CN108947978B - 3R-indolylmethyl-6R-Tyr modified piperazine-2, 5-diketone and synthesis, activity and application thereof - Google Patents
3R-indolylmethyl-6R-Tyr modified piperazine-2, 5-diketone and synthesis, activity and application thereof Download PDFInfo
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Abstract
The invention discloses (3R,6R) -3- (Tyr-amino n-hexanoylamino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione with the following formula. Discloses a preparation method thereof, discloses the antitumor activity thereof, discloses the anti-tumor metastasis activity thereof and discloses the anti-inflammatory activity thereof, and thus the invention discloses the application thereof in preparing antitumor drugs, anti-tumor metastasis drugs and anti-inflammatory drugs.
Description
Technical Field
The invention relates to (3R,6R) -3- (Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione. Relates to its preparation method, its antitumor activity, its anti-tumor metastasis activity and its anti-inflammatory activity, so that the present invention relates to its application in preparing antitumor medicine, antitumor metastasis medicine and anti-inflammatory medicine. 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 R, R-configuration. After 3 years of exploration, the N-butylamino of diketopiperazine with R, R-configuration acylated with L-Tyr acylated amino caproic acid can not only reduce the minimum effective dose of anti-tumor metastasis to 0.5 mu mol/kg, but also reduce the minimum effective dose of anti-tumor and anti-inflammatory to 0.5 mu mol/kg. Because the toxic and side effects of the medicine can disappear along with the reduction of the dosage, the reduction of the effective dosage by 10 times 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 provides (3R,6R) -3- (Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione of the formula.
The second content of the invention is to provide a synthesis method of (3R,6R) -3- (Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-diketone, which comprises the following steps:
(1) D-Boc-Lys (Cbz) and D-Trp-OBzl are condensed 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 saturated ethyl acetate containing 5 percent of sodium bicarbonate water solution to generate (3R,6R) -3- (benzyloxycarbonylamino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (1);
(4) the compound 1 is subjected to hydrogenolysis to remove benzyloxycarbonyl to obtain (3R,6R) -3- (amino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (2);
(5) condensing the amino n-hexanoic acid methyl ester and Cbz-L-Tyr to obtain Cbz-Tyr-amino n-hexanoic acid methyl ester (3);
(6) saponifying and removing methyl ester from the compound 3 to obtain Cbz-Tyr-amino n-hexanoic acid (4);
(7) condensing the compound 2 and the compound 4 to obtain (3R,6R) -3- (Cbz-Tyr-amino n-hexanoyl amino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-diketone (5);
(8) the compound 5 is subjected to hydrogenolysis in dimethylformamide to remove Cbz protection to obtain (3R,6R) -3- (Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-diketone (6).
The third aspect of the present invention is to evaluate the anti-lung cancer metastasis activity of (3R,6R) -3- (Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione in C57BL/6 mice.
The fourth aspect of the present invention is to evaluate the inhibitory effect of (3R,6R) -3- (Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione on the inflammation of ICR mice.
The fifth aspect of the present invention is to evaluate the use of (3R,6R) -3- (Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione for inhibition of tumor growth in S180 mice.
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FIG. 1(3R,6R) -3- (Tyr-amino-N-hexanoylamino-N-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione synthetic route. 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(ii) a v) Dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), N, N-Dimethylformamide (DMF); vi) methanol, NaOH (2M).
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) Boc-Lys (Cbz) was suspended in 100mL dry Tetrahydrofuran (THF), and 2.7g (20mmol) 1-hydroxybenzene was added to the suspension successively under ice bathTriazole (HOBt) and 5.0g (25mmol) Dicyclohexylcarbodiimide (DCC) and then stirred 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% KHSO4The aqueous solution was washed 3 times, and the saturated NaCl aqueous 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) 12.0g (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
3.8g (5mmol) Boc-Lys (Cbz) -Trp-OBzl was slowly mixed with 52mL of an ethyl acetate solution of hydrogen chloride (4M) with stirring in an ice bath. 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 3.41g (93%) of the title compound as a yellow powder. ESI-MS (M/e):557[ M + H ]]+。
EXAMPLE 3 preparation of (3R,6R) -3- (benzyloxycarbonylamino-n-butyl) -6- (indole-3-methyl) -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. 1.8g (51%) of the title compound are filtered off. ESI-MS (M/e):449[ M + H ]]+。
EXAMPLE 4 preparation of (3R,6R) -3- (amino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (2)
To a solution of 1.9g (4.2mmol) of (3R,6R) -3- (benzyloxycarbonyl butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (1) in 20mL of anhydrous N, N-Dimethylformamide (DMF) was added 200mg of Pd/C, and H was bubbled through2The reaction was stirred at room temperature for 48 h. Filtering to remove Pd/C, filteringThe solution was concentrated under reduced pressure to give 1.2g (92%) of the title compound as a colorless powder. ESI-MS (m/e): 315[ M + H ]]+.
EXAMPLE 5 preparation of amino-n-hexanoic acid methyl ester
5.6mL of thionyl chloride was added dropwise to 40mL of methanol, and after activation for 30min, 2.62g (20mmol) of aminohexanoic acid was added thereto and stirred at room temperature for 12 hours. Pumping the reaction solution under reduced pressure by using a water pump under stirring of the reaction compound in a 37 ℃ warm water bath, adding dry methanol for dissolving, then pumping the reaction solution under reduced pressure by using a water pump, and repeating the steps for 3 times; the suspension was suspended by adding anhydrous ether, and the mixture was dried under reduced pressure with stirring in a warm water bath at 37 ℃ and repeated 3 times to obtain 2.72g (95%) of the title compound. ESI-MS (M/e) 145[ M + H]+
EXAMPLE 6 preparation of Cbz-Tyr-amino-n-hexanoic acid methyl ester (3b)
Using the method of example 1, from 1580mg (5.0mmol) of Cbz-Tyr and 720mg (5.0mmol) of methyl aminohexanoate, 1830mg (83%) of the title compound are obtained as a colorless solid. ESI-MS (M/e):443[ M + H]+。
EXAMPLE 7 preparation of Cbz-Tyr-amino-n-hexanoic acid (4)
1.32g (3.0mmol) Cbz-Tyr-amino-n-hexanoic acid methyl ester (3) in 20mL CH3OH is dissolved. And adding NaOH aqueous solution (2M) into the obtained solution under the stirring of ice bath to adjust the pH value to 12, and stirring and reacting for 6 hours in ice bath. Stirring in ice bath, and reacting with saturated KHSO4The pH value of the solution is adjusted to 7, and the obtained solution is concentrated under reduced pressure. The residue was treated with 5% KHSO4The aqueous solution adjusted the pH to 2. The resulting solution was extracted 3 times with ethyl acetate, and the ethyl acetate solution was washed with saturated aqueous NaCl solution to neutrality. Anhydrous Na for ethyl acetate layer2SO4Drying for 12h, filtering, and concentrating the filtrate under reduced pressure to dryness. 1.45g of a pale yellow syrup was obtained as the title compound. ESI-MS (M/e):429[ M + H ]]+。
EXAMPLE 8 preparation of (3R,6R) -3- (Cbz-Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (5)
From 1450mg of light yellow syrup of Cbz-Tyr-amino-n-hexanoic acid (4) and 940mg (3.0mmol) of (3R,6R) -3-butylamino-6- (indole-3-methyl) -piperazine-2, 5-dione (2) using the method of example 1, 620mg (28%) of the title compound are obtained as colorless solid. ESI-MS (m-e):725[M+H]+；1H NMR(300MHz,DMSO-d6):/ppm＝10.890(m,1H),9.207(s,1H),8.074(d,J＝1.5Hz,1H),7.955(d,J＝2.1Hz,1H),7.575(m,2H),7.316(m,6H),7.031(m,4H),6.947(m,1H),6.632(m,2H),4.945(m,2H),4.111(m,2H),3.498(m,1H),3.250(dd,J1＝4.2Hz,J2＝14.4Hz,2H),3.170(d,J＝5.1Hz,2H),2.986(m,3H),2.777(m,3H),1.993(m,2H),1.409(m,4H),1.199(m,2H),0.956(m,3H),0.554(m,3H)。
EXAMPLE 9 preparation of (3R,6R) -3- (Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (6)
From 300mg (1mmol) of (3R,6R) -3- (Cbz-Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (5) 220mg (92%) of the title compound are obtained as colorless solid according to the method of example 4. ESI-MS (M/e):591[ M + H]+；Mp:123–124℃；
1H NMR(500MHz,DMSO-d6):/ppm＝10.863(s,1H),9.138(s,1H),8.009(s,1H),7.915(s,1H),7.728(s,1H),7.550(m,2H),7.297(d,J＝8.0Hz,1H),7.027(m,2H),6.966(d,J＝8.0Hz,2H),6.924(t,J＝7.5Hz,1H),6.649(d,J＝8.5Hz,2H),4.106(m,1H),3.501(m,1H),3.249(m,2H),3.012(m,3H),2.770(m,3H),2.479(m,1H),2.002(t,J＝7.5Hz,2H),1.739(m,2H),1.452(m,2H),1.341(m,2H),1.163(m,2H),0.976(m,3H),0.603(m,3H)。
EXAMPLE 10 preparation of Boc-aminocaproic acid
Add 5.23g (Boc) to a solution of 2.62g (20mmol) aminocaproic acid and 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, and continuously reducing the pressure and exhausting gas in the period. 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 11 preparation of (3R,6R) -3- (Boc-aminocaproyl butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (7)
From 0.97g (4.2mmol) Boc-aminocaproic acid and 1.9g (3.5mmol) (3R,6R) -3-butylamino-6- (indole-3-methyl) -piperazine-2, 5-dione (2) 0.641g (20.6%) of the title compound was obtained as a colorless solid using the method of example 1. ESI-MS (M/e):528[ M + H]+；1H NMR(300MHz,DMSO-d6):/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)。
EXAMPLE 12 preparation of (3R,6R) -3- (aminocaproyl-butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (8)
From 2.21g (4mmol) (3R,6R) -3- (Boc-aminocaproyl butylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (7) 1.45g (82%) of the title compound was obtained as colorless powder using the method of example 3. ESI-MS (M/e):428[ M + H]+；1HNMR(300MHz,DMSO-d6):/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)。
EXAMPLE 13 determination of the anti-metastatic Activity of Compound 6
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 maleSex mice (SPF grade, body weight 20. + -.2 g), left hand fixed mice. 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 compound 6 (dose of 0.5. mu. mol/kg/day) or compound 8 (dose of 5. mu. mol/kg/day) or compound 8 (dose of 10 mL/kg/day) 1 time daily for 12 consecutive days, and tumor volumes were measured and recorded every two days. The next day of the last administration, tumor volume was measured, cervical spine was removed by ether anesthesia and sacrificed, tumor of the mice was weighed, lung of the mice was taken and tumor nodules transferred from the lung of the tumor were counted. Statistical analysis of the data was performed using the t-test. The results are shown in Table 1. Compound 6 was not only effective in inhibiting tumor lung metastasis at 0.5 μmol/kg dose, but there was no significant difference in activity from RGDS at 40-fold higher doses and compound 8 at 10-fold higher doses. These data indicate that the present invention has significant technical effects.
TABLE 1 antitumor metastatic Activity of Compound 6
a) P <0.01 to saline, p >0.05 to RGDS and compound 8; n is 11
EXAMPLE 14 determination of the anti-tumor growth Activity of Compound 6
Doxorubicin, compound 8 and compound 6 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 saline solution of doxorubicin (dose 2. mu. mol/kg/day g), or daily orally administered with a saline solution of Compound 8 (dose 5. mu. mol/kg/day), or daily orally administered with a saline solution of Compound 6 (dose 0.5. mu. mol/kg/day). The administration is once daily for 12 days. The day after the last dose, tumor volume was measured, cervical spine was removed under ether anesthesia and sacrificed, then the right axillary tumor growth site of the mouse was fixed with forceps, and the skin was excised and the tumor was blunt-stripped 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. Compound 6 was not only effective at 0.5 μmol/kg dose in inhibiting tumor growth, but also had no significant difference in activity from compound 8, which was 10-fold higher in dose. These data indicate that the present invention has significant technical effects.
TABLE 2 Effect of Compound 6 on tumor growth in S180 mice
a) P <0.01 to saline, p >0.05 to compound 8; n is 12.
EXAMPLE 15 determination of anti-inflammatory Activity of Compound 6
Since xylene-induced ear swelling in mice is recognized as an acute inflammation model, the present invention measures the therapeutic effect of compound 6 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 20 ± 2g) were allowed to rest for 2 days at 22 ℃ with free access to water and food. Thereafter, 12 mice were randomly divided into a saline group (dose of 0.2 mL/mouse), an aspirin group (dose of 1.11mmol/kg), a compound 8 group (dose of 5. mu. mol/kg) and a compound 6 group (dose of 0.5. mu. mol/kg), each group. Mice were tested either orally with normal saline, orally with aspirin, orally with compound 8, or orally with compound 6, 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. The results are shown in Table 3. Compound 6 was not only effective in inhibiting xylene-induced ear swelling in mice at the 0.5 μmol/kg dose, but also had no significant difference in activity from compound 8, which was 10-fold higher than the dose. These data indicate that the present invention has significant technical effects.
TABLE 3 Effect of Compound 6 on xylene-induced ear swelling in mice
a) P <0.01 to saline, p >0.05 to compound 8; n is 12.
Claims (5)
1. (3R,6R) -3- (Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione of the formula,
2. a process for the preparation of (3R,6R) -3- (Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione as claimed in claim 1, which 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 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 5% aqueous sodium bicarbonate solution, followed by cyclization to give (3R,6R) -3- (benzyloxycarbonylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (1);
(4) the compound 1 is subjected to hydrogenolysis to remove benzyloxycarbonyl to obtain (3R,6R) -3- (amino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (2);
(5) condensing the amino n-hexanoic acid methyl ester and Cbz-L-Tyr to obtain Cbz-Tyr-amino n-hexanoic acid methyl ester (3);
(6) saponifying and removing methyl ester from the compound 3 to obtain Cbz-Tyr-amino n-hexanoic acid (4);
(7) condensing the compound 2 and the compound 4 to obtain (3R,6R) -3- (Cbz-Tyr-amino n-hexanoyl amino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-diketone (5);
(8) the compound 5 is subjected to hydrogenolysis in dimethylformamide to remove Cbz protection to obtain (3R,6R) -3- (Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-diketone (6).
3. The use of (3R,6R) -3- (Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1 for the preparation of a medicament for the treatment of tumor metastasis.
4. The use of (3R,6R) -3- (Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1 for the preparation of an anti-tumor medicament.
5. Use of (3R,6R) -3- (Tyr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1 for the preparation of an anti-inflammatory medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710364185.8A CN108947978B (en) | 2017-05-22 | 2017-05-22 | 3R-indolylmethyl-6R-Tyr modified piperazine-2, 5-diketone and synthesis, activity and application thereof |
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| CN201710364185.8A CN108947978B (en) | 2017-05-22 | 2017-05-22 | 3R-indolylmethyl-6R-Tyr modified piperazine-2, 5-diketone and synthesis, activity and application thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0181152A1 (en) * | 1984-11-02 | 1986-05-14 | Fujisawa Pharmaceutical Co., Ltd. | Piperazine compound as PAF-antagonist |
| JPS61112060A (en) * | 1984-11-02 | 1986-05-30 | Fujisawa Pharmaceut Co Ltd | Piperazine compound |
| CN104098549A (en) * | 2014-08-01 | 2014-10-15 | 华东理工大学 | Piperazinedione derivative and preparation and application thereof |
| CN105294660A (en) * | 2014-06-10 | 2016-02-03 | 首都医科大学 | 3R, 6S-3, 6-disubstituted piperazine-2, 5-diketone, preparation therefor and application thereof |
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2017
- 2017-05-22 CN CN201710364185.8A patent/CN108947978B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0181152A1 (en) * | 1984-11-02 | 1986-05-14 | Fujisawa Pharmaceutical Co., Ltd. | Piperazine compound as PAF-antagonist |
| JPS61112060A (en) * | 1984-11-02 | 1986-05-30 | Fujisawa Pharmaceut Co Ltd | Piperazine compound |
| CN105294660A (en) * | 2014-06-10 | 2016-02-03 | 首都医科大学 | 3R, 6S-3, 6-disubstituted piperazine-2, 5-diketone, preparation therefor and application thereof |
| CN104098549A (en) * | 2014-08-01 | 2014-10-15 | 华东理工大学 | Piperazinedione derivative and preparation and application thereof |
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