CN1807404A - Resveratrol derivative and its production method and uses - Google Patents

Abstract

A class of derivatives of resveratrol, which has the following general formula: R ¹ in formula I is hydrogen or methyl; R ² is CH ₂ NHR ³ or CH=NR ³ , wherein R ³ is cyclopropyl, cyclobutyl radical, cyclopentyl or cyclohexyl, or R ³ is a group (chemical formulas A and B) having the following structures: X in formula B is fluorine, chlorine, bromine, iodine or hydroxyl. Experiments show that the derivatives of resveratrol of the present invention show cytotoxicity to S180, EAC and HepA cells, and have obvious inhibitory effects on nasopharyngeal carcinoma, breast cancer, liver cancer, lung cancer and colorectal cancer. Veratrol derivatives can be used to prepare antitumor drugs. The invention discloses its preparation method.

Description

A kind of derivative of resveratrol and its preparation method and application

technical field

The present invention relates to a class of novel resveratrol derivatives with multiple anticancer functions, its preparation method and application.

technical background

Resveratrol (Resveratrol, 3,5,4'-trihydroxystilbene) is a class of phenolic compounds with multiple hydroxyl groups. It has both cis and trans structures, and the trans structure is dominant in nature. Resveratrol exists in more than 70 kinds of plants such as knotweed, mulberry, peanut, grape, etc., and has various physiological activities: anti-platelet aggregation, inhibiting the occurrence of cardiovascular diseases, protecting the liver, and anti-oxidation. However, it was not until the 1990s that scientists discovered that resveratrol had an inhibitory effect on the three main stages of cell and tissue variation (induction, initiation, and development) in the process of carcinogenesis, and became the most effective in inhibiting and treating tissue carcinogenesis and tumorigenesis. One of the most promising drugs, resveratrol has only attracted the attention of pharmacologists.

Studies have found that resveratrol itself cannot be used clinically, and its structure must be modified to become an excellent clinical anticancer drug. At present, only a few resveratrol derivatives have entered clinical trials as anticancer drugs, and all of them are fully synthetic compounds. Taking the active ingredients in natural products as the parent compound, according to the basic principles of medicinal chemistry, designing semi-synthetic compounds that may have high activity, high selectivity and low toxicity and side effects, so as to discover new compounds that may be used in clinical practice is the current development of new drugs. an important means.

Contents of the invention

The object of the present invention is to provide a new class of resveratrol derivatives and their preparation method and application.

Technical scheme of the present invention is as follows:

A class of derivatives of resveratrol, which has the following general formula:

In formula I, R ¹ is hydrogen (H) or methyl (CH ₃ ); R ² is CH ₂ NHR ³ or CH=NR ³ , R ³ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or is a group (chemical formulas A and B) having the following structure:

X in Formula B is fluorine (F), chlorine (Cl), bromine (Br), iodine (I), or hydroxyl (OH).

A method for preparing derivatives of the above-mentioned resveratrol, which comprises 3,5,4'-trimethoxystilbene (compound C) dissolved in anhydrous DMF, and slowly added dropwise under ice bath and stirring SOCl ₂ or POCl ₃ , 3,5,4'-trimethoxy stilbene and SOCl ₂ or _POCl The ratio of the amount of substance is 1: 1～1: 0.1, and the resveratrol derivative represented by the following formula is obtained Compound (Compound D):

A method for preparing derivatives of the above-mentioned resveratrol, which is to dissolve the compound D prepared by the above-mentioned method in absolute ethanol, and slowly add R ³ NH ₂ primary amine compounds (ratio of the amount of substances) Compound D: R ³ NH ₂ =1:1 ~ 1:1.2), stirred at room temperature for 4 hours to obtain the resveratrol derivative of the compound of formula II:

In formula II, R ¹ =CH ₃ , R ³ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or R ³ is a group with the following structure (chemical formulas A and B):

X in Formula B is fluorine (F), chlorine (Cl), bromine (Br), iodine (I), or hydroxyl (OH).

A method for preparing derivatives of the above-mentioned resveratrol, which is to react the compound of product formula II prepared by the above-mentioned method with BBr ₃ in dichloromethane, and the ratio of the amount of substance is: compound of formula II: BBr ₃ = 1:1～1:1.5, namely obtain the compound of structural formula such as formula II, but in the formula, R ¹ =H, R ³ is still cyclopropyl, cyclobutyl: base, cyclopentyl or cyclohexyl, or R ³ has Groups of the following structures (chemical formulas A and B):

X in Formula B is fluorine (F), chlorine (Cl), bromine (Br), iodine (I), or hydroxyl (OH).

A method for preparing the derivatives of above-mentioned resveratrol, which is to dissolve the product formula II compound obtained by the above method in absolute ethanol, and add NaBH in batches ₄ (ratio of the amount of substance is: formula II compound: NaBH ₄ =1:0.5～1:1.5), stirring at room temperature for 2 hours, the resveratrol derivative with the structure formula III is obtained:

In formula III, R ¹ =CH ₃ , R ³ =cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or R ³ is a group with the following structure (chemical formulas A and B):

A method for preparing the derivative of above-mentioned resveratrol, it is that the product formula III compound that above-mentioned method is made and BBr ₃ react in dichloromethane (ratio of substance amount is: formula III compound: BBr ₃ = 1:1～1:1.5), promptly obtain the resveratrol derivative of structural formula such as formula III, but R ¹ =H in the formula, R ³ is still cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, Or ^R is a group with the following structure (Formulas A and B):

Experiments show that the derivatives of resveratrol of the present invention show cytotoxicity to S180, EAC and HepA cells, and have obvious inhibitory effects on nasopharyngeal carcinoma, breast cancer, liver cancer, lung cancer and colorectal cancer. Veratrol derivatives can be used to prepare antitumor drugs.

Detailed ways

The present invention is further described in detail by the following examples, but it should be noted that the scope of the present invention is not limited by these examples.

Embodiment 1: the preparation of 3,5,4'-trimethoxystilbene

Resveratrol (22.8g, 0.1mol), was dissolved in the 10% NaOH solution of 100ml, under _N under the protection and ice bath condition, slowly added dropwise 37.9ml dimethyl sulfate (0.4mol) under stirring, controlled dropwise The temperature of the reaction system was kept below 40°C, and the resulting white solid was filtered out after 2 hours of reaction, and recrystallized in petroleum ether-ethyl acetate (9:1) to obtain colorless needle crystals with a yield of 92%. Mp 52-54°C; ESI-MS: 270.1249 (calc.270.1255); ¹ HNMR (DMSO-d ₆ ) δppm: 3.77 (s, 9H, 3×OCH3), 6.39 (t, 1H, C ₄ -H), 6.74 (d, 2H, C _{2, 6-} H), 7.01 (d, 1H, C ₇ -H), 7.20 (d, 1H, C ₈ -H), 6.94 (d, 2H, C _{3′, 5′} -H), 7.53 (d, 2H, C _{2', 6'} -H).

Example 2: Preparation of 2-formyl-3,5,4'-trimethoxystilbene

27.0 g (0.1 mol) of 3,5,4'-trimethoxystilbene obtained in Example 1 was dissolved in 50 ml of anhydrous DMF, and 15.3 g (0.1 mol) was added dropwise while stirring under ice-bath conditions. POCl ₃ was added dropwise within 15 minutes. The reaction product was slowly poured into 400ml of ice-water mixture, left to stand overnight, the solid was filtered off, and recrystallized from acetone to obtain colorless needle crystals with a yield of 84%. Mp 63-65°C; ESI-MS: 298.1209 (calc.298.1205); IR (KBr) cm ^-1 : 1705 (CO); ¹ HNMR (DMSO-d ₆ ) δppm: 3.78 (s, 3H, C _4′ - OCH3), 3.90(s, 3H, C ₃ -OCH3), 3.92(s, 3H, C ₅ -OCH3), 6.62(t, 1H, C ₄ -H), 6.91(t, 1H, C ₆ -H) , 6.97(d, 2H, C _{3′, 5′} -H), 7.50(d, 2H, C _{2′, 6′-} H), 7.21(d, 1H, C _7- H), 7.95(d, 1H , C ₈ -H).

Example 3: Preparation of N-cyclopentyl-(3,4,5'-trimethoxydistyryl-2-methylene)imine

29.8 g (0.1 mol) of 2-formyl-3,5,4'-trimethoxystilbene obtained in Example 2 and 8.5 g (0.1 mol) of cyclopentylamine were dissolved in 100 ml of absolute ethanol, at room temperature After stirring at low temperature for 2 hours, part of absolute ethanol was distilled off under reduced pressure, and recrystallized to obtain colorless needle crystals with a yield of 94%. Mp 76-78°C; ESI-MS: 365.1986 (calc.365.1990); IR (KBr) cm ^-1 : 1680 (C=N); ¹ H NMR (DMSO-d ₆ ) δppm: 1.63 (m, 4H, CH ₂ CH ₂ ), 1.82 (m, 4H, CH ₂ CH), 3.72 (t, 1H, CH), 3.77 (s, 3H, C _4′- OCH ₃ ), 3.84 (s, 3H, C ₃ -OCH3) , 3.86(s, 3H, C ₅ -OCH3), 6.53(d, 1H, C ₄ -H), 6.91(d, 1H, C ₆ -H), 6.94(d, 2H, C _{3′, 5′-} H), 7.43 (d, 2H, C _{2′, 6′-} H), 7.10 (d, 1H, C ₇ -H), 8.08 (d, 1H, C ₈ -H), 8.61 (s, 1H, CH =N).

Example 4: Preparation of N-cyclopentyl-(3,4,5'-trihydroxydistyryl-2-methylene)imine

36.5 g (0.1 mol) of N-cyclopentyl-(3,4,5′-trimethoxydistyryl-2-methylene) imine obtained in Example 3 was dissolved in 40 ml of anhydrous dichloro In methane, add 75.2g (0.3mol) of _BBr3 anhydrous dichloromethane solution dropwise while stirring at normal temperature. After reacting for 4 hours, the product was washed three times with saturated aqueous sodium chloride solution and distilled water respectively, and then washed with anhydrous sodium sulfate. The dichloromethane fraction was dried and recovered under reduced pressure to obtain a white solid with a yield of 94%. Mp 96-98°C; ESI-MS: 323.1528 (calc.323.1521); IR (KBr) cm ^-1 : 1680 (C=N), 3610 (OH); ¹ HNMR (DMSO-d ₆ ) δppm: 1.63 (m , 4H, CH ₂ CH ₂ ), 1.82 (m, 4H, CH ₂ CH), 2.73 (t, 1H, CH), 6.63 (d, 1H, C ₄ -H), 6.94 (d, 1H, C ₆ - H), 6.73 (d, 2H, C _{3′, 5′-} H), 7.35 (d, 2H, C _{2′, 6′-} H), 7.12 (d, 1H, C ₇ -H), 8.11 (d , 1H, C ₈ -H), 8.61 (s, 1H, CH=N), 9.12 (s, 1H, C _4' -OH), 9.43 (s, 2H, C _3,5 -OH).

Example 5: Preparation of N-cyclopentyl-(3,4,5'-trimethoxydistyryl-2-methyl)amine

Dissolve 73.0 g (0.2 mol) of N-cyclopentyl-(3,4,5'-trimethoxydistyryl-2-methylene)imine obtained in Example 3 in 50 ml of absolute ethanol 3.8g (0.1mol) NaBH ₄ was added in batches within 30 minutes while stirring at 40°C. After 2 hours of reaction, the product was evaporated to dryness under reduced pressure, dissolved in dichloromethane and washed three times with saturated aqueous sodium chloride solution and distilled water. The dichloromethane part was then dried with anhydrous sodium sulfate and recovered under reduced pressure to obtain a white solid with a yield of 96%. Mp 72-74℃; ESI-MS: 367.2152 (calc.367.2147); IR (KBr) cm ^-1 : 1180 (CN), 3320 (NH); ¹ H NMR (DMSO-d ₆ ) δppm: 1.63 (m, 4H, _{CH2CH2 )} , 1.83(m, 4H, _CH2CH ), 2.72(t, 1H, CH), 3.75(s, 3H, _C4'- OCH3), 3.77(s, 3H, _C3- OCH3), 3.78 (s, 3H, C ₅ -OCH3), 3.80 (s, 2H, CH ₂ NH), 6.52 (d, 1H, C ₄ -H), 6.93 (d, 1H, C ₆ -H), 6.92 (d, 2H, C _{3′, 5′-} H), 7.44 (d, 2H, C _{2′, 6′-} H), 7.10 (d, 1H, C ₇ -H), 8.08 (d, 1H, _C8 -H).

Example 6: Preparation of N-cyclopentyl-(3,4,5'-trihydroxydistyryl-2-methyl)amine

36.7 g (0.1 mol) of the N-cyclopentyl-(3,4,5'-trimethoxydistyryl-2-methyl)amine obtained in Example 5 was dissolved in 40 ml of anhydrous dichloromethane 75.2g (0.3mol) of _BBr3 was added dropwise while stirring at normal temperature. After 4 hours of reaction, the product was washed three times with saturated aqueous sodium chloride solution and distilled water respectively, and then dried with anhydrous sodium sulfate. The dichloromethane fraction was recovered under reduced pressure to obtain a white solid with a yield of 94%. Mp 81-83℃; ESI-MS: 325.1681(calc.325.1677); IR(KBr)cm ^-1 : 1175(CN), 3310(NH), 3620(OH); ¹ H NMR(DMSO-d ₆ )δppm : 1.62(m, 4H, _CH2CH2 ), 1.83(m, 4H _{, CH2CH} ), 2.72(t, 1H, CH), 3.80(s, 2H, _CH2NH ), 6.63(d, 1H, C ₄ -H), 6.94 (d, 1H, C ₆ -H), 6.73 (d, 2H, C _{3', 5'} -H), 7.35 (d, 2H, C _{2', 6'} -H), 7.12 (d, 1H, C ₇ -H), 8.11 (d, 1H, C ₈ -H), 9.12 (s, 1H, C _4' -OH), 9.43 (s, 2H, C _3,5 -OH) .

Example 7: Preparation of N-(4-hydroxy-phenethyl)-3,4,5'-trimethoxydistyryl-2-methylene)imine

29.8g (0.1mol) of 2-formyl-3,5,4'-trimethoxystilbene obtained in Example 2 and 13.7g (0.1mol) of tyramine were dissolved in 100ml of absolute ethanol, and After stirring for 2 hours, part of the absolute ethanol was distilled off under reduced pressure, and recrystallized to obtain colorless needle crystals with a yield of 94%. Mp 125-127°C; ESI-MS: 417.1942 (calc.417.1940); IR (KBr) cm ^-1 : 1680 (C=N), 3610 (OH); ¹ H NMR (DMSO-d ₆ ) δppm: 2.74 ( t, 2H, ArCH ₂ ), 2.98 (t, 2H, CH ₂ N), 3.75 (s, 3H, C _4′- OCH3), 3.77 (s, 3H, C ₃ -OCH3), 3.78 (s, 3H, C ₅ -OCH3), 6.47(d, 1H, C ₄ -H), 6.81(d, 1H, C ₆ -H), 6.63(d, 2H, C _{3', 5'} -H), 7.52(d, 2H, C2 _{', 6'-} H), 7.10(d, 1H, _C7 -H), 7.34(d, 1H, _C8 -H), 6.95(m, 4H, ArH), 8.61(s, 1H , CH=N), 9.15 (s, 1H, Ar-OH).

Example 8: Preparation of N-(4-hydroxyl-phenethyl)-(3,4,5'-trihydroxydistyryl-2-methylene)imine

Dissolve 41.8 g (0.1 mol) of N-(4-hydroxyl-phenethyl)-(3,4,5'-trimethoxydistyryl-2-methylene)imine obtained in Example 7 In 100ml of anhydrous dichloromethane, 75.2g (0.3mol) of BBr was added dropwise while stirring at normal temperature Anhydrous dichloromethane solution, after reacting for 4 hours, _the product was washed three times with saturated aqueous sodium chloride solution and distilled water respectively, The dichloromethane part was then dried with anhydrous sodium sulfate and recovered under reduced pressure to obtain a white solid with a yield of 94%. Mp 154-156°C; ESI-MS: 375.1468 (calc.375.1470); IR (KBr) cm ^-1 : 1680 (C=N), 3610 (OH); ¹ H NMR (DMSO-d ₆ ) δppm: 2.74 ( t, 2H, ArCH ₂ ), 2.98 (t, 2H, CH ₂ N), 6.46 (d, 1H, C ₄ -H), 6.82 (d, 1H, C ₆ -H), 6.64 (d, 2H, C _{3', 5'-} H), 7.54 (d, 2H, C _{2', 6'-} H), 7.11 (d, 1H, C ₇ -H), 7.35 (d, 1H, C ₈ -H), 6.95 (m, 4H, ArH), 8.61 (s, 1H, CH=N), 9.15 (s, 1H, Ar-OH), 9.12 (s, 1H, _C4'- OH), 9.43 (s, 2H,, C _3,5 -OH).

Example 9: Preparation of N-(4-hydroxyl-phenethyl)-(3,4,5'-trimethoxydistyryl-2-methyl)amine

Dissolve 83.6 g (0.2 mol) of N-(4-hydroxyl-phenethyl)-(3,4,5'-trimethoxydistyryl-2-methylene)imine obtained in Example 7 In 50ml of absolute ethanol, 3.8g (0.1mol) NaBH ₄ was added in batches within 30 minutes while stirring at 40°C. After 2 hours of reaction, the product was evaporated to dryness under reduced pressure, dissolved in dichloromethane and washed with saturated aqueous sodium chloride solution and distilled water were washed three times respectively, and then the dichloromethane part was dried with anhydrous sodium sulfate, and recovered under reduced pressure to obtain a white solid with a yield of 96%. Mp 115-117℃; ESI-MS: 419.2099(calc.419.2096); IR(KBr)cm ^-1 : 1175(CN), 3310(NH), 3622(OH); ¹ H NMR(DMSO-d ₆ )δppm : 2.64(t, 2H, _ArCH2 ), 2.79(t, 2H, _CH2NH ), 3.75(s, 3H, C4' _- OCH3), 3.77(s, 3H, _C3- OCH3), 3.78(s , 3H, C ₅ -OCH3), 3.80 (s, 2H, CH ₂ NH), 6.47 (d, 1H, C ₄ -H), 6.81 (d, 1H, C ₆ -H), 6.63 (d, 2H, C _{3', 5'-} H), 7.52 (d, 2H, C _{2', 6'-} H), 7.10 (d, 1H, C ₇ -H), 7.34 (d, 1H, C ₈ -H), 6.95 (m, 4H, ArH), 9.15 (s, 1H, Ar-OH).

Example 10: Preparation of N-(4-hydroxyl-phenethyl)-(3,4,5'-trihydroxydistyryl-2-methyl)amine

42.0 g (0.1 mol) of N-(4-hydroxyl-phenethyl)-(3,4,5'-trimethoxydistyryl-2-methyl)amine obtained in Example 9 was dissolved in 100 ml In anhydrous dichloromethane, add dropwise the anhydrous dichloromethane solution of 75.2g (0.3mol) BBr while stirring at normal temperature, after reacting for ₄ hours, the product was washed three times with saturated aqueous sodium chloride solution and distilled water respectively, and then The dichloromethane part was dried with anhydrous sodium sulfate and recovered under reduced pressure to obtain a white solid with a yield of 94%. Mp 130-132℃: ESI-MS: 377.1624 (calc.377.1627); IR (KBr) cm ^-1 : 1175 (CN), 3310 (NH), 3618 (OH); ¹ H NMR (DMSO-d ₆ ) δppm : 2.64(t, 2H, _ArCH2 ), 2.79(t, 2H, _CH2NH ), 3.80(s, 2H, _CH2NH ), 6.46(d, 1H, _C4 -H), 6.82(d, 1H , C ₆ -H), 6.64 (d, 2H, C _{3', 5'} -H), 7.54 (d, 2H, C _{2', 6'} -H), 7.11 (d, 1H, C ₇ -H) , 7.35(d, 1H, C ₈ -H), 6.95(m, 4H, ArH), 9.15(s, 1H, Ar-OH), 9.12(s, 1H, C _4'- OH), 9.43(s, 2H, _C3,5 -OH).

Example 11:

The resveratrol derivatives listed in Table 1 were prepared in a similar manner to the above.

Table 1. The substituent represented by R group in the resveratrol derivative general formula II of the present invention

Continued table 1. The substituent represented by the R group in the resveratrol derivative general formula III of the present invention

Example 12: Cytotoxic effects of resveratrol and its main derivatives on S180, EAC, HepA

Method: MTT method. S180, EAC and HepA cells with logarithmic growth were taken, diluted to 2×10 ⁴ cells/ml, and distributed in 96-well plates (0.2ml/well). A 5-fluorouracil control group, a DMSO control group and 8 different concentrations of test compounds were set up, 10 μl per well. Four parallel wells were set up in each group, and cultured in 5% CO ₂ at 37°C for 72 hours, injected with 10 μl/well of MTT solution (5 mg/ml) 4 hours before the end of the experiment, and cultured for another 4 hours. Discard the culture solution, add DMSO 100 μl/hole, mix and shake, under the wavelength of 570nm, measure the OD value with the BioRad 550 type microplate reader produced in the United States, calculate the cell growth inhibition rate according to the following formula (half inhibitory concentration, IC ₅₀ ).

Growth inhibition rate=(1-average OD value of the drug group/average OD value of the control group)×100% The smaller the IC ₅₀ , the greater the cytotoxicity of the compound. The results are shown in Table 2.

Table 2 Cytotoxicity (IC ₅₀ ) of resveratrol and its main derivatives to S180, EAC and HepA cell line Compound No./IC ₅₀ (μg/ml) 1 5 6 7 12 15 Resveratrol 5-fluorouracil S180EACHepA 4.2410.262.36 24418.28 21.340.222.14 16451.29 0.283.422.53 4.362312 346356 1.320.261.87

The results show that: the main resveratrol derivatives of the present invention all show stronger cytotoxicity than resveratrol to S180, EAC and HepA cells, and most of them are equivalent to the positive control 5-fluorouracil. cells, the cytotoxicity of compound 6 to EAC cells and compound 7 to HepA cells was even stronger than that of 5-fluorouracil.

Example 13: Inhibitory effects of resveratrol and its main derivatives on 5 kinds of human cancer cells

Method: MTT method. The experimental method is the same as in Example 12, and the results are shown in Table 3.

Table 3. Inhibitory effects of resveratrol and its main derivatives on 5 kinds of human cancer cells group Drug concentration (μg/ml) Inhibition rate(%) Nasopharyngeal carcinoma (CNE2) Breast cancer (MCF-7) Liver cancer (Bel-7402) Lung cancer (GLC-82) Colorectal cancer (HT-29) Compound 4 0.81.42.0 29.862.395.2 32.156.885.4 45.268.791.3 26.655.282.4 18.945.988.2 Compound 10 0.81.42.0 19.472.188.2 22.166.491.1 33.261.980.4 45.775.293.8 31.459.286.2 Compound 15 0.81.42.0 17.946.591.2 25.458.180.8 46.966.896.4 25.344.789.8 33.558.789.4 Compound 22 0.81.42.0 29.455.384.2 12.849.188.9 34.258.996.8 32.765.290.8 21.658.180.8 Compound 35 0.81.42.0 49.888.699.7 33.859.196.5 40.272.297.8 35.166.990.1 44.460.792.6 Compound 40 0.81.42.0 22.852.679.9 18.149.980.4 19.251.383.6 33.566.790.6 40.467.196.4 Resveratrol 205080 27.447.275.5 31.241.270.5 38.543.869.9 29.439.977.1 21.840.162.3 5-fluorouracil 0.81.42.0 48.877.698.2 39.669.892.8 46.872.293.6 43.968.695.5 36.669.891.7

The results showed that compounds 4, 10, 15, 22, 35, and 40 had significant inhibitory effects on nasopharyngeal cancer, breast cancer, liver cancer, lung cancer, and colorectal cancer, and the inhibitory effects were significantly higher than those of resveratrol.

Example 14: Inhibitory effect of resveratrol and its main derivatives on nasopharyngeal carcinoma and liver carcinoma transplanted in nude mice

Take the logarithmic growth of human nasopharyngeal carcinoma cell CNE2 or liver cancer cell Bel-7402, digest with trypsin, make 1× ¹⁰⁷ cells/ml single cell suspension, and inoculate in BALB/C nude mice under sterile conditions Take 0.2ml subcutaneously in the right fluid fossa (equivalent to 2×10 ⁶ cells). 7 days after inoculation, when the tumor grew to a diameter of 3-5nm, they were randomly divided into control group, 5-fluorouracil (positive control group) and low-, medium-, and high-dose groups of compounds 12 and 28 according to their volume, with 8 in each group. mice. On the day after the grouping, the drug was administered, intraperitoneally injected, once a day, 6 times a week, for 3 consecutive weeks, and the body weight was weighed the next day after the drug was stopped. The nude mice were sacrificed, the tumor mass was stripped off, weighed and recorded, and the average tumor weight was calculated. The tumor inhibition rate was calculated according to the following formula, and a t test was performed:

Tumor inhibition rate=(1-average tumor weight of experimental group/average tumor weight of control group)×100%

The results are shown in Table 4

Table 4. Inhibitory effect of resveratrol and its derivatives on nasopharyngeal carcinoma and liver cancer transplanted tumors in nude mice group Dose (mg/Kg) Tumor strain and inhibition rate (%) nasopharyngeal carcinoma cells CNE2 Liver cancer cells Bel-7402 control group NS 0 0 5-fluorouracil 25 63.5 58.4 Compound 8 205080 36.259.579.8 42.557.472.9 Compound 31 205080 60.171.888.6 55.168.283.5

The results showed that compounds 8 and 31 had a good inhibitory effect on nasopharyngeal carcinoma and liver cancer cell xenograft models in nude mice under the animal tolerance dose, and the inhibition rate was positively correlated with the dose.

The above examples of the present invention show that the anticancer activity of resveratrol is significantly improved after chemical modification, and its application as a drug is safe under normal dosage.

Attachment: Melting point, high-resolution mass spectrum, infrared and hydrogen spectrum data of compounds 1-40

N-Cyclopropyl-(3,4,5'-trihydroxydistyryl-2-methylene)imine (1):

Mp 92-94°C; ESI-MS: 295.1211 (calc.295.1208); IR (KBr) cm ^-1 : 1682 (C=N), 3614 (OH); ¹ H NMR (DMSO-d ₆ ) δppm: 0.46 ( t, 2H, 2 _{× CHaHb} ), 0.62(t, 2H, 2 _{× CHaHb} ), 3.34(m, 1H, CHNH), 6.65(d, 1H, _C4 -H), 6.91(d , 1H, C ₆ -H), 6.74 (d, 2H, C _{3', 5'} -H), 7.35 (d, 2H, C _{2', 6'} -H), 7.14 (d, 1H, C ₇ - H), 8.10 (d, 1H, C ₈ -H), 8.62 (s, 1H, CH=N), 9.11 (s, 1H, C _4' -OH), 9.42 (s, 2H, C _{3, 5} - OH).

N-Cyclobutyl-(3,4,5'-trihydroxydistyryl-2-methylene)imine (2):

Mp 89-91°C; ESI-MS: 309.1366 (calc.309.1364); IR (KBr) cm ^-1 : 1680 (C=N), 3610 (OH); ¹ H NMR (DMSO-d ₆ ) δppm: 1.96 ( t, 4H, 2×CH ₂ CH), 1.82 (d, 2H, CH ₂ ), 3.24 (m, 1H, CHNH), 6.63 (d, 1H, C ₄ -H), 6.91 (d, 1H, C ₆ -H), 6.72 (d, 2H, C _{3', 5'} -H), 7.33 (d, 2H, C _{2', 6'} -H), 7.14 (d, 1H, C ₇ -H), 8.12 ( d, 1H, C ₈ -H), 8.61 (s, 1H, CH=N), 9.11 (s, 1H, C _4' -OH), 9.41 (s, 2H, C _3,5 -OH).

N-cyclopentyl-(3,4,5'-trihydroxydistyryl-2-methylene)imine (3):

See Example 4.

N-cyclohexyl-(3,4,5'-trihydroxydistyryl-2-methylene)imine (4):

Mp 102-104°C; ESI-MS: 337.1672 (calc.337.1677); IR (KBr) cm ^-1 : 1688 (C=N), 3622 (OH); ¹ H NMR (DMSO-d ₆ ) δppm: 1.07～ 1.19 (m, 6H, CH ₂ CH ₂ CH ₂ ), 1.64 (m, 2H, CH ₂ ), 1.83 (m, 2H, CH ₂ ), 2.42 (t, 1H, CHNH), 6.63 (d, 1H, C ₄ -H), 6.94 (d, 1H, C ₆ -H), 6.73 (d, 2H, C _{3′, 5′-} H), 7.35 (d, 2H, C _{2′, 6′-} H), 7.12 (d, 1H, C ₇ -H), 8.11 (d, 1H, C ₈ -H), 8.59 (s, 1H, CH=N), 9.12 (s, 1H, C _4'- OH), 9.43 (s , 2H, C _3,5 -OH).

N-Aminoethylmorpholine-(3,4,5'-trihydroxydistyryl-2-methylene)imine (5):

Mp 161-163°C; ESI-MS: 368.1738 (calc.368.1736); IR (KBr) cm ^-1 : 1678 (C=N), 3614 (OH); ¹ H NMR (DMSO-d ₆ ) δppm: 2.22 ( t, 4H, CH ₂ NCH ₂ ), 2.35 (t, 2H, CH ₂ ), 2.62 (t, 2H, CH ₂ ), 3.75 (t, 4H, CH ₂ OCH ₂ ), 6.48 (d, 1H, C ₄ -H), 6.94 (d, 1H, C ₆ -H), 6.73 (d, 2H, C _{3', 5'} -H), 7.35 (d, 2H, C _{2', 6'} -H), 7.12 ( d, 1H, C ₇ -H), 8.11 (d, 1H, C ₈ -H), 8.62 (s, 1H, CH=N), 9.17 (s, 1H, C _4' -OH), 9.52 (s, 2H, _C3,5 -OH).

N-(4-Hydroxy-phenethyl)-(3,4,5'-trihydroxydistyryl-2-methylene)imine (6):

See Example 8.

N-(4-fluoro-phenethyl)-(3,4,5'-trihydroxydistyryl-2-methylene)imine (7):

Mp 144-146°C; ESI-MS: 377.1429 (calc.377.1427); IR (KBr) cm ^-1 : 1678 (C=N), 3616 (OH); ¹ H NMR (DMSO-d ₆ ) δppm: 2.44 ( t, 2H, ArCH ₂ ), 2.72 (t, 2H, CH ₂ N), 6.46 (d, 1H, C ₄ -H), 6.64 (d, 2H, C _{3', 5'} -H), 6.82 (d , 1H, C ₆ -H), 6.88 (m, 4H, ArH), 7.54 (d, 2H, C _{2', 6'} -H), 7.11 (d, 1H, C ₇ -H), 7.35 (d, 1H, C ₈ -H), 8.63 (s, 1H, CH=N), 9.13 (s, 1H, C _4' -OH), 9.38 (s, 2H, C _3,5 -OH).

N-(4-Chloro-phenethyl)-(3,4,5'-trihydroxydistyryl-2-methylene)imine (8):

Mp 149-151°C; ESI-MS: 393.1133 (calc.393.1131); IR (KBr) cm ^-1 : 1678 (C=N), 3617 (OH); ¹ H NMR (DMSO-d ₆ ) δppm: 2.44 ( t, 2H, ArCH ₂ ), 2.72 (t, 2H, CH ₂ N), 6.45 (d, 1H, C ₄ -H), 6.66 (d, 2H, C _{3', 5'} -H), 6.81 (d , 1H, C ₆ -H), 6.83(m, 4H, ArH), 7.54(d, 2H, C _{2′, 6′-} H), 7.11(d, 1H, C ₇ -H), 7.35(d, 1H, C ₈ -H), 8.42 (s, 1H, CH=N), 9.15 (s, 1H, C _4' -OH), 9.32 (s, 2H, C _3,5 -OH).

N-(4-bromo-phenethyl)-(3,4,5'-trihydroxydistyryl-2-methylene)imine (9):

Mp 162-164°C; ESI-MS: 437.0628 (calc.437.0626); IR (KBr) cm ^-1 : 1675 (C=N), 3622 (OH); ¹ H NMR (DMSO-d ₆ ) δppm: 2.44 ( t, 2H, ArCH ₂ ), 2.72 (t, 2H, CH ₂ N), 6.46 (d, 1H, C ₄ -H), 6.64 (d, 2H, C _{3', 5'} -H), 6.79 (m , 4H, ArH), 6.82(d, 1H, C ₆ -H), 7.54(d, 2H, C _{2', 6'} -H), 7.11(d, 1H, C ₇ -H), 7.35(d, 1H, C ₈ -H), 8.61 (s, 1H, CH=N), 9.09 (s, 1H, C _4' -OH), 9.41 (s, 2H, C _3,5 -OH).

N-(4-iodo-phenethyl)-(3,4,5'-trihydroxydistyryl-2-methylene)imine (10):

Mp 181-183°C; ESI-MS: 485.0481 (calc.485.0487); IR (KBr) cm ^-1 : 1676 (C=N), 3628 (OH); ¹ H NMR (DMSO-d ₆ ) δppm: 2.44 ( t, 2H, ArCH ₂ ), 2.72 (t, 2H, CH ₂ N), 6.43 (d, 1H, C ₄ -H), 6.61 (d, 2H, C _{3′, 5′-} H), 6.69 (m , 4H, ArH), 6.82(d, 1H, C ₆ -H), 7.54(d, 2H, C _{2', 6'} -H), 7.11(d, 1H, C ₇ -H), 7.35(d, 1H, C ₈ -H), 8.66 (s, 1H, CH=N), 9.18 (s, 1H, C _4' -OH), 9.33 (s, 2H, C _3,5 -OH).

N-cyclopropyl-(3,4,5'-trimethoxydistyryl-2-methylene)imine (11):

Mp 72-74°C; ESI-MS: 337.1682 (calc. 337.1677); IR (KBr) cm ^-1 : 1688 (C=N);

¹ H NMR (DMSO-d ₆ ) δppm: 0.46 (t, 2H, 2×CH _a H _b ), 0.62 (t, 2H, 2×CH _a H _b ), 3.34 (m, 1H, CHNH), 3.77 ( s, 3H, C _4' -OCH ₃ ), 3.84 (s, 3H, C ₃ -OCH ₃ ), 3.86 (s, 3H, C ₅ -OCH ₃ ), 6.65 (d, 1H, C ₄ -H), 6.91 (d, 1H, C ₆ -H), 6.74 (d, 2H, C _{3′, 5′-} H), 7.35 (d, 2H, C _{2′, 6′-} H), 7.14 (d, 1H, _C7 -H), 8.10 (d, 1H, _C8 -H), 8.62 (s, 1H, CH=N).

N-Cyclobutyl-(3,4,5'-trimethoxydistyryl-2-methylene)imine (12):

Mp 67-69°C; ESI-MS: 351.1838 (calc.351.1834); IR (KBr) cm ^-1 : 1680 (C=N); ¹ H NMR (DMSO-d ₆ ) δppm: 1.96 (t, 4H, 2 ×CH ₂ CH), 1.82 (d, 2H, CH ₂ ), 3.24 (m, 1H, CHNH), 3.81 (s, 3H, C _4′- OCH ₃ ), 3.87 (s, 3H, C ₃ -OCH ₃ ), 3.89 (s, 3H, C ₅ -OCH ₃ ), 6.61 (d, 1H, C ₄ -H), 6.94 (d, 1H, C ₆ -H), 6.73 (d, 2H, C _{3′, 5 '} -H), 7.33 (d, 2H, C _{2', 6'-} H), 7.14 (d, 1H, C ₇ -H), 8.12 (d, 1H, C ₈ -H), 8.63 (s, 1H , CH=N).

N-cyclopentyl-(3,4,5'-trimethoxydistyryl-2-methylene)imine (13):

See Example 3.

N-cyclohexyl-(3,4,5'-trimethoxydistyryl-2-methylene)imine (14):

Mp 81-83℃; ESI-MS: 379.2149 (calc.379.2147); IR (KBr) cm ^-1 : 1681 (C=N); ¹ H NMR (DMSO-d ₆ ) δppm: 1.07～1.19 (m, 6H , CH ₂ CH ₂ CH ₂ ), 1.64 (m, 2H, CH ₂ ), 1.83 (m, 2H, CH ₂ ), 2.42 (t, 1H, CHNH), 3.71 (s, 3H, C _4′ -OCH ₃ ), 3.82 (s, 3H, C ₃ -OCH ₃ ), 3.88 (s, 3H, C ₅ -OCH ₃ ), 6.69 (d, 1H, C ₄ -H), 6.92 (d, 1H, C ₆ -H ), 6.73 (d, 2H, C _{3′, 5′-} H), 7.38 (d, 2H, C _{2′, 6′-} H), 7.12 (d, 1H, C ₇ -H), 8.11 (d, 1H, C ₈ -H), 8.69 (s, 1H, CH=N).

N-Aminoethylmorpholine-(3,4,5'-trimethoxydistyryl-2-methylene)imine (15):

Mp 142-144°C; ESI-MS: 410.2201 (calc.410.2205): IR (KBr) cm ^-1 : 1678 (C=N); ¹ H NMR (DMSO-d ₆ ) δppm: 2.22 (t, 4H, CH ₂ NCH ₂ ), 2.35 (t, 2H, CH ₂ ), 2.62 (t, 2H, CH ₂ ), 3.71 (t, 4H, CH ₂ OCH ₂ ), 3.76 (s, 3H, C _4′- OCH ₃ ) , 3.85(s, 3H, C ₃ -OCH ₃ ), 3.86(s, 3H, C ₅ -OCH ₃ ), 6.48(d, 1H, C ₄ -H), 6.94(d, 1H, C ₆ -H) , 6.75(d, 2H, C _{3′, 5′} -H), 7.35(d, 2H, C _{2′, 6′-} H), 7.18(d, 1H, C _7- H), 8.12(d, 1H , C ₈ -H), 8.59 (s, 1H, CH=N).

N-(4-Hydroxy-phenethyl)-(3,4,5'-trimethoxydistyryl-2-methylene)imine (16):

See Example 7.

N-(4-fluoro-phenethyl)-(3,4,5'-trimethoxydistyryl-2-methylene)imine (17):

Mp 133-135°C; ESI-MS: 419.1899 (calc.419.1896); IR (KBr) cm ^-1 : 1678 (C=N); ¹ H NMR (DMSO-d ₆ ) δppm: 2.44 (t, 2H, ArCH ₂ ), 2.71(t, 2H, CH ₂ N), 3.81(s, 3H, C _4′ -OCH ₃ ), 3.87(s, 3H, C ₃ -OCH ₃ ), 3.90(s, 3H, C ₅ - OCH ₃ ), 6.46 (d, 1H, C ₄ -H), 6.64 (d, 2H, C _{3', 5'} -H), 6.82 (d, 1H, C ₆ -H), 6.87 (m, 4H, ArH), 7.54 (d, 2H, C _{2′, 6′-} H), 7.11 (d, 1H, C ₇ -H), 7.33 (d, 1H, C ₈ -H), 8.67 (s, 1H, CH =N).

N-(4-Chloro-phenethyl)-(3,4,5'-trimethoxydistyryl-2-methylene)imine (18):

Mp 149-151°C; ESI-MS: 435.1605 (calc.435.1601); IR (KBr) cm ^-1 : 1678 (C=N), 3617 (OH); ¹ H NMR (DMSO-d ₆ ) δppm: 2.44 ( t, 2H, ArCH ₂ ), 2.72 (t, 2H, CH ₂ N), 3.82 (s, 3H, C _4′ -OCH ₃ ), 3.89 (s, 3H, C ₃ -OCH ₃ ), 3.92 (s, 3H, C ₅ -OCH ₃ ), 6.46 (d, 1H, C ₄ -H), 6.64 (d, 2H, C _{3', 5'} -H), 6.82 (d, 1H, C ₆ -H), 6.83 (m, 4H, ArH), 7.54 (d, 2H, C _{2′, 6′-} H), 7.11 (d, 1H, C ₇ -H), 7.35 (d, 1H, C ₈ -H), 8.59 ( s, 1H, CH=N).

N-(4-Bromo-phenethyl)-(3,4,5'-trimethoxydistyryl-2-methylene)imine (19):

Mp 169-171°C; ESI-MS: 479.1099 (calc.479.1096); IR (KBr) cm ^-1 : 1676 (C=N), 3622 (OH); ¹ H NMR (DMSO-d ₆ ) δppm: 2.45 ( t, 2H, ArCH ₂ ), 2.71 (t, 2H, CH ₂ N), 3.82 (s, 3H, C _4′ -OCH ₃ ), 3.83 (s, 3H, C ₃ -OCH ₃ ), 3.91 (s, 3H, C ₅ -OCH ₃ ), 6.49 (d, 1H, C ₄ -H), 6.63 (d, 2H, C _{3', 5'} -H), 6.82 (d, 1H, C ₆ -H), 6.84 (m, 4H, ArH), 7.54 (d, 2H, C _{2′, 6′-} H), 7.12 (d, 1H, C ₇ -H), 7.39 (d, 1H, C ₈ -H), 8.64 ( s, 1H, CH=N).

N-(4-iodo-phenethyl)-(3,4,5'-trimethoxydistyryl-2-methylene)imine (20):

Mp 169-171°C; ESI-MS: 527.0952 (calc.527.0957); IR (KBr) cm ^-1 : 1676 (C=N), 3622 (OH); ¹ H NMR (DMSO-d ₆ ) δppm: 2.45 ( t, 2H, ArCH ₂ ), 2.71 (t, 2H, CH ₂ N), 3.81 (s, 3H, C _4′ -OCH ₃ ), 3.87 (s, 3H, C ₃ -OCH ₃ ), 3.90 (s, 3H, C ₅ -OCH ₃ ), 6.49 (d, 1H, C ₄ -H), 6.63 (d, 2H, C _{3', 5'} -H), 6.82 (d, 1H, C ₆ -H), 6.84 (m, 4H, ArH), 7.54 (d, 2H, C _{2′, 6′-} H), 7.12 (d, 1H, C ₇ -H), 7.39 (d, 1H, C ₈ -H), 8.61 ( s, 1H, CH=N).

N-Cyclopropyl-(3,4,5'-trihydroxydistyryl-2-methyl)amine (21):

Mp 82-84℃; ESI-MS: 297.1362(calc.297.1364); IR(KBr)cm ^-1 : 1175(CN), 3310(NH), 3620(OH); ¹ H NMR(DMSO-d ₆ )δppm : 0.46(t, 2H, 2×CH _a H _b ), 0.62(t, 2H, 2×CH _a H _b ), 3.32(m, 1H, CHNH), 3.81(s, 2H, CH ₂ ), 6.65( d, 1H, C ₄ -H), 6.91 (d, 1H, C ₆ -H), 6.74 (d, 2H, C _{3', 5'} -H), 7.35 (d, 2H, C _{2', 6'} -H), 7.14 (d, 1H, C ₇ -H), 8.10 (d, 1H, C ₈ -H), 8.61 (s, 1H, CH=N), 9.13 (s, 1H, C _4' -OH ), 9.46 (s, 2H, _C3,5 -OH).

N-Cyclobutyl-(3,4,5'-trihydroxydistyryl-2-methyl)amine (22):

Mp 82-84℃; ESI-MS: 311.1522 (calc.311.1521); IR (KBr) cm ^-1 : 1172 (CN), 3314 (NH), 3618 (OH); ¹ H NMR (DMSO-d ₆ ) δppm : 1.95(t, 4H, 2×CH ₂ CH), 1.84(d, 2H, CH ₂ ), 3.26(m, 1H, CHNH), 3.84(s, 2H, CH ₂ ), 6.63(d, 1H, C ₄ -H), 6.91 (d, 1H, C ₆ -H), 6.72 (d, 2H, C _{3′, 5′-} H), 7.33 (d, 2H, C _{2′, 6′-} H), 7.14 (d, 1H, C ₇ -H), 8.12 (d, 1H, C ₈ -H), 8.61 (s, 1H, CH=N), 9.11 (s, 1H, C _4' -OH), 9.41 (s , 2H, C _3,5 -OH).

N-cyclopentyl-(3,4,5'-trihydroxydistyryl-2-methyl)amine (23):

See Example 6.

N-cyclohexyl-(3,4,5'-trihydroxydistyryl-2-methyl)amine (24):

Mp 87-89°C; ESI-MS: 339.1838 (calc.339.1834); IR (KBr) cm ^-1 : 1172 (CN), 3314 (NH), 3618 (OH); ¹ HNMR (DMSO-d ₆ ) δppm: 1.07～1.21(m, 6H, _CH2CH2CH2 ), 1.66(m, 2H, _CH2 ), 1.81(m, _2H , _CH2 ), 2.42 ₍ t, 1H, CHNH), 3.81(s, 2H , ArCH ₂ ), 6.63 (d, 1H, C ₄ -H), 6.94 (d, 1H, C ₆ -H), 6.73 (d, 2H, C _{3', 5'} -H), 7.35 (d, 2H , C _{2′, 6′-} H), 7.12 (d, 1H, C ₇ -H), 8.11 (d, 1H, C ₈ -H), 9.09 (s, 1H, C _4′- OH), 9.38 ( s, 2H, _C3,5 -OH).

N-Aminoethylmorpholine-(3,4,5'-trihydroxydistyryl-2-methyl)amine (25):

Mp 148-150℃; ESI-MS: 370.1898(calc.370.1892); IR(KBr)cm ^-1 : 1160(CN), 3322(NH), 3632(OH); ¹ H NMR(DMSO-d ₆ )δppm : 2.22(t, 4H, CH ₂ NCH ₂ ), 2.35(t, 2H, CH ₂ ), 2.62(t, 2H, CH ₂ ), 3.75(t, 4H, CH ₂ OCH ₂ ), 3.81(s, 2H , ArCH ₂ ), 6.46(d, 1H, C ₄ -H), 6.94(d, 1H, C ₆ -H), 6.74(d, 2H, C _{3', 5'} -H), 7.35(d, 2H , C _{2′, 6′-} H), 7.12 (d, 1H, C ₇ -H), 8.11 (d, 1H, C ₈ -H), 9.19 (s, 1H, C _4′- OH), 9.43 ( s, 2H, _C3,5 -OH).

N-(4-Hydroxy-phenethyl)-(3,4,5'-trihydroxydistyryl-2-methyl)amine (26):

See Example 10.

N-(4-Fluoro-phenethyl)-(3,4,5'-trihydroxydistyryl-2-methyl)amine (27):

Mp 124-126℃; ESI-MS: 379.1580(calc.379.1583); IR(KBr)cm ^-1 : 1172(CN), 3314(NH), 3618(OH); ¹ H NMR(DMSO-d ₆ )δppm : 2.45(t, 2H, ArCH ₂ ), 2.74(t, 2H, CH ₂ N), 3.82(s, 2H, ArCH ₂ N), 6.46(d, 1H, C ₄ -H), 6.82(d, 1H , C ₆ -H), 6.64 (d, 2H, C _{3', 5'} -H), 7.54 (d, 2H, C _{2', 6'} -H), 7.11 (d, 1H, C ₇ -H) , 7.35 (d, 1H, C ₈ -H), 6.89 (m, 4H, ArH), 9.14 (s, 1H, C _4' -OH), 9.44 (s, 2H, C _3,5 -OH).

N-(4-Chloro-phenethyl)-(3,4,5'-trihydroxydistyryl-2-methyl)amine (28):

Mp 129-131℃; ESI-MS: 395.1293(calc.395.1288); IR(KBr)cm ^-1 : 1172(CN), 3315(NH), 3616(OH); ¹ H NMR(DMSO-d ₆ )δppm : 2.45(t, 2H, ArCH ₂ ), 2.74(t, 2H, CH ₂ N), 3.82(s, 2H, ArCH ₂ N), 6.46(d, 1H, C ₄ -H), 6.82(d, 1H , C ₆ -H), 6.64 (d, 2H, C _{3', 5'} -H), 7.54 (d, 2H, C _{2', 6'} -H), 7.11 (d, 1H, C ₇ -H) , 7.35 (d, 1H, C ₈ -H), 6.78 (m, 4H, ArH), 9.11 (s, 1H, C _4' -OH), 9.46 (s, 2H, C _3,5 -OH).

N-(4-bromo-phenethyl)-(3,4,5'-trihydroxydistyryl-2-methyl)amine (29):

Mp 136-138℃; ESI-MS: 439.0779(calc.439.0783); IR(KBr)cm ^-1 : 1178(CN), 3319(NH), 3617(OH); ¹ H NMR(DMSO-d ₆ )δppm : 2.45(t, 2H, ArCH ₂ ), 2.74(t, 2H, CH ₂ N), 3.82(s, 2H, ArCH ₂ N), 6.46(d, 1H, C ₄ -H), 6.82(d, 1H , C ₆ -H), 6.64 (d, 2H, C _{3', 5'} -H), 7.54 (d, 2H, C _{2', 6'} -H), 7.11 (d, 1H, C ₇ -H) , 7.35 (d, 1H, C ₈ -H), 6.76 (m, 4H, ArH), 9.18 (s, 1H, C _4' -OH), 9.53 (s, 2H, C _3,5 -OH).

N-(4-iodo-phenethyl)-(3,4,5'-trihydroxydistyryl-2-methyl)amine (30):

Mp 149-151℃; ESI-MS: 487.0648(calc.487.0644); IR(KBr)cm ^-1 : 1178(CN), 3319(NH), 3622(OH); ¹ H NMR(DMSO-d ₆ )δppm : 2.45(t, 2H, ArCH ₂ ), 2.74(t, 2H, CH ₂ N), 3.82(s, 2H, ArCH ₂ N), 6.46(d, 1H, C ₄ -H), 6.81(d, 1H , C ₆ -H), 6.64 (d, 2H, C _{3', 5'} -H), 7.54 (d, 2H, C _{2', 6'} -H), 7.11 (d, 1H, C ₇ -H) , 7.36 (d, 1H, C ₈ -H), 6.68 (m, 4H, ArH), 9.13 (s, 1H, C _4' -OH), 9.42 (s, 2H, C _3,5 -OH).

N-Cyclopropyl-(3,4,5'-trimethoxydistyryl-2-methyl)amine (31):

Mp 48-50℃; ESI-MS: 367.2145 (calc.367.2147); IR (KBr) cm ^-1 : 1175 (CN), 3310 (NH); ¹ H NMR (DMSO-d ₆ ) δppm: 0.46 (t, 2H, 2×CH _a H _b ), 0.62(t, 2H, 2×CH _a H _b ), 3.32(m, 1H, CHNH), 3.81(s, 2H, CH ₂ ), 3.78(s, 3H, C _4'- OCH ₃ ), 3.90(s, 3H, C ₃ -OCH ₃ ), 3.92(s, 3H, C ₅ -OCH ₃ ), 6.65(d, 1H, C ₄ -H), 6.91(d, 1H , C ₆ -H), 6.74 (d, 2H, C _{3', 5'} -H), 7.35 (d, 2H, C _{2', 6'} -H), 7.14 (d, 1H, C ₇ -H) , 8.09 (d, 1H, _C8 -H).

N-Cyclobutyl-(3,4,5'-trimethoxydistyryl-2-methyl)amine (32):

Mp41-43℃; ESI-MS: 381.2307 (calc.381.2303); IR (KBr) cm ^-1 : 1172 (CN), 3314 (NH); ¹ H NMR (DMSO-d ₆ ) δppm: 1.95 (t, 4H , 2×CH ₂ CH), 1.84 (d, 2H, CH ₂ ), 3.26 (m, 1H, CHNH), 3.84 (s, 2H, CH ₂ ), 3.78 (s, 3H, C _4′- OCH ₃ ) , 3.90(s, 3H, C ₃ -OCH ₃ ), 3.92(s, 3H, C ₅ -OCH ₃ ), 6.65(d, 1H, C ₄ -H), 6.91(d, 1H, C ₆ -H) , 6.72 (d, 2H, C _{3′, 5′} -H), 7.33 (d, 2H, C _{2′, 6′-} H), 7.14 (d, 1H, C _7- H), 8.09 (d, 1H , C ₈ -H).

N-cyclopentyl-(3,4,5'-trimethoxydistyryl-2-methyl)amine (33):

See Example 5.

N-cyclohexyl-(3,4,5'-trimethoxydistyryl-2-methyl)amine (34):

Mp 59-61°C; ESI-MS: 409.2610 (calc.409.2616); IR (KBr) cm ^-1 : 1172 (CN), 3314 (NH); ¹ H NMR (DMSO-d ₆ ) δppm: 1.07～1.21 ( m, 6H, CH ₂ CH ₂ CH ₂ ), 1.66 (m, 2H, CH ₂ ), 1.81 (m, 2H, CH ₂ ), 2.42 (t, 1H, CHNH), 3.81 (s, 2H, ArCH ₂ ) , 3.79(s, 3H, C _4′ -OCH ₃ ), 3.90(s, 3H, C ₃ -OCH ₃ ), 3.91(s, 3H, C ₅ -OCH ₃ ), 6.63(d, 1H, C ₄ - H), 6.94 (d, 1H, C ₆ -H), 6.73 (d, 2H, C _{3′, 5′-} H), 7.35 (d, 2H, C _{2′, 6′-} H), 7.12 (d , 1H, C ₇ -H), 8.12(d, 1H, C ₈ -H).

N-Aminoethylmorpholine-(3,4,5'-trimethoxydistyryl-2-methyl)amine (35):

Mp 64-66℃; ESI-MS: 412.2365(calc.412.2362); IR(KBr)cm ^-1 : 1160(CN), 3322(NH); ¹ HNMR(DMSO-d ₆ )δppm: 2.22(t, 4H , CH ₂ NCH ₂ ), 2.35 (t, 2H, CH ₂ ), 2.62 (t, 2H, CH ₂ ), 3.75 (t, 4H, CH ₂ OCH ₂ ), 3.81 (s, 2H, ArCH ₂ ), 3.79 (s, 3H, C _4' -OCH ₃ ), 3.90 (s, 3H, C ₃ -OCH ₃ ), 3.92 (s, 3H, C ₅ -OCH ₃ ), 6.48 (d, 1H, C ₄ -H) , 6.94 (d, 1H, C ₆ -H), 6.73 (d, 2H, C _{3′, 5′-} H), 7.35 (d, 2H, C _{2′, 6′-} H), 7.12 (d, 1H , C ₇ -H), 8.11(d, 1H, C ₈ -H).

N-(4-Hydroxy-phenethyl)-(3,4,5'-trimethoxydistyryl-2-methyl)amine (36):

See Example 9.

N-(4-fluoro-phenethyl)-(3,4,5'-trimethoxydistyryl-2-methyl)amine (37):

Mp 91-93°C; ESI-MS: 421.2057 (calc.421.2053); IR (KBr) cm ^-1 : 1172 (CN), 3314 (NH); ¹ H NMR (DMSO-d ₆ ) δppm: 2.51 (t, 2H, ArCH ₂ ), 2.74 (t, 2H, CH ₂ N), 3.82 (s, 2H, ArCH ₂ N), 3.77 (s, 3H, C _4′- OCH ₃ ), 3.89 (s, 3H, C ₃ -OCH ₃ ), 3.90 (s, 3H, C ₅ -OCH ₃ ), 6.45 (d, 1H, C ₄ -H), 6.82 (d, 1H, C ₆ -H), 6.64 (d, 2H, C _{3 ', 5'} -H), 7.54 (d, 2H, C _{2', 6'} -H), 7.11 (d, 1H, C ₇ -H), 7.35 (d, 1H, C ₈ -H), 6.88 ( m, 4H, ArH).

N-(4-Chloro-phenethyl)-(3,4,5'-trimethoxydistyryl-2-methyl)amine (38):

Mp 98-100℃; ESI-MS: 437.1761 (calc.437.1757); IR (KBr) cm ^-1 : 1172 (CN), 3315 (NH); ¹ H NMR (DMSO-d ₆ ) δppm: 2.41 (t, 2H, ArCH ₂ ), 2.73 (t, 2H, CH ₂ N), 3.81 (s, 2H, ArCH ₂ N), 3.76 (s, 3H, C _4′- OCH ₃ ), 3.90 (s, 3H, C ₃ -OCH ₃ ), 3.91 (s, 3H, C ₅ -OCH ₃ ), 6.46 (d, 1H, C ₄ -H), 6.82 (d, 1H, C ₆ -H), 6.64 (d, 2H, C _{3 ', 5'} -H), 7.54 (d, 2H, C _{2', 6'} -H), 7.12 (d, 1H, C ₇ -H), 7.35 (d, 1H, C ₈ -H), 6.79 ( m, 4H, ArH).

N-(4-Bromo-phenethyl)-(3,4,5'-trimethoxydistyryl-2-methyl)amine (39):

Mp 107-109℃; ESI-MS: 481.1255 (calc.481.1252); IR (KBr) cm ^-1 : 1178 (CN), 3319 (NH); ¹ H NMR (DMSO-d ₆ ) δppm: 2.46 (t, 2H, ArCH ₂ ), 2.73 (t, 2H, CH ₂ N), 3.82 (s, 2H, ArCH ₂ N), 3.77 (s, 3H, C _4′- OCH ₃ ), 3.89 (s, 3H, C ₃ -OCH ₃ ), 3.90 (s, 3H, C ₅ -OCH ₃ ), 6.46 (d, 1H, C ₄ -H), 6.82 (d, 1H, C ₆ -H), 6.64 (d, 2H, C _{3 ', 5'} -H), 7.54 (d, 2H, C _{2', 6'} -H), 7.09 (d, 1H, C ₇ -H), 7.34 (d, 1H, C ₈ -H), 6.75 ( m, 4H, ArH).

N-(4-iodo-phenethyl)-(3,4,5'-trimethoxydistyryl-2-methyl)amine (40):

Mp 112-114°C; ESI-MS: 529.1116 (calc.529.1113); IR (KBr) cm ^-1 : 1178 (CN), 3322 (NH); ¹ H NMR (DMSO-d ₆ ) δppm: 2.45 (t, 2H, ArCH ₂ ), 2.74 (t, 2H, CH ₂ N), 3.83 (s, 2H, ArCH ₂ N), 3.79 (s, 3H, C _4′- OCH ₃ ), 3.91 (s, 3H, C ₃ -OCH ₃ ), 3.92 (s, 3H, C ₅ -OCH ₃ ), 6.44 (d, 1H, C ₄ -H), 6.85 (d, 1H, C ₆ -H), 6.61 (d, 2H, C _{3 ', 5'} -H), 7.55 (d, 2H, C _{2', 6'} -H), 7.12 (d, 1H, C ₇ -H), 7.33 (d, 1H, C ₈ -H), 6.68 ( m, 4H, ArH).

Claims (7)

1. a class of derivatives of resveratrol, characterized in that it has the following general formula: In formula I, R ¹ is hydrogen or methyl; R ² is CH ₂ NHR ³ or CH=NR ³ , wherein R ³ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or R ³ has the following structure The group: X in formula B is fluorine, chlorine, bromine, iodine or hydroxyl. 2. a method for preparing a derivative of resveratrol as claimed in claim 1 is characterized in that: 3,5,4'-trimethoxystilbene (compound C) is dissolved in anhydrous DMF, Slowly add SOCl ₂ or POCl ₃ dropwise under ice bath and stirring, the ratio of compound C to SOCl ₂ or POCl ₃ is 1:1～1:0.1 to obtain the resveratrol derivative represented by the following formula (Compound D): 3. A method for preparing a derivative of resveratrol as claimed in claim 1, characterized in that: the compound D obtained in claim 2 is dissolved in dehydrated alcohol, and slowly added dropwise R ³ NH ₂ primary For amine compounds, the ratio of compound D to R ₃ NH ₂ is 1:1 to 1:2, and stirred at room temperature for 4 hours to obtain a derivative of resveratrol such as formula II: In formula II, R ¹ =CH ₃ , R ³ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or R ³ is a group with the following structure (chemical formulas A and B): X in formula B is fluorine, chlorine, bromine, iodine or hydroxyl. 4. a method for preparing a derivative of resveratrol as claimed in claim 1 is characterized in that: the product formula II compound obtained by claim ₃ is reacted with BBr in dichloromethane, and the formula II compound and The ratio of the amount of substance of _BBr3 is 1:1～1:1.5, promptly obtains the resveratrol derivative of structural formula such as formula II, but R ¹ =H in the formula, R ³ still is cyclopropyl, cyclobutyl , cyclopentyl or cyclohexyl, or R ³ is a group with the following structure (chemical formulas A and B):

X in formula B is fluorine, chlorine, bromine, iodine or hydroxyl. 5. A method for preparing a derivative of resveratrol as claimed in claim 1, characterized in that: the product formula II compound obtained in claim 3 is dissolved in absolute ethanol, and NaBH is added in batches ₄ , the formula Compound II and _NaBH The ratio of the amount of substance is 1: 0.5～1: 1.5, stirring at normal temperature for 2 hours, the derivative of resveratrol with structural formula such as formula III is obtained, In formula III, R ¹ =CH ₃ , R ³ =cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or R ³ is a group with the following structure (chemical formulas A and B):

X in formula B is fluorine, chlorine, bromine, iodine or hydroxyl. 6. a method for preparing a derivative of resveratrol as claimed in claim 1 is characterized in that: the product formula III compound obtained by claim 5 is reacted with _BBr in dichloromethane, and the formula III compound and The ratio of the amount of substance of _BBr3 is 1:1～1:1.5, promptly obtains the derivative of resveratrol such as formula III, but in the formula, R ¹ =H, R ³ is still cyclopropyl, cyclobutyl radical, cyclopentyl or cyclohexyl, or ^R is a group with the following structure (chemical formulas A and B): X in formula B is fluorine, chlorine, bromine, iodine or hydroxyl. 7. The derivative of resveratrol according to claim 1 is characterized in that it is used in the preparation of antitumor drugs.