Pterostilbene derivative and application thereof in preparation of medicine for treating and / or preventing related diseases caused by oxidative stress

Abstract

The invention belongs to the technical field of biological medicines, and provides a pterostilbene derivative and application thereof in preparation of medicines for treating and / or preventing related diseases caused by oxidative stress. The chemical structures of the pterostilbene derivative are as shown in formulas (I)-(III). The scavenging effects of the obtained derivative on free radicals such as DPPH., O2. And ABTS +. And the total reducing capacity of the derivative are detected respectively. In the aspects of DPPH, total reducing capacity and the like, the scavenging capacity of some derivatives is equivalent to that of pterostilbene or vitamin C. The scavenging efficacy of the derivatives 2a, 4a, 4c, 4e, 4h, 4i and 4m-4p on O2-free radicals is equivalent to that of pterostilbene or vitamin C; the removal effect of the derivative 2b on ABTS < + > is equivalent to that of vitamin C and is superior to that of pterostilbene. The pterostilbene derivative has a potential application prospect in the aspect of preparing the antioxidant. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and in particular relates to a preparation method of a pterostilbene analogue and an application thereof in antioxidant activity. Background Art

[0002] Oxidative stress (OS) refers to the phenomenon that the imbalance of reactive oxygen and antioxidant levels in animals triggers lipid peroxidation and produces a large amount of peroxide. Free radicals are a class of chemical substances containing unpaired electrons. They are highly active and easily react with active ingredients in cells. Excessive free radical concentrations in the body can lead to a large accumulation of reactive oxygen and reactive nitrogen in cells, leading to oxidative damage. Excessive free radicals can induce the denaturation of intracellular lipids, proteins, DNA and other biological macromolecules, causing cell dysfunction such as inflammation and necrosis, further endangering the body's normal physiological and metabolic functions.

[0003] Free radicals play an important role in the occurrence and development of cancer. By scavenging free radicals, DNA damage can be reduced and the proliferation and invasion of tumor cells can be inhibited. For example, certain antioxidants (such as vitamin E, vitamin C, etc.) have been studied as potential anticancer drugs, which can scavenge free radicals and inhibit the growth of tumor cells. Diabetic patients usually have higher levels of free radicals, which aggravates insulin resistance and vascular damage. Free radical scavengers help alleviate these pathological processes. Existing free radical scavengers have been used to prevent and treat chronic complications of diabetes, especially vascular complications, showing good application prospects. The occurrence of cardiovascular diseases is closely related to free radical-mediated oxidative stress. Free radical scavengers can protect the cardiovascular system from oxidative damage. For example, some antioxidant enzymes have been used in the treatment and prevention of cardiovascular diseases, and they can efficiently scavenge oxygen free radicals in the body. Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are related to free radical-mediated neuronal damage. Free radical scavengers help protect neurons and slow down disease progression. Some studies have shown that compounds with free radical scavenging ability (such as chitosan oligosaccharides, DMSO, etc.) show potential application value in the treatment of neurodegenerative diseases.

[0004] Free radical scavenging compounds can directly react with free radicals and convert them into harmless or low-activity substances, thereby reducing the damage of free radicals to tissues. They can also reduce inflammatory responses by regulating inflammation-related signaling pathways and the production of cytokines. For example, they can inhibit the activation of inflammation-related transcription factors such as NF-κB and reduce the release of inflammatory factors, thereby inhibiting the development of inflammatory responses.

[0005] Natural plants have the advantages of high efficiency and low toxicity, and their extracts have both antioxidant properties and free radical scavenging effects. Therefore, natural plants have become an important resource for natural antioxidants. Pterostilbene (PTE) is a natural polyphenol substance widely found in plants such as rosewood, blueberries, nuts and grape leaves. In terms of chemical structure, pterostilbene contains an additional dimethoxy group and is a homologue of resveratrol. Pterostilbene itself has a certain ability to scavenge free radicals and improves the body's antioxidant level by enhancing the activity of antioxidant enzymes. In recent years, pterostilbene has performed more prominently in cardiovascular diseases, metabolic diseases and nervous system diseases. The above findings suggest that PTE can be used as an effective antioxidant active lead drug molecule. Summary of the invention

[0006] The present invention uses pterostilbene as a structural skeleton and provides a method for preparing pterostilbene analogs, aiming to broaden the structural types of pterostilbene derivatives. At the same time, the target product is evaluated for its effects on DPPH·, superoxide anion, ABTS + ·'s scavenging ability and total reducing capacity, in order to explore the application of pterostilbene derivatives in antioxidant capacity.

[0007] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0008] The general chemical structures of pterostilbene derivatives are shown in the following formulas (I), (II) and (III):

[0009]

[0010] Wherein, R1 is one of the following structural formulas:

[0011]

[0012] Wherein, R2 is one of the following structural formulas:

[0013]

[0014] Wherein, R3 is one of the following structural formulas:

[0015]

[0016] The preparation route of the pterostilbene derivative of the present invention is as follows:

[0017]

[0018] Preferably, the experimental steps are as follows:

[0019] (i) Pterostilbene is dissolved in a dichloromethane solution, a triethylamine solution is added dropwise, and chloroacetyl chloride is slowly added dropwise at 0°C, and then the reaction system is stirred at room temperature for 4-6 hours. After the reaction is complete, extraction is performed with dichloromethane, the organic layers are combined, and the organic layers are washed with distilled water and saturated brine respectively, the organic phase is dried over anhydrous Na2SO4, and the dichloromethane is evaporated under reduced pressure. An appropriate amount of n-hexane is added dropwise until a yellow solid, namely the intermediate compound 1, is precipitated, and the operation is repeated for 2-3 times of recrystallization.

[0020] (ii) Compound 1 and potassium carbonate are dissolved in acetonitrile, a nitrogen heterocyclic compound is added dropwise thereto, and the mixture is heated under reflux at 80° C. for 8 h. After the reaction of the raw materials is complete, the acetonitrile is removed under reduced pressure, the mixture is extracted with ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and separated and purified by rapid column chromatography (dichloromethane and methanol as eluents) to obtain compounds 2a and 2b of formula (I).

[0021] (iii) Pterostilbene and potassium carbonate were dissolved in acetonitrile, 3-bromopropyne was added dropwise while stirring, and the mixture was heated to 80°C in an oil bath and reacted for 12 hours. After the reaction was completed, the acetonitrile was evaporated under reduced pressure, the mixture was spin-dried, and a suitable amount of n-hexane was used to slurry the mixture, and the mixture was filtered to obtain a dark yellow solid, which was intermediate 3.

[0022] (iv) Add toluene solution to the intermediate 3 and copper thiophene-2-carboxylate, then add sulfonyl azide or benzyl azide compounds, and continue stirring for 1-2 hours. After the reaction is completed, extract with ethyl acetate, wash with distilled water and saturated brine respectively, combine the organic layers, dry over anhydrous Na2SO4, remove ethyl acetate under reduced pressure, separate and purify by rapid column chromatography (petroleum ether and ethyl acetate as eluents), and obtain derivatives 4a-4p described in formula (II).

[0023] (v) Pterostilbene, potassium carbonate and potassium iodide were dissolved in acetonitrile, and then 1,3-dibromopropane was added, heated to 80°C, and stirred for 12 hours. After the raw materials were completely reacted, they were extracted with dichloromethane, the organic layers were combined, and the dichloromethane was removed by decompression. The crude product was eluted by flash chromatography (petroleum ether and ethyl acetate as eluents) to obtain intermediate 5.

[0024] (vi) The intermediate 5, potassium hydroxide and an amine compound are dissolved in acetonitrile, stirred at 80°C, and reacted for 12 hours. After the reaction is completed, the acetonitrile is evaporated under reduced pressure. The derivatives 6a-6n of formula (III) are obtained by separation and purification by rapid column chromatography (petroleum ether and ethyl acetate as eluents).

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The present invention provides a method for preparing a pterostilbene derivative and its application in antioxidant activity. The obtained derivatives were tested for DPPH·, O2- ·ABTS + · free radical scavenging effect, as well as its total reducing capacity. In terms of DPPH free radical and total reducing capacity, it was found that some derivatives had scavenging ability comparable to that of pterostilbene or vitamin C. Derivatives 2a, 4a, 4c, 4e, 4h, 4i and 4m-4p had no significant difference in the scavenging effect on O 2- The free radical scavenging effect is equivalent to that of PTE or Vc; the scavenging effect of derivative 2b on ABTS free radicals is equivalent to that of vitamin C and is better than that of PTE. The pterostilbene derivative has potential application prospects in the preparation of antioxidants. DETAILED DESCRIPTION

[0027] The present invention is further described in conjunction with the implementation modes. The following implementation modes are only used to more clearly illustrate the technical solutions of the present invention, and cannot be used to limit the protection scope of the present invention.

[0028] Example 1

[0029] 1:

[0030] Pterostilbene (1000 mg, 3.9 mM), triethylamine (473.6 mg, 4.7 mM) and dichloromethane solution were added to a round-bottom flask in sequence. The system was placed at 0°C, and chloroacetyl chloride (660.7 mg, 5.9 mM) was slowly added dropwise, and then the temperature was raised to room temperature and stirred for 4-6 hours. After the reaction was complete by TLC thin layer monitoring, dichloromethane was used for extraction (3×30 mL), the organic layers were combined, washed with distilled water and saturated brine, the organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure. An appropriate amount of n-hexane was added dropwise until a yellow solid was precipitated, and recrystallization was repeated 2-3 times to obtain intermediate 1.

[0031] (E)-4-(3,5-Dimethoxybenzoate)-2-chloroacetic acid phenyl (1): Yield: 97%. 1 H NMR (400MHz, CDCl3) δ (ppm): 7.51 (d, J = 8.8Hz, 2H), 7.13 (d, J = 8.7Hz, 2H), 7.06 (d, J = 8.3Hz, 1H) ,6.97(d,J=16.4Hz,1H),6.66(d,J=2.3Hz,2H),6.41(t,J=4.5Hz,1H),4.31(s,2H),3.83(s,6H). 13 C NMR (75MHz, CDCl3) δ (ppm): 165.9, 161.0 (2C), 149.7, 139.0, 135.5, 129.3, 127.9, 127.6 (2C), 121.4 (2C), 104.6 (2C), 100.1, 55.4 (2C), 40.9.

[0032] Example 2

[0033] 2a:

[0034] Intermediate 1 (50.0 mg, 0.15 mM), anhydrous potassium carbonate (31.2 mg, 0.22 mM) and N-methylpiperazine (18.1 mg, 0.18 mM) were placed in a 20 mL Shrek tube, acetonitrile (2 mL) was added to dissolve, and the reaction system was refluxed at 80 ° C for 12 h. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate (3×10 mL), washed with distilled water and saturated brine, and the EtOAc layer was dried over anhydrous Na2SO4. The crude product was eluted by silica gel column chromatography (dichloromethane: methanol = 80: 1) and concentrated under reduced pressure to obtain derivative 2a.

[0035] (E)-4-(3,5-Dimethoxybenzoyl)benzene-2-(4-methylpiperazin-1-yl)acetic acid (2a): white solid, yield 73%. 1 H NMR (300MHz, CDCl3) δ (ppm): 7.48 (d, J = 8.7Hz, 2H), 7.08 (d, J = 8.7Hz, 2H), 6.99 (t, J = 9.8Hz, 2H), 6.64 (d, J = 2.3Hz, 2H),6.39(t,J=4.5Hz,1H),6.37(t,J=4.5Hz,1H),3.82(s,6H),3.49(s,2H),2.75(s,4H),2.59(s,4H),2.34(s,3H). 13 C NMR (75MHz, CDCl3) δ (ppm): 168.1, 160.9 (2C), 149.8, 139.1, 135.1, 129.0, 127.5 (2C),121.7(2C),104.6(2C),100.1,59.2,55.4(2C),54.6(2C),52.6(2C),45.7.

[0036] Example 3

[0037] 2b:

[0038] The synthesis method was the same as that of Example 2, except that morpholine was used instead of N-methylpiperazine. The target product 2b was obtained by eluting with silica gel column chromatography (dichloromethane:methanol=80:1).

[0039] (E)-4-(3,5-Dimethoxyphenyl)benzimidazole-2-carboxamide (2b): white solid with a yield of 80%. 1H NMR (300MHz, CDCl3) δ (ppm): 7.51 (d, J = 8.7Hz, 2H), 7.10 (d, J = 8.7Hz, 2H), 7.00 (t, J = 9.5Hz, 2H), 6.66 (d, J =2.2Hz,2H),6.39(t,J=4.5Hz,1H),3.83(s,6H),3.79(t,J=9.4Hz,4H),3.49(s,2H),2.69(t,J=9.4Hz,4H). 13 C NMR (75MHz, CDCl3) δ (ppm): 160.9 (2C), 155.7, 139.7, 130.2, 130.1, 129.9, 128.7, 12 8.1(2C),126.5,115.7,115.6(2C),115.5,104.4(2C),99.6,55.4(2C),42.58,34.6.

[0040] Example 4

[0041] 3:

[0042] Pterostilbene (1000 mg, 3.9 mM), anhydrous potassium carbonate (808.5 mg, 5.8 mM) and acetonitrile solution were added to a round-bottom flask in sequence, followed by dropwise addition of 3-bromopropyne (556.7 mg, 4.7 mM) under stirring, and the temperature was raised to 80 °C for stirring and reaction for 12 h. After the reaction was complete as monitored by TLC thin layer, DCM was used for extraction (3 × 30 mL), the organic layers were combined, washed with distilled water and saturated brine, the organic phase was dried over anhydrous Na2SO4, and dichloromethane was removed under reduced pressure. An appropriate amount of n-hexane was added dropwise, stirred and slurried, and suction filtered to obtain intermediate 3.

[0043] (E)-1,3-Dimethoxy-5-(4-(prop-2-yn-1-yloxy)phenylvinyl)benzene (3): dark yellow solid, yield 91%. 1 H NMR (300MHz, CDCl3) δ (ppm): 7.45 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 16.2 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 16. 3Hz, 1H), 6.66 (d, J = 2.3Hz, 2H), 6.40 (t, J = 4.5Hz, 1H), 4.71 (d, J = 2.3Hz, 2H), 3.83 (s, 6H), 2.69 (t, J = 4.8Hz, 4H). 13C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 157.3, 139.6, 130.8, 128.6, 127.8 (2C), 127.1, 115.1 (2C), 104.4 (2C), 99.7, 78.5, 75.7, 55.8, 55.3 (2C).

[0044] Example 5

[0045] 4a:

[0046] Intermediate 3 (50.00 mg, 0.17 mM) and copper thiophene-2-carboxylate (9.72 mg, 0.05 mM) were added to a dry toluene solution (2 mL), followed by addition of p-toluenesulfonyl azide, and continued stirring at room temperature for 1-2 h. After the reaction was completed, it was extracted with ethyl acetate (3×10 mL), washed with distilled water and saturated brine, the EtOAc layer was dried over anhydrous Na2SO4, ethyl acetate was removed under reduced pressure, and the target product 4a was obtained by separation and purification by flash column chromatography (petroleum ether: ethyl acetate = 10:1).

[0047] (E)-4-((4-(3,5-dimethoxyphenyl)phenoxy)methyl)-1-methanesulfonyl-1H-1,2,3-triazole (4a): white solid, yield 95%. 1 H NMR (300MHz, CDCl3) δ (ppm): 7.43 (d, J = 8.8Hz, 2H), 7.39 (d, J = 8.7Hz, 2H), 7.00 (d, J = 16.2Hz, 1H), 6.95 (d, J = 6.7Hz ,2H),6.90(d,J=14.0Hz,1H),6.64(d,J=2.3Hz,2H),6.38(t,J=4.5Hz,1H),5.20(s,2H),3.83(s,6H),2.45(s,3H). 13 C NMR (75MHz, CDCl3) δ (ppm): 160.9 (2C), 157.6, 147.5, 143.9, 139.5, 132.8, 130.8, 130.5 (2C), 1 28.8(2C),128.4,127.9(2C),127.2,122.5,114.9(2C),104.4(2C),99.7,61.6,55.3(2C),21.8.

[0048] Example 6

[0049] 4b:

[0050] The synthesis method is the same as that of Example 5, except that 4-acetamidobenzenesulfonyl azide is used instead of p-toluenesulfonyl azide. The target product 4b is obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=4:1).

[0051] (E)-N-(4-((4-((4-(3,5-dimethoxyphenyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)sulfonyl)phenyl)acetamide (4b): white solid, yield 93%. 1 HNMR (300MHz, CDCl3) δ (ppm): 10.63 (s, 1H), 9.01 (s, 1H), 8.10 (d, J = 8.8Hz, 2H), 7.94 (d, J = 8.8Hz, 2H), 7.56 (d, J = 8.5H z,2H),7.23(d,J=16.4Hz,2H),7.05(d,J=8.6Hz,2H),6.75(s,2H),6.40(s,1H),5.21(s,2H),3.78(s,6H),2.11(s,3H). 13 C NMR(75MHz, CDCl3)δ(ppm):168.8,161.1(2C),158.2,143.4,142.2,139.8(2C),130.4,128.9,128 .3(2C),126.8,126.5(2C),121.6,118.2(2C),115.4(2C),104.6(2C),99.9,61.2,55.6(2C),24.5.

[0052] Example 7

[0053] 4c:

[0054] The synthesis method was the same as that of Example 5, except that 4-fluorobenzenesulfonyl azide was used instead of p-toluenesulfonyl azide. The target product 4c was obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=10:1).

[0055] (E)-4-((4-(3,5-dimethoxyphenyl)phenoxy)methyl)-1-((4-fluorophenyl)sulfonyl)-1H-1,2,3-triazole (4c): white solid, yield 94%. 1H NMR (300MHz, CDCl3) δ (ppm): 8.18 (s, 1H), 8.12 (m, 2H), 7.40 (d, J = 8.8Hz, 2H), 6.98 (t, J = 17.1Hz, 2H), 6.98 (d, J = 16.3Hz, 1 H), 6.90 (d, J = 5.8Hz, 2H), 6.86 (d, J = 13.2Hz, 1H), 6.61 (d, J = 2.3Hz, 2H), 6.35 (t, J = 4.5Hz, 1H), 5.16 (s, 2H), 3.78 (s, 6H). 13 C NMR (75MHz, CDCl3) δ (ppm): 168.7, 165.2, 160.9 (2C), 157.5, 144.1, 139.5, 132.0, 131.9, 131.8, 131.7 ,130.8,128.4,127.9(2C),127.1,122.7,117.6,117.3,114.9(2C),104.4(2C),99.7,61.5,55.3(2C).

[0056] Example 8

[0057] 4d:

[0058] The synthesis method is the same as that of Example 5, except that 4-trifluoromethoxybenzenesulfonyl azide is used instead of p-toluenesulfonyl azide. The target derivative 4d is obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=10:1).

[0059] (E)-4-((4-(3,5-dimethoxyphenyl)phenoxy)methyl)-1-((4-(trifluoromethoxy)phenyl)sulfonyl)-1H-1,2,3-triazole (4d): white solid, yield 92%. 1 H NMR (300MHz, CDCl3) δ (ppm): 8.22 (s, 1H), 8.17 (d, J = 8.9Hz, 2H), 7.43 (d, J = 8.8Hz, 2H), 7.39 (d, J = 10.1Hz, 2H), 7.03 (d, J = 16.2 Hz,1H),6.94(d,J=5.7Hz,2H),6.90(d,J=13.2Hz,1H),6.64(d,J=2.3Hz,2H),6.38(t,J=4.5Hz,1H),5.19(s,2H),3.82(s,6H). 13C NMR (75MHz, CDCl3) δ (ppm): 160.9 (2C), 157.5, 154.4, 144.2, 139.4, 133.3, 131.2 (2C), 130 .9,128.3,127.9(2C),127.2,122.7,121.2,114.8(2C),104.1(2C),99.7,61.4,55.3(2C).

[0060] Example 9

[0061] 4e:

[0062] The synthesis method was the same as that of Example 5, except that 4-trifluoromethylbenzenesulfonyl azide was used instead of p-toluenesulfonyl azide. The target product 4e was obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=10:1).

[0063] (E)-4-((4-(3,5-dimethoxyphenyl)phenoxy)methyl)-1-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-1,2,3-triazole (4e): white solid, yield 95%. 1 H NMR (300MHz, CDCl3) δ (ppm): 9.17 (s, 1H), 8.48 (m, 4H), 7.41 (d, J = 8.8Hz, 2H), 7.23 (d, J = 16.4Hz, 1H), 7.07 (d, J = 9.9Hz, 2 H),7.03(d,J=4.4Hz,1H),7.07(d,J=4.8Hz,1H),6.76(d,J=2.2Hz,2H),6.40(t,J=4.4Hz,1H),5.23(s,2H),3.78(s,6H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.1 (2C), 158.2, 152.4, 142.1, 139.8, 130.4, 130.1, 129.5, 129.1, 128.9, 128 .3(2C),126.8,126.8(2C),126.4,125.5,125.4,125.4,125.3,122.8,115.4,104.6,99.9,61.2,55.6(2C).

[0064] Example 10

[0065] 4f:

[0066] The synthesis method is the same as that of Example 5, except that 4-bromobenzenesulfonyl azide is used instead of p-toluenesulfonyl azide. The target product 4f is obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=20:1).

[0067] (E)-1-((4-bromophenyl)sulfonyl)-4-((4-(3,5-dimethoxyphenylvinyl)phenoxy)methyl)-1H-1,2,3-triazole (4f): white colloid in nature, with a yield of 92%. 1 H NMR (300MHz, CDCl3) δ (ppm): 8.01 (s, 1H), 7.57 (d, J = 13.5Hz, 2H), 7.41 (d, J = 5.3Hz, 2H), 7.54 (d, J = 1.2Hz, 2H), 7.46 (d, J = 27.2Hz, 2H), 7. 23(d,J=16.4Hz,1H),7.05(d,J=8.6Hz,2H),7.03(d,J=8.1Hz,1H),6.75(d,J=2.3Hz,2H),6.39(t,J=4.5Hz,1H),5.21(s,2H),3.74(s,6H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.1 (2C), 158.2, 147.8, 142.1, 139.8, 131.1, 130.3, 130.1, 1 28.9,128.3(2C),128.2(2C),126.8,122.3,115.4(2C),104.6(2C),99.9,61.2,55.6(2C).

[0068] Embodiment 11

[0069] 4g:

[0070] The synthesis method is the same as that of Example 5, except that 4-tert-butylbenzenesulfonyl azide is used instead of p-toluenesulfonyl azide. Elution by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) gives 4 g of the target product.

[0071] (E)-1-[(4-(tert-Butyl)phenyl]sulfonyl]-4-[(4-(3,5-dimethoxyphenyl)phenoxy)methyl]-1H-1,2,3-triazole (4 g): white solid, yield 91%. 1H NMR (300MHz, CDCl3) δ (ppm): 7.36 (d, J = 8.8Hz, 2H), 7.18 (s, 1H), 6.97 (d, J = 16.2Hz, 1H), 6.84 (t, J = 10.1Hz, 2H), 6.80 (d, J = 6.7Hz, 1H), 6.58 (d, J = 2.3Hz, 2H), 6.30 (t, J = 5.4Hz, 1H), 4.02 (t, J = 12.6Hz, 1H), 4.12 (t, J = 12. 1Hz,1H),3.99(t,J=12.3Hz,1H),3.75(s,6H),2.20(m,1H),2.01(m,2H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.1 (2C), 158.2, 151.9, 145.0, 142.0, 139.8, 130.4, 130.0, 128. 9,128.3,126.8,125.7(2C),125.0(2C),115.4,104.6,99.7,61.1,55.6(2C),34.8,31.4(2C).

[0072] Example 12

[0073] 4h:

[0074] The synthesis method is the same as that of Example 5, except that 4-nitrobenzenesulfonyl azide is used instead of p-toluenesulfonyl azide. The target product 4h is obtained by eluting with silica gel column chromatography (petroleum ether: ethyl acetate = 5:1).

[0075] (E)-4-((4-(3,5-dimethoxyphenyl)phenoxy)methyl)-1-((4-nitrophenyl)sulfonyl)-1H-1,2,3-triazole (4h): yellow solid, yield 92%. 1 H NMR (300MHz, CDCl3) δ (ppm): 8.03 (s, 1H), 7.65 (d, J = 8.5Hz, 2H), 7.53 (d, J = 8.8Hz, 2H), 7.42 (d, J = 8.4Hz, 2H), 7.24 (d, J = 16.4Hz, 1H), 7. 34(d,J=8.6Hz,2H),7.02(d,J=7.9Hz,1H),7.03(d,J=8.1Hz,1H),6.75(d,J=2.3Hz,2H),6.40(t,J=4.5Hz,1H),5.21(s,2H),3.76(s,6H). 13C NMR (75MHz, CDCl3) δ (ppm): 161.1 (2C), 158.1, 147.1, 142.1, 139.8, 133.7, 130.4, 129. 9,128.9,128.3(2C),127.9(2C),126.8,115.4(2C),104.6(2C),99.7,61.1,55.6(2C).

[0076] Embodiment 13

[0077] 4i:

[0078] The synthesis method is the same as that of Example 5, except that 4-chlorobenzenesulfonyl azide is used instead of p-toluenesulfonyl azide. The target product 4i is obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=10:1).

[0079] (E)-1-(4-Chlorophenyl)sulfonyl-4-[(4-(3,5-dimethoxyphenyl)phenoxy)methyl]-1H-1,2,3-triazole (4i): yellow colloid in nature, with a yield of 95%. 1 H NMR (300MHz, CDCl3) δ (ppm): 8.01 (s, 1H), 7.82 (d, J = 8.2Hz, 2H), 7.70 (d, J = 8.4Hz, 1H), 7.54 (d, J = 8.8Hz, 2H), 7.23 (d, J = 16.4 Hz,1H),7.05(d,J=6.5Hz,2H),7.02(d,J=8.3Hz,2H),6.74(d,J=2.3Hz,3H),6.40(d,J=4.5Hz,1H),5.21(s,2H),3.77(s,6H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.2, 154.7, 147.7, 142.2, 139.8, 130.4, 128.9, 128.3(2C),127.4(2C),126.8,123.8(2C),115.4(2C),104.6(2C),99.9,61.2,55.6(2C).

[0080] Embodiment 14

[0081] 4j:

[0082] The synthesis method is the same as that of Example 5, except that 2-thiophenesulfonyl azide is used instead of p-toluenesulfonyl azide. The target product 4j is obtained by eluting with silica gel column chromatography (petroleum ether: ethyl acetate = 3:1).

[0083] (E)-4-((4-(3,5-dimethoxyphenyl)phenoxy)methyl)-1-(thiophen-2-ylsulfonyl)-1H-1,2,3-triazole (4j): yellow solid, yield 92%. 1 H NMR (300MHz, CDCl3) δ (ppm): 9.07 (s, 1H), 8.38 (d, J = 5.0Hz, 1H), 8.22 (dd, J = 3.9Hz, 1H), 7.52 (d, J = 6.6Hz, 2H), 7.36 (t, J = 8.9Hz, 1H), 7.2 3(d,J=16.4Hz,1H),7.05(d,J=8.9Hz,2H),7.02(d,J=6.2Hz,1H),6.75(d,J=2.3Hz,2H),6.40(d,J=2.2Hz,1H),5.21(s,2H),3.76(s,6H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.1 (2C), 158.1, 142.0, 139.8, 130.4, 129.9, 128.9, 128 .3(2C),126.9(2C),126.5(2C),126.3,115.4(2C),104.6(2C),99.9,61.1,55.6(2C).

[0084] Embodiment 15

[0085] 4k:

[0086] The synthesis method is the same as that of Example 5, except that 4-fluorobenzyl azide is used instead of p-toluenesulfonyl azide. The target product 4k is obtained by eluting with silica gel column chromatography (petroleum ether: ethyl acetate = 3:1).

[0087] (E)-4-((4-(3,5-dimethoxyphenyl)phenoxy)methyl)-1-(4-fluorobenzyl)-1H-1,2,3-triazole (4k): white solid, yield 96%. 1 H NMR (300MHz, CDCl3) δ (ppm): 7.44 (s, 1H), 7.36 (d, J = 11.8Hz, 2H), 7.18 (t, J = 13.9Hz, 2H), 6.98 (d, J = 8.5Hz, 2H ),6.89(d,J=10.8Hz,2H),6.55(d,J=2.3Hz,2H),6.29(t,J=4.5Hz,1H),5.40(s,2H),5.11(s,2H),3.74(s,6H). 13CNMR(75MHz, CDCl3)δ(ppm):164.5,161.2,160.9(2C),157.9,144.6,139.5,130.5,130.4,130.3,130.1,1 29.9,128.5,127.8(2C),126.9,122.5,116.3,116.0,115.0(2C),104.3(2C),99.6,62.1,55.3(2C),53.5.

[0088] Example 16

[0089] 4l:

[0090] The synthesis method is the same as that of Example 5, except that benzyl azide is used instead of p-toluenesulfonyl azide. The target product 41 is obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=3:1).

[0091] (E)-1-Phenyl-4-((4-(3,5-dimethoxyphenyl)phenoxy)methyl)-1H-1,2,3-triazole (41): Appears as flaky white solid with a yield of 92%. 1 H NMR (300MHz, CDCl3) δ (ppm): 8.34 (s, 1H), 7.59 (d, J = 8.8Hz, 2H), 7.41 (d, J = 5.3Hz, 2H), 7.37 (d, J = 7.8Hz, 2H), 7.28 (d, J = 16.4 Hz,1H),7.09(d,J=8.7Hz,2H),7.07(d,J=4.8Hz,1H),6.81(s,2H),6.45(t,J=2.3Hz,1H),3.82(s,6H),3.47(t,J=5.1Hz,1H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.1 (2C), 158.2, 134.4, 139.8, 136.4, 130.3, 129.2 (2C), 128.9 ,128.6,128.4(2C),128.3,126.8,125.1,115.4(2C),104.6(2C),99.9,61.5,55.6(2C),53.3.

[0092] Embodiment 17

[0093] 4m:

[0094] The synthesis method is the same as that of Example 5, except that 4-trifluoromethylbenzyl azide is used instead of p-toluenesulfonyl azide. The target product 4m is obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=5:1).

[0095] (E)-4-[(4-(3,5-dimethoxyphenyl)phenoxy)methyl]-1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazole (4m): white solid, yield 95%. 1 H NMR (300MHz, CDCl3) δ (ppm): 8.35 (s, 1H), 7.74 (d, J = 8.2Hz, 2H), 7.54 (d, J = 8.9Hz, 2H), 7.50 (d, J = 7.9Hz, 2H), 7.23 (d, J = 9.0Hz, 1H) ,7.04(d,J=9.0Hz,1H),7.01(d,J=6.7Hz,1H),6.75(d,J=2.3Hz,2H),6.40(t,J=4.5Hz,1H),5.18(s,2H),3.77(s,6H),3.39(s,1H). 13 CNMR(75MHz, CDCl3)δ(ppm):161.1(2C),158.2,143.5,141.1,139.8,130.4,129.3,129.1(2C),128.9,128.3(2C) ),126.8,126.3,126.2,126.1,126.1,126.0,125.5,122.7,115.4(2C),104.6(2C),99.9,61.5,55.6(2C),52.6.

[0096] Embodiment 18

[0097] 4n:

[0098] The synthesis method is the same as that of Example 5, except that 4-chlorobenzyl azide is used instead of p-toluenesulfonyl azide. The target product 4n is obtained by eluting with silica gel column chromatography (petroleum ether: ethyl acetate = 5:1).

[0099] (E)-1-(4-chlorobenzyl)-4-((4-(3,5-dimethoxyphenyl)phenoxy)methyl)-1H-1,2,3-triazole (4n): white colloid, yield 96%. 1H NMR (300MHz, CDCl3) δ (ppm): 8.30 (s, 1H), 7.53 (d, J = 8.6Hz, 2H), 7.48 (d, J = 8.4Hz, 2H), 7.35 (d, J = 8.5Hz, 2H), 7.23 (d, J = 14.2 Hz,1H),7.04(d,J=7.8Hz,2H),7.02(d,J=5.9Hz,1H),6.75(d,J=2.4Hz,2H),6.40(t,J=2.6Hz,1H),5.62(s,2H),3.77(s,6H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.1 (2C), 158.2, 143.4, 139.8, 135.4, 133.4, 130.3 (2C), 129. 2(2C),128.9,128.3(2C),126.8,125.4,115.4(2C),104.6(2C),99.9,61.5,55.6(2C),52.5.

[0100] Embodiment 19

[0101] 4o:

[0102] The synthesis method is the same as that of Example 5, except that 4-methylbenzyl azide is used instead of p-toluenesulfonyl azide. The target product 4o is obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=5:1).

[0103] (E)-4-((4-(3,5-dimethoxyphenyl)phenoxy)methyl)-1-(4-methylphenyl)-1H-1,2,3-triazole (4o): pale yellow solid, yield 93%. 1 H NMR (300MHz, CDCl3) δ (ppm): 8.26 (s, 1H), 7.55 (d, J = 8.9Hz, 2H), 7.22 (d, J = 10.0Hz, 2H), 7.18 (d, J = 5.9Hz, 2H), 7.07 (d, J = 3.7Hz, 2H), 7.03 ( d,J=4.3Hz,1H),6.77(s,2H),6.41(d,J=2.1Hz,1H),6.40(t,J=2.6Hz,1H),5.56(s,2H),5.16(s,2H),3.78(s,6H),3.43(s,2H),2.27(s,3H). 13C NMR (75MHz, CDCl3) δ (ppm): 161.1 (2C), 158.2, 143.3, 139.8, 138.1, 133.4, 130.3, 129.7 (2C) ,128.9,128.4(2C),128.3,126.8,125.0,115.4(2C),104.6(2C),99.9,61.5,55.6(2C),53.1.

[0104] Embodiment 20

[0105] 4p:

[0106] The synthesis method is the same as that of Example 5, except that 4-nitrobenzyl azide is used instead of p-toluenesulfonyl azide. The target product 4p is obtained by eluting with silica gel column chromatography (petroleum ether: ethyl acetate = 3:1).

[0107] (E)-4-[(4-(3,5-dimethoxyphenyl)phenoxy)methyl]-1-(4-nitrophenyl)-1H-1,2,3-triazole (4p): yellow solid, yield 92%. 1 H NMR (300MHz, CDCl3) δ (ppm): 8.38 (s, 1H), 8.23 ​​(d, J = 8.9Hz, 2H), 7.56 (d, J = 2.7Hz, 2H), 7.52 (d, J = 2.7Hz, 2H), 7.23 (d, J = 16.4Hz, 1H), 7.05 (d,J=8.8Hz,2H),7.03(d,J=8.3Hz,1H),6.75(d,J=2.3Hz,2H),6.40(t,J=2.6Hz,1H),5.81(s,2H),5.19(s,2H),3.77(s,6H),3.42(s,2H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.1 (2C), 158.2, 147.6, 143.8, 143.6, 139.8, 130.4, 129.4 (2C), 1 28.9,128.3(2C),126.8,125.6,124.3(2C),115.4(2C),104.6(2C),99.8,61.5,55.6(2C),52.6.

[0108] Embodiment 21

[0109] 5:

[0110] Pterostilbene (50.0 mg, 0.19 mM), 1,3-dibromopropane (46.4 mg, 0.23 mM), anhydrous potassium carbonate (40.4 mg, 0.29 mM) and potassium iodide (9.7 mg, 0.06 mM) were placed in a 20 mL Shrek tube, acetonitrile (2 mL) was added to dissolve, and the reaction system was refluxed at 80 ° C for 12 h. After the reaction was completed, it was cooled to room temperature, extracted with EtOAc (3×10 mL), washed with distilled water and saturated brine, and the EtOAc layer was dried over anhydrous Na2SO4, and eluted by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain intermediate 5.

[0111] (E)-1-(4-(3-bromopropoxy)phenylvinyl)-3,5-dimethoxybenzene (5): yellow-white solid, yield 90%. 1 H NMR (300MHz, CDCl3) δ (ppm): 7.46 (d, J = 8.7Hz, 2H), 7.06 (d, J = 16.2Hz, 1H), 6.95 (d, J = 16.2Hz, 1H), 6.92 (d, J = 8.7Hz, 1H), 6.68 (d,J=2.3Hz,2H),6.41(t,J=2.2Hz,1H),4.13(t,J=5.8Hz,2H),3.85(s,6H),3.63(t,J=6.4Hz,2H),2.34(quint,J=6.1Hz,2H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.5, 139.7, 130.2, 128.7, 127.9 (2C), 126.7, 114.8 (2C), 104.4 (2C), 99.7, 65.4, 55.4 (2C), 32.4, 30.1.

[0112] Embodiment 22

[0113] 6a:

[0114] Intermediate 5 (50.0 mg, 0.13 mM), potassium hydroxide (11.2 mg, 0.20 mM) and 5-methoxyindole (22.9 mg, 0.15 mM) were added to a 20 mL Shrek tube and dissolved with acetonitrile (2 mL), and then the reaction system was stirred at 80 ° C for 12 h. After the reaction was completed, acetonitrile was evaporated under reduced pressure, and the target product 6a was obtained by rapid column chromatography separation and purification (petroleum ether: ethyl acetate = 50: 1).

[0115] (E)-1-(3-(4-(3-)dimethoxyphenylvinyl)phenoxy)propyl)-5-methoxy-1H-indole (6a): colorless oily liquid, yield 94%.1 H NMR (300MHz, CDCl3) δ (ppm): 7.61 (d, J = 8.7Hz, 2H), 7.43 (d, J = 8.9Hz, 1H), 7.29 (d, J = 2 .4Hz,1H),7.23(d,J=17.6Hz,1H),7.21(d,J=3.1Hz,1H),7.10(d,J=17.6Hz,1H),7.06( d,J=8.7Hz,1H),7.03(d,J=8.7Hz,2H),6.85(d,J=2.2Hz,2H),6.58(m,2H),4.49(t,J=6 .5Hz,2H),4.03(t,J=6.5Hz,2H),4.03(s,3H),4.01(s,6H),2.43(quint,J=6.1Hz,2H). 13 CNMR(75MHz, CDCl3)δ(ppm):161.0(2C),158.5,154.1,139.7,131.3,130.2,129.0,128.7(2C),127.9(2 C),126.7,114.8(2C),112.0,110.1,104.4(2C),102.6,100.9,99.7,64.3,55.9,55.4(2C),42.9,29.9.

[0116] Embodiment 23

[0117] 6b:

[0118] The synthesis method is the same as that of Example 22, except that 5-methylindole is used instead of 5-methoxyindole. The target product 6b is obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=30:1).

[0119] (E)-1-(3-(4-(3-)dimethoxyphenylvinyl)phenoxy)propyl)-5-methyl-1H-indole (6b): colorless oily liquid, yield 96%. 1 H NMR (300MHz, CDCl3) δ (ppm): 7.50 (m, 3H), 7.31 (d, J = 8.4Hz, 1H), 7.11 (d, J = 16.4Hz, 1H), 7.08 (m, 2H), 6.97 (d, J = 16.4Hz, 1H), 6.91 (d, J = 8.7H z,2H),6.72(d,J=2.2Hz,2H),6.45(m,2H),4.37(t,J=6.5Hz,2H),3.89(t,J=6.5Hz,2H),3.88(s,6H),2.51(s,3H),2.30(quint,J=6.1Hz,2H).13 C NMR (75MHz, CDCl3) δ (ppm): 161.1 (2C), 158.6, 139.7, 134.4, 130.2, 129.0, 128.8, 128.6, 128.3, 127.9 ( 2C),126.7,123.2,120.7,114.8(2C),109.1,104.4(2C),100.8,99.7,64.4,55.4(2C),42.8,29.9,21.5.

[0120] Embodiment 24

[0121] 6c:

[0122] The synthesis method is the same as that of Example 22, except that 5-nitroindole is used instead of 5-methoxyindole. The target product 6c is obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=15:1).

[0123] (E)-1-(3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl)-5-nitro-1H-indole (6c): yellow solid, yield 92%. 1 H NMR (300MHz, CDCl3) δ (ppm): 8.57 (d, J = 2.2Hz, 1H), 8.07 (dd, J = 9.2, 2.2Hz, 1H), 7.44 (d,J=8.3Hz,2H),7.37(d,J=9.1Hz,1H),7.24(d,J=3.3Hz,1H),7.04(d,J=16.2Hz,1H ),6.91(d,J=16.2Hz,1H),6.86(d,J=8.3Hz,2H),6.66(m,3H),6.39(t,J=2.2Hz,1H), 4.43(t,J=6.6Hz,2H), 3.89(t,J=5.6Hz,2H), 3.83(s,6H), 2.31(quint,J=6.1Hz,2H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.2, 141.6, 139.6, 138.9, 131.3, 130.4, 128.5, 127.9 (2C), 127.8,126.9,118.3,117.3,114.7,109.2,104.4(2C),104.2,99.7,64.0,55.4(2C),43.3,29.8,29.7.

[0124] Embodiment 25

[0125] 6d:

[0126] The synthesis method is the same as that of Example 22, except that 6-chloroindole is used instead of 5-methoxyindole. The target product 6d is obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=20:1).

[0127] (E)-6-Chloro-1-[3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl]-1H-indole (6d): bright yellow solid, yield 90%. 1 H NMR (300MHz, CDCl3) δ (ppm): 7.54 (d, J = 8.4Hz, 1H), 7.46 (d, J = 8.7Hz, 2H), 7.38 (m, 1H), 7.0 9(d,J=8.7Hz,1H),7.08(d,J=16.6Hz,1H),7.07(d,J=1.8Hz,1H),6.93(d,J=16.6Hz,1H),6 .89(d,J=8.8Hz,2H),6.69(d,J=2.3Hz,2H),6.47(dd,J=3.1,0.9Hz,1H),6.42(t,J=2.2Hz, 1H), 4.33 (t, J = 6.6Hz, 2H), 3.87 (d, J = 6.6Hz, 2H), 3.85 (s, 6H), 2.26 (quint, J = 6.2Hz, 2H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.4, 139.7, 136.4, 130.3, 128.9, 128.7, 127.9 (2C), 127.6, 127.2,126.8,121.9,120.1,114.7(2C),109.5,104.4(2C),101.6,99.7,64.2,55.4(2C),42.9,29.7.

[0128] Embodiment 26

[0129] 6e:

[0130] The synthesis method is the same as that of Example 22, except that 5-bromoindole is used instead of 5-methoxyindole. The target product 6e is obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=20:1).

[0131] (E)-5-Bromo-1-[3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl]-1H-indole (6e): white solid, yield 88%. 1H NMR (300MHz, CDCl3) δ (ppm): 7.82 (d, J = 1.7Hz, 1H), 7.50 (d, J = 8.7Hz, 2H), 7.30 (m, 2H), 7.13 (d, J = 3.4Hz, 1H), 7.12 (d, J = 16.3Hz, 1H), 6.98 (d, J = 16.3H) z,1H),6.92(d,J=8.7Hz,2H),6.73(d,J=2.2Hz,2H),6.47(m,2H),4.39(t,J =6.6Hz,2H),3.91(t,J=6.6Hz,2H),3.90(s,6H),2.31(quint,J=6.2Hz,2H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.4, 139.7, 134.7, 130.32, 130.27, 129.3, 128.7, 127.9 (2C) ,126.8,124.4,123.5,114.7(2C),112.7,110.8,104.4(2C),101.0,99.7,64.1,55.4(2C),42.9,29.8.

[0132] Embodiment 27

[0133] 6f:

[0134] The synthesis method is the same as that of Example 22, except that 1,2,3,4-tetrahydroisoquinoline is used instead of 5-methoxyindole. The target product 6f is obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=10:1).

[0135] (E)-2-[3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl]-1,2,3,4-tetrahydroisoquinoline (6f): white solid, yield 94%. 1 H NMR (300MHz, CDCl3) δ (ppm): 7.45 (d, J = 8.7Hz, 2H), 7.16-7.12 (m, 3H), 7.08-7.03 (m, 2H), 6.94-6.89 (m, 3H), 6.67 (d, J = 2.3Hz, 2H), 6.39 (t, J = 2.2Hz, 1H),4.10(t,J=6.4Hz,2H),3.84(s,6H),3.68(s,2H),2.94(t,J=5.9Hz,2H ),2.78(t,J=5.9Hz,2H),2.72(t,J=7.2Hz,2H),2.10(quint,J=7.5Hz,2H). 13C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.9, 139.7, 134.8, 134.3, 129.8, 128.8, 128.7, 127.8 (2C), 1 26.6,126.5,126.2,125.6,114.8(2C),104.3(2C),99.6,66.3,56.3,55.4(2C),55.0,51.0,29.2,27.1.

[0136] Embodiment 28

[0137] 6g:

[0138] The synthesis method is the same as that of Example 22, except that p-aminoanisole is used instead of 5-methoxyindole. Elution by silica gel column chromatography (petroleum ether: ethyl acetate = 25:1) gives 6 g of the target product.

[0139] (E)-N-(3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl)-4-methoxyaniline (6 g): bright yellow solid, yield 83%. 1 H NMR (300MHz, CDCl3) δ (ppm): 7.45 (d, J = 8.7Hz, 2H), 7.05 (d, J = 16.3Hz, 1H), 6. 90(d,J=8.8Hz,2H),6.88(d,J=16.3Hz,1H),6.79(d,J=9.0Hz,2H),6.66(d,J= 2.4Hz,2H),6.61(d,J=8.9Hz,2H),6.38(t,J=2.2Hz,1H),4.11(t,J=5.9Hz,2H ),3.83(s,6H),3.75(s,3H),3.32(t,J=6.7Hz,2H),2.10(quint,J=6.2Hz,2H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.6, 152.1, 142.5, 139.7, 130.0, 128.7, 127.8 (2C), 126.6,115.0(2C),114.7(2C),114.2(2C),104.3(2C),99.6,66.1,55.8,55.4(2C),42.2,29.2.

[0140] Embodiment 29

[0141] 6h:

[0142] The synthesis method is the same as that of Example 22, except that 4-fluoroaniline is used instead of 5-methoxyindole. The target product 6h is obtained by eluting with silica gel column chromatography (petroleum ether: ethyl acetate = 20:1).

[0143] (E)-N-(3-(4-(3,5-dimethoxyphenylvinyl)phenoxy)propyl)-4-fluoroaniline (6h): bright yellow oily liquid with a yield of 81%. 1 H NMR (300MHz, CDCl3) δ (ppm): 7.45 (d, J = 8.7Hz, 2H), 7.05 (d, J = 16.3Hz, 1H), 6.94-6.87 (m, 5H), 6.66 (d, J = 2.3Hz, 2H), 6.57 (d, J = 9.0Hz, 1H), 6.56 (d, J = 9.0Hz, 1H), 6.39 (t, J = 2.2Hz, 1H), 4.11 (t, J = 5.8Hz, 2H), 3.84 (s, 6H), 3.32 (t, J = 6.6Hz, 2H), 2.10 (quint, J = 6.6Hz, 2H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.6, 157.4, 154.2, 144.61, 144.59, 139.7, 130.1, 128.7, 127 .9(2C),126.7,115.8,115.5,114.7(2C),113.6,113.5,104.4(2C),99.6,66.1,55.4(2C),41.9,29.0.

[0144] Embodiment 30

[0145] 6i:

[0146] The synthesis method is the same as that of Example 22, except that 4-nitroaniline is used instead of 5-methoxyindole. The target product 6i is obtained by eluting with silica gel column chromatography (petroleum ether: ethyl acetate = 15:1).

[0147] (E)-N-(3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl)-4-nitroaniline (6i): bright yellow solid, yield 87%. 1H NMR (300MHz, CDCl3) δ (ppm): 8.57 (d, J = 2.2Hz, 1H), 8.07 (dd, J = 9.2, 2.2Hz, 1H), 7.44 (d,J=8.3Hz,2H),7.37(d,J=9.1Hz,1H),7.24(d,J=3.3Hz,1H),7.04(d,J=16.2Hz,1H ),6.91(d,J=16.2Hz,1H),6.86(d,J=8.3Hz,2H),6.66(m,3H),6.39(t,J=2.2Hz,1H), 4.43(t,J=6.6Hz,2H), 3.89(t,J=5.6Hz,2H), 3.83(s,6H), 2.31(quint,J=6.1Hz,2H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.2, 141.6, 139.6, 138.9, 131.3, 130.4, 128.5, 127.9 (2C), 127.8,126.9,118.3,117.3,114.7,109.2,104.4(2C),104.2,99.7,64.0,55.4(2C),43.3,29.8,29.7.

[0148] Embodiment 31

[0149] 6j:

[0150] The synthesis method is the same as that of Example 22, except that pyrrole is used instead of 5-methoxyindole. The target product 6j is obtained by eluting with silica gel column chromatography (petroleum ether: ethyl acetate = 20:1).

[0151] (E)-1-(3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl)-1H-pyrrole (6j): white crystals with a yield of 95%. 1 HNMR (300MHz, CDCl3) δ (ppm): 7.46 (d, J = 8.7Hz, 2H), 7.07 (d, J = 16.2Hz, 1H), 6.94 (d, J = 16.2Hz, 1H), 6.90 (d, J = 8.7Hz, 2H), 6.68 (d, J = 2.1H z, 4H), 6.41 (t, J = 2.3Hz, 1H), 6.18 (t, J = 2.1Hz, 2H), 4.14 (t, J = 6.7Hz, 2H), 3.92 (t, J = 5.8Hz, 2H), 3.92 (s, 6H), 2.23 (quint, J = 6.2Hz, 2H). 13C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.6, 139.7, 130.2, 128.7, 127.9 (2C), 126. 7,120.8(2C),114.7(2C),108.2(2C),104.4(2C),99.7,64.3,55.4(2C),46.0,31.3.

[0152] Embodiment 32

[0153] 6k:

[0154] The synthesis method is the same as that of Example 22, except that pyrazole is used instead of 5-methoxyindole. The target product 6k is obtained by eluting with silica gel column chromatography (petroleum ether: ethyl acetate = 1:2).

[0155] (E)-1-(3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl)-1H-imidazole (6k): white solid, yield 91%. 1 H NMR (300MHz, CDCl3) δ (ppm): 7.46 (s, 1H), 7.42 (d, J = 8.7Hz, 2H), 7.05-7.00 (m, 2H), 6.92-6.83 (m, 4H), 6.64 (d, J = 2.2 Hz,2H),6.37(t,J=2.2Hz,1H),4.16(t,J=6.8Hz,2H),3.89(t,J=5.7Hz,2H),3.81(s,6H),2.20(quint,J=6.2Hz,2H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.2, 139.6, 137.3, 130.4, 129.6, 128.6, 1 27.9(2C),126.8,119.0,114.7(2C),104.4(2C),99.7,63.8,55.4(2C),43.4,30.8.

[0156] Embodiment 33

[0157] 6l:

[0158] The synthesis method is the same as that of Example 22, except that piperidine is used instead of 5-methoxyindole. The target product 61 is obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=1:3).

[0159] (E)-1-(3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl)piperidine (61): white solid with a yield of 93%.1 H NMR (300MHz, CDCl3) δ (ppm): 7.43 (d, J = 8.7Hz, 2H), 7.04 (d, J = 16.3Hz, 1H), 6.90 (d, J = 16.3Hz, 1H), 6.89 (d, J = 8.8Hz, 2H), 6.65 (d, J=2.2Hz,2H),6.37(t,J=2.2Hz,1H),4.02(t,J=6.4Hz,2H),3.82(s,6H),2.54-2.34(m,6H),1.98(m,2H),1.60(m,4H),1.45(m,2H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.9, 139.7, 129.8, 128.8, 127.8 (2C), 126.4 ,114.7(2C),104.3(2C),99.6,66.6,56.0,55.4(2C),54.7(2C),26.8,26.0(2C),24.4.

[0160] Embodiment 34

[0161] 6m:

[0162] The synthesis method is the same as that of Example 22, except that morpholine is used instead of 5-methoxyindole. The target product 6m is obtained by eluting with silica gel column chromatography (petroleum ether: ethyl acetate = 1:1).

[0163] (E)-4-[3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl]morpholine (6m): white solid, yield 89%. 1 H NMR (300MHz, CDCl3) δ (ppm): 7.43 (d, J = 8.7Hz, 2H), 7.04 (d, J = 16.2Hz, 1H), 6.90 (d, J = 16.2Hz, 1H), 6.89 (d, J = 8.8Hz, 2H), 6.65 (d, J = 2.2 Hz,2H),6.38(t,J=2.2Hz,1H),4.03(t,J=6.3Hz,2H),3.82(s,6H),3.75(t,J=4.5Hz,4H),2.56-2.40(m,6H),1.97(quint,J=6.6Hz,2H). 13C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.8, 139.7, 129.9, 128.7, 127.8 (2C), 126 .5,114.7(2C),104.3(2C),99.6,67.0(2C),66.2,55.6,55.4(2C),53.8(2C),26.5.

[0164] Embodiment 35

[0165] 6n:

[0166] The synthesis method is the same as that of Example 22, except that N-methylpiperazine is used instead of 5-methoxyindole. The target product 6n is obtained by eluting with silica gel column chromatography (petroleum ether:ethyl acetate=30:1).

[0167] (E)-1-(3-(4-(3-)dimethoxyphenylvinyl)phenoxy)propyl)-4-methylpiperazine (6n): white solid, yield 86%. 1 H NMR (300MHz, CDCl3) δ (ppm): 7.52 (d, J = 8.3Hz, 2H), 7.21 (d, J = 16.3Hz, 1H), 7.02 (d, J = 16.3Hz, 1H), 6.93 (d, J = 8.3Hz, 2H), 6.74 (d, J = 2.2H z,2H),6.39(t,J=2.2Hz,1H),4.01(t,J=6.4Hz,2H),3.77(s,6H),2.51(m,2H),2.45-2.24(m,8H),2.17(s,3H),1.86(quint,J=6.8Hz,2H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.1 (2C), 158.9, 139.9, 129.9, 129.0, 128.3 (2C), 126.5 ,115.1(2C),104.6(2C),99.9,66.3,55.6(2C),55.1(2C),54.8,53.0(2C),46.1,26.6.

[0168] Example 36 In vitro antioxidant activity detection

[0169] According to the pterostilbene derivatives described in Examples 1-35, the present invention uses vitamin C (Vc) as a positive control, DPPH free radical, superoxide anion free radical, ABTS free radical scavenging ability and total reducing power as measurement indicators, and uses an ELISA method to evaluate the antioxidant activity of the pterostilbene derivatives.

[0170] Test Example 1: Determination of DPPH free radical scavenging ability

[0171] 1. Experimental Principle

[0172] 1,1-Diphenyl-2-trinitrophenylhydrazine (DPPH) is a stable free radical with a nitrogen atom as the center and three benzene rings around it. DPPH· has a single electron, and the spectrum scan has strong absorption at 517nm. Its ethanol aqueous solution is dark purple, and the concentration is linearly related to the absorbance value. When there is a free radical scavenger in the solution, DPPH· can combine with or replace the free radical scavenger, so that the number of DPPH· decreases, resulting in a decrease in absorbance, and the color gradually becomes lighter, that is, the degree of fading is quantitatively related to the number of electrons accepted. Therefore, the scavenging rate of the compound on DPPH· can be calculated based on the absorbance value at this wavelength, so as to evaluate the scavenging of the drug on the DPPH free radical.

[0173] 2. Solution Preparation

[0174] (1) Weigh an appropriate amount of the sample to be tested and prepare a stock solution of a certain concentration. Pipette the stock solution and continue to dilute it with DMSO to obtain a sample solution with an initial concentration of 600 μM.

[0175] (2) Accurately weigh ascorbic acid and pterostilbene, and add DMSO to dissolve them into a 600 μM solution.

[0176] (3) Accurately weigh solid DPPH and add anhydrous ethanol to prepare a 0.2 mM DPPH solution for later use.

[0177] 3. Experimental Methods

[0178] 50 μL of 600 μM sample solution was added to a 96-well plate, and then 100 μL of DPPH solution was added to the reaction volume, and the total reaction volume was 150 μL. The control group was 50 μL of sample solution added with 100 μL of anhydrous ethanol, and the blank group was 50 μL of DMSO solution added with 100 μL of DPPH solution. The plates were kept at room temperature and protected from light for 30 minutes, and then oscillated to mix. After the reaction was completed, the absorbance value of each well at a wavelength of 517 nm was measured using an ELISA instrument, and the DPPH free radical scavenging rate of the sample was calculated according to formula (1).

[0179] DPPH free radical scavenging rate (%) = [1-(OD 样品 -OD 对照 ) / OD 空白 ]×100% formula (1)

[0180] 4. Experimental results and analysis

[0181] According to the experimental results in Table 1, when the maximum final concentration was 200 μM, the scavenging rates of all tested samples on DPPH free radicals were between 1.53% and 55.09%, and their scavenging effect was significantly weaker than that of Vc (93.01%). The scavenging rates of derivatives 2b and 4e-4j were between 49.23% and 55.09%, indicating that their scavenging abilities were comparable to those of PTE (51.22%). In the azido-pterostilbene derivatives (4a-4p), the introduction of aromatic sulfonyl groups can enhance the scavenging effects of the compounds on DPPH free radicals (4e-4j vs. 3; 4e-4j vs. 4k-4p).

[0182] Table 1. Scavenging ability of the obtained pterostilbene derivatives on DPPH free radicals

[0183]

[0184] Test Example 2: Determination of superoxide anion free radical scavenging ability

[0185] 1. Experimental Principle

[0186] Pyrogallol can undergo self-oxidation under alkaline conditions, releasing O2 - ·, and then an orange-red intermediate product is generated. This intermediate product has strong absorption at 320nm. - · In the presence of scavengers, it can quickly react with O2 - · reaction, thereby preventing the accumulation of intermediate products, resulting in a weakened absorption of the solution at a wavelength of 320nm. That is, the amount of intermediate products is positively correlated with the strength of absorbance. Therefore, the present invention can determine the O2 - ·The clearing effect.

[0187] 2. Solution Preparation

[0188] (1) Take an appropriate amount of 20% hydrochloric acid solution and add distilled water to prepare a 10mmol / L hydrochloric acid solution.

[0189] (2) Accurately weigh Tris solid powder and use 10 mmol / L hydrochloric acid solution to prepare 50 mmol / L Tris-HCl solution with a pH of 8.2.

[0190] (3) Accurately weigh pyrogallol, dissolve it in 10 mmol / L hydrochloric acid solution and make up to volume to prepare a 3 mmol / L pyrogallol solution.

[0191] 3. Experimental Methods

[0192] 30 μL of 200 μM sample solution and Vc solution were added to a 96-well plate, and then 150 μL Tris-HCl solution was added to mix evenly, and then placed in a 25°C gas bath and incubated for 20 minutes before being taken out. 30 μL of pyrogallol solution was added to mix evenly, and then placed in a 25°C gas bath and incubated for 5 minutes before being taken out. The control group was reacted in the system with distilled water instead of pyrogallol solution, and the blank group was reacted in the system with DMSO solution instead of the sample solution.

[0193] The absorbance value of each well at a wavelength of 320 nm was measured by an enzyme-labeled instrument, and the scavenging rate of the sample for superoxide anion free radicals was calculated according to formula (2).

[0194] O2 - · Clearance rate (%) = [1-(OD 样品 -OD 对照 ) / OD 空白 ]×100% formula (2)

[0195] 4. Experimental results and analysis

[0196] Table 2. Scavenging rate of superoxide anion by some pterostilbene derivatives

[0197]

[0198] The present invention adopts the pyrogallol self-oxidation method to determine the O2 - The results are shown in Table 2. At the maximum initial concentration of 200 μM, the scavenging rates of derivatives 2a, 4a, 4c, 4e, 4h, 4i and 4m-4p on superoxide anion free radicals ranged from 89.20% to 98.29%, which was comparable to that of PTE (90.33%) or Vc (99.66%). It is worth noting that derivative 2a showed the best O2 - · Scavenging ability, with a scavenging rate of 98.29%. For azido-pterostilbene derivatives, the introduction of electron-withdrawing groups (such as -CF3, -NO2 and -Cl) on the aromatic rings of aromatic sulfonyl and aromatic benzyl groups helps to improve the scavenging effect of the compounds on superoxide anions (4c, 4e, 4h vs. 4d, 4f, 4g; 4m-4p vs. 4o).

[0199] Test Example 3: Determination of total reducing capacity

[0200] 1. Experimental Principle

[0201] When there are reducing substances in the system, Fe 3+ Can be reduced to Fe 2+ , followed by Fe 2+It can react with o-phenanthroline to form a purple-red substance with a maximum absorption peak at a wavelength of 510nm. 3+ It reacts with o-phenanthroline to produce a colorless substance with no maximum characteristic peak at this wavelength. Therefore, the absorbance value is closely related to the reducing ability of the sample. The smaller the △OD value, the stronger the reducing ability of the sample.

[0202] 2. Solution Preparation

[0203] (1) Accurately weigh 1,2-phenanthroline solid and add appropriate amount of ultrapure water to prepare a 2 mM 1,2-phenanthroline solution;

[0204] (2) Accurately weigh FeSO4 solid and add appropriate amount of ultrapure water to prepare 2 mM FeSO4 solution;

[0205] (3) Accurately weigh FeCl3 solid and add appropriate amount of ultrapure water to prepare 2 mM FeCl3 solution;

[0206] (4) Mix equal volumes of solutions (1) and (2) to obtain a test solution; mix equal volumes of solutions (1) and (3) to obtain a control solution.

[0207] 3. Experimental Methods

[0208] Add 180 μL of the assay solution to the 96-well plate, then add 20 μL of the 200 μM sample to be tested and Vc solution, and incubate at room temperature in the dark for 30 minutes. The control group is 180 μL of the control solution instead of the assay solution to react in the system. Finally, use an ELISA reader to measure the absorbance OD of each well at a wavelength of 510 nm.

[0209] △OD value = OD 测试 -OD 对照 Formula (3)

[0210] 4. Experimental results and analysis

[0211] Table 3. Total reducing ability of some pterostilbene derivatives

[0212]

[0213]

[0214] The present invention adopts o-phenanthroline-Fe 2+ The total reducing ability of the derivatives was tested by the reduction method. As shown in Table 3, the total reducing ability of most derivatives was comparable to that of PTE (△OD = 1.7832), and their △OD values ​​fluctuated between 1.7 and 1.9. In particular, the total reducing ability of derivatives 2b, 4i, 4j and 6g (△OD = 1.5456-1.5801) was slightly stronger than that of PTE.

[0215] Test Example 4: Determination of ABTS free radical cation scavenging ability

[0216] 1. Experimental Principle

[0217] Under the action of oxidants such as K2S2O8 and H2O2, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) can be oxidized to green or blue-green ABTS + ·, which has a maximum characteristic absorption peak at 734nm. When the antioxidant in the system is + When the reaction occurs, the system will turn into colorless ABTS, and the ABTS in the system + The content of · is linearly related to the absorbance value. Therefore, the present invention determines the activity of the compound to ABTS based on the measured absorbance value. + Free radical scavenging effect.

[0218] 2. Solution Preparation

[0219] (1) Accurately weigh K2S2O8 solid and add appropriate amount of ultrapure water to prepare a 2.6 mM K2S2O8 solution;

[0220] (2) Accurately weigh ABTS solid and add appropriate amount of ultrapure water to prepare 7.4 mM ABTS solution;

[0221] (3) Mix equal volumes of the solutions prepared in (1) and (2) and store at 4°C in the dark for 12-16 h to obtain the ABTS stock solution;

[0222] (4) Accurately pipette the ABTS stock solution and dilute it with ultrapure water to obtain ABTS + ·Assay fluid.

[0223] 3. Experimental Methods

[0224] Pipette 20 μL of 600 μM sample solution and Vc solution into a 96-well plate, then add 200 μL of ABTS + · Assay solution. The control group is 20 μL of the sample solution added with 200 μL of ultrapure water, and the blank group is 20 μL of DMSO solution added with 200 μL of ABTS + · Assay solution. Stand at room temperature in the dark for 10 min, shake and mix. After the reaction is complete, use an ELISA reader to measure the absorbance of each well at 734 nm, and calculate the scavenging rate of the sample on ABTS free radicals according to formula (4).

[0225] ABTS + · Clearance rate = [1-(OD 样品 -OD 对照 ) / OD 空白 ]×100% Formula (4)

[0226] 4. Experimental results and analysis

[0227] Table 4. Scavenging rate of some pterostilbene derivatives on ABTS free radicals

[0228]

[0229]

[0230] The present invention adopts ABTS method to detect the derivatives to ABTS + Free radical scavenging ability. As shown in the results of Table 4, most derivatives have weak scavenging ability against ABTS free radicals, and their scavenging rates are only between 1.63% and 22.99%. At the maximum initial concentration of 600 μM, only derivatives 2a (77.19%) and 2b (94.39%) have stronger scavenging effects against ABTS free radicals than the prototype drug PTE (62.25%). In addition, the scavenging effect of derivative 2b on ABTS free radicals is similar to that of Vc (94.68%).

[0231] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A pterostilbene derivative, characterized in that: The chemical structure of the derivative is as follows: Wherein, R1 is one of the following structural formulas: R2 is one of the following structural formulas: R3 is one of the following structural formulas:

2. Use of the pterostilbene derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating and / or preventing diseases related to oxidative stress.

3. The use according to claim 2, characterized in that: The compound is used in preparing medicine for treating or preventing cancer, diabetes, cardiovascular disease, inflammatory disease and neurodegenerative disease caused by oxidative stress.

4. The use according to claim 3, characterized in that: The dosage form of the drug is powder, granule, tablet, capsule, pill, solution, suspension or injection.

5. A pharmaceutical composition, characterized in that The invention comprises at least one of the compound as claimed in claim 1, or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof, and optionally a pharmaceutically acceptable excipient or carrier.

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