VINYLATION COUPLED DERIVATIVE OF BETA-ELEMENE, AND PREPARATION METHOD AND USE THEREOF IN PREPARATION OF ANTITUMOR DRUG

Abstract

The present disclosure provides a vinylation coupled derivative of -elemene, and a preparation method and use thereof in preparation of an antitumor drug. The present disclosure provides a vinylation coupled derivative of -elemene having a structure shown in Formula (I), a pharmaceutical composition and a hydrate including a compound shown in Formula (I), as well as an isotopic derivative, a chiral isomer, a variant, a salt, a prodrug, and a preparation of the compound shown in Formula (I). The present disclosure further provides a preparation method and use of the vinylation coupled derivative of -elemene, and an inhibitory activity of the derivative on proliferation of various tumor cell lines. The vinylation coupled derivative of -elemene is expected to be an antitumor drug candidate for treating colon cancer and lung cancer.

##STR00001##

Claims

1. A vinylation coupled derivative of -elemene, or an optical isomer, a racemate, a single enantiomer, and a diastereomer thereof, or a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, and a solvate thereof, wherein the vinylation coupled derivative of -elemene has a structure shown in formula (I): ##STR00023## R is selected from the group consisting of aryl, heteroaryl, and alkyl in formula (I).

2. The vinylation coupled derivative of -elemene, or an optical isomer, a racemate, a single enantiomer, and a diastereomer thereof, or a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, and a solvate thereof according to claim 1, wherein R in the structure shown in Formula (I) of the vinylation coupled derivative of -elemene is any one independently selected from the group consisting of the following structural fragments: ##STR00024## ##STR00025## ##STR00026##

3. The vinylation coupled derivative of -elemene, or an optical isomer, a racemate, a single enantiomer, and a diastereomer thereof, or a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, and a solvate thereof according to claim 1, wherein the vinylation coupled derivative of -elemene has a structure shown in any one of Compounds 1 to 22: ##STR00027## ##STR00028## ##STR00029## ##STR00030##

4. A preparation method of the vinylation coupled derivative of -elemene according to claim 1, wherein the preparation method has the following synthetic route: ##STR00031## and the preparation method comprises the following steps: (1) subjecting -elemene A-1 to monobromine substitution at an allyl position to obtain an intermediate A-2; (2) subjecting the intermediate A-2 to selective nucleophilic substitution to obtain an intermediate A-3; and (3) allowing the intermediate A-3 and alkenyl bromide A-4 to have vinylation coupling to obtain the vinylation coupled derivative of -elemene having a structure shown in Formula (I); wherein R is any one independently selected from the group consisting of the following structural fragments: ##STR00032## ##STR00033## ##STR00034##

5. A method for treating a tumor, comprising administering the vinylation coupled derivative of -elemene, or an optical isomer, a racemate, a single enantiomer, and a diastereomer thereof, or a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, and a solvate thereof according to claim 1 to a subject in need.

6. The method according to claim 5, wherein the antitumor drug is used for treating colon cancer, lung cancer, liver cancer, gastric cancer, prostate cancer, ovarian cancer, breast cancer, or glioma.

7. The method according to claim 5, wherein the vinylation coupled derivative of -elemene, or an optical isomer, a racemate, a single enantiomer, and a possible diastereomer thereof, or a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, and a solvate thereof is applied by oral administration, intratumoral administration, rectal administration, parenteral administration, and topical administration.

8. The method according to claim 7, wherein a solid dosage form for the oral administration comprises a capsule, a tablet, a pill, a powder, and a granule; in the solid dosage form, the vinylation coupled derivative of -elemene, or an optical isomer, a racemate, a single enantiomer, and a possible diastereomer thereof, or a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, and a solvate thereof is mixed with at least one inert excipient or carrier; the inert excipient or carrier is selected from the group consisting of sodium citrate and dicalcium phosphate; alternatively, the vinylation coupled derivative of -elemene, or an optical isomer, a racemate, a single enantiomer, and a possible diastereomer thereof, or a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, and a solvate thereof is mixed with a filler or a solubilizer, a binder, a humectant, a disintegrant, a retarding solvent, an absorption accelerator, a wetting agent, an adsorbent, and a lubricant; the filler or the solubilizer is selected from the group consisting of starch, lactose, sucrose, glucose, mannitol, and silicic acid; the binder is selected from the group consisting of hydroxymethylcellulose, an alginate, gelatin, polyvinylpyrrolidone, sucrose, and arabic gum; the humectant is glycerin; the disintegrant is selected from the group consisting of agar, calcium carbonate, potato starch or tapioca starch, alginic acid, a complex silicate, and sodium carbonate; the retarding solvent is paraffin; the absorption accelerator is a quaternary ammonium compound; the wetting agent is selected from the group consisting of cetyl alcohol and glyceryl monostearate; the adsorbent is kaolin; and the lubricant is selected from the group consisting of talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium lauryl sulfate and a mixture thereof.

9. The method according to claim 5, wherein a daily dosage is 1 mg to 5,000 mg for a person weighing 60 kg.

10. An antitumor drug, comprising a safe and effective dosage of the vinylation coupled derivative of -elemene, or an optical isomer, a racemate, a single enantiomer, and a possible diastereomer thereof, or a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, and a solvate thereof according to claim 1.

11. The antitumor drug according to claim 10, wherein R in the structure shown in Formula (I) of the vinylation coupled derivative of -elemene is any one independently selected from the group consisting of the following structural fragments: ##STR00035## ##STR00036## ##STR00037##

12. The antitumor drug according to claim 10, wherein the vinylation coupled derivative of -elemene has a structure shown in any one of Compounds 1 to 22: ##STR00038## ##STR00039## ##STR00040## ##STR00041##

13. The antitumor drug according to claim 10, further comprising a pharmaceutically acceptable excipient or carrier.

14. The antitumor drug according to claim 11, further comprising a pharmaceutically acceptable excipient or carrier.

15. The antitumor drug according to claim 12, further comprising a pharmaceutically acceptable excipient or carrier.

16. The antitumor drug according to claim 10, wherein the antitumor drug is used for treating colon cancer and lung cancer.

17. The antitumor drug according to claim 11, wherein the antitumor drug is used for treating colon cancer and lung cancer.

18. The antitumor drug according to claim 10, wherein the antitumor drug carries the vinylation coupled derivative of -elemene, or an optical isomer, a racemate, a single enantiomer, and a possible diastereomer thereof, or a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, and a solvate thereof at 1 mg/dose to 2,000 mg/dose; and one dose refers to one capsule or one tablet.

19. The antitumor drug according to claim 10, wherein the pharmaceutically acceptable carrier comprises cellulose and a derivative thereof, gelatin, talc, a solid lubricant, calcium sulfate, vegetable oil, a polyol, an emulsifier, a wetting agent, a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, and pyrogen-free water.

20. The method according to claim 8, wherein the tablet, the capsule, the pill, and the granule each are prepared from a coating and a shell material.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0037] The present disclosure will be further described below with reference to specific examples. It should be understood that these embodiments are only intended to describe the present disclosure, rather than to limit the scope of the present disclosure. In the following examples, the experimental methods in which specific conditions are not stated are generally conducted according to conventional conditions or according to the conditions recommended by the manufacturer.

Example 1: Preparation of Compound 1

##STR00008##

Intermediate 1d

[0038] (1) CBr.sub.4 (30 mmol, 150 mol %) was added to a dichloromethane (DCM, 80 mL) solution of Compound 1a (20 mmol, 100 mol %) at 0 C.; under nitrogen protection, a DCM (70 mL) solution of PPh.sub.3 (60 mmol, 300 mol %) was added dropwise through a constant-pressure dropping funnel into a resulting mixture. A reaction was monitored by TLC. After the reaction was completed, about half of the volume of DCM was removed under reduced pressure, and then petroleum ether (PE, 100 mL) was added to precipitate triphenylphosphine oxide (TPPO). After filtration by diatomaceous earth and evaporation, an obtained residue was dissolved in PE (50 mL) to further precipitate the TPPO. The above steps were repeated several times to obtain a crude dibromide 1b (20 mmol, 100 mol %), which was directly used in the next step.

[0039] (2) An anhydrous N,N-dimethylformamide (DMF, 20 mL) solution of the crude dibromide 1b (20 mmol, 100 mol %) and NEt.sub.3 (60 mmol, 300 mol %) was added with dimethyl phosphite (60 mmol, 300 mol %) and stirred overnight under room temperature. DMF was distilled off under reduced pressure, an aqueous solution (60 mL) was added, a resulting product was extracted with PE (2100 mL), an obtained combined organic phase was washed with an aqueous hydrochloric acid solution (1 M, 55 mL), and dried over anhydrous sodium sulfate. The above desiccant was removed by filtration, and a resulting filtrate was concentrated under reduced pressure to obtain a crude product 1c, which was directly used in the next step.

[0040] (3) The crude product 1c (20 mmol, 100 mol %) was dissolved in isopropanol (i-PrOH, 30 mL). The solid sodium hydroxide (17 mmol, 85 mol %) was added to conduct reflux by heating for more than 5 h. A resulting reaction mixture was cooled to room temperature, extracted with n-hexane (100 mL), and an obtained combined organic phase was washed successively with an aqueous hydrochloric acid solution (1 M, 75 mL) and an aqueous solution (2100 mL), and then dried over anhydrous sodium sulfate. The above desiccant was removed by filtration, an obtained filtrate was concentrated under reduced pressure, and an obtained crude product was purified by silica gel column chromatography (eluted with an ethyl acetate/petroleum ether (0.5%) system) to obtain a white solid 1d (2.65 g, yield 62%). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.25-7.21 (m, 2H), 7.04 (d, J=14.0 Hz, 1H), 6.87-6.83 (m, 2H), 6.61 (d, J=13.9 Hz, 1H), 3.81 (s, 3H).

Compound 1

[0041] The intermediate 1d (0.150 mmol, 1.0 equiv), intermediate 1e (0.300 mmol, 2.0 equiv), a catalyst NiCl.sub.2 (PPh.sub.3).sub.2 (9.8 mg, 0.015 mmol, 10 mol %), a reducing agent Zn powder (19.6 mg, 0.300 mmol, 2.0 equiv), a ligand 4,4-di-tert-butyl-2,2-bipyridine (4.0 mg, 0.015 mmol, 10 mol %), and an additive MgCl.sub.2 (28.6 mg, 0.300 mmol, 2.0 equiv) were added sequentially to an oven-dried Schlenk tube equipped with a magnetic stirrer. The Schlenk tube was evacuated three times through a double-row tube to ensure that the reaction system was under a nitrogen atmosphere, and finally an N,N-dimethylacetamide (DMA, 1.0 mL) solution was added with a syringe and stirred at 25 C. for 12 h. After the reaction was completed, an obtained reaction mixture was directly purified by silica gel column chromatography (eluted with an ethyl acetate/petroleum ether (2%) system) without post-treatment to obtain a colorless oily liquid 1 (43.3 mg, yield 86%). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.31 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 6.37 (d, J=15.8 Hz, 1H), 6.08 (dt, J=15.7, 7.1 Hz, 1H), 5.83 (dd, J=17.4, 10.9 Hz, 1H), 4.92 (dd, J=8.1, 1.2 Hz, 1H), 4.89 (s, 1H), 4.87 (s, 1H), 4.83 (dd, J=5.0, 1.3 Hz, 2H), 4.61 (s, 1H), 3.81 (s, 3H), 2.95 (d, J=7.0 Hz, 2H), 2.02 (dd, J=11.8, 4.3 Hz, 2H), 1.72 (s, 3H), 1.64-1.59 (m, 2H), 1.54-1.42 (m, 4H), 1.02 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 158.92, 153.40, 150.38, 147.81, 130.81, 130.65, 127.27, 126.63, 114.06, 112.26, 110.01, 108.76, 55.41, 52.90, 44.30, 40.09, 39.98, 38.83, 33.36, 27.33, 24.93, 16.76. HRMS (ESI) m/z ([MH].sup.) calcd for C.sub.24H.sub.31O: 335.2380. Found: 335.2380.

Example 2: Preparation of Compound 2

##STR00009##

Intermediate 2d

[0042] Referring to the synthesis steps of the intermediate 1d in Example 1, a colorless oily liquid 2d (881 mg, yield 21%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) 8.07 (d, J=2.5 Hz, 1H), 7.55 (dd, J=8.6, 2.5 Hz, 1H), 7.03 (d, J=14.0 Hz, 1H), 6.71 (d, J=8.7 Hz, 1H), 6.66 (d, J=14.0 Hz, 1H), 3.94 (s, 3H).

Compound 2

[0043] Referring to the synthesis steps of the Compound 1 in Example 1, a colorless oily liquid 2 (36.9 mg, yield 73%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) 8.08 (t, J=5.5 Hz, 1H), 7.64 (dd, J=8.6, 2.4 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 6.34 (d, J=15.9 Hz, 1H), 6.10 (dt, J=15.8, 7.0 Hz, 1H), 5.81 (dd, J=17.3, 11.0 Hz, 1H), 4.99-4.75 (m, 5H), 4.59 (s, 1H), 3.93 (s, 3H), 2.95 (d, J=6.9 Hz, 2H), 1.99 (ddd, J=15.9, 11.2, 5.0 Hz, 2H), 1.71 (s, 3H), 1.65-1.56 (m, 3H), 1.50-1.41 (m, 3H), 1.01 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 163.43, 153.06, 150.32, 147.77, 145.08, 135.54, 128.25, 127.52, 126.97, 112.29, 110.93, 110.07, 109.01, 53.61, 52.90, 44.41, 40.02 (d, J=11.8 Hz), 38.83, 33.37, 29.84, 27.32, 24.93, 16.76. HRMS (ESI) m/z ([M+H].sup.+) calcd for C.sub.23H.sub.32NO: 338.2478. Found: 338.2475.

Example 3: Preparation of Compound 3

##STR00010##

Compound 3

[0044] Referring to the synthesis steps of the Compound 1 in Example 1, a colorless oily liquid 3 (39.7 mg, yield 80%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.75 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 6.36 (ddd, J=30.6, 15.8, 11.4 Hz, 2H), 5.81 (dd, J=17.3, 11.0 Hz, 1H), 4.94-4.87 (m, 3H), 4.82 (d, J=5.9 Hz, 2H), 4.59 (s, 1H), 2.99 (d, J=6.8 Hz, 2H), 2.01 (dt, J=18.0, 10.4 Hz, 2H), 1.71 (s, 3H), 1.64-1.56 (m, 3H), 1.52-1.42 (m, 3H), 1.01 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 169.12, 152.70, 150.29, 147.77, 141.53, 131.61, 130.50, 127.86, 126.29, 112.31, 110.10, 109.32, 100.12, 52.89, 44.48, 40.01 (d, J=9.9 Hz), 38.82, 33.36, 29.84, 27.30, 24.93, 16.77. HRMS (ESI) m/z ([M+H].sup.+) calcd for C.sub.24H.sub.30N: 332.2373. Found: 332.2378.

Example 4: Preparation of Compound 4

##STR00011##

Compound 4

[0045] Referring to the synthesis steps of the Compound 1 in Example 1, a colorless oily liquid 4 (43.1 mg, yield 77%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) 8.54 (s, 1H), 8.10 (s, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.6 Hz, 2H), 6.44 (d, J=15.8 Hz, 1H), 6.29 (dt, J=15.8, 7.0 Hz, 1H), 5.82 (dd, J=17.3, 11.0 Hz, 1H), 4.97-4.87 (m, 3H), 4.83 (d, J=1.4 Hz, 2H), 4.60 (s, 1H), 2.99 (d, J=6.9 Hz, 2H), 2.06-1.97 (m, 2H), 1.71 (s, 3H), 1.64-1.58 (m, 3H), 1.52-1.42 (m, 3H), 1.01 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 152.81, 152.68, 150.29, 147.77, 140.84, 137.95, 135.73, 130.55, 130.06, 127.38, 120.29, 112.32, 110.11, 109.26, 52.90, 44.49, 40.06, 39.98, 38.78, 33.37, 27.32, 24.94, 16.77. HRMS (ESI) m/z ([M+H].sup.+) calcd for C.sub.25H.sub.32N.sub.3: 374.2591. Found: 374.2590.

Example 5: Preparation of Compound 5

##STR00012## ##STR00013##

Intermediate 5g

[0046] Referring to the synthesis steps of intermediate 1d in Example 1, a white solid 5d was obtained. In an ice bath, DMAP (37 mg, 0.3 mmol) and DCC (464 mg, 2.25 mmol) were sequentially added to an anhydrous DCM (10 mL) solution of the Compound 5d (358 mg, 1.58 mmol) and Compound 5f (288.4 mg, 1.5 mmol), and stirred overnight. DCM was distilled off under reduced pressure, and an aqueous solution (40 mL) was added to a resulting residue, followed by extraction with ethyl acetate (320 mL). A resulting combined organic phase was washed with saturated brine (220 mL), and then dried over anhydrous sodium sulfate. The above desiccant was removed by filtration, an obtained filtrate was concentrated under reduced pressure, and an obtained crude product was purified by silica gel column chromatography (eluted with an ethyl acetate/petroleum ether (0.5%) system) to obtain a white solid 5g (581 mg, yield 97%). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.93 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H), 7.15-7.07 (m, 3H), 6.90 (d, J=14.0 Hz, 1H), 4.42-4.33 (m, 2H), 3.26-3.18 (m, 1H), 2.45 (d, J=7.2 Hz, 2H), 1.84 (dt, J=13.5, 6.8 Hz, 1H), 1.38 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.6 Hz, 6H).

Compound 5

[0047] Referring to the synthesis steps of the Compound 1 in Example 1, a colorless oily liquid 5 (67.6 mg, yield 86%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.91 (d, J=7.9 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.19 (d, J=7.7 Hz, 2H), 7.10 (d, J=7.7 Hz, 2H), 6.49-6.30 (m, 2H), 5.82 (d, J=6.4 Hz, 1H), 5.01 (s, 1H), 4.93-4.92 (m, 1H), 4.89 (s, 1H), 4.83 (s, 2H), 4.58-4.57 (m, 1H), 4.42-4.31 (m, 2H), 3.21 (dd, J=13.9, 7.0 Hz, 1H), 2.99 (d, J=6.7 Hz, 2H), 2.45 (d, J=7.1 Hz, 2H), 2.09 (s, 3H), 2.01 (d, J=6.8 Hz, 2H), 1.85 (dt, J=13.3, 6.7 Hz, 1H), 1.60 (s, 2H), 1.47 (s, 4H), 1.38 (d, J=6.8 Hz, 3H), 0.99 (s, 3H), 0.90 (d, J=6.6 Hz, 6H). .sup.13C NMR (126 MHz, CDCl.sub.3) 194.56, 170.79, 166.38, 152.57, 150.20, 150.07, 148.49, 147.40, 142.14, 140.45, 140.09, 131.70, 130.66, 129.96, 129.30, 127.11, 125.95, 112.38, 111.02, 110.13, 109.28, 70.02, 66.20, 52.77, 45.13, 44.42, 41.93, 39.90, 38.79, 33.13, 30.29, 27.13, 24.90, 22.48 (d, J=3.1 Hz), 21.08, 18.13, 16.69. HRMS (ESI) m/z ([M+H].sup.+) calcd for C.sub.37H.sub.49O.sub.2: 525.3727. Found: 525.3722.

Example 6: Preparation of Compound 6

##STR00014## ##STR00015##

Intermediate 6g

[0048] Referring to the synthesis steps of the intermediate 5g in Example 5, a colorless oily liquid 6g (267 mg, yield 82%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.98 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 7.13 (d, J=14.0 Hz, 1H), 6.91 (d, J=14.0 Hz, 1H), 5.09 (t, J=7.1 Hz, 1H), 4.40-4.29 (m, 2H), 1.99 (dd, J=22.5, 7.6 Hz, 2H), 1.80 (dt, J=12.5, 6.3 Hz, 1H), 1.66 (s, 3H), 1.59 (s, 3H), 1.34-1.28 (m, 2H), 1.24 (dd, J=15.0, 7.7 Hz, 2H), 0.96 (d, J=6.6 Hz, 3H).

Compound 6

[0049] Referring to the synthesis steps of the Compound 1 in Example 1, a colorless oily liquid 6 (63.7 mg, yield 87%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.97 (d, J=7.9 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 6.50-6.29 (m, 2H), 5.82 (dd, J=17.4, 10.8 Hz, 1H), 5.10 (dd, J=6.9, 5.9 Hz, 1H), 4.92 (s, 1H), 4.91 (s, 1H), 4.89 (d, J=2.6 Hz, 1H), 4.82 (d, J=5.1 Hz, 2H), 4.60 (s, 1H), 4.46-4.27 (m, 2H), 2.99 (d, J=6.8 Hz, 2H), 2.07-1.97 (m, 4H), 1.92 (d, J=10.1 Hz, 1H), 1.86-1.79 (m, 1H), 1.75 (d, J=9.2 Hz, 1H), 1.71 (s, 3H), 1.68 (s, 3H), 1.61 (s, 3H), 1.56 (d, J=8.1 Hz, 1H), 1.51-1.44 (m, 3H), 1.31 (dd, J=17.7, 7.5 Hz, 4H), 1.01 (s, 3H), 0.97 (d, J=6.5 Hz, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 166.64, 152.66, 150.27, 147.72, 142.14, 131.72, 131.48, 130.72, 130.00, 129.01 125.99, 124.71, 112.30, 110.08, 109.31, 63.53, 52.87, 44.47, 40.00 (d, J=10.8 Hz), 38.84, 37.13, 35.66, 35.06, 33.35, 29.72, 27.30, 25.84, 25.54, 24.93, 19.65, 17.80, 16.75. HRMS (ESI) m/z ([M+H].sup.+) calcd for C.sub.34H.sub.49O.sub.2: 489.3727. Found: 489.3730.

Example 7: Preparation of Compound 7

##STR00016## ##STR00017##

Intermediate 7g

[0050] Referring to the synthesis steps of the intermediate 5g in Example 5, a colorless oily liquid 7g (281 mg, yield 89%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) 8.00 (d, J=8.2 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H), 7.13 (d, J=14.0 Hz, 1H), 6.91 (d, J=14.0 Hz, 1H), 5.84 (s, 1H), 4.73-4.70 (m, 3H), 2.17 (d, J=3.6 Hz, 1H), 1.93-1.89 (m, 2H), 1.74 (s, 3H), 1.58-1.49 (m, 2H), 1.30 (d, J=9.8 Hz, 2H).

Compound 7

[0051] Referring to the synthesis steps of the Compound 1 in Example 1, a colorless oily liquid 7 (59.5 mg, yield 82%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.97 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 6.38 (dt, J=15.8, 12.4 Hz, 2H), 5.82-5.80 (m, 2H), 5.00 (s, 1H), 4.91 (s, 1H), 4.88 (d, J=2.1 Hz, 1H), 4.81 (s, 2H), 4.71 (dd, J=8.9, 5.0 Hz, 4H), 4.57 (s, 1H), 2.98 (d, J=6.7 Hz, 2H), 2.17 (d, J=5.1 Hz, 3H), 2.08 (s, 3H), 2.01 (s, 2H), 1.90 (d, J=10.0 Hz, 3H), 1.70-1.69 (m, 3H), 1.59 (s, 2H), 1.46 (d, J=3.4 Hz, 4H), 1.29 (s, 1H), 1.00-0.99 (m, 3H). 13C NMR (126 MHz, CDCl.sub.3) 194.56, 170.79, 154.90, 152.57, 150.06, 148.48, 147.40, 132.89, 131.73, 130.66, 130.02, 125.96, 125.59, 112.36, 111.01, 110.12, 108.90, 68.78, 66.20, 55.80, 52.76, 48.46, 45.71, 44.42, 41.92, 40.95, 39.89, 38.79, 36.51, 35.00, 33.12, 30.56. HRMS (ESI) m/z ([M+H].sup.+) calcd for C.sub.34H.sub.45O.sub.2: 485.3414. Found: 485.3409.

Example 8: Preparation of Compound 8

##STR00018##

Compound 8

[0052] Referring to the synthesis steps of the Compound 1 in Example 1, a colorless oily liquid 8 (50.1 mg, yield 75%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) 8.01 (d, J=7.7 Hz, 1H), 7.59 (d, J=3.6 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.24 (t, J=3.9 Hz, 1H), 6.72 (d, J=3.3 Hz, 2H), 6.32 (dt, J=15.7, 7.1 Hz, 1H), 5.80 (dd, J=17.4, 10.9 Hz, 1H), 4.93-4.77 (m, 5H), 4.58 (s, 1H), 3.02 (d, J=7.0 Hz, 2H), 2.00 (dd, J=12.0, 3.9 Hz, 2H), 1.70 (s, 3H), 1.65 (s, 12H), 1.46 (ddd, J=9.0, 7.8, 2.6 Hz, 3H), 1.00 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 153.17, 150.37, 147.82, 135.65, 134.23, 130.42 (d, J=8.5 Hz), 128.63, 125.92, 124.48, 119.37, 115.42, 114.66, 113.93, 112.29, 110.04, 109.06, 105.62, 83.83, 52.92, 44.45, 40.05 (d, J=12.6 Hz), 39.20, 33.41, 29.85, 28.34, 27.36, 24.94, 16.78. HRMS (ESI) m/z ([MH].sup.) calcd for C.sub.30H.sub.38NO.sub.2: 444.2908. Found: 444.2908.

Example 9: Preparation of Compound 9

##STR00019## ##STR00020##

Intermediate 9g

[0053] Referring to the synthesis steps of the intermediate 5g in Example 5, a colorless oily liquid 9g (416 mg, yield 69%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.99 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 7.13 (d, J=14.1 Hz, 1H), 6.90 (d, J=14.0 Hz, 1H), 5.45 (t, J=7.0 Hz, 1H), 4.83 (d, J=7.0 Hz, 2H), 2.04 (d, J=5.1 Hz, 2H), 1.75 (s, 3H), 1.51 (dd, J=13.3, 6.7 Hz, 1H), 1.39-1.11 (m, 20H), 0.88-0.81 (m, 12H).

Compound 9

[0054] Referring to the synthesis steps of the Compound 1 in Example 1, a colorless oily liquid 9 (73.6 mg, yield 78%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.98 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.54-6.26 (m, 2H), 5.82 (dd, J=17.3, 11.0 Hz, 1H), 5.46 (dd, J=7.0, 6.0 Hz, 1H), 4.93-4.89 (m, 2H), 4.83 (dd, J=5.9, 4.0 Hz, 3H), 4.60 (s, 1H), 3.20 (dt, J=13.3, 5.0 Hz, 1H), 2.99 (d, J=6.8 Hz, 2H), 2.07-1.98 (m, 5H), 1.95-1.89 (m, 2H), 1.75 (s, 3H), 1.71 (s, 3H), 1.63-1.57 (m, 5H), 1.48 (ddd, J=13.1, 9.9, 5.1 Hz, 8H), 1.16-1.12 (m, 5H), 1.09-1.05 (m, 5H), 1.01 (s, 3H), 0.86 (d, J=5.5 Hz, 12H). .sup.13C NMR (126 MHz, CDCl.sub.3) 166.66, 152.68, 150.29, 147.74, 142.87, 142.13, 131.69, 130.74, 130.07, 129.03, 125.98, 118.37, 112.31, 110.08, 109.32, 61.98, 55.89, 52.88, 44.47, 40.05, 39.79, 39.52, 38.85, 37.57, 37.51, 37.44, 36.77, 35.07, 33.36, 32.87 (d, J=15.3 Hz), 29.85, 28.12, 27.30, 25.60, 25.19, 24.94, 24.61, 22.82 (d, J=11.7 Hz), 19.88 (d, J=3.7 Hz), 16.69 (d, J=18.4 Hz), 14.27. HRMS (ESI) m/z ([M+H].sup.+) calcd for C.sub.44H.sub.69O.sub.2: 629.5292. Found: 629.5291.

Example 10: Preparation of Compound 10

##STR00021## ##STR00022##

Intermediate 10g

[0055] Referring to the synthesis steps of the intermediate 5g in Example 5, a white solid log (1.07 g, yield 91%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.97 (dd, J=8.5, 1.6 Hz, 2H), 7.39-7.34 (m, 2H), 7.34-7.30 (m, 2H), 7.30-7.27 (m, 2H), 7.20 (dd, J=8.1, 6.8 Hz, 2H), 7.16-7.10 (m, 4H), 6.91 (d, J=14.1 Hz, 1H), 6.82-6.76 (m, 2H), 6.62-6.56 (m, 2H), 4.57 (dd, J=5.5, 3.9 Hz, 2H), 4.16 (dd, J=5.6, 3.9 Hz, 2H), 3.41 (t, J=7.4 Hz, 2H), 2.92 (t, J=7.5 Hz, 2H).

Compound 10

[0056] Referring to the synthesis steps of the Compound 1 in Example 1, a colorless oily liquid 10 (86.4 mg, yield 81%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.96 (d, J=8.2 Hz, 2H), 7.42-7.36 (m, 4H), 7.31 (d, J=6.2 Hz, 3H), 7.23-7.19 (m, 2H), 7.16 (d, J=7.2 Hz, 3H), 6.82 (d, J=8.7 Hz, 2H), 6.61 (d, J=8.7 Hz, 2H), 6.51-6.31 (m, 2H), 5.86-5.80 (m, 1H), 5.11 (d, J=13.8 Hz, 1H), 4.92 (s, 1H), 4.91 (s, 1H), 4.84 (d, J=6.9 Hz, 2H), 4.61 (s, 1H), 4.59-4.56 (m, 2H), 4.20-4.14 (m, 2H), 3.43 (t, J=7.4 Hz, 2H), 3.00 (d, J=8.7 Hz, 2H), 2.95-2.91 (m, 2H), 2.05-2.00 (m, 2H), 1.73 (s, 3H), 1.62 (dd, J=7.5, 3.3 Hz, 2H), 1.51-1.45 (m, 4H), 1.03 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 166.44, 156.86, 152.58, 150.24, 148.88, 147.68, 142.94, 142.41, 141.75, 141.03, 135.41 (d, J=5.3 Hz), 131.93, 131.86, 130.62, 130.16, 129.63, 129.49, 128.46, 128.34, 127.07, 126.73, 125.98, 113.72, 113.13, 112.29, 110.07, 109.33, 79.52, 65.88, 63.33, 52.83, 44.43, 42.93, 41.65, 39.96 (d, J=9.6 Hz), 38.75 (d, J=14.8 Hz), 33.31, 29.81, 27.26, 24.92. HRMS (ESI) m/z ([M+Na].sup.+) calcd for C.sub.48H.sub.51ClNaO.sub.3: 733.3419. Found: 733.3482.

Example 11: Experiment of Tumor Cell Proliferation Inhibition

Evaluation of Antitumor Activity In Vitro

1. Experimental Equipment and Reagents

1.1 Instrument

[0057] Biological safety cabinet (Shanghai Bio-Gene Biotechnology Co., Ltd.), constant-temperature carbon dioxide incubator (THERMO), enzyme-linked immunoassay analyzer (Spark), inverted microscope (Nikon), a set of pipette guns (eppendorf), and centrifuge (beckman coulter).

1.2 Reagents

[0058] McCoy'S 5A (Zhejiang Cienry Biotechnology Co., Ltd.), RPMI 1640 (Zhejiang Cienry Biotechnology Co., Ltd.), Fatal Bovine Serum (BI), PBS (Zhejiang Cienry Biotechnology Co., Ltd.), Trypsin (Zhejiang Cienry Biotechnology Co., Ltd.), DMSO (Coolaber), and CCK-8 (Coolaber).

1.3 Cell Lines

[0059] Human colon cancer cells (HCT116), human lung cancer cells (A549).

2. Experimental Methods

[0060] 1) The test cells in a logarithmic growth phase were trypsinized and counted, inoculated in a 96-well culture plate at a concentration of 510.sup.4/mL, 100 L per well (510.sup.3 cells per well), and incubated at 37 C. in a 5% CO.sub.2 incubator for 24 h.

[0061] 2) A drug to be tested was diluted to different concentrations with McCoy'S 5A or RPMI 1640 complete medium. The experimental group was replaced with a culture solution containing different concentrations of the tested samples, and the control group was replaced with a culture solution containing the same volume of solvent (DMSO). Three parallel wells were set up in each group, and the culture was continued for 48 h in a 5% CO.sub.2 incubator at 37 C.

[0062] HCT116 cells used the McCoy'S 5A complete medium, and A549 cells used the RPMI 1640 complete medium.

[0063] 3) 10 L of a CCK-8 solution was added to each well, incubated at 37 C. for 1 h to 4 h, and an absorbance (OD value) of each well at 490 nm was measured with a microplate reader.

[0064] 4) A survival rate and an inhibition rate were calculated with the following formulas:

Cell survival rate=[(A.sub.sA.sub.b)/(A.sub.cA.sub.b)]100%

Inhibition rate=[(A.sub.cA.sub.s)/(A.sub.cA.sub.b)]100%

[0065] An S-type dose-survival curve was plotted using GraphPad Prism 7.0 software and a nonlinear regression model, and IC.sub.50 values were calculated. [0066] A.sub.s: absorbance of the experimental well (medium containing cells, CCK-8, and the drug to be tested) [0067] A.sub.c: absorbance of control wells (medium containing cells, CCK-8, and solvent (DMSO)) [0068] A.sub.b: absorbance of blank wells (medium without cells and drug to be tested, CCK-8)

3. Experimental Results

[0069] The inhibitory effects of the target compound and the positive control drug -elemene on the proliferation of two tumor cells were determined according to the above experimental method. The results were shown in Table 1.

TABLE-US-00001 TABLE 1 Effect of target compounds on tumor cell inhibition rate Anti-proliferative activity at 100 M by concentration (%) Compound No. HCT116 A549 4 99.8 0.08 97.5 0.4 6 21.7 0.8 14.4 0.5 10 13.5 0.3 40.4 0.6 -elemene 0.6 0.5 10.6 0.5

[0070] 100 M of the compound acted on tumor cells for 48 h.

[0071] The results showed that Compound 4 showed an anti-tumor cell proliferation effect significantly stronger than that of the positive control -elemene.

[0072] The compound 4 was selected to determine the IC.sub.50 value according to the above experimental method. The results were shown in Table 2.

TABLE-US-00002 TABLE 2 IC.sub.50 of target compounds on tumor cells IC.sub.50 (M) Compound No. HCT116 A549 4 50.9 0.8 57.21 2.95 -elemene 781.9 51 227.0 1.2

[0073] The results showed that Compound 4 exhibited significantly stronger cell proliferation-inhibiting activity than the positive control -elemene.

[0074] In addition, it should be understood that various changes or modifications may be made to the present disclosure by those skilled in the art after reading the above teaching content of the present disclosure, and these equivalent forms also fall within the scope defined by the appended claims of the present disclosure.