A pterostilbene piperidamide derivative, a preparation method thereof and medical uses thereof

Abstract

The present application relates to a kind of pterostilbene piperidine amide derivatives, its preparation method and medical use, belong to the field of medicinal chemistry and pharmacotherapy.The present application uses pterostilbene as raw material, designs, synthesizes a series of pterostilbene piperidine amide compounds with new structure, and its structure is characterized.The method used in the present application to prepare these compounds has the characteristics of easy-to-get raw material, simple operation and high yield, and can quickly synthesize target compounds.Compared with pterostilbene, the pterostilbene piperidine amide derivatives provided in the present application have significant cell proliferation inhibitory effect on tumor cells.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry and pharmacology, and particularly relates to a pterostilbene piperidylamide derivative, a preparation method and medical use thereof. BACKGROUND

[0002] Malignant tumor seriously threatens people's life and health. How to develop safe and effective anticancer drugs has been the focus of medical researchers.

[0003] Pterostilbene is a homolog of resveratrol, mainly from blueberries and grapes. Studies have found that pterostilbene has less side effects, and has the effects of anti-cancer, anti-oxidation, anti-inflammation, and reducing blood lipids. Compared with resveratrol, the two additional methoxy groups in its structure make it more lipophilic and have stronger cell penetration ability, so it has better anti-tumor activity. Pterostilbene has a significant inhibitory effect on the proliferation of various tumor cells, and can inhibit the proliferation of various types of cancer, including lung cancer, breast cancer, prostate cancer, gastric cancer, colon cancer, pancreatic cancer, thyroid cancer, ovarian cancer and cervical cancer.

[0004] However, pterostilbene has the disadvantages of low bioavailability, poor stability and unclear target, which limits its clinical application and medical value. In addition, pterostilbene analogs have attracted great attention as promising multi-target anticancer agents. Therefore, it is of great theoretical and practical significance to develop safe and effective new pterostilbene anti-tumor drugs by using pterostilbene as a lead compound and adopting drug chemical structure modification and transformation to improve its anti-cancer effect and overcome its shortcomings. SUMMARY

[0005] In view of the above problems, the present application provides a pterostilbene piperidylamide derivative, a preparation method and medical use thereof.

[0006] The first object of the present application is to provide a pterostilbene piperidylamide derivative, the chemical structural formula of which is shown as formula (1):

[0007]

[0008] In formula I:

[0009] R is one of benzene, substituted benzene and cyclohexane.

[0010] Further, R is benzene, substituted benzene and cyclohexane. It includes but is not limited to one of phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl and cyclohexyl.

[0011] The second object of the present application is to provide a preparation method of pterostilbene piperidine amide derivatives, comprising:

[0012] Under the condition of anhydrous potassium carbonate, Williamson etherification reaction of pterostilbene and ethyl bromoacetate is carried out to obtain intermediate 2;

[0013] Under ice bath, phosphorus oxychloride is added dropwise into the solution of intermediate 2, and the reaction is stirred to obtain intermediate 3;

[0014] Under alkaline condition, hydrolysis reaction of intermediate 3 is carried out to obtain intermediate 4;

[0015] Under the action of a first amide condensation catalyst, first amide condensation reaction of intermediate 4 and piperidine is carried out to obtain intermediate 5;

[0016] Under the action of an oxidant, aldehyde group oxidation reaction of intermediate 5 and 2-methyl-2-butene is carried out to obtain intermediate 6;

[0017] Under the action of a second amide condensation catalyst, second amide condensation reaction of intermediate 6 and an amine compound is carried out to obtain pterostilbene piperidine amide derivatives;

[0018] The synthesis route is shown as follows:

[0019]

[0020] In formula I:

[0021] R is one of benzene, substituted benzene and cyclohexane.

[0022] Further, the reaction of pterostilbene and ethyl bromoacetate is a solution reaction, the solvent used is acetonitrile, and the molar ratio of pterostilbene, anhydrous potassium carbonate and ethyl bromoacetate is 1:1-1.5:1-1.5.

[0023] Further, the solution of intermediate 2 is a DMF solution of intermediate 2, and the molar ratio of intermediate 2 and phosphorus oxychloride is 1:1.2-1.5.

[0024] Further, in the hydrolysis reaction, the solvent used is an ethanol solution with a mass fraction of 8-10%, the amount of the ethanol solution with a mass fraction of 8-10% used is 4-5 mL per millimole of intermediate 3, the base used is a sodium hydroxide solution with a mass fraction of 10%, and the amount of the sodium hydroxide solution with a mass fraction of 10% used is 2 mL per millimole of intermediate 3.

[0025] Further, in the first amide condensation reaction, the reaction solvent is DMF; the first condensation catalyst is HATU and DIPEA, the molar ratio of intermediate 4, piperidine, HATU and DIPEA is 1:1.2-1.4:1.5:1.5, and the temperature of the first amide condensation reaction is room temperature.

[0026] The aldehyde group oxidation reaction is a solution reaction, the solvent used is acetone, the oxidant is an aqueous solution of NaClO2 and NaH2PO2·2H2O, the molar ratio of the intermediate 5, 2-methyl-2-butene, NaClO2, NaH2PO2·2H2O is 1:4-4.5:8:8, and the temperature of the aldehyde group oxidation reaction is room temperature.

[0027] The second amide condensation reaction is a solution reaction, the solvent used is DCM, the second condensing agent is DMAP and EDC·HCl; the molar ratio of the intermediate 6, the amine compound, DMAP and EDC·HCl is 1:2-2.5:1.2:1.2, and the temperature of the second amide condensation reaction is room temperature.

[0028] Further, the amine compound is aniline, 4-methylaniline, 4-trifluoromethylaniline, 4-methoxyaniline, 3,4-dimethoxyaniline, 2-fluoro-4-methoxyaniline, 2-fluoroaniline, 3-fluoroaniline, 4-fluoroaniline, cyclohexylamine.

[0029] A third object of the present application is to provide a pharmaceutical composition.

[0030] The pharmaceutical composition comprises the pterostilbene piperidamide derivative prepared by the preparation method.

[0031] Further, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0032] Further, the pharmaceutical composition can be prepared into a pharmaceutically acceptable dosage form, such as a tablet, a dripping pill, a capsule, a powder, a syrup, a liquid, a suspension, a freeze-dried powder injection or an injection, a nano preparation.

[0033] A fourth object of the present application is to provide the use of the pterostilbene piperidamide derivative or the pharmaceutical composition in the preparation of an antitumor drug.

[0034] The tumor includes osteosarcoma, lung cancer, liver cancer, breast cancer, colon cancer.

[0035] The present application has the following advantages:

[0036] The present application designs and synthesizes a series of pterostilbene piperidamide derivatives with novel structures, and the structures are characterized; the method for preparing the compounds has the characteristics of easy availability of raw materials, simple operation and high yield; and the antitumor activities of the compounds are tested; compared with pterostilbene, the pterostilbene piperidamide derivatives provided by the present application have a significant cell proliferation inhibition effect on tumor cells, and have the potential to be used as an antitumor drug for treating tumors.

[0037] Other features and advantages of the present invention will be described in the following description, and in part will become apparent from the description, or will be understood by practicing the present invention. The purpose and other advantages of the present invention can be realized and obtained by the structures pointed out in the description, claims and drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following is a brief introduction to the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0039] Figure 1 The chemical structural formula of the pterostilbene piperidine amide derivatives according to an embodiment of the present invention is shown;

[0040] Figure 2 The figure shows a synthetic route of the pterostilbene piperidine amide derivatives according to the embodiments of the present invention. DETAILED DESCRIPTION

[0041] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts shall fall within the scope of protection of the present invention.

[0042] Figure 1 The chemical structural formula I of the pterostilbene piperidine amide derivatives according to an embodiment of the present invention is shown.

[0043] In Formula 1:

[0044] R is one of benzene, substituted benzene and cyclohexane.

[0045] In certain embodiments of the present invention, R is one of phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl and cyclohexyl.

[0046] like Figure 2 As shown, a method for preparing a pterostilbene piperidine amide derivative according to an embodiment of the present invention comprises:

[0047] Step a, Williamson etherification reaction of tanshinone IIA with ethyl bromoacetate in the presence of anhydrous potassium carbonate to obtain intermediate 2;

[0048] Step b, dropwise add phosphorus oxychloride to the solution of intermediate 2 under ice bath, and stir the reaction to obtain intermediate 3;

[0049] Step c, hydrolysis reaction of intermediate 3 under alkaline conditions to obtain intermediate 4;

[0050] Step d, first amide condensation reaction of intermediate 4 and piperidine under the action of a first condensation catalyst to obtain intermediate 5;

[0051] Step e, aldehyde group oxidation reaction of intermediate 5 and 2-methyl-2-butene under the action of an oxidizing agent to obtain intermediate 6;

[0052] Step f, second amide condensation reaction of intermediate 6 and an amine compound under the action of a second condensation catalyst to obtain a tanshinone IIA piperidine amide derivative;

[0053] In step a, the reaction of tanshinone IIA with ethyl bromoacetate is a solution reaction, the solvent used is acetonitrile, and the molar ratio of tanshinone IIA, anhydrous potassium carbonate and ethyl bromoacetate is 1:1-1.5:1-1.5.

[0054] In step b, the molar ratio of intermediate 2 and phosphorus oxychloride is 1:1.2-1.5.

[0055] In step c, in the hydrolysis reaction, the solvent used is an ethanol solution with a mass fraction of 8-10%, the amount of the ethanol solution with a mass fraction of 8-10% used is 4-5 mL per millimole of intermediate 3; the base used is a sodium hydroxide solution with a mass fraction of 10%, and the amount of the sodium hydroxide solution with a mass fraction of 10% used is 2 mL per millimole of intermediate 3.

[0056] In step d, in the first amide condensation reaction, the reaction solvent is DMF; the first condensation catalyst is HATU and DIPEA, the molar ratio of piperidine, intermediate 4, HATU and DIPEA is 1.2-1.4:1:1.5:1.5, and the temperature of the first amide condensation reaction is room temperature.

[0057] In step e, the aldehyde group oxidation reaction is a solution reaction, the solvent used is acetone, the oxidizing agent is an aqueous solution of NaClO2 and NaH2PO2·2H2O, the molar ratio of intermediate 5, 2-methyl-2-butene, NaClO2 and NaH2PO2·2H2O is 1:4-4.5:8:8, and the temperature of the aldehyde group oxidation reaction is room temperature.

[0058] In step f, the second amide condensation reaction is a solution reaction, the solvent used is DCM, the second condensing agent is DMAP and EDC-HCl; the molar ratio of the intermediate 6, the amine-based compound, DMAP and EDC-HCl is 1:2-2.5:1.2:1.2, and the temperature of the second amide condensation reaction is room temperature.

[0059] The amine-based compound is aniline, 4-methylaniline, 4-trifluoromethylaniline, 4-methoxyaniline, 3,4-dimethoxyaniline, 2-fluoro-4-methoxyaniline, 2-fluoroaniline, 3-fluoroaniline, 4-fluoroaniline, or cyclohexylamine.

[0060] According to the above synthesis route, by selecting a specific amine-based compound in step e, the synthesis of the following specific pterostilbene piperidinamide derivative is exemplarily given as follows:

[0061] Example 1

[0062] The amine-based compound is aniline, and the specific chemical structure of the obtained pterostilbene piperidinamide derivative is as follows:

[0063]

[0064] The name is: (E)-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1-yl)ethoxy)styryl)-N-phenylbenzamide (hereinafter referred to as C-1)

[0065] Preparation method:

[0066] a. Add pterostilbene (10.00 g, 39.02 mmol) to a clean 250 mL round-bottom flask, then add 150 mL of acetonitrile to the reaction bottle, and then add anhydrous potassium carbonate (5.39 g, 39.02 mmol), ethyl bromoacetate (9.77 g, 58.52 mmol), stir at 80°C for 20 h, and monitor the reaction by TLC. The reaction is basically complete. The solvent is recovered to dryness under reduced pressure, then 150 mL of ethyl acetate is added, washed with water (60 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a white product, which is intermediate 2. 1 HNMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 16.2 Hz, 1H), 6.94-6.88 (m, 3H), 6.67-6.62 (m, 2H), 6.38 (s, 1H), 4.63 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.82 (s, 6H), 1.30 (t, J = 7.1 Hz, 3H). 13CNMR (100 MHz, CDC13) δ 168.8, 160.9, 157.5, 139.5, 130.9, 128.4, 127.8, 127.1, 114.8, 104.3, 99.7, 65.4, 61.4, 55.3, 14.2; ESI-HRMS (m / z): C 20 H 22 O5[M+H] + : calcd: 343.1467; found: 343.1529.

[0067] b. Intermediate 2 (12.00 g, 35.05 mmol) was weighed into a clean 250 mL round bottom flask, then 135 mL of DMF was added, and the ice-salt bath was cooled to below 0°C. Phosphorus oxychloride (8.06 g, 52.57 mmol) was slowly added dropwise, and the reaction was stirred at room temperature after the dropwise addition was completed. The reaction was monitored by TLC, and after the reaction was completed, the reaction solution was slowly added dropwise into ice water, and the pH of the reaction solution was adjusted to weak alkaline with NaHC03. After filtration, the crude product was obtained, and column chromatography purification (DCM:PE = 3:1) yielded a yellow-green solid, which was intermediate 3. 1 HNMR (600 MHz, CDC13) δ 10.52 (s, 1H), 8.06 (d, J = 16.2 Hz, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.00-6.89 (m, 3H), 6.73 (s, 1H), 6.39 (s, 1H), 4.64 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13 CNMR (100 MHz, CDC13) δ 190.6, 168.8, 165.0, 164.5, 157.7, 142.9, 131.78, 131.0, 128.4, 126.1, 116.0, 114.8, 103.4, 96.9, 65.4, 61.4, 55.8, 55.5, 14.2; ESI-HRMS (m / z): C 21 H 22 O6[M+H] + : calcd: 371.1416; found: 371.1490.

[0068] c. Intermediate 3 (6.60 g, 17.82 mmol) was added to a clean 100 mL round bottom flask, then 20 mL of 10% ethanol was added, followed by 36 mL of 10% sodium hydroxide solution. The reaction was stirred at 50°C for 2 h, and after the reaction was completed, 20 mL of ice water was added, and the pH was adjusted to acidic with 3 mol / L HC1. After filtration, a dark yellow solid 5.74 g was obtained, which was intermediate 3.1 HNMR (400 MHz, CDC13) δ 10.53 (s, 1H), 8.08 (d, J = 16.0 Hz, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.00-6.90 (m, 4H), 6.74 (s, 1H), 6.40 (s, 1H), 4.71 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H). 13 CNMR (100 MHz, DMSO-d6) δ 194.9, 175.3, 170.0, 169.7, 163.0, 146.9, 137.1, 135.3, 133.2, 129.8, 120.3, 120.0, 108.7, 102.6, 69.6, 61.4, 60.9; ESI-HRMS (m / z): C 20 H 22 O5[M+H] + : calcd: 343.1103; found: 343.1166.

[0069] d. PIPERIDINE (993.0 μL, 10.53 mmol) was added to a clean 25 mL round bottom flask, followed by 1 mL DMF, then INTERMEDIATE 3 (1.00 g, 5.85 mmol), HATU (3.34 g, 8.78 mmol), DIPEA (1.14 g, 8.78 mmol) were added in sequence. The reaction was stirred at room temperature, and monitored by TLC. When the reaction was completed, an appropriate amount of water was added dropwise to the reaction solution, and a solid precipitated. The solid was directly filtered, and the filter cake was recovered and dried to obtain yellow solid 1.08 g, which was INTERMEDIATE 5, in a yield of 90.32%. 1 H NMR (400 MHz, CDC13) δ 10.53 (s, 1H), 8.08 (d, J = 16.0 Hz, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.00-6.90 (m, 4H), 6.74 (s, 1H), 6.40 (s, 1H), 4.71 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 190.7, 166.0, 165.0, 164.5, 157.9, 143.1, 131.9, 130.8, 128.4, 126.0, 116.1, 114.8, 103.3, 97.0, 67.8, 55.9, 55.6, 46.5, 43.3, 26.5, 25.5, 24.4; ESI-HRMS (m / z): C 24 H27 NO6[M+H] + : calcd: 410.1923; found: 410.1958.

[0070] e. Intermediate 5 (4.00 g, 9.77 mmol) was added to a clean 50 mL round bottom flask, followed by the addition of 30 mL of acetone and 2-methyl-2-butene (3.215 mL, 39.10 mmol), then a solution of NaClO2(7.07 g, 78.20 mmol) and NaH2PO2·2H2O (10.95 g, 78.20 mmol) in water (30 mL) was added, the reaction mixture was stirred for 1 h, after the reaction was completed, 30 mL of water was added, extracted with EA (3 x 30 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM:MeOH = 30:1) to obtain a white solid, which was intermediate 6. 1 H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 16.2 Hz, 1H), 7.01 - 6.86 (m, 4H), 6.49 (s, 1H), 4.81 (s, 2H), 3.83 (s, 3H), 3.75 (s, 3H), 3.44 - 3.39 (m, 4H), 1.61 - 1.43 (m, 6H). 13 CNMR (100 MHz, CDC13) δ 170.5, 165.2, 165.2, 163.2, 162.0, 140.3, 135.1, 134.9, 132.8, 128.6, 120.1, 105.6, 103.0, 102.0, 71.3, 60.8, 60.6, 50.4, 47.3, 31.1, 30.5, 29.1; ESI-HRMS (m / z): C 24 H 27 NO5[M+H] + : calcd: 426.1872; found: 426.1900.

[0071] f.Aniline (44.7 mg, 0.48 mol) was added to a clean 25 mL round bottom flask, followed by 1 mL DCM, then intermediate 6 (0.10 g, 0.24 mmol), DMAP (34.48 mg, 0.28 mmol) and EDC HCI (54.09 mg, 0.28 mmol) were added in sequence. The reaction was stirred at room temperature and monitored by TLC. After the reaction was completed, saturated NaCl solution was added to wash twice, the organic layer was recovered, dried over anhydrous Na2S04, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (DCM:MeOH = 120:1) gave 44.00 mg of white solid, with a yield of 37.41%. 1 H NMR (400 MHz, CDC13) δ 7.68-7.59 (m, 3H), 7.42-7.34 (m, 4H), 7.14 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 16.1 Hz, 1H), 6.90 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 2.1 Hz, 1H), 6.43 (d, J = 2.1 Hz, 1H), 4.68 (s, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.57-3.47 (m, 4H), 1.67-1.57 (m, 6H). 13 C NMR (100 MHz, CDC13) δ 166.1, 165.5, 161.5, 158.0, 158.0, 138.7, 138.3, 131.0, 130.6, 129.1, 128.4, 124.4, 124.2, 119.9, 118.8, 114.9, 101.7, 97.9, 77.4, 77.1, 76.8, 67.9, 56.1, 55.7, 46.6, 43.4, 26.6, 25.6, 24.5; ESI-HRMS (m / z): C 30 H 32 N2O5[M+H] + : calcd: 501.2389; found: 501.2415.

[0072] Example 2

[0073] The amine compound is 4-methylaniline, and the specific chemical structure of the obtained pterostilbene piperidine amide derivative is as follows:

[0074]

[0075] Its name is: (E)-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-l-yl)ethoxy)styryl)-N-(p-tolyl)benzamide (hereinafter referred to as C-2)

[0076] Preparation method:

[0077] The same as Example 1, except that p-methylaniline was used instead of aniline in step f, to obtain the target product E)-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1-yl)ethoxy)phenyl)-N-(p-tolyl)benzamide as a white solid (44.48 mg) in a yield of 36.78%. 1 H NMR (400MHz, CDCl3) δ7.53(d,J=8.2Hz,2H),7.38(d,J=8.4Hz,2H),7.23-7.13(m,3H),7.01(d,J=16.0Hz,1H),6.89(d,J=8.4Hz,2H),6 .80(d,J=1.2Hz,1H),6.41(d,J=1.5Hz,1H),4.66(s,2H),3.89(s,3H),3.83(s,3H),3.56-3.46(m,4H),2.34(s,3H),1.65-1.53(m,6H). 13 C NMR (100MHz, CDCl3) δ165.3,164.7,160.6,157.3,157.2,137.8,135.0,133.3,130.2,129.8,128.8,127.6,123.4,119. 3,118.2,114.1,100.8,97.1,76.7,76.4,76.0,67.1,55.3,54.9,45.8,42.6,25.8,24.9,23.8,20.3; ESI-HRMS(m / z):C 31 H 34 N2O5[M+H] + :calcd:515.2546; found:515.2563.

[0078] Example 3

[0079] The amino compound is trifluoromethylaniline, and the specific chemical structure of the obtained pterostilbene piperidine amide derivative is as follows:

[0080]

[0081] Its name is: (E)-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1-yl)ethoxy)phenyl)-N-(4-(trifluoromethyl)phenyl)benzamide (hereinafter referred to as C-3)

[0082] Preparation method:

[0083] The same as example 1, except that in step d, p-trifluoromethylaniline instead of aniline, the target product (E)-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1-yl)ethoxy)styryl)-N-(4-(trifluoromethyl)phenyl)benzamide, white solid. 1 H NMR (400 MHz, CDC13) δ 7.71 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.35-7.30 (m, 2H), 6.96 (d, J = 5.1 Hz, 1H), 6.93-6.80 (m, 4H), 6.77-6.64 (m, 2H), 6.35 (d, J = 16.0 Hz, 1H), 4.60 (s, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.51-3.46 (m, 2H), 3.44-3.38 (m, 2H), 1.54 (d, J = 20.2 Hz, 6H). 13 C NMR (100 MHz, CDC13) δ 167.1, 164.5, 160.0, 156.7, 156.5, 136.2, 129.6, 128.9, 126.6, 122.1, 114.2, 113.3, 99.7, 96.3, 75.9, 75.5, 75.2, 66.2, 54.5, 54.0, 45.0, 41.8, 25.0, 24.1, 23.0; ESI-HRMS (m / z): C 31 H 31 F3N2O5[M+H] + : calcd: 569.2263; found: 569.2288.

[0084] Example 4

[0085] The amine compound is p-methoxyaniline, and the specific chemical structure of the obtained pterostilbene piperidine amide derivative is as follows:

[0086]

[0087] Its name is: (E)-2,4-dimethoxy-N-(4-methoxyphenyl)-6-(4-(2-oxo-2-(piperidin-1-yl)ethoxy)styryl)benzamide (hereinafter referred to as C-4)

[0088] Preparation method:

[0089] The same as example 1, except that in step f, p-methoxyaniline instead of aniline, the target product (E)-2,4-dimethoxy-N-(4-methoxyphenyl)-6-(4-(2-oxo-2-(piperidin-1-yl)ethoxy)styryl)benzamide, white solid.1 H NMR (400 MHz, CDC13) δ 7.60-7.53 (m, 3H), 7.39 (d, J = 8.6 Hz, 2H), 7.22 (s, 1H), 7.01 (d, J = 16.1 Hz, 1H), 6.90 (dd, J = 8.9, 2.9 Hz, 4H), 6.80 (d, J = 2.1 Hz, 1H), 6.42 (d, J = 2.1 Hz, 1H), 4.67 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 3.56-3.46 (m, 4H), 1.63 (q, J = 5.9, 5.3 Hz, 6H). 13 C NMR (100 MHz, CDC13) δ 166.0, 165.4, 161.3, 158.0, 158.0, 156.4, 138.5, 131.5, 130.8, 130.6, 128.3, 124.2, 121.7, 114.8, 114.2, 101.5, 97.8, 77.4, 77.1, 76.8, 67.7, 56.1, 55.6, 46.5, 43.3, 26.5, 25.6, 24.5; ESI-HRMS (m / z): C 31 H 34 N2O6[M+H] + : calcd: 531.2495; found: 531.2518.

[0090] Example 5

[0091] The amine compound is 3,4-dimethoxyaniline, and the specific chemical structure of the obtained pterostilbene piperidinamide derivative is as follows:

[0092]

[0093] The name of which is: (E)-N-(3,4-dimethoxyphenyl)-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1- yl)ethoxy)styryl)benzamide (hereinafter referred to as C-5)

[0094] Preparation method:

[0095] The preparation method is the same as that of Example 1, except that 3,4-dimethoxyaniline is used instead of aniline in step f to obtain the target product (E)-N-(3,4-dimethoxyphenyl)-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1- yl)ethoxy)styryl)benzamide, a purple solid. 1H NMR (400 MHz, CDC13) δ 7.52 (d, J = 1.6 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 16.1 Hz, 1H), 7.03 (d, J = 16.1 Hz, 1H), 6.97 (dd, J = 8.6, 2.1 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 1H), 6.80 (d, J = 1.8 Hz, 1H), 6.43 (d, J = 1.4 Hz, 1H), 4.68 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 3.56 - 3.47 (m, 4H), 1.68 - 1.55 (m, 6H). 13 C NMR (100 MHz, CDC13) δ 165.9, 165.3, 161.3, 157.9, 157.9, 149.0, 145.8, 138.4, 131.9, 130.9, 130.4, 128.2, 124.0, 118.8, 114.7, 111.7, 111.3, 104.7, 101.5, 97.7, 77.3, 77.0, 76.7, 67.7, 56.1, 56.0, 56.0, 55.5, 46.4, 43.2, 26.4, 25.5, 24.4; ESI-HRMS (m / z): C 32 H 36 N2O7[M+H] + : calcd: 561.2601; found: 561.2636.

[0096] Example 6

[0097] The amine compound is 2-fluoro-4-methoxyaniline, and the specific chemical structure of the obtained pterostilbene piperidinamide derivative is as follows:

[0098]

[0099] Its name is: (E)-N-(2-fluoro-4-methoxyphenyl)-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1- yl)ethoxy)styryl)benzamide (hereinafter referred to as C-6)

[0100] Preparation method:

[0101] The preparation method is the same as that in Example 1, except that 2-fluoro-4- methoxy aniline is used instead of aniline in step f to obtain the target product (E)-N-(2-fluoro-4- methoxyphenyl)-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1-yl)ethoxy)styryl)benzamide, a white solid. 1 H NMR (400 MHz, CDC13) δ 7.85 - 7.77 (m, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 16.1 Hz, 1H), 7.01 (d, J = 16.0 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 1.9 Hz, 1H), 6.76 - 6.70 (m, 2H), 6.43 (d, J = 1.9 Hz, 1H), 4.69 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 3.81 (s, 3H), 3.57 - 3.47 (m, 4H), 1.69 - 1.55 (m, 6H). 13 C NMR (100 MHz, CDC13) δ 165.8, 164.9, 161.2, 157.8, 157.7, 156.4, 156.3, 138.9, 130.6, 128.0, 124.2, 123.0, 119.4, 117.8, 114.5, 109.1, 101.7, 101.6, 101.4, 97.5, 77.1, 76.8, 76.5, 67.6, 55.8, 55.5, 55.3, 46.2, 43.0, 26.2, 25.3, 24.6; ESI-HRMS (m / z): C 31 H 33 FN2O6[M+H] + : calcd: 549.2401; found: 549.2422.

[0102] Example 7

[0103] The amine compound is 2-fluoroaniline, and the specific chemical structural formula of the obtained pterostilbene piperidine amide derivative is as follows:

[0104]

[0105] Its name is: (E)-N-(2-fluorophenyl)-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1- yl)ethoxy)styryl)benzamide (hereinafter referred to as C-7)

[0106] Preparation method:

[0107] The preparation method is the same as that in Example 1, except that 2-fluoroaniline is used instead of aniline in step f to obtain the target product (E)-N-(2-fluorophenyl)-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1-yl)ethoxy)styryl)benzamide, white solid. 1 H NMR (400 MHz, CDC13) δ 8.03 - 7.99 (m, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 16.1 Hz, 1H), 7.16 - 7.09 (m, 2H), 7.04 - 6.99 (m, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 2.0 Hz, 1H), 6.37 (d, J = 2.0 Hz, 1H), 4.61 (s, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.50 - 3.47 (m, 2H), 3.42 (d, J = 5.2 Hz, 2H), 1.61 - 1.51 (m, 6H). 13 C NMR (100 MHz, CDC13) δ 165.4, 165.4, 161.0, 160.9, 157.6, 157.3, 138.9, 137.1, 130.5, 130.3, 130.0, 129.9, 127.7, 127.6, 123.9, 123.1, 121.3, 114.2, 114.2, 101.6, 100.6, 97.1, 76.8, 76.5, 76.1, 67.2, 55.4, 55.0, 45.9, 42.7, 25.9, 25.0, 23.9; ESI-HRMS (m / z): C 30 H 31 FN2O5[M+H] + : calcd: 519.2295; found: 519.2314.

[0108] Example 8

[0109] The amine compound is 3-fluoroaniline, and the specific chemical structural formula of the pterostilbene piperidine amide derivative obtained is as follows:

[0110]

[0111] Its name is: (E)-N-(3-fluorophenyl)-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1-yl)ethoxy)styryl)benzamide (hereinafter referred to as C-8)

[0112] Preparation method:

[0113] The same as example 1, except that in step d, 3-fluoroaniline was used instead of aniline to obtain the target product (E)-N-(3-fluorophenyl)-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1- yl)ethoxy)styryl)benzamide, white solid. 1 H NMR (400 MHz, CDC13) δ 7.73 - 7.65 (m, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 6.2 Hz, 2H), 7.02 (d, J = 15.9 Hz, 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.86 - 6.81 (m, 2H), 6.43 (d, J = 1.7 Hz, 1H), 4.68 (s, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.56 - 3.48 (m, 4H), 1.67 - 1.58 (m, 6H). 13 C NMR (100 MHz, CDC13) δ 165.9, 165.4, 161.8, 161.5, 158.0, 157.9, 139.8, 138.9, 131.0, 130.4, 130.1, 130.0, 128.2, 124.0, 118.1, 114.9, 114.8, 111.0, 107.4, 107.1, 101.8, 97.7, 77.3, 77.0, 76.7, 67.7, 56.0, 55.5, 46.4, 43.2, 26.4 25.5, 24.4; ESI-HRMS (m / z): C 30 H 31 FN2O5[M+H] + : calcd: 519.2295; found: 519.2320.

[0114] Example 9

[0115] The amine compound is 4-fluoroaniline, and the specific chemical structure of the pterostilbene piperidine amide derivative obtained is as follows:

[0116]

[0117] Its name is: (E)-N-(4-fluorophenyl)-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1- yl)ethoxy)styryl)benzamide (hereinafter referred to as C-9)

[0118] Preparation method:

[0119] The same as example 1, except that in step f, 4-fluoroaniline was used instead of aniline to obtain the target product (E)-N-(4-fluorophenyl)-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1- yl)ethoxy)styryl)benzamide, white solid. 1 H NMR (400 MHz, CDC13) δ 7.62 - 7.59 (m, 2H), 7.40 (d, J = 8.3 Hz, 2H), 7.08 - 7.04 (m, 2H), 7.00 - 6.90 (m, 4H), 6.81 (d, J = 1.3 Hz, 1H), 6.43 (d, J = 2.1 Hz, 1H), 4.68 (s, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.55 - 3.49 (m, 4H), 1.67 - 1.62 (m, 6H). 13 C NMR (100 MHz, d-DMSO) δ 165.6, 161.1, 159.6, 158.5, 157.8, 157.3, 136.6, 136.3, 136.3, 130.9, 130.0, 128.4, 128.0, 123.0, 121.4, 121.3, 120.5, 115.8, 115.6, 115.4, 101.1, 98.3, 66.4, 56.2, 56.0, 45.6, 42.6, 40.5, 40.3, 40.1, 39.9, 39.7, 39.3, 39.3, 26.4, 25.7, 24.4; ESI-HRMS (m / z): C 30 H 31 FN2O5[M+H] + : calcd: 519.2295; found: 519.2321.

[0120] Example 10

[0121] The amine compound is cyclohexylamine, and the specific chemical structure of the obtained pterostilbene piperidine amide derivative is as follows:

[0122]

[0123] Its name is: (E)-N-cyclohexyl-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1- yl)ethoxy)styryl)benzamide (hereinafter referred to as C-10)

[0124] Preparation method:

[0125] The same as example 1, except that in step f, cyclohexylamine was used instead of aniline to obtain the target product (E)-N-cyclohexyl-2,4-dimethoxy-6-(4-(2-oxo-2-(piperidin-1-yl)ethoxy)styryl)benzamide, white solid. 1 H NMR (400 MHz, CDC13) δ 7.34 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 16.2 Hz, 1H), 6.92 (d, J = 16.2 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 1.8 Hz, 1H), 6.30 (d, J = 1.8 Hz, 1H), 4.63 (s, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 3.52-3.48 (m, 2H), 3.44-3.40 (m, 2H), 2.00-1.95 (m, 2H), 1.67-1.52 (m, 8H), 1.38-1.33 (m, 2H), 1.19-1.12 (m, 4H). 13 C NMR (100 MHz, CDC13) δ 165.7, 165.1, 160.0, 157.0, 156.8, 136.6, 129.7, 129.5, 127.2, 123.1, 118.6, 113.9, 100.1, 96.9, 76.5, 76.1, 75.8, 66.8, 55.0, 54.6, 47.6, 45.6, 42.4, 32.2, 28.8, 28.8, 25.6, 24.7, 23.9, 23.5, 21.8; ESI-HRMS (m / z): C 30 H 38 N2O5[M+H] + : calcd: 507.2859; found: 507.2877.

[0126] Example 11: Evaluation of Anti-tumor Activity

[0127] 1. CCK-8 method for determining in vitro anti-tumor activity

[0128] The CCK-8 (Cell Counting Kit-8) method was used to determine the inhibition rate of the pterostilbene derivatives on human lung cancer cells A549, human liver cancer cells HepG2, colon cancer cells HCT116 and human osteosarcoma cells U-2OS.

[0129] Four kinds of human tumor cells were stored in RPMI-1640 medium containing 10% fetal bovine serum (BI), 100 U / mL of penicillin and 0.1 mg / mL of streptomycin at 37°C, 5% CO2 cell incubator; when the cells were in logarithmic phase, the cells were collected and counted, diluted to an appropriate density, inoculated into 96-well plates; the inoculation number of adherent cells was 5000 / well, and the inoculation number of suspension cells was 8000 / well, and the edge wells were covered with PBS, and placed in the incubator (condition: 37°C, 5% CO2) overnight; the prepared 100 μM concentration of the test compound and the positive drug stock solution were diluted according to the gradient dilution method to prepare different concentrations of test solutions with cell culture solution. 100 μL of test solution was added to each well, 5 concentrations of each compound were set, and 3 replicate wells were set for each concentration. The blank group was without cells, and the negative control group was without drugs, and the same volume of culture medium was used as a control. After adding the drugs (C-1, C-2-C-10, pterostilbene, 5-FU) to them, the culture medium was returned to the incubator and continued to be cultured at 37°C, 5% CO2 cell incubator for 48 h. Then 10 μL of CCK-8 solution was added to each well, and incubated for about 2 h under the same conditions. Finally, the absorbance (OD value) at 450 nm was determined by a microplate reader. Each group of experiments was repeated three times, and each experiment was independent.

[0130] The inhibition rate of cell growth was calculated according to the following formula:

[0131] The growth inhibition rate = (1-survival rate) x 100% = [1-(OD experiment-OD empty) / (OD control-OD empty)] x 100% (OD experiment represents the absorbance of the test drug group, OD control represents the absorbance of the control group, and OD blank represents the absorbance of the blank group).

[0132] Half maximal inhibitory concentration (IC 50 ) is defined as the drug concentration when 50% of tumor cells survive. According to the measured absorbance (OD value), the inhibition rate was calculated, and then the IC 50 value was fitted using Origin.

[0133] The measured IC 50 values are shown in Table 1.

[0134] Table 1

[0135]

[0136] From Table 1, it can be seen that the inhibitory activity of compound C-1 on A549, HepG2, HCT116 and U-2OS tumor cells is stronger than that of pterostilbene and 5-FU.

[0137] Although the present application has been described in detail with reference to the foregoing embodiments, it should be understood that modifications can be made to the foregoing embodiments, or additional implementations of the present application can be implemented, without departing from the spirit or scope of the application. Accordingly, the present application is not limited except as by the appended claims.

Claims

1. A pterostilbene piperidine amide derivative, characterized in that: The chemical structure of the pterostilbene piperidine amide derivatives is shown in formula (1): In Formula 1: The R is one of phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3, 4-dimethoxyphenyl, 2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, and 4-fluorophenyl.

2. A method for preparing a pterostilbene piperidine amide derivative, characterized in that: The pterostilbene piperidine amide derivative according to claim 1 is prepared, comprising: Pterostilbene reacted with ethyl bromoacetate in the presence of anhydrous potassium carbonate to produce intermediate 2. Phosphorus oxychloride was added dropwise to the solution of intermediate 2 under ice bath, and the mixture was stirred to react to obtain intermediate 3; Under alkaline conditions, intermediate 3 undergoes hydrolysis to obtain intermediate 4; Intermediate 4 and piperidine undergo a first amide condensation reaction in the presence of a first condensation catalyst to obtain intermediate 5; Intermediate 5 and 2-methyl-2-butene undergo aldehyde oxidation reaction in the presence of an oxidant to obtain intermediate 6; The intermediate 6 and the amino compound undergo a second amide condensation reaction in the presence of a second condensation catalyst to obtain a pterostilbene piperidine amide derivative; The synthetic route is as follows: In Formula 1: R is one of phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3, 4-dimethoxyphenyl, 2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, and 4-fluorophenyl; The amino compound is aniline, 4-methylaniline, 4-trifluoromethylaniline, 4-methoxyaniline, 3, 4-dimethoxyaniline, 2-fluoro-4-methoxyaniline, 2-fluoroaniline, 3-fluoroaniline, and 4-fluoroaniline.

3. The method for preparing the pterostilbene piperidine amide derivatives according to claim 2, wherein: The reaction between pterostilbene and ethyl bromoacetate is a solution reaction, the solvent used is acetonitrile, and the molar ratio of the pterostilbene, anhydrous potassium carbonate and ethyl bromoacetate is 1:1-1.5:1-1.

5.

4. The method for preparing the pterostilbene piperidine amide derivatives according to claim 2, wherein: The solution of the intermediate 2 is a DMF solution of the intermediate 2, and the molar ratio of the intermediate 2 to phosphorus oxychloride is 1:1.2-1.

5.

5. The method for preparing the pterostilbene piperidine amide derivatives according to claim 2, wherein: In the hydrolysis reaction, the solvent used is an 8-10% ethanol solution by mass, and the amount of the 8-10% ethanol solution by mass is 4-5 mL per mmol of intermediate 3; the base used is a 10% sodium hydroxide solution by mass, and the amount of the 10% sodium hydroxide solution by mass is 2 mL per mmol of intermediate 3.

6. The method for preparing the pterostilbene piperidine amide derivatives according to claim 2, wherein: In the first amide condensation reaction, the reaction solvent is DMF; the first condensation catalyst is HATU and DIPEA, the molar ratio of the intermediate 4, piperidine, HATU and DIPEA is 1:1.2-1.4:1.5:1.5, and the temperature of the first amide condensation reaction is room temperature; The aldehyde oxidation reaction is a solution reaction, the solvent used is acetone, the oxidant is an aqueous solution of NaClO2 and NaH2PO2·2H2O, the molar ratio of the intermediate 5, 2-methyl-2-butene, NaClO2, and NaH2PO2·2H2O is 1:4-4.5:8:8, and the temperature of the aldehyde oxidation reaction is room temperature; The second amide condensation reaction is a solution reaction, the solvent used is DCM, the second condensation catalyst is DMAP and EDC·HCl; the molar ratio of the intermediate 6, the amino compound, DMAP and EDC·HCl is 1:2-2.5:1.2:1.2, and the temperature of the second amide condensation reaction is room temperature.

7. A pharmaceutical composition, characterized in that: A pharmaceutically acceptable dosage form comprising a pterostilbene piperidine amide derivative prepared by the preparation method according to any one of claims 2 to 6 as an active ingredient and a pharmaceutically acceptable carrier; The dosage form is any one of tablets, pills, capsules, powders, syrups, liquids, suspensions and injections.

8. Use of the pterostilbene piperidine amide derivatives according to claim 1 or the pharmaceutical composition according to claim 7 in the preparation of anticancer cell drugs, When R is phenyl, the cancer is lung cancer, liver cancer, or colon cancer; When R is 4-methylphenyl, 4-methoxyphenyl, 3-fluorophenyl, or 4-fluorophenyl, the cancer is lung cancer or colon cancer; When R is 4-trifluoromethylphenyl, 2-fluoro-4-methoxyphenyl, or 2-fluorophenyl, the cancer is colon cancer; When R is 3,4-dimethoxyphenyl, the cancer is lung cancer.

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