CN106317205A - Pyridoindoloimidazolone butyryl-Nω-glucuronyl-Lys-OBzl, its preparation, activity and application - Google Patents

Abstract

The invention discloses pyridoindoloimidazolone butyryl-Nω-glucuronyl-Lys-OBzl of the following formula, its preparation method, and its anti-tumor and anti-inflammatory effects. Therefore, the present invention discloses Its application in the preparation of antitumor drugs and anti-inflammatory drugs has been demonstrated.

Description

Pyridoindoloimidazolone butyryl-Nω-glucuronyl-Lys-OBzl, its preparation, activity and application

technical field

The present invention relates to N ^α -2,3,4,9-tetrahydro-1H-pyridoindolo-2,2-dimethyl-imidazol-4-one-3-yl-2-methylbutyryl- Nω-glucuronyl-Lys-OBzl relates to its preparation method, its anti-tumor effect and anti-inflammatory activity, so the present invention relates to its application in the preparation of anti-tumor drugs and anti-inflammatory drugs. The invention belongs to the field of biomedicine.

technical background

Tumor is a new organism formed by abnormal proliferation of cells in local tissues. All malignant tumors are collectively called cancer. Malignant tumors seriously threaten human health. Among the surgical treatment, radiotherapy and chemotherapy of clinical tumors, chemotherapy is the most widely used. Inventing new anti-tumor drugs with good curative effect and low side effects has always been a hot spot in drug research. In the study of new anti-tumor drugs, the inventors have disclosed that the compound with the following structure (where AA is an amino acid residue) has an anti-tumor effect when administered intraperitoneally at a dose of 1 μmol/kg once a day for 7 consecutive days. The inventors were not satisfied with this efficacy.

After 5 years of research, the inventors found that the replacement of AA-OBzl in the above structure with Lys-OBzl acylated with side chain glucosamine can not only enhance the anti-tumor activity, but also obtain additional anti-inflammatory activity. Based on these findings, the inventors have proposed the present invention.

Contents of the invention

The first content of the present invention is to provide [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl -imidazol-4-on-3-yl)]-2-methylbutyryl-(Nω-glucuronyl-Lys-OBzl).

The second content of the present invention is to provide [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazole- 4-keto-3-yl)]-2-methylbutyryl-(Nω-glucuronyl-Lys-OBzl) preparation method, the method may further comprise the steps:

(1) L-tryptophan carries out Pictet-Spengler condensation with formaldehyde under the catalysis of sulfuric acid to prepare (S)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid;

(2) (S)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid reacts with (Boc) ₂ O under the catalysis of N-methylmorpholine to obtain N-Boc-(S )-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid;

(3) N-Boc-(S)-2,3,4,9-tetrahydro-β-carboline in the presence of dicyclohexylcarbodiimide (DCC) and N-hydroxybenzotriazole (HOBt) -Condensation of 3-carboxylic acid with L-leucine methyl ester to N-Boc-(S)-2,3,4,9-tetrahydro-β-carboline-3-formyl-L-leucine methyl ester;

(4) N-Boc-(S)-2,3,4,9-tetrahydro-β-carboline-3-formyl-L-leucine methyl ester is removed in 4N hydrogen chloride-ethyl acetate solution Boc generates (S)-2,3,4,9-tetrahydro-β-carboline-3-formyl-L-leucine methyl ester;

(5) Triethylamine catalyzes (S)-2,3,4,9-tetrahydro-beta-carboline-3-formyl-L-leucine methyl ester reacting in the dark in methanol and acetone to obtain [( S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazol-4-one-3-yl)]-2 - methyl methyl butyrate;

(6) [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl- Imidazol-4-on-3-yl)]-2-methylbutanoic acid methyl ester to generate [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole And (2,2-dimethyl-imidazol-4-one-3-yl)]-2-methylbutanoic acid;

(7) In the presence of DCC and HOBt [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazole- 4-keto-3-yl)]-2-methylbutanoic acid is condensed with L-Lys(Boc)-OBzl to [(S)-2,3,4,9-tetrahydro-1H-pyrido[3, 4-b] Indolo(2,2-dimethyl-imidazol-4-on-3-yl)]-2-methylbutyryl-Lys(Boc)-OBzl;

(8) [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl- Imidazol-4-one-3-yl)]-2-methylbutyryl-Lys(Boc)-OBzl removes Boc and generates [(S)-2,3,4,9-tetrahydro-1H-pyrido[ 3,4-b]indolo(2,2-dimethyl-imidazol-4-one-3-yl)]-2-methylbutyryl-Lys-OBzl;

(9) In the presence of DCC and HOBt [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazole- 4-keto-3-yl)]-2-methylbutyryl-Lys-OBzl is condensed with D-glucuronic acid in anhydrous N,N-dimethylformamide solution to [(S)-2,3 , 4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazol-4-one-3-yl)]-2-methylbutyryl- (Nω-glucuronyl-Lys-OBzl).

The third content of the present invention is to evaluate [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazole- 4-keto-3-yl)]-2-methylbutyryl-(Nω-glucuronyl-Lys-OBzl) inhibits tumor growth in S180 tumor mice.

The fourth content of the present invention is to evaluate [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazole- Inhibitory effect of 4-keto-3-yl)]-2-methylbutyryl-(Nω-glucuronyl-Lys-OBzl) on inflammation in ICR mice.

Description of drawings

Figure 1 [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazol-4-one-3-yl )]-2-methylbutyryl-(Nω-glucuronyl-Lys-OBzl) synthetic route. i) dilute sulfuric acid, 40% formaldehyde; ii) (Boc) ₂ O, DMF, triethylamine; iii) DCC, HOBt, NMM; iv) 4N hydrogen chloride/ethyl acetate, methanol, acetone, triethylamine; v) 2N NaOH; vi) 4N hydrogen chloride/ethyl acetate.

detailed description

In order to further illustrate the present invention, a series of examples are given below. These examples are entirely illustrative, and they are only used to specifically describe the present invention, and should not be construed as limiting the present invention.

Example 1 Preparation of (S)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid (1)

Put 2500mL of distilled water in a 2500mL reaction bottle, slowly add 1.3mL of concentrated sulfuric acid, stir for 2min, then add 32.6g (159mmol) L-tryptophan to the obtained dilute sulfuric acid, sonicate until completely dissolved, then add 65mL of 40% formaldehyde The solution was stirred at room temperature for 7 h and the termination reaction was monitored by TLC (CH ₂ Cl ₂ :CH ₃ OH, 5:1). Slowly add concentrated ammonia water dropwise to the reaction solution, adjust the pH to 6, let stand for half an hour, filter, filter the cake with distilled water, wash 3 times with acetone, collect the filter cake and transfer it to a watch glass to dry, finally get 31.5g (91 %) the title compound as a colorless solid. ESI-MS (m/e) 215 [MH]-.

Example 2 Preparation of N-Boc-(S)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid (2)

Add 41.9g (193.9mmol) (S)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid into 300mL DMF, add 50.8g (233mmol )(Boc) ₂ O, then add triethylamine dropwise to adjust the pH of the reaction solution to 10, react at room temperature for 48 hours, pump air once every 8 hours, TLC (CH ₂ Cl ₂ :CH ₃ OH, 5:1) shows the raw material point disappear, the reaction is terminated. Concentrated under reduced pressure, the residue was dissolved in 300 mL ethyl acetate, washed 3 times with 5% KHSO ₄ solution, the ethyl acetate layer was dried over anhydrous sodium sulfate for 12 h, filtered, and the filtrate was concentrated under reduced pressure. The residue was added with a small amount of CH ₂ Cl ₂ and sonicated to form a suspension, and then filtered to collect the filter cake. After the filtrate was concentrated, the above steps were repeated until there was no suspended matter in the solution. The filter cake was collected to give 33.94 g (55%) of the title compound as a colorless solid. ESI-MS (m/e) 315 [MH]-.

Example 3 Preparation of N-Boc-(S)-2,3,4,9-tetrahydro-β-carboline-3-formyl-L-leucine methyl ester (3)

Under ice bath, 31.35g (99.7mmol) N-Boc-(S)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid was dissolved in 250mL anhydrous THF and 13.39g (99.7 mmol) HOBt, then add a solution of 24.51g (119.6mmol) DCC and 150mL anhydrous THF, react for 30min; add 19.87g (99.7mmol) L-leucine methyl ester, use NMM to adjust the pH of the reaction solution to 9, at room temperature Reaction 24h. TLC (petroleum ether: acetone, 3:1) showed that the starting point disappeared, and the reaction was terminated. Filter and concentrate the filtrate under reduced pressure. The residue was dissolved in 250 mL of ethyl acetate, washed successively with saturated NaHCO ₃ solution 3 times, saturated NaCl solution 3 times, 5% KHSO ₄ solution 3 times, saturated NaCl solution 3 times, 5% NaHCO ₃ solution 3 times , washed three times with saturated NaCl solution. The combined ethyl acetate layers were dried over anhydrous sodium sulfate for 12 h, filtered, and the filtrate was concentrated under reduced pressure to obtain 43.42 g (99%) of the title compound as a yellow solid. ESI-MS (m/e) 444 [M+H]+.

Example 4 Preparation of [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazol-4-one-3 -yl)]-2-methylbutyric acid methyl ester (4)

Add 21.0g (48.4mmol) N-Boc-(S)-2,3,4,9-tetrahydro-β-carboline-3-formyl-L-leucine methyl ester dropwise to 220mL under stirring in an ice bath Hydrogen chloride-ethyl acetate solution (4N), reacted under ice bath for 4h TLC (petroleum ether: acetone, 3:1) monitored the disappearance of the raw material point. The solvent was drained, the residue was dissolved in 110 mL CH ₃ OH, 110 mL acetone was added, the pH of the reaction solution was adjusted to 9 with triethylamine, and the reaction was carried out at room temperature in the dark for 2 weeks. TLC (petroleum ether: acetone, 3:1) showed that the starting point disappeared, and the reaction was terminated. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and a precipitate was precipitated. After filtering again, the filtrate was concentrated under reduced pressure and precipitated out again. Repeat this step until no precipitate separates out. Collect the filter cake. After concentration, the filtrate was dissolved in 400 mL of ethyl acetate, washed 8 times with saturated NaCl solution, the combined ethyl acetate layer was dried with anhydrous sodium sulfate for 12 h and filtered, the filtrate was concentrated under reduced pressure, the residue was suspended with a small amount of CH ₃ OH, and filtered. Collect the filter cake. Repeat this step for the filtrate until no precipitate separates out. All filter cakes collected were combined and air dried to give 11.75 g (65%) of the title compound as a colorless solid. ESI-MS (m/e) 384 [M+H]+.

Example 5 Preparation of [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazol-4-one-3 -yl)]-2-methylbutanoic acid (5)

To 10.32g (26.9mmol) [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazole-4- Keto-3-yl)]-2-methylbutanoic acid methyl ester was added to ₃₀₀ mL THF and 100 mL CH3OH. The pH of the reaction solution was adjusted to 12 with 4N NaOH under stirring in an ice bath. After 48 hours of reaction in ice bath, TLC (petroleum ether: acetone, 3:1) monitored the disappearance of the raw material point, and the reaction was terminated. The pH of the reaction solution was adjusted to 7 with saturated KHSO ₄ solution under ice cooling. After concentrating under reduced pressure to remove THF and CH ₃ OH, the pH of the residue solution was adjusted to 2 with 5% KHSO ₄ solution under ice cooling, resulting in the precipitation of a large amount of colorless precipitates. After filtration, the filter cake was washed with a small amount of distilled water, and the filter cake was air-dried to obtain 9.45 g (95%) of the title compound as a pale yellow solid. ESI-MS (m/e) 368 [MH]-.

Example 6 Preparation of [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazol-4-one-3 -yl)]-2-methylbutyryl-Lys(Boc)-OBzl(6)

1.0 g (2.74 mmol) of [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazole-4- Keto-3-yl)]-2-methylbutanoic acid was dissolved in 70mL of anhydrous THF, stirred in an ice bath and added 0.37g (2.74mmol) HOBt and 0.62g (3.28mmol) EDC, and added 1.51g (2.74 mmol) L-Lys(Boc)-OBzl. The pH of the reaction mixture was adjusted to 9 with NMM, and the reaction was carried out for 21 h. TLC (petroleum ether: acetone, 3:1) monitored the disappearance of the raw material point, and the reaction was terminated. Filtrate, concentrate the filtrate under reduced pressure, dissolve the residue with 150 mL of ethyl acetate, wash with saturated NaHCO solution ₃ times, saturated NaCl solution 3 times, 5% KHSO ₄ solution 3 times, saturated NaCl solution 3 times, 5 %NaHCO ₃ solution washed 3 times, saturated NaCl solution washed 3 times. The combined ethyl acetate layers were dried over anhydrous sodium sulfate for 12 h, filtered, and the filtrate was concentrated under reduced pressure to give 1.65 g (89%) of the title compound as a yellow solid. ESI-MS (m/e) 688 [M+H]+.

Example 7 Preparation of [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazol-4-one-3 -yl)]-2-methylbutyryl-Lys-OBzl(7)

600 mg (0.87 mmol) [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazole- 4-keto-3-yl)]-2-methylbutyryl-Lys(Boc)-OBzl was reacted with 30 mL hydrogen chloride-ethyl acetate solution (4N) for 5 h. TLC (petroleum ether: acetone, 3:1) monitored the disappearance of the starting point, and the reaction was terminated. The reaction mixture was concentrated under reduced pressure, and the residue was added with a small amount of anhydrous ether and concentrated to dryness under reduced pressure. This operation was repeated twice to afford 600 mg (100%) of the title compound as an off-white solid. ESI-MS (m/e) 588 [M+H]+.

Example 8 Preparation of [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazol-4-one-3 -yl)]-2-methylbutyryl-(Nω-glucuronyl-Lys-OBzl)(8)

100 mg (0.17 mmol) of [(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolo(2,2-dimethyl-imidazol-4-one -3-yl)]-2-methylbutyryl-Lys-OBzl was dissolved in 40 mL of anhydrous DMF, and 23 mg (0.17 mmol) of HOBt and 42 mg (0.2 mmol) of DCC were added successively under stirring in an ice bath. After 30 minutes of reaction, 132 mg of (0.68mmol) glucuronic acid, then adjusted the pH of the reaction solution to 9 with NMM, reacted at room temperature in the dark for 48h, monitored by TLC (CH ₂ Cl ₂ :CH ₃ OH:CH ₃ CO ₂ H, 15:1:1.5) The raw material point disappeared and the reaction was terminated. After filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in a mixed solvent of 10 mL CH ₃ OH and 10 mL distilled water, and filtered through a MILLEX GP 0.22 μm filter membrane, and the filtrate was purified by HPLC with a purity of 98%. Lyophilization afforded 30 mg (23%) of the title compound as a pale yellow solid. ESI-MS (m/e) 798[M+Cl]-; Mp=136-139°C; (c＝0.1，CH ₃ OH)；IR(KBr)：3319.49，2956.87，2868.15，2808.36，1681.93，1558.48，1539.20，1456.26，1435.04，1369.46，1334.74，1311.59，1224.80，1190.08，1143.79，1103.28，1055.06，746.45 cm ^-1 ; ¹ HNMR (300MHz, DMSO-d6) δ/ppm: 10.886 (s, 1H, H12), 8.204 (d, J=7.5Hz, 1H, H39), 7.963 (m, 1H, H25), 7.428 (d, J=7.5Hz, 1H, H10), 7.297(m, 6H, H7, H30, H31, H32, H33, H34), 7.055(t, J=6.9Hz, 1H, H8), 7.005(t, J=6.9Hz, 1H, H9), 6.650(m, 1H, H42), 5.094(s, 2H, H28), 4.805(m, 4H, H46, H47, H48, H49), 4.305(m, 2H, H26 , H19), 3.954(m, 1H, H3), 3.770(m, 2H, H1), 3.418(m, 4H, H41, H42, H43, H44), 3.010(m, 2H, H38), 2.878(m, 2H, H4), 1.897(m, 2H, H20), 1.871(m, 2H, H35), 1.644(m, 2H, H37), 1.492(m, 1H, H21), 1.347(s, 3H, H15), 1.267 (s, 3H, H16), 1.150 (m, 2H, H36), 0.908 (m, 6H, H22, H23).

Experimental example 1 evaluates the activity of compound 8 in inhibiting tumor growth in S180 mice

Compound 8 and doxorubicin were dissolved in physiological saline before measurement. Under sterile conditions, take the S180 sarcoma inoculated in ICR mice for 10 days, add an appropriate amount of normal saline to prepare a suspension with the number of tumor cells ¹ ×107/mL, and inoculate it under the skin of the forelimb armpit of healthy male ICR mice. Mice were injected with 0.2 mL to create the S180 mouse model. 24 hours after tumor inoculation, mice were intraperitoneally injected once a day with 0.2 mL of compound 8 in normal saline solution at a dose of 0.01 μmol/kg for 9 consecutive days, or intraperitoneally injected with 0.2 mL of normal saline once a day for 9 consecutive days , or a daily intraperitoneal injection of 0.2 mL of doxorubicin in normal saline solution at a dose of 2 μmol/kg. On the 10th day of the experiment, the mice were weighed, anesthetized with ether, and the tumors of the mice in each group were dissected and weighed. The results are listed in Table 1. The results showed that the tumor weight of S180 mice treated with 0.01 μmol/kg compound 8 was significantly lighter than that of S180 mice treated with normal saline. In addition, the tumor weight of S180 mice treated with 0.01 μmol/kg compound 8 was not significantly different from that of S180 mice treated with 2 μmol/kg doxorubicin. It shows that compound 8 has good antitumor activity. Compared with the disclosed compounds mentioned in the background of the invention, the effective dose is reduced by 100 times, and unexpected technical effects are obtained.

Table 1 Compound Pair 8 Effects on Tumor Growth in S180 Tumor-bearing Mice

n=15; a) p<0.01 compared with normal saline, and p>0.05 compared with doxorubicin.

Experimental example 2 evaluates the anti-inflammatory activity of compound 8

20±2g ICR male mice were randomly divided into blank control group, positive medication group, and medication group. The mice rested for 1 day before use, and the room temperature was kept at 22°C in the operating room. There were 10 mice in each group. Oral normal saline (dose 0.2mL/20g) or aspirin normal saline solution (dose 1.11mmol/kg) or compound 8 normal saline solution (dose 1μmol/kg) 30 minutes later, to the left side of the mouse Xylene (0.045 mL) was applied to the outer pinna of the ear, and the mice were anesthetized 1 hour later, and sacrificed by cervical dislocation. Cut off the left and right ears of the mouse, use a hole puncher with a diameter of 7 mm to take the circular ear pieces at the same position on the two ears, weigh them respectively, and obtain the weight difference between the two circular ear pieces as the degree of swelling. express. The statistical data in this experiment were analyzed by t-test and analysis of variance. The results are shown in Table 3. It can be seen that the ear swelling degree of the compound 8 treatment group is significantly different from that of the normal saline group, indicating that the compound 8 also has an anti-inflammatory effect while exerting an anti-tumor effect in vivo. The anti-inflammatory activity is an unexpected technical effect compared to the already disclosed compounds mentioned in the background of the invention.

Anti-inflammatory activity evaluation of compound 8 in table 2

n=10; a) p<0.01 compared with normal saline group.

Claims (4)

1. the N of following formula definition^α-2,3,4,9-tetrahydrochysene-1H-pyrido indole also-2,2-dimethyl-imidazol-4-ketone-3-base-2-methylbutyryl- N ω-glucal acyl-Lys-OBzl

2. the N of claim 1^α-2,3,4,9-tetrahydrochysene-1H-pyrido indole also-2,2-dimethyl-imidazol-4-ketone-3-base-2-methyl The preparation method of butyryl-N ω-glucal acyl-Lys-OBzl, the method includes:

(1) L-Trp carries out Pictet-Spengler condensation under the catalysis of sulphuric acid and prepares (S)-2 with formaldehyde, and 3,4,9-tetra- Hydrogen-B-carboline-3-carboxylic acid；

(2) 2,3,4,9-tetrahydro-beta-carboline-3-carboxylic acid and Boc₂O reaction under N-methylmorpholine is catalyzed obtains N-Boc-2, and 3,4,9- Tetrahydro-beta-carboline-3-carboxylic acid；

(3) at dicyclohexylcarbodiimide, DCC, and N-hydroxybenzotriazole, HOBt, in the presence of N-Boc-2,3,4,9-tetra- Hydrogen-B-carboline-3-carboxylic acid and the condensation of L-Leu methyl ester are N-Boc-2,3,4, the 9-tetrahydro-beta-carboline-3-bright ammonia of formyl-L- Acid methyl ester；

(4) N-Boc-2 in 4N hydrogen chloride-ethyl acetate solution, 3,4,9-tetrahydro-beta-carboline-3-formyls-L-Leu methyl ester takes off Boc is gone to generate 2,3,4,9-tetrahydro-beta-carboline-3-formyls-L-Leu methyl ester；

(5) triethylamine catalysis 2,3,4,9-tetrahydro-beta-carboline-3-formyls-L-Leu methyl ester lucifuge in methanol and acetone is reacted To 2,3,4,9-tetrahydrochysene-1H-pyrido indole also-2,2-dimethyl-imidazol-4-ketone-3-base-methyl 2-methylbutyrate；

(6) 2,3,4,9-tetrahydrochysene-1H-pyrido indole also-2 in 2N NaOH water/methanol solution, 2-dimethyl-imidazol-4-ketone-3- Base-methyl 2-methylbutyrate generates 2,3,4,9-tetrahydrochysene-1H-pyrido indole also-2,2-dimethyl-imidazol-4-ketone-3-base-2- Methylbutanoic acid；

(7) 2,3,4,9-tetrahydrochysene-1H-pyrido indole also-2 in the presence of DCC and HOBt, 2-dimethyl-imidazol-4-ketone-3-base -2-Methyl Butyric Acid and Boc-Lys ()-OBzl condensation are N^α-2,3,4,9-tetrahydrochysene-1H-pyrido indole also-2,2-dimethyl- Imidazol-4-one-3-base-2-methylbutyryl-N ω-Boc-Lys-OBzl；

(8) N in hydrogen chloride-ethyl acetate solution^α-2,3,4,9-tetrahydrochysene-1H-pyrido indole also-2,2-dimethyl-imidazol-4-ketone -3-base-2-methylbutyryl-N ω-Boc-Lys-OBzl sloughs Boc and generates N^α-2,3,4,9-tetrahydrochysene-1H-pyrido indole are also -2,2-dimethyl-imidazol-4-ketone-3-base-2-methylbutyryl-Lys-OBzl；

(9) N in the presence of DCC and HOBt^α-2,3,4,9-tetrahydrochysene-1H-pyrido indole also-2,2-dimethyl-imidazol-4-ketone-3- Base-2-methylbutyryl-Lys-OBzl with the condensation of D-Glucose aldehydic acid is in anhydrous DMF solution N^α-2,3,4,9-tetrahydrochysene-1H-pyrido indole also-2,2-dimethyl-imidazol-4-ketone-3-base-2-methylbutyryl-N ω-glucose Aldehyde acyl-Lys-OBzl.

3. the N of claim 1^α-2,3,4,9-tetrahydrochysene-1H-pyrido indole also-2,2-dimethyl-imidazol-4-ketone-3-base-2-methyl Butyryl-N ω-glucal acyl-Lys-OBzl application in preparing antitumor drug.

4. the N of claim 1^α-2,3,4,9-tetrahydrochysene-1H-pyrido indole also-2,2-dimethyl-imidazol-4-ketone-3-base-2-methyl Butyryl-N ω-glucal acyl-Lys-OBzl application in preparing anti-inflammatory medicaments.