6S) -3- (AA-amino-n-hexylamido-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1 for the preparation of a medicament for the prevention of lung cancer metastasis.
4. Use of (3S,6S) -3- (AA-amino-n-hexylamido-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1 for the preparation of a medicament against S180 ascites tumor.
5. Use of (3S,6S) -3- (AA-amino-n-hexylamido-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1 for the preparation of a medicament for the treatment of acute inflammation.
CN201710350297.8A 2017-05-18 2017-05-18 3S-indolylethyl-6S-polar amino acid modified piperazine-2, 5-diketone and synthesis, activity and application thereof Expired - Fee Related CN108948137B (en)

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EP2594134A2 (en) * 2010-07-15 2013-05-22 Republic of Korea (Management: Rural Development Administration) Agricultural chemical containing 2,5-diketopiperazine derivative as active ingredient
CN104098549A (en) * 2014-08-01 2014-10-15 华东理工大学 Piperazinedione derivative and preparation and application thereof
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