CN108976203B - 3S-indolylmethyl-6R-Lys modified piperazine-2, 5-dione, and synthesis, activity and application thereof - Google Patents
3S-indolylmethyl-6R-Lys modified piperazine-2, 5-dione, and synthesis, activity and application thereof Download PDFInfo
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Abstract
The invention discloses (3S,6R) -3- (Lys-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione of the formula. Discloses a preparation method 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 anti-tumor metastasis medicaments and anti-inflammatory medicaments.
Description
Technical Field
The invention relates to (3S,6R) -3- (Lys-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione. Relates to its preparation method, its anti-tumor metastasis activity and its anti-inflammatory activity, so that the present invention relates to its application in preparing anti-tumor 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 diketopiperazines of the R, S-configuration. After 3 years of exploration, the L-Lys acylated amino n-hexanoic acid is used for acylating the butylamino group of the diketopiperazine with R, S-configuration, so that the lowest effective dose of the diketopiperazine not only for resisting tumor metastasis can be reduced to 0.5 mu mol/kg, but also for resisting inflammation can be reduced 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 (3S,6R) -3- (Lys-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione of the formula.
The second aspect of the present invention provides a method for synthesizing (3S,6R) -3- (Lys-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione, which comprises:
(1) L-Boc-Lys (Cbz) and D-Trp-OBzl are condensed to obtain Boc-Lys (Cbz) -D-Trp-OBzl;
(2) Boc-Lys (Cbz) -D-Trp-OBzl is subjected to Boc removal in an ethyl acetate solution of hydrogen chloride to obtain Lys (Cbz) -D-Trp-OBzl;
(3) an ethyl acetate solution of Lys (Cbz) -D-Trp-OBzl is adjusted to pH 9 by triethylamine and cyclized to generate (3S,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 (3S,6R) -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,6R) -3- (Boc-amino n-hexanoylamino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (3);
(6) removing Boc from the compound 3 in an ethyl acetate solution of hydrogen chloride to obtain (3S,6R) -3- (amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (4);
(7) condensing the compound 4 with Boc-Lys (Cbz) to obtain (3S,6R) -3- [ Boc-Lys (Cbz) -amino-n-hexanoylamino-n-butyl ] -6- (indole-3-methyl) -piperazine-2, 5-diketone (5);
(8) compound 5 is subjected to hydrogenolysis to remove benzyloxycarbonyl and Boc in a solution of hydrogen chloride in ethyl acetate to give (3S,6R) -3- (Lys-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (6).
The third aspect of the present invention is to evaluate the activity of (3S,6R) -3- (Lys-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione in inhibiting the metastasis of lung cancer in C57BL/6 mice.
The fourth aspect of the present invention is to evaluate the inhibitory effect of (3S,6R) -3- (Lys-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione on ICR mouse inflammation.
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FIG. 1(3S,6R) -3- (Lys-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。
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) -D-Trp-OBzl
4.56g (10mmol) of L-Boc-Lys (Cbz) was suspended in 100mL of anhydrous Tetrahydrofuran (THF), and 1.35g (10mmol) of 1-hydroxybenzotriazole (HOBt) and 2.47g (12mmol) of Dicyclohexylcarbodiimide (DCC) were added to the suspension in this order under ice bath, followed by stirring for 30 min. Then, 3.31g (10mmol) of D-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) 4.95g (87%) of the title compound are obtained as a colorless solid. ESI-MS (M/e):657[ M + H]+。
EXAMPLE 2 preparation of Lys (Cbz) -D-Trp-OBzl
3.28g (5mmol) Boc-Lys (Cbz) -D-Trp-OBzl was slowly mixed with 52mL of hydrogen chloride in ethyl acetate 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 2.36g (85%) of the title compound as a colorless powder. ESI-MS (M/e):557[ M + H ]]+。
EXAMPLE 3 preparation of (3S,6R) -3- (benzyloxycarbonylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (1)
2.22g (4mmol) of L-Lys (Cbz) -D-Trp-OBzl were dissolved in 100ml of ethyl acetate, adjusted to pH 9 with triethylamine and stirred at 80 ℃ for 100 hours. The colorless solid was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column Chromatography (CH)2Cl2/CH3OH, 100/1). A total of 1.32g (65%) of the title compound are obtained. ESI-MS (M/e):449[ M + H ]]+。
EXAMPLE 4 preparation of (3S,6R) -3-amino-n-butyl-6- (indole-3-methyl) -piperazine-2, 5-dione (2)
Add 200mg Pd/C to a solution of 1.30g (2.9mmol) of (3S,6R) -3- (benzyloxycarbonylamino N-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (1) in 20mL of anhydrous N, N-Dimethylformamide (DMF) and let go of H at room temperature2And (5) 48 h. Pd/C was filtered off, and the filtrate was concentrated under reduced pressure to give 0.51g (56%) of the title compound as a colorless powder. ESI-MS (m/e): 315[ M + H ]]+。
EXAMPLE 5 preparation of Boc-amino-n-hexanoic acid
Add 2.83g (Boc) to a solution of 1.311g (10mmol) amino-n-hexanoic acid in 30mL distilled water2Solution of O in 30mL dioxane to give the transThe pH of the application solution is adjusted to 9 by using a NaOH aqueous solution with the concentration of 2N. Stirring at room temperature for 24h, and continuously reducing the pressure and exhausting gas in the period. KHSO is used for the reaction mixture4Adjusting pH of the aqueous solution to 7, and concentrating under reduced pressure. The remaining solution was further treated with KHSO4The pH was adjusted to 2 and extracted with 100mL of ethyl acetate. Anhydrous NaSO for ethyl acetate layer4Drying for 8 h. Filtration and concentration of the filtrate under reduced pressure gave 2.18g (94%) of the title compound. ESI-MS (M/e):232[ M + H]+。
EXAMPLE 6 preparation of (3S,6R) -3- (Boc-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (3)
From 0.97g (4.2mmol) Boc-amino-n-hexanoic acid and 1.9g (3.5mmol) (3S,6R) -3-amino-n-butyl-6- (indole-3-methyl) -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/z): 528[ M + H ]]+.1H-NMR(300MHz,DMSO-d6):/ppm＝10.878(s,1H),8.044(s,1H),7.848(s,1H),7.681(m,1H),7.564(d,J＝7.8Hz,1H),7.313(d,J＝7.8Hz,1H),7.056(m,2H),6.943(m,1H),6.766(m,1H),4.063(m,1H),3.251(m,1H),2.969(m,6H),1.993(t,J＝7.5Hz,2H),1.291(m,21H)。
EXAMPLE 7 preparation of (3S,6R) -3- (amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (4)
From 0.3g (0.5mmol) (3S,6R) -3- (Boc-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (3) 0.14g (58%) of the title compound was obtained as colorless powder by the method of example 2. ESI-MS (m/z): 428[ M + H]+；Mp:129-131℃；
(C＝0.1,CH3OH)；IR(cm-1):3213,3054,2928，2861,1660,1547,1455,1324,1259,1099,743；1HNMR(300MHz,DMSO-d6):/ppm＝10.887(s,1H),8.007(s,1H),7.820(s,1H),7.681(t,J＝3.6Hz,1H),7.560(d,J＝7.8Hz,1H),7.312(d,J＝7.8Hz,1H),7.036(m,2H),6.942(t,J1＝4.5Hz,1H),4.065(m,1H),3.040(m,2H),3.002(m,1H),2.939(m,1H),2.012(t,J＝4.5Hz,2H),1.474(m,7H),1.263(m,7H)。
EXAMPLE 8 preparation of (3S,6R) -3- [ Boc-Lys (Cbz) -amino-n-hexanoylamino-n-butyl ] -6- (indole-3-methyl) -piperazine-2, 5-dione (5)
From 2.152g (5.6mmol) Boc-Lys (Cbz) and 2.186g (4.7mmol) (3S,6R) -3- (amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (4) using the method of example 1, 1.236g (33.21%) of the title compound are obtained as a colourless solid. ESI-MS (M/z) 790[ M + H ]]+；1H NMR(300MHz,DMSO-d6):/ppm＝10.899(s,1H),8.047(s,1H),7.858(s,1H),7.707(m,2H),7.57 3(d,J＝7.8Hz,1H),7.348(s,5H),7.234(m,2H),7.044(m,2H),6.949(t,J＝7.2Hz,1H),6.731(d,J＝8.1Hz,1H),5.005(s,2H),4.108(m,1H),3.817(m,1H),3.283(dd,J1＝16.8Hz,J2＝5.1Hz,1H),2.976(m,7H)2.001(t,J＝6.9Hz,2H),1.373(m,27H)。
EXAMPLE 9 preparation of (3S,6R) -3- (Lys-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (6)
Following the procedure of example 4, 0.966g (1.2mmol) of (3S,6R) -3- [ Boc-Lys (Cbz) -amino-n-hexanoylamino-n-butyl]Cbz was removed from-6- (indole-3-methyl) -piperazine-2, 5-dione (5) and then Boc was removed as in example 2 to give 0.310g (46%) of the title compound as a colorless powder. ESI-MS (M/z):556[ M + H]+；Mp 164-166℃；
(C＝0.1,CH3OH)；IR(cm-1):3213,3057,2927,2860,1659,1551,1454,1323,1257,1098,742；1H NMR(300MHz，DMSO-d6):/ppm＝10.980(s,1H),8.458(t,J＝5.4Hz,1H),8.320(s,3H),8.081(m,4H),7.872(s,1H),7.817(m,1H),7.568(d,J＝8.1Hz,1H),7.322(d,J＝7.8Hz,1H),7.038(m,2H),6.943(t,J＝6.9Hz,1H),4.075(m,1H),3.742(m,1H),3.252(dd,J1＝14.7Hz,J2＝4.2Hz,1H),3.087(m,6H),2.749(m,2H),2.029(t,J＝7.2Hz,2H),1.737(m,2H),1.546(m,10H),1.179(m,6H)。
EXAMPLE 10 determination of the anti-tumor metastasis 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, 1 × 10)5U/L penicillin and 100mg/L streptomycin), passaging every two days according to an adherent cell culture method, enriching cells, digesting the cells when the cells are in a good growth state and in a logarithmic growth phase, and adjusting the cell density to 1 × 10 by using physiological saline7one/mL. Staining with placental blue to count viable cells>95 percent, inbred line C57BL/6 male mice (SPF grade, weight 20 +/-2 g) are taken, mice are fixed by the left hand, the right forelimb armpit skin of the mice is disinfected by 75 percent ethanol, LLC tumor cell suspension is injected to the armpit part of the mice by holding 1mL sterile injector in the right hand, each mouse is injected with 0.2mL, after the mice are inoculated for 10 days, tumors with the diameter of about 4-5mm are grown out, namely tumor sources, the Lewis lung cancer tumor-bearing mice inoculated for 10 days are anesthetized by ethyl ether, cervical vertebra is removed and killed, the mice are soaked for 10min by 75 percent ethanol, disinfected and tumor bodies are stripped on an ultra-clean workbench, well-grown tumor tissues are selected to be cut into pieces in an aseptic flat dish, the pieces are placed in a tissue homogenizer made of glass, physiological saline with the temperature of 4 ℃ is added according to the ratio of the weight of the tumor mass to the volume of 1 to 3(g to mL), the weight of the physiological saline is lightly ground to prepare cell suspension, the cell suspension passes through a 200-mesh cell sieve to prepare the single cell suspension, and the cell density is adjusted to 17one/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 4 (dose of 5. mu. mol/kg/day) or compound 4 (dose of 10 mL/kg/day) 1 time daily for 12 consecutive days, and tumor volumes were measured and recorded every two days. Tumor volume was measured the day after the last dose, diethyl etherAnaesthetizing, taking off cervical vertebra, weighing the tumor of the mouse, taking the lung of the mouse and calculating the tumor node number of the tumor lung metastasis. 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 4 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 4; n-12
EXAMPLE 11 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 compounds 6a-j 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, 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 4 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 4, 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 2. 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 4, which was 10-fold higher than the dose. These data indicate that the present invention has significant technical effects.
TABLE 2 Effect of Compound 6 on xylene-induced ear swelling in mice
a) P <0.01 to saline, p >0.05 to RGDS and compound 4; n is 12.
Claims (4)
1. (3S,6R) -3- (Lys-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione of the formula,
2. a process for the preparation of (3S,6R) -3- (AA-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1, which comprises:
(1) L-Boc-Lys (Cbz) and D-Trp-OBzl are condensed to obtain Boc-Lys (Cbz) -D-Trp-OBzl;
(2) Boc-Lys (Cbz) -D-Trp-OBzl is subjected to Boc removal in an ethyl acetate solution of hydrogen chloride to obtain Lys (Cbz) -D-Trp-OBzl;
(3) an ethyl acetate solution of Lys (Cbz) -D-Trp-OBzl is adjusted to pH 9 by triethylamine and cyclized to generate (3S,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 (3S,6R) -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,6R) -3- (Boc-amino n-hexanoylamino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (3);
(6) removing Boc from the compound 3 in an ethyl acetate solution of hydrogen chloride to obtain (3S,6R) -3- (amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (4);
(7) condensing the compound 4 with Boc-Lys (Cbz) to obtain (3S,6R) -3- [ Boc-Lys (Cbz) -amino-n-hexanoylamino-n-butyl ] -6- (indole-3-methyl) -piperazine-2, 5-diketone (5);
(8) compound 5 is subjected to hydrogenolysis to remove benzyloxycarbonyl and Boc in a solution of hydrogen chloride in ethyl acetate to give (3S,6R) -3- (Lys-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (6).
3. Use of (3S,6R) -3- (Lys-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1 for the preparation of a medicament against tumor metastases.
4. Use of (3S,6R) -3- (Lys-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.
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| 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 |
| WO2006132594A1 (en) * | 2005-06-10 | 2006-12-14 | Viogard Ab | Novel dipodazine compounds and applications |
| 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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