CN104086617B - Close dimethylamine derivative, the preparation method and its usage of flowers and trees ketone Cleistanone - Google Patents

Abstract

The invention relates to the fields of organic synthesis and medicinal chemistry, and in particular to a Cleistanone derivative, a preparation method and its application in the preparation of antitumor drugs. The invention synthesizes a new Cleistanone derivative and discloses its preparation method. Pharmacological experiments show that the Cleistanone derivatives of the present invention have anti-tumor effects and are valuable for the development of anti-tumor drugs.

Description

Dimethylamine derivatives of cleistanone, preparation method and use thereof

technical field

The present invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a Cleistanone derivative, a preparation method and an application thereof.

Background technique

Cancer is one of the most harmful diseases to human life and health, and a large number of people die of cancer every year. The research and development of anticancer drugs has always been a hot spot in pharmaceutical research. 74% of the antineoplastic drugs are natural products or their derivatives, such as paclitaxel and its derivatives are currently clinically effective antineoplastic drugs. Therefore, it is most valuable to find compounds or lead compounds from natural products and carry out structural modification to obtain their derivatives, so as to obtain potential drugs with high efficiency and low toxicity.

The compound Cleistanone involved in the present invention is a compound published in 2011 (Van TrinhThiThanhetal., 2011. Cleistanone: ATriterpenoid from Cleistanthus indochinensis with a New Carbon Skeleton. Volume2011, Issue22, pages4108-4111, August2011), we modified the structure of the compound Cleistanone A new Cleistanone derivative was developed and its antitumor activity was evaluated. It has antitumor activity.

Contents of the invention

The invention discloses a Cleostanone derivative, the structure of which is:

Cleistanone derivatives (III) of the present invention can be prepared by the following method:

(1) Reaction of Cleistanone (I) with 1,2-dibromoethane to obtain O-bromoethyl derivative (II) of Cleistanone;

(2) O-bromoethyl derivative of Cleistanone (II) undergoes a substitution reaction with dimethylamine to obtain Cleistanone derivative (III).

The preparation method of further cleistanone Cleistanone derivative (III) is:

(1) Dissolve 440 mg of the compound Cleistanone (I) in 10 mL of benzene, add 0.04 g of tetrabutylammonium bromide, 3.760 g of 1,2-dibromoethane and 6 mL of 50% hydroxide Sodium solution; the mixture was stirred at 25 degrees Celsius for 24h; after 24h, the reaction solution was poured into ice water, extracted twice with dichloromethane immediately, and the organic phase solution was combined; then the organic phase solution was washed with water and saturated brine three times in sequence, and then Dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure to remove the solvent to obtain the crude product; the crude product is purified by silica gel column chromatography, the mobile phase is: petroleum ether/acetone=100:1, v/v, and the yellow concentrated elution band is collected as The O-bromoethyl derivative (II) of Cleistanone was obtained as a yellow solid.

(2) Dissolve 273 mg of the O-bromoethyl derivative of Cleistanone in 20 mL of acetonitrile, add 345 mg of anhydrous potassium carbonate, 84 mg of potassium iodide and 900 mg of dimethylamine, and heat the mixture under reflux for 16 h; After completion, the reaction solution was poured into ice water, extracted three times with an equal amount of dichloromethane, and the organic phases were combined; the combined organic phases were washed with water and saturated brine in turn, dried with anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent to obtain Crude product; the crude product is purified by silica gel column chromatography, the mobile phase is: petroleum ether/acetone=100:1, v/v, and the light yellow concentrated elution band is collected to obtain the light yellow color of cleistanone derivative (III) solid.

The compounds disclosed in the present invention can be made into pharmaceutically acceptable salts or pharmaceutically acceptable carriers.

Pharmacodynamic experiments show that the Cleistanone derivative (III) of the present invention has better antitumor effect. The pharmaceutically acceptable salts of the present invention have the same medicinal effects as the compounds thereof.

The present invention will be described in further detail below through examples, but the protection scope of the present invention is not limited by any specific examples, but is defined by the claims.

detailed description

Preparation of Example 1 Compound Cleistanone

The preparation method of the compound Cleistanone (I) refers to the literature published by VanTrinhThiThanh et al.

Synthesis of O-bromoethyl derivatives (II) of cleistanone Cleistanone of embodiment 2

Compound I (440 mg, 1.00 mmol) was dissolved in 10 mL of benzene, and tetrabutylammonium bromide (TBAB) (0.04 g), 1,2-dibromoethane (3.760 g, 20.00 mmol) and 6 mL of 50% sodium hydroxide solution. The mixture was stirred at 25 °C for 24 h. After 24 hours, the reaction solution was poured into ice water, extracted twice with dichloromethane immediately, and the organic phase solutions were combined. Then the organic phase solution was washed with water and saturated brine three times successively, then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether/acetone=100:1, v/v), and the yellow concentrated elution band was collected to obtain compound II as a yellow solid (344 mg, 63%).

1HNMR (500MHz, DMSO-d ₆ )δ5.04(s,1H), 4.82(s,1H), 3.94(d, J=26.5Hz, 1H), 3.87(d, J=26.5Hz, 2H), 3.57 (s,2H),2.40(d,J=14.0Hz,1H),2.39(d,J=14.0Hz,1H),2.27(s,1H),2.21(s,1H),2.15(s,1H) ,1.82(s,1H),1.62(s,2H),1.57(d,J=3.3Hz,1H),1.54(d,J=3.3Hz,1H),1.50(d,J=1.2Hz,1H) ,1.47(d,J=1.2Hz,1H),1.39(d,J=15.3Hz,2H),1.34(d,J=15.3Hz,1H),1.26(dd,J=32.6,13.7Hz,4H) , 1.13 (d, J=18.0Hz, 2H), 1.05 (s, 6H), 0.98 (s, 1H), 0.88 (s, 12H), 0.78 (s, 3H), 0.74 (s, 1H).

13CNMR (125MHz, DMSO-d6) δ216.59(s), 154.50(s), 105.23(s), 74.63(s), 69.85(s), 59.71(s), 52.55(s), 51.21(s), 47.92(s), 44.10(s), 42.25(s), 41.73(s), 40.64(s), 40.16(s), 38.88(s), 38.65(s), 37.21(s), 36.23(s), 33.34(d, J=1.1Hz), 32.96(s), 29.91(s), 27.18(s), 26.03(s), 24.23(s), 23.96(s), 20.77(s), 18.48(s), 17.98(s), 16.93(s).

HRMS (ESI) m/z [M+H] ⁺ calcd for C ₃₂ H ₅₂ BrO ₂ : 547.3151; found 547.3159.

Example 3 Synthesis of O-(dimethylamino)ethyl derivatives (III) of cleistanone Cleistanone

Compound II (273mg, 0.5mmol) was dissolved in 20mL of acetonitrile, anhydrous potassium carbonate (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and dimethylamine (900mg, 20mmol) were added thereto, and the mixture was heated to reflux for 16h . After the reaction was completed, the reaction solution was poured into ice water, extracted three times with an equal amount of dichloromethane, and the organic phases were combined. The combined organic phases were successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether/acetone=100:1, v/v), and the light yellow concentrated elution band was collected to obtain compound III as a light yellow solid (160.7 mg, 61%).

1HNMR(500MHz,DMSO-d6)δ5.02(s,1H),4.81(s,1H),3.85(s,1H),3.51(s,2H),2.84(s,6H),2.64(s,2H ),2.38(d,J=13.0Hz,2H),2.26(s,1H),2.17(s,1H),2.17(s,1H),1.83(s,1H),1.66(s,2H),1.54 (d, J = 6.0Hz, 2H), 1.46 (d, J = 0.9Hz, 2H), 1.34 (d, J = 13.5Hz, 3H), 1.26 (dd, J = 31.1, 13.9Hz, 4H), 1.16 (d,J=13.5Hz,2H),1.07(s,6H),0.98(s,1H),0.85(s,12H),0.76(s,3H),0.73(s,1H).

13CNMR (125MHz, DMSO-d6) δ216.60(s), 154.51(s), 105.19(s), 74.62(s), 65.68(s), 59.75(s), 57.63(s), 52.57(s), 51.18(s), 47.87(s), 45.54(s), 44.12(s), 42.29(s), 41.79(s), 40.62(s), 40.12(s), 38.82(s), 38.67(s), 37.25(s), 36.29(s), 33.32(s), 32.92(s), 29.85(s), 27.20(s), 26.07(s), 24.29(s), 23.94(s), 20.73(s), 18.42(s), 18.00(s), 16.97(s).

HRMS (ESI): m/z [M+H] ⁺ calcdfor C ₃₄ H ₅₈ NO ₂ : 512.4468; found: 512.4463.

Example 4 In Vitro Antitumor Activity Screening

Screening cell lines are HepG2 (human liver cancer cells), PANC-1 (human pancreatic cancer cells), MCF-7 (human breast cancer cells), SW620 (human colon cancer cells), A549 (human lung cancer cells), HGC-27 (human gastric cancer cells).

experimental method:

Cells in good logarithmic growth phase were taken and digested with trypsin to make a suspension of 5×10 ⁴ cells/mL. The cell suspension was transferred into a 96-well culture plate, 100 μL per well, and cultured at 37° C. and 5% CO ₂ for 24 hours.

The test compound III was prepared into a certain concentration of mother solution with DMSO, and then diluted with RPMI1640 medium to dilute the derivative mother solution into different concentration dilutions. Remove the old medium, add different concentrations of drug-containing medium, 100 μL per well. A blank control group was also set up. After 48 hours of drug action, discard the drug-containing medium, add 100 μL of serum-free and phenol red-free 1640 medium to each well, and then add 10 μL of MTT solution (5 mg/mL), and continue to incubate for 4 hours.

Aspirate the supernatant in each well, add 150 μL of DMSO to each well, shake in the dark for 10 minutes to fully dissolve the crystals, measure the light absorption value (OD value) of each well at 490 nm with a microplate reader, and calculate the inhibition rate of cell proliferation: Inhibition Rate (%)=(1-average OD value of medication group/average OD value of blank control group)×100%. SPSS 16.0 software was used for data processing and the half inhibitory concentration (IC ₅₀ ) of cancer cell proliferation was calculated. The results are shown in Table 1.

Table 1 The in vitro proliferation inhibitory effect of dehydroabietic acid indole derivatives on 7 kinds of cancer cells

As shown in the results in Table 1, the synthesized derivatives all have certain proliferation inhibitory effects on different tumor cells. It shows that the synthesized derivatives show good anticancer activity and have the potential of developing anticancer drugs.

Embodiment 5 The preparation of compound II and III tablet involved in the present invention

Take 20 grams of compound III or one of its pharmaceutically acceptable salts, add 180 grams of conventional excipients for tablet preparation, mix well, and make 1000 tablets with a conventional tablet machine.

Embodiment 6 The preparation of compound II and III capsules involved in the present invention

Take 20 grams of Compound III or one of its pharmaceutically acceptable salts, add conventional excipients for capsule preparation such as 180 grams of starch, mix well, and pack into capsules to make 1000 capsules.

Claims (7)

1. A Cleistanone derivative having a structure shown in formula III and a pharmaceutically acceptable salt thereof: 2. the preparation method of Cleistanone derivatives as claimed in claim 1, is characterized in that: (1) Reaction of Cleistanone (I) with 1,2-dibromoethane to obtain O-bromoethyl derivative (II) of Cleistanone; (2) O-bromoethyl derivative (II) of cleistanone Cleistanone is substituted with dimethylamine to obtain Cleistanone derivative (III); 3. the preparation method of Cleistanone derivatives as claimed in claim 2, is characterized in that: (1) Dissolve 440 mg of the compound Cleistanone (I) in 10 mL of benzene, add 0.04 g of tetrabutylammonium bromide, 3.760 g of 1,2-dibromoethane and 6 mL of 50% hydroxide Sodium solution; the mixture was stirred at 25 degrees Celsius for 24h; after 24h, the reaction solution was poured into ice water, extracted twice with dichloromethane immediately, and the organic phase solution was combined; then the organic phase solution was washed with water and saturated brine three times in sequence, and then Dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure to remove the solvent to obtain the crude product; the crude product is purified by silica gel column chromatography, the mobile phase is: petroleum ether/acetone=100:1, v/v, and the yellow concentrated elution band is collected as A yellow solid of the O-bromoethyl derivative (II) of Cleistanone was obtained; (2) Dissolve 273 mg of the O-bromoethyl derivative of Cleistanone in 20 mL of acetonitrile, add 345 mg of anhydrous potassium carbonate, 84 mg of potassium iodide and 900 mg of dimethylamine, and heat the mixture under reflux for 16 h; After completion, the reaction solution was poured into ice water, extracted three times with an equal amount of dichloromethane, and the organic phases were combined; the combined organic phases were washed with water and saturated brine in turn, dried with anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent to obtain Crude product; the crude product is purified by silica gel column chromatography, the mobile phase is: petroleum ether/acetone=100:1, v/v, and the light yellow concentrated elution band is collected to obtain the light yellow color of cleistanone derivative (III) solid. 4. The application of the Cleistanone derivatives and pharmaceutically acceptable salts thereof as claimed in claim 1 in the preparation of antitumor drugs. 5 . The use of Cleistanone derivatives and pharmaceutically acceptable salts thereof in the preparation of antitumor drugs as claimed in claim 4 , characterized in that: the tumor is a tumor of the digestive system. 6. The application of Cleistanone derivatives and pharmaceutically acceptable salts thereof in the preparation of antitumor drugs as claimed in claim 5, characterized in that: the digestive system tumor is liver cancer, pancreatic cancer, colon cancer or stomach cancer. 7 . The use of Cleistanone derivatives and pharmaceutically acceptable salts thereof in the preparation of antitumor drugs as claimed in claim 4 , characterized in that: the tumor is breast cancer or lung cancer.