CN108947980B - 3R-indolylmethyl-6S-Thr modified piperazine-2, 5-dione, and synthesis, activity and application thereof - Google Patents
3R-indolylmethyl-6S-Thr modified piperazine-2, 5-dione, and synthesis, activity and application thereof Download PDFInfo
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Abstract
The invention discloses (3R,6S) -3- (Thr-amino-n-hexanoylamino) -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 therefore the invention discloses the application thereof in preparing anti-tumor metastasis medicaments and anti-inflammatory medicaments.
Description
Technical Field
The invention relates to (3R,6S) -3- (Thr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione. Relates to its preparation method, to its anti-tumor metastasis activity, and to its anti-inflammatory activity, and thus the present invention relates to its use in anti-tumor metastasis 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 amino n-butyl group of the diketopiperazine in the S, R-configuration. After 3 years of exploration, the amino n-butyl of diketopiperazine with S, R-configuration acylated with amino n-hexanoic acid acylated by Thr 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-inflammation 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
In a first aspect of the invention there is provided (3R,6S) -3- (Thr-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 (3R,6S) -3- (Thr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione, which comprises:
(1) D-Boc-Lys (Cbz) and L-Trp-OBzl are condensed to obtain D-Boc-Lys (Cbz) -L-Trp-OBzl;
(2) removing Boc from D-Boc-Lys (Cbz) -L-Trp-OBzl in ethyl acetate solution of hydrogen chloride to obtain D-Lys (Cbz) -L-Trp-OBzl;
(3) the ethyl acetate solution of D-Lys (Cbz) -L-Trp-OBzl is fully washed by saturated sodium bicarbonate aqueous solution, and then cyclization is carried out to obtain (3R,6S) -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,6S) -3- (amino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (2);
(5) condensing the compound 2 with Boc-amino n-hexanoic acid to obtain (3R,6S) -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 (3R,6S) -3- (amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (4);
(7) condensing the compound 4 with Cbz-Thr to obtain (3R,6S) -3- (Cbz-Thr-amino n-hexanoyl amino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-diketone (5).
(8) Compound 5 is subjected to hydrogenolysis to remove benzyloxycarbonyl and benzyl to obtain (3R,6S) -3- (Thr-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 (3R,6S) -3- (Thr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione in inhibiting the metastasis of lung cancer in C57BL/6 mice.
A fourth aspect of the present invention is the evaluation of the inhibitory effect of (3R,6S) -3- (Thr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione on inflammation in ICR mice.
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FIG. 1(3R,6S) -3- (Thr-amino-N-hexanoylamino-N-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione synthetic route. i) Dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM); ii) a solution of hydrogen chloride in ethyl acetate; iii) ethyl acetate, 5% aqueous sodium bicarbonate; iv) 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 D-Boc-Lys (Cbz) -L-Trp-OBzl
To a solution of 1.90g (5.0mmol) of D-Boc-Lys (Cbz) and 20mL of dried Tetrahydrofuran (THF) were added 0.68g (5.0mmol) of 1-hydroxybenzotriazole (HOBt) and 1.24g (6.0mmol) of Dicyclohexylcarbodiimide (DCC) under ice-cooling and stirred for 30 minutes to obtain reaction solution A. 1.47g (5.0mmol) of L-Trp-OBzl was dissolved in 20mL of dry THF, and N-methylmorpholine (NMM) was added to adjust the pH to 9 to obtain reaction solution B. The reaction solution B was added to the reaction solution A and reacted at room temperature for 12 hours, and TLC (methylene chloride/methanol, 40/1) showed completion of the reaction. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 50mL of ethyl acetate. The resulting solution was sequentially saturated NaHCO3Aqueous wash (25 mL. times.3) and saturated aqueous NaCl wash (25)mL×3),5％KHSO4Aqueous wash (25 mL. times.3), saturated aqueous NaCl wash (25 mL. times.3), saturated aqueous NaHCO3An aqueous wash (25 mL. times.3) and a saturated aqueous NaCl wash (25 mL. times.3). Anhydrous Na for ethyl acetate layer2SO4Drying for 12 hours. Filtering off Na2SO4The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol, 40/1) to give 2.94g (90%) of the title compound as a colorless solid. ESI-MS (M/z):657[ M + H]+。
EXAMPLE 2 preparation of D-Lys (Cbz) -L-Trp-OBzl
To 2.62g (4.0mmol) of D-Boc-Lys (Cbz) -L-Trp-OBzl was slowly added 30mL of a solution of hydrogen chloride in ethyl acetate (4M) under ice-bath and stirred for 4 hours, TLC (dichloromethane/methanol, 40/1) showed the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 30mL of anhydrous ethyl acetate, and the resulting solution was concentrated under reduced pressure, and the residue was dissolved in 30mL of anhydrous ethyl acetate. This operation was repeated three times. The residue was suspended with 30mL of anhydrous ether by means of a sonicator and after standing the ether was removed to give 2.07g (93%) of the title compound as a yellow powder. ESI-MS (M/z):557[ M + H ]]+。
EXAMPLE 3 preparation of (3R,6S) -3- (benzyloxycarbonylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (1)
A solution of 1.95g (3.5mmol) D-Lys (Cbz) -L-Trp-OBzl and 50mL ethyl acetate was treated with saturated NaHCO3After the aqueous solution was sufficiently washed (25 mL. times.3), the ethyl acetate layer was stirred at 80 ℃ for 56 hours. TLC (dichloromethane/methanol, 20/1) showed the reaction was complete. The reaction mixture was allowed to stand well at room temperature and filtered to give 0.72g (46%) of the title compound as a colorless solid. ESI-MS (M/z):449[ M + H ]]+。
EXAMPLE 4 preparation of (3R,6S) -3- (amino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (2)
To a solution of 0.67g (1.5mmol) of (3R,6S) -3- (benzyloxycarbonylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (1) in 10mL of Dimethylformamide (DMF) was added 0.07g of Pd/C (10%) and the mixture was taken up in H at room temperature2TLC (dichloromethane/methanol, 20/1) showed the reaction was complete for 48 hours. Pd/C was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure to give 0.48g of (C: (A))95%) the title compound as a colorless solid. ESI-MS (M/z) 315[ M + H ]]+。
EXAMPLE 5 preparation of Boc-amino-n-hexanoic acid
To a solution of 0.26g (2.0mmol) of aminon-hexanoic acid in 5mL of distilled water was added 0.58g (2.6mmol) (Boc) with stirring2Solution of O with 5mL dioxane. The resulting solution was adjusted to pH 9 with an aqueous solution of NaOH (2M) in ice bath. After stirring for 30 minutes in an ice bath, the mixture was stirred at room temperature and pumped down by a water pump. The pH was monitored during stirring and kept at 9 all the time until TLC (dichloromethane/methanol, 3/1) indicated completion of the reaction. The reaction mixture was saturated with KHSO under ice-bath4Adjusting pH of the aqueous solution to 7, and concentrating under reduced pressure. The aqueous phase is saturated KHSO4Adjusting pH to 2 with water solution, washing with 10mL ethyl acetate for three times, washing with 10mL saturated NaCl water solution for three times to make solution pH 7, and adding anhydrous Na2SO4Drying for 12 hours. Filtering to remove Na2SO4The filtrate was concentrated under reduced pressure to give 0.41g (89%) of the title compound as a colorless solid. ESI-MS (M/e):232[ M + H]+。
EXAMPLE 6 preparation of (3R,6S) -3- (Boc-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (3)
To a solution of 0.28g (1.2mmol) of Boc-amino-n-hexanoic acid and 5mL of anhydrous DMF was added 0.16g (1.2mmol) of HOBt and 0.29g (1.4mmol) of DCC under ice-bath, and the mixture was stirred for 30 minutes to obtain reaction solution A. 0.38g (1.2mmol) of (3R,6S) -3- (amino-N-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (2) was dissolved in 5mL of anhydrous DMF, and pH was adjusted to 9 with N-methylmorpholine to give reaction solution B. Reaction B was added to reaction A and stirred at room temperature for 12 hours, and TLC (dichloromethane/methanol, 10/1) showed completion of the reaction. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol, 50/1) to give 0.12g (19%) of the title compound as a colorless solid. ESI-MS (M/z):528[ M + H]+；1HNMR(300MHz,DMSO-d6)δ/ppm＝10.903(s,1H),8.046(d,J＝1.8Hz,1H),7.851(s,1H),7.686(t,J＝5.4Hz,1H),7.556(d,J＝7.8Hz,1H),7.314(d,J＝7.8Hz,1H),7.039(m,2H),6.943(td,J1＝7.8Hz,J2＝0.6Hz,1H),6.758(t,J＝5.4Hz,1H),4.068(m,1H),3.252(dd,J1＝14.4Hz,J2＝4.2Hz,1H),2.924(m,6H),1.995(t,J＝7.2Hz,2H),1.292(m,21H)。
EXAMPLE 7 preparation of (3R,6S) -3- (amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (4)
From 0.11g (0.2mmol) (3R,6S) -3- (Boc-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (3) 0.08g (96%) of the title compound was obtained as colorless solid by the method of example 2. ESI-MS (M/z):428[ M + H]+；1H NMR(300MHz,DMSO-d6)δ/ppm＝10.924(s,1H),8.071(s,1H),7.866(s,1H),7.729(t,J＝5.4Hz,1H),7.568(d,J＝7.5Hz,1H),7.321(d,J＝7.5Hz,1H),7.044(m,2H),6.949(t,J＝7.5Hz,1H),4.070(m,1H),3.239(dd,J1＝14.4Hz,J2＝3.6Hz,1H),2.991(m,4H),2.694(m,2H),2.021(t,J＝7.5Hz,2H),1.467(m,6H),1.240(m,6H)。
EXAMPLE 8 preparation of (3R,6S) -3- (Cbz-Thr-amino-n-hexanoylamino) -6- (indole-3-methyl) -piperazine-2, 5-dione (5)
From 0.05g (0.18mmol) Cbz-Thr and 0.08g (0.18mmol) of (3R,6S) -3- (amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (4) by the method of example 6, 0.03g (22%) of the title compound are obtained as colorless solid. ESI-MS (M/z):663[ M + H]+；1H NMR(300MHz,DMSO-d6)δ/ppm＝10.901(s,1H),8.047(s,1H),7.855(s,1H),7.807(t,J＝5.4Hz,1H),7.688(t,J＝5.4Hz,1H),7.332(m,6H),7.019(m,2H),6.972(t,J＝7.2Hz,1H),5.045(s,2H),4.752(d,J＝5.4Hz,1H),4.075(m,1H),3.879(m,2H),3.256(dd,J1＝14.4Hz,J2＝3.6Hz,1H),3.003(m,6H),2.001(t,J＝7.2Hz,2H),1.431(m,6H),1.232(m,6H),1.074(d,J＝7.2Hz,3H)。
EXAMPLE 9 preparation of (3R,6S) -3- (Thr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (6)
From 0.02g (0.03mmol) of (3R,6S) -3- (Cbz-Thr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (5) 0.02g (95%) of the title compound are obtained as colorless solid according to the method of example 4. ESI-MS (M/z):529[ M + H]+；Mp 100-102℃；
(c ═ 0.1, methanol); IR (cm)-1):3397,3295,3102,2929,2862,1639,1537,1455,1325,1100,1010,922,740；1H NMR(500MHz,DMSO-d6)δ/ppm＝10.882(d,J＝1.5Hz,1H),8.026(d,J＝2.0Hz,1H),7.825(m,2H),7.670(t,J＝5.5Hz,1H),7.562(d,J＝8.0Hz,1H),7.059(d,J＝2.0Hz,1H),7.035(td,J1＝8.0Hz,J2＝1.0Hz,1H),6.942(td,J1＝8.0Hz,J2＝1.0Hz,1H),4.559(d,J＝4.5Hz,1H),4.064(m,1H),3.744(m,1H),3.246(dd,J1＝14.5Hz,J2＝4.5Hz,1H),3.017(m,4H),2.934(m,2H),2.867(d,J＝5.0Hz,1H),1.997(t,J＝7.5Hz,2H),1.503(m,1H),1.406(m,5H),1.206(m,5H),1.095(m,1H),1.024(d,J＝6.5Hz,3H)。
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, 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. With physiological saltsAdjusting the cell density of the single cell suspension to 1.5X 107one/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 were inoculated with tumors on day 11 either orally with a recognized physiological saline solution of the anti-tumor metastatic peptide RGDS (at a dose of 20. mu. mol/kg/day) or compound 6 (at a dose of 0.5. mu. mol/kg/day) or compound 4 (at a dose of 5. mu. mol/kg/day) or oral physiological saline (at a dose of 10 mL/kg/day) 1 time daily for 12 consecutive days. The next day of the last administration, cervical spine was removed by ether anesthesia, and the lungs of the mice were taken and the number of tumor nodules that metastasized in the tumor lungs was calculated. 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 is 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 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 (SPF grade, 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 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. Not only compound 6 was effective in inhibiting ear swelling in mice caused by xylene at a dose of 0.5 μmol/kg, but there was no significant difference in activity from aspirin at a dose 2220-fold higher than them and compound 4 at a dose 10-fold higher than them. 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 aspirin and compound 4; n is 12.
Claims (4)
1. (3R,6S) -3- (Thr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione of the formula,
2. a process for the preparation of (3R,6S) -3- (Thr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione according to claim 1, which comprises:
(1) D-Boc-Lys (Cbz) and L-Trp-OBzl are condensed to obtain D-Boc-Lys (Cbz) -L-Trp-OBzl;
(2) removing Boc from D-Boc-Lys (Cbz) -L-Trp-OBzl in ethyl acetate solution of hydrogen chloride to obtain D-Lys (Cbz) -L-Trp-OBzl;
(3) the ethyl acetate solution of D-Lys (Cbz) -L-Trp-OBzl is fully washed by saturated sodium bicarbonate aqueous solution, and then cyclization is carried out to obtain (3R,6S) -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,6S) -3- (amino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-diketone (2);
(5) condensing the compound 2 with Boc-amino n-hexanoic acid to obtain (3R,6S) -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 (3R,6S) -3- (amino-n-hexanoyl amino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-diketone (4);
(7) condensing the compound 4 with Cbz-Thr to obtain (3R,6S) -3- (Cbz-Thr-amino n-hexanoyl amino n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-diketone (5);
(8) the compound 5 is subjected to hydrogenolysis to remove benzyloxycarbonyl to obtain (3R,6S) -3- (Thr-amino-n-hexanoylamino-n-butyl) -6- (indole-3-methyl) -piperazine-2, 5-dione (6).
3. Use of (3R,6S) -3- (Thr-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. Use of (3R,6S) -3- (Thr-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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| 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 |
| CN105503833A (en) * | 2014-10-20 | 2016-04-20 | 首都医科大学 | Indole piperazine dione compound, and preparation and treatment effect thereof |
-
2017
- 2017-05-27 CN CN201710391495.9A patent/CN108947980B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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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| CN108947980A (en) | 2018-12-07 |
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