Use of a daidzein derivative and its preparation in treating and / or preventing diseases related to oxidative stress

Abstract

The application belongs to the technical field of biological medicine, and proposes a use of a pterostilbene derivative and a preparation of a medicine for treating and / or preventing diseases caused by oxidative stress. The chemical structure of the pterostilbene derivative is shown as formula (I)-(III). The scavenging effect of the obtained derivative on DPPH·, O2 ‑ · and ABTS + · free radicals and its total reducing capacity are detected respectively. In terms of DPPH· and total reducing capacity, it is found that the scavenging capacity of some derivatives is equivalent to that of pterostilbene or vitamin C. Derivatives 2a, 4a, 4c, 4e, 4h, 4i and 4m-4p have the same scavenging effect on O2 ‑ · free radicals as pterostilbene or vitamin C; the scavenging effect of derivative 2b on ABTS + · is equivalent to that of vitamin C and is superior to that of pterostilbene. The pterostilbene derivative has potential application prospects in the preparation of antioxidants.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to a preparation method of a pterostilbene analogue and its use in antioxidant activity. BACKGROUND

[0002] Oxidative stress (OS) refers to the imbalance between the levels of reactive oxygen species and antioxidants in the animal body, leading to lipid peroxidation and the production of a large number of peroxides. Free radicals are a class of chemical substances containing unpaired electrons, which have strong activity and are prone to chemical reactions with active ingredients in cells. High concentration of free radicals in the body can lead to accumulation of reactive oxygen species and reactive nitrogen species in cells, and further cause oxidative damage. Excessive free radicals can cause cell function disorders such as inflammation and necrosis by inducing denaturation of biological macromolecules such as lipids, proteins and DNA, and further harm the normal physiological and metabolic functions of the body.

[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, some 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. The level of free radicals in diabetic patients is usually high, which exacerbates insulin resistance and vascular damage. Free radical scavengers help to alleviate these pathological processes. Existing free radical scavengers have been used to prevent and treat diabetic chronic complications, especially vascular complications, showing good application prospects. The occurrence of cardiovascular diseases is closely related to oxidative stress mediated by free radicals. Free radical scavengers can protect the cardiovascular system from oxidative damage. For example, some antioxidant enzymes have been used for the treatment and prevention of cardiovascular diseases, which 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 to protect neurons and slow down the progression of the disease. Some studies have shown that compounds with free radical scavenging ability (such as chitosan oligosaccharide, DMSO, etc.) show potential application value in the treatment of neurodegenerative diseases.

[0004] Free radical scavenging compounds can directly react with free radicals, converting them into harmless or low-activity substances, thereby reducing the damage of free radicals to tissues. They can also reduce inflammatory response 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, reduce the release of inflammatory factors, and thus inhibit the development of inflammatory response.

[0005] Natural plants have the advantages of high efficiency and low toxicity, and their extracts have antioxidant properties and free radical scavenging effects. Therefore, natural plants have become an important resource of natural antioxidants. Pterostilbene (PTE) is a natural polyphenol widely found in plants such as Pterocarpus, blueberry, nuts and grape leaves. In terms of chemical structure, Pterostilbene contains an additional dimethoxy group and belongs to the homologues of resveratrol. Pterostilbene itself has a certain free radical scavenging ability and can improve the antioxidant level of the body by enhancing the activity of antioxidant enzymes. In recent years, Pterostilbene has shown more prominent performance 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

[0006] The present application takes Pterostilbene as the structural skeleton and provides a preparation method of Pterostilbene analogues, aiming to broaden the structural types of Pterostilbene derivatives. At the same time, the scavenging ability of the target product on DPPH·, superoxide anion, ABTS + · and total reducing power are evaluated in order to explore the application of Pterostilbene derivatives in antioxidant capacity.

[0007] To achieve the above purpose, the technical scheme adopted by the present application is as follows:

[0008] The chemical structure of the Pterostilbene derivative is shown in the following formula (I), (II) and (III):

[0009]

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

[0011]

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

[0013]

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

[0015]

[0016] The Pterostilbene derivative of the present application has the following preparation route:

[0017]

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

[0019] (i) Dissolve the pterostilbene in dichloromethane solution, drop in triethylamine solution, slowly drop in chloroacetyl chloride at 0°C, then put the reaction system in room temperature condition and stir for 4-6h. After the reaction is completed, extract with dichloromethane, wash with distilled water and saturated brine respectively, dry the organic phase with anhydrous Na2SO4, and evaporate dichloromethane under reduced pressure. Drop in appropriate amount of n-hexane until yellow solid, i.e. intermediate compound 1, is precipitated, and repeat the operation for 2-3 times of recrystallization.

[0020] (ii) Dissolve compound 1 and potassium carbonate in acetonitrile, drop in azacycle compound, and heat to reflux at 80°C for 8h. After the raw material is completely reacted, remove acetonitrile under reduced pressure, extract with ethyl acetate, collect the organic layer, dry with anhydrous Na2SO4, filter, concentrate under reduced pressure, and separate and purify by flash column chromatography (dichloromethane and methanol as eluent) to obtain compound 2a and 2b of formula (I).

[0021] (iii) Dissolve pterostilbene and potassium carbonate in acetonitrile, drop in 3-bromopropynyl under stirring, heat to 80°C in an oil bath, and react for 12h. After the reaction is completed, evaporate acetonitrile under reduced pressure, spin dry, and beat with appropriate amount of n-hexane, and extract with ethyl acetate, and then wash with distilled water and saturated brine respectively, dry the organic layer with anhydrous Na2SO4, and evaporate ethyl acetate under reduced pressure to obtain intermediate 3.

[0022] (iv) Add toluene solution to intermediate 3 and copper thiophene-2-carboxylate, then add sulfonyl azide or benzyl azide compound, and continue to stir for 1-2h. After the reaction is completed, extract with ethyl acetate, and then wash with distilled water and saturated brine respectively, dry the organic layer with anhydrous Na2SO4, evaporate ethyl acetate under reduced pressure, and separate and purify by flash column chromatography (petroleum ether and ethyl acetate as eluent) to obtain derivatives 4a-4p of formula (II).

[0023] (v) Dissolve pterostilbene, potassium carbonate and potassium iodide in acetonitrile, then add 1,3-dibromopropane, heat to 80°C, and stir for 12h. After the raw material is completely reacted, extract with dichloromethane, combine the organic layers, and evaporate dichloromethane under reduced pressure. The crude product is eluted by flash column chromatography (petroleum ether and ethyl acetate as eluent) to obtain intermediate 5.

[0024] (vi) Dissolve intermediate 5, potassium hydroxide and amine compound in acetonitrile, and stir at 80°C for 12h. After the reaction is completed, evaporate acetonitrile under reduced pressure. Separate and purify by flash column chromatography (petroleum ether and ethyl acetate as eluent) to obtain derivatives 6a-6n of formula (III).

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

[0026] The present application provides a preparation method of pterostilbene derivatives and application thereof in antioxidant activity. The obtained derivatives are detected by enzyme marker instrument method, and the antioxidant activities of the obtained derivatives on DPPH· and O2- ·, ABTS + ·, scavenging effect on free radicals and its total reducing power. In terms of DPPH free radical and total reducing power, some derivatives were found to have scavenging ability comparable to that of pterostilbene or vitamin C. Derivatives 2a, 4a, 4c, 4e, 4h, 4i and 4m-4p had O 2- ·, scavenging effect on free radicals comparable to PTE or Vc; derivative 2b had ABTS free radical scavenging effect equivalent to vitamin C and superior to PTE. The pterostilbene derivatives have potential application prospects in the preparation of antioxidants. DETAILED DESCRIPTION

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

[0028] Example 1

[0029] 1:

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

[0031] (E)-4-(3,5-dimethoxybenzoate)-2-chloroacetic acid phenyl (1): yield 97%. 1 H NMR (400 MHz, CDC13) δ (ppm): 7.51 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.3 Hz, 1H), 6.97 (d, J = 16.4 Hz, 1H), 6.66 (d, J = 2.3 Hz, 2H), 6.41 (t, J = 4.5 Hz, 1H), 4.31 (s, 2H), 3.83 (s, 6H). 13 C NMR (75 MHz, CDC13) 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 Schlenk tube, dissolved in acetonitrile (2 mL), 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 x 10 mL) in turn, 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), concentrated under reduced pressure, and derivative 2a was obtained.

[0035] (E)-4-(3,5-dimethoxybenzoyl)benzoic acid-2-(4-methylpiperazin-1-yl) acetic acid (2a): white solid, yield 73%. 1 H NMR (300 MHz, CDC13) δ (ppm): 7.48 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H), 6.99 (t, J = 9.8 Hz, 2H), 6.64 (d, J = 2.3 Hz, 2H), 6.39 (t, J = 4.5 Hz, 1H), 6.37 (t, J = 4.5 Hz, 1H), 3.82 (s, 6H), 3.49 (s, 2H), 2.75 (s, 4H), 2.59 (s, 4H), 2.34 (s, 3H). 13 C NMR (75 MHz, CDC13) 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 is the same as Example 2, except that morpholine is used instead of N-methylpiperazine, and the target product 2b is obtained by silica gel column chromatography (dichloromethane:methanol = 80:1).

[0039] (E)-4-(3,5-dimethoxyphenyl)benzimidazole-2-carboxamide (2b): white solid, yield 80%. 1H NMR (300 MHz, CDC13) δ (ppm): 7.51 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 7.00 (t, J = 9.5 Hz, 2H), 6.66 (d, J = 2.2 Hz, 2H), 6.39 (t, J = 4.5 Hz, 1H), 3.83 (s, 6H), 3.79 (t, J = 9.4 Hz, 4H), 3.49 (s, 2H), 2.69 (t, J = 9.4 Hz, 4H). 13 C NMR (75 MHz, CDC13) δ (ppm): 160.9 (2C), 155.7, 139.7, 130.2, 130.1, 129.9, 128.7, 128.1 (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] To a round bottom flask was added pterostilbene (1000 mg, 3.9 mM), anhydrous potassium carbonate (808.5 mg, 5.8 mM) and acetonitrile solution, followed by dropwise addition of 3-bromopropyne (556.7 mg, 4.7 mM) with stirring, the temperature was raised to 80 °C and stirred for 12 h. After TLC monitoring of the reaction was complete, it was extracted with DCM (3 x 30 mL), the organic layers were combined, distilled water and saturated brine were washed, the organic phase was dried over anhydrous Na2S04, and the dichloromethane was removed under reduced pressure. An appropriate amount of n-hexane was added with stirring and slurry, and filtered to obtain the intermediate 3.

[0043] (E)-1,3-Dimethoxy-5-(4-(prop-2-yn-1-yloxy)styryl)benzene (3): It was a dark yellow solid with a yield of 91%. 1 H NMR (300 MHz, CDC13) δ (ppm): 7.51 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 7.00 (t, J = 9.5 Hz, 2H), 6.66 (d, J = 2.2 Hz, 2H), 6.39 (t, J = 4.5 Hz, 1H), 3.83 (s, 6H), 3.79 (t, J = 9.4 Hz, 4H), 3.49 (s, 2H), 2.69 (t, J = 9.4 Hz, 4H). 13C NMR (75 MHz, CDC13) 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 p-toluenesulfonyl azide, and stirring was continued at room temperature for 1-2 h. After completion of the reaction, extraction was performed with ethyl acetate (3 x 10 mL), distilled water and saturated brine were washed, the EtOAc layer was dried over anhydrous Na2SO4, ethyl acetate was removed under reduced pressure, and purification was performed by flash column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the target product 4a.

[0047] (E)-4-((4-(3,5-dimethoxyphenyl)phenoxy)methyl)-1-methanesulfonyl-1H-1,2,3-triazole (4a): white solid, yield 95%. 1 H NMR (300 MHz, CDC13) δ (ppm): 7.43 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 16.2 Hz, 1H), 6.95 (d, J = 6.7 Hz, 2H), 6.90 (d, J = 14.0 Hz, 1H), 6.64 (d, J = 2.3 Hz, 2H), 6.38 (t, J = 4.5 Hz, 1H), 5.20 (s, 2H), 3.83 (s, 6H), 2.45 (s, 3H). 13 C NMR (75 MHz, CDC13) δ (ppm): 160.9 (2C), 157.6, 147.5, 143.9, 139.5, 132.8, 130.8, 130.5 (2C), 128.8 (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 synthetic method is the same as Example 5, except that 4-acetamidobenzenesulfonyl azide is used instead of p-toluenesulfonyl azide, and the target product 4b is obtained by silica gel column chromatography elution (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 (300 MHz, CDC13) δ (ppm): 10.63 (s, 1H), 9.01 (s, 1H), 8.10 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 16.4 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 6.75 (s, 2H), 6.40 (s, 1H), 5.21 (s, 2H), 3.78 (s, 6H), 2.11 (s, 3H). 13 C NMR (75 MHz, CDC13) 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 synthetic method is the same as Example 5, except that 4-acetamidobenzenesulfonyl azide is used instead of p-toluenesulfonyl azide, and the target product 4b is obtained by silica gel column chromatography elution (petroleum ether: ethyl acetate = 4:1).

[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 (300 MHz, CDC13) δ (ppm): 8.18 (s, 1H), 8.12 (m, 2H), 7.40 (d, J = 8.8 Hz, 2H), 6.98 (t, J = 17.1 Hz, 2H), 6.98 (d, J = 16.3 Hz, 1H), 6.90 (d, J = 5.8 Hz, 2H), 6.86 (d, J = 13.2 Hz, 1H), 6.61 (d, J = 2.3 Hz, 2H), 6.35 (t, J = 4.5 Hz, 1H), 5.16 (s, 2H), 3.78 (s, 6H). 13 C NMR (75 MHz, CDC13) 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] Synthesis method is the same as Example 5, except that 4-trifluoromethoxy benzene sulfonyl azide is used instead of p-toluenesulfonyl azide, and eluted by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the target derivative 4d.

[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 (300 MHz, CDC13) δ (ppm): 8.18 (s, 1H), 8.12 (m, 2H), 7.40 (d, J = 8.8 Hz, 2H), 6.98 (t, J = 17.1 Hz, 2H), 6.98 (d, J = 16.3 Hz, 1H), 6.90 (d, J = 5.8 Hz, 2H), 6.86 (d, J = 13.2 Hz, 1H), 6.61 (d, J = 2.3 Hz, 2H), 6.35 (t, J = 4.5 Hz, 1H), 5.16 (s, 2H), 3.78 (s, 6H). 13C NMR (75 MHz, CDC13) 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 is the same as Example 5, except that 4-trifluoromethylbenzenesulfonyl azide is used instead of p-toluenesulfonyl azide, and the target product 4e is obtained by silica gel column chromatography elution (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 (300 MHz, CDC13) δ (ppm): 9.17 (s, 1H), 8.48 (m, 4H), 7.41 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 16.4 Hz, 1H), 7.07 (d, J = 9.9 Hz, 2H), 7.03 (d, J = 4.4 Hz, 1H), 7.07 (d, J = 4.8 Hz, 1H), 6.76 (d, J = 2.2 Hz, 2H), 6.40 (t, J = 4.4 Hz, 1H), 5.23 (s, 2H), 3.78 (s, 6H). 13 C NMR (75 MHz, CDC13) 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 synthetic method is the same as Example 5, except that 4-tert-butylbenzenesulfonyl azide is used instead of p-toluenesulfonyl azide, and the target product 4g is obtained by silica gel column chromatography elution (petroleum ether: ethyl acetate = 10:1).

[0067] (E)-1-[(4-(tert-Butyl)phenyl]sulfonyl]-4-[(4-(3,5-dimethoxyphenyl)phenoxy)methyl]-1H-1,2,3-triazole (4g): white solid, yield 91%. 1 H NMR (300 MHz, CDC13) δ (ppm): 8.01 (s, 1H), 7.57 (d, J = 13.5 Hz, 2H), 7.41 (d, J = 5.3 Hz, 2H), 7.54 (d, J = 1.2 Hz, 2H), 7.46 (d, J = 27.2 Hz, 2H), 7.23 (d, J = 16.4 Hz, 1H), 7.05 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 8.1 Hz, 1H), 6.75 (d, J = 2.3 Hz, 2H), 6.39 (t, J = 4.5 Hz, 1H), 5.21 (s, 2H), 3.74 (s, 6H). 13 C NMR (75 MHz, CDC13) δ (ppm): 161.1 (2C), 158.2, 147.8, 142.1, 139.8, 131.1, 130.3, 130.1, 128.9, 128.3 (2C), 128.2 (2C), 126.8, 122.3, 115.4 (2C), 104.6 (2C), 99.9, 61.2, 55.6 (2C).

[0068] Example 11

[0069] 4g:

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

[0071] (E)-1-[(4-(tert-Butyl)phenyl]sulfonyl]-4-[(4-(3,5-dimethoxyphenyl)phenoxy)methyl]-1H-1,2,3-triazole (4g): white solid, yield 91%. 1H NMR (300 MHz, CDC13) δ (ppm): 7.36 (d, J = 8.8 Hz, 2H), 7.18 (s, 1H), 6.97 (d, J = 16.2 Hz, 1H), 6.84 (t, J = 10.1 Hz, 2H), 6.80 (d, J = 6.7 Hz, 1H), 6.58 (d, J = 2.3 Hz, 2H), 6.30 (t, J = 5.4 Hz, 1H), 4.02 (t, J = 12.6 Hz, 1H), 4.12 (t, J = 12.1 Hz, 1H), 3.99 (t, J = 12.3 Hz, 1H), 3.75 (s, 6H), 2.20 (m, 1H), 2.01 (m, 2H). 13 C NMR (75 MHz, CDC13) 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] Synthesis method is the same as Example 5, except that 4-nitrobenzenesulfonyl azide is used instead of p-toluenesulfonyl azide, and the target product 4h is obtained by silica gel column chromatography elution (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 (300 MHz, CDC13) δ (ppm): 7.36 (d, J = 8.8 Hz, 2H), 7.18 (s, 1H), 6.97 (d, J = 16.2 Hz, 1H), 6.84 (t, J = 10.1 Hz, 2H), 6.80 (d, J = 6.7 Hz, 1H), 6.58 (d, J = 2.3 Hz, 2H), 6.30 (t, J = 5.4 Hz, 1H), 4.02 (t, J = 12.6 Hz, 1H), 4.12 (t, J = 12.1 Hz, 1H), 3.99 (t, J = 12.3 Hz, 1H), 3.75 (s, 6H), 2.20 (m, 1H), 2.01 (m, 2H). 13C NMR (75 MHz, CDC13) 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] Example 13

[0077] 4i:

[0078] The synthesis was carried out in the same manner as in Example 5, except that 4- chlorobenzenesulfonyl azide was used instead of p-toluenesulfonyl azide, and the target product 4i was obtained by silica gel column chromatography elution (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 gum, yield 95%. 1 H NMR (300 MHz, CDC13) δ (ppm): 8.01 (s, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 16.4 Hz, 1H), 7.05 (d, J = 6.5 Hz, 2H), 7.02 (d, J = 8.3 Hz, 2H), 6.74 (d, J = 2.3 Hz, 3H), 6.40 (d, J = 4.5 Hz, 1H), 5.21 (s, 2H), 3.77 (s, 6H). 13 C NMR (75 MHz, CDC13) 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] Example 14

[0081] 4j:

[0082] The synthesis was carried out in the same manner as in Example 5, except that 2- thienylsulfonyl azide was used instead of p-toluenesulfonyl azide, and the target product 4j was obtained by silica gel column chromatography elution (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, 92% yield. 1 H NMR (300 MHz, CDC13) δ (ppm): 9.07 (s, 1H), 8.38 (d, J = 5.0 Hz, 1H), 8.22 (dd, J = 3.9 Hz, 1H), 7.52 (d, J = 6.6 Hz, 2H), 7.36 (t, J = 8.9 Hz, 1H), 7.23 (d, J = 16.4 Hz, 1H), 7.05 (d, J = 8.9 Hz, 2H), 7.02 (d, J = 6.2 Hz, 1H), 6.75 (d, J = 2.3 Hz, 2H), 6.40 (d, J = 2.2 Hz, 1H), 5.21 (s, 2H), 3.76 (s, 6H). 13 C NMR (75 MHz, CDC13) 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] Example 15

[0085] 4k:

[0086] Synthesis method is the same as Example 5, except that 4-fluorobenzyl azide is used instead of p-toluenesulfonyl azide, and the target product 4k is obtained by silica gel column chromatography elution (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, 96% yield. 1 H NMR (300 MHz, CDC13) δ (ppm): 7.44 (s, 1H), 7.36 (d, J = 11.8 Hz, 2H), 7.18 (t, J = 13.9 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 10.8 Hz, 2H), 6.55 (d, J = 2.3 Hz, 2H), 6.29 (t, J = 4.5 Hz, 1H), 5.40 (s, 2H), 5.11 (s, 2H), 3.74 (s, 6H). 13H NMR (300 MHz, CDC13) δ (ppm): 8.34 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 5.3 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 16.4 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 4.8 Hz, 1H), 6.81 (s, 2H), 6.45 (t, J = 2.3 Hz, 1H), 3.82 (s, 6H), 3.47 (t, J = 5.1 Hz, 1H).

[0088] Example 16

[0089] 4l:

[0090] The synthesis was carried out as in Example 5, except that 4- trifluoromethylbenzyl azide was used instead of p-toluenesulfonyl azide, and the target product 4l was obtained by silica gel column chromatography elution (petroleum ether: ethyl acetate = 3: 1).

[0091] (E)-1-phenyl-4-((4-(3,5-dimethoxyphenyl)phenoxy)methyl)-1H-1,2,3-triazole (4l): It was a scaly white solid with a yield of 92%. 1 H NMR (300 MHz, CDC13) δ (ppm): 8.34 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 5.3 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 16.4 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 4.8 Hz, 1H), 6.81 (s, 2H), 6.45 (t, J = 2.3 Hz, 1H), 3.82 (s, 6H), 3.47 (t, J = 5.1 Hz, 1H). 13 H NMR (300 MHz, CDC13) δ (ppm): 8.34 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 5.3 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 16.4 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 4.8 Hz, 1H), 6.81 (s, 2H), 6.45 (t, J = 2.3 Hz, 1H), 3.82 (s, 6H), 3.47 (t, J = 5.1 Hz, 1H).

[0092] Example 17

[0093] 4m:

[0094] The synthesis was carried out as in Example 5, except that 4- trifluoromethylbenzyl azide was used instead of p-toluenesulfonyl azide, and the target product 4l was obtained by silica gel column chromatography elution (petroleum ether: ethyl acetate = 3: 1).

[0095] (E)-4-[(4-(3,5-dimethoxyphenyl)phenoxy)methyl]-l-(4-(trifluoromethyl)phenyl)-lH-l,2,3- triazole (4m): white solid, 95% yield. 1 H NMR (300 MHz, CDC13) δ (ppm): 8.35 (s, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 9.0 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 7.01 (d, J = 6.7 Hz, 1H), 6.75 (d, J = 2.3 Hz, 2H), 6.40 (t, J = 4.5 Hz, 1H), 5.18 (s, 2H), 3.77 (s, 6H), 3.39 (s, 1H). 13 CNMR (75 MHz, CDC13) 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] Example 18

[0097] 4n:

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

[0099] (E)-l-(4-chlorobenzyl)-4-((4-(3,5-dimethoxyphenyl)phenoxy)methyl)-lH-l,2,3-triazole (4n): white gum, 96% yield. 1H NMR (300 MHz, CDC13) δ (ppm): 8.30 (s, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 14.2 Hz, 1H), 7.04 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 5.9 Hz, 1H), 6.75 (d, J = 2.4 Hz, 2H), 6.40 (t, J = 2.6 Hz, 1H), 5.62 (s, 2H), 3.77 (s, 6H). 13 C NMR (75 MHz, CDC13) 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] Example 19

[0101] 4o:

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

[0103] (E)-4-((4-(3,5-dimethoxyphenyl)phenoxy)methyl)-1-(4-methylphenyl)-1H-1,2,3-triazole (4o): yellowish solid, yield 93%. 1 H NMR (300 MHz, CDC13) δ (ppm): 8.30 (s, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 14.2 Hz, 1H), 7.04 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 5.9 Hz, 1H), 6.75 (d, J = 2.4 Hz, 2H), 6.40 (t, J = 2.6 Hz, 1H), 5.62 (s, 2H), 3.77 (s, 6H). 13C NMR (75 MHz, CDC13) δ (ppm): 161.1 (2C), 158.2, 147.6, 143.8, 143.6, 139.8, 130.4, 129.4 (2C), 128.9, 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.

[0104] Example 20

[0105] 4p:

[0106] The synthesis method is the same as Example 5, except that 4-nitrobenzyl azide is used instead of p-toluenesulfonyl azide, and the target product 4p is obtained by silica gel column chromatography elution (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 (300 MHz, CDC13) δ (ppm): 8.38 (s, 1H), 8.23 (d, J = 8.9 Hz, 2H), 7.56 (d, J = 2.7 Hz, 2H), 7.52 (d, J = 2.7 Hz, 2H), 7.23 (d, J = 16.4 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 2.3 Hz, 2H), 6.40 (t, J = 2.6 Hz, 1H), 5.81 (s, 2H), 5.19 (s, 2H), 3.77 (s, 6H), 3.42 (s, 2H). 13 C NMR (75 MHz, CDC13) δ (ppm): 161.1 (2C), 158.2, 147.6, 143.8, 143.6, 139.8, 130.4, 129.4 (2C), 128.9, 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] Example 21

[0109] 5:

[0110] Diosgenyl (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 Schlenk tube, dissolved with acetonitrile (2 mL), and the reaction system was refluxed at 80°C for 12 h. After the reaction was completed, it was cooled to room temperature, sequentially extracted with EtOAc (3 x 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)styryl)-3,5-dimethoxybenzene (5): yellow-white solid, yield 90%. 1 H NMR (300 MHz, CDC13) δ (ppm): 7.46 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 16.2 Hz, 1H), 6.95 (d, J = 16.2 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.68 (d, J = 2.3 Hz, 2H), 6.41 (t, J = 2.2 Hz, 1H), 4.13 (t, J = 5.8 Hz, 2H), 3.85 (s, 6H), 3.63 (t, J = 6.4 Hz, 2H), 2.34 (quint, J = 6.1 Hz, 2H). 13 C NMR (75 MHz, CDC13) 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] Example 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 placed in a 20 mL Schlenk tube, dissolved with acetonitrile (2 mL), and then the reaction system was stirred at 80°C for 12 h. After the reaction was completed, the acetonitrile was evaporated under reduced pressure, and the target product 6a was obtained by separation and purification by flash column chromatography (petroleum ether: ethyl acetate = 50:1).

[0115] (E)-1-(3-(4-(3-)dimethoxyphenylstyryl)phenoxy)propyl)-5-methoxy-1H-indole (6a): colorless oily liquid, yield 94%.1 H NMR (300 MHz, CDC13) δ (ppm): 7.61 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 17.6 Hz, 1H), 7.21 (d, J = 3.1 Hz, 1H), 7.10 (d, J = 17.6 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 2.2 Hz, 2H), 6.58 (m, 2H), 4.49 (t, J = 6.5 Hz, 2H), 4.03 (t, J = 6.5 Hz, 2H), 4.03 (s, 3H), 4.01 (s, 6H), 2.43 (quint, J = 6.1 Hz, 2H). 13 CNMR (75 MHz, CDC13) δ (ppm): 161.0 (2C), 158.5, 154.1, 139.7, 131.3, 130.2, 129.0, 128.7 (2C), 127.9 (2C), 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] Example 23

[0117] 6b:

[0118] Synthesis method is the same as example 22, except that 5-methoxyindole is replaced by 5-methylindole, eluted by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1), to obtain the target product 6b.

[0119] (E)-1-(3-(4-(3-)dimethoxy styryl) phenoxy) propyl)-5-methyl-1H-indole (6b): the property is colorless oily liquid, the yield is 96%. 1 H NMR (300 MHz, CDC13) δ (ppm): 7.50 (m, 3H), 7.31 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 16.4 Hz, 1H), 7.08 (m, 2H), 6.97 (d, J = 16.4 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.72 (d, J = 2.2 Hz, 2H), 6.45 (m, 2H), 4.37 (t, J = 6.5 Hz, 2H), 3.89 (t, J = 6.5 Hz, 2H), 3.88 (s, 6H), 2.51 (s, 3H), 2.30 (quint, J = 6.1 Hz, 2H).13 C NMR (75 MHz, CDC13) 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] Example 24

[0121] 6c:

[0122] The synthesis method is the same as Example 22, except that 5-nitroindole is used instead of 5-methoxyindole, and the target product 6c is obtained by silica gel column chromatography elution (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 (300 MHz, CDC13) δ (ppm): 8.57 (d, J = 2.2 Hz, 1H), 8.07 (dd, J = 9.2, 2.2 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 9.1 Hz, 1H), 7.24 (d, J = 3.3 Hz, 1H), 7.04 (d, J = 16.2 Hz, 1H), 6.91 (d, J = 16.2 Hz, 1H), 6.86 (d, J = 8.3 Hz, 2H), 6.66 (m, 3H), 6.39 (t, J = 2.2 Hz, 1H), 4.43 (t, J = 6.6 Hz, 2H), 3.89 (t, J = 5.6 Hz, 2H), 3.83 (s, 6H), 2.31 (quint, J = 6.1 Hz, 2H). 13 C NMR (75 MHz, CDC13) 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.

[0124] Example 25

[0125] 6d:

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

[0127] (E)-6-chloro-l-[3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl]-lH-indole (6d): It was a bright yellow solid with a yield of 90%. 1 H NMR (300 MHz, CDC13) δ (ppm): 7.54 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.38 (m, 1H), 7.09 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 16.6 Hz, 1H), 7.07 (d, J = 1.8 Hz, 1H), 6.93 (d, J = 16.6 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 2.3 Hz, 2H), 6.47 (dd, J = 3.1, 0.9 Hz, 1H), 6.42 (t, J = 2.2 Hz, 1H), 4.33 (t, J = 6.6 Hz, 2H), 3.87 (d, J = 6.6 Hz, 2H), 3.85 (s, 6H), 2.26 (quint, J = 6.2 Hz, 2H). 13 C NMR (75 MHz, CDC13) 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] Example 26

[0129] 6e:

[0130] The synthetic method was the same as Example 22, except that 6-chloroindole was used instead of 5-methoxyindole, and the target product 6d was obtained by silica gel column chromatography elution (petroleum ether: ethyl acetate = 20: 1).

[0131] (E)-5-bromo-l-[3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl]-lH-indole (6e): It was a white solid with a yield of 88%. 1H NMR (300 MHz, CDC13) δ (ppm): 7.82 (d, J = 1.7 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.30 (m, 2H), 7.13 (d, J = 3.4 Hz, 1H), 7.12 (d, J = 16.3 Hz, 1H), 6.98 (d, J = 16.3 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 6.73 (d, J = 2.2 Hz, 2H), 6.47 (m, 2H), 4.39 (t, J = 6.6 Hz, 2H), 3.91 (t, J = 6.6 Hz, 2H), 3.90 (s, 6H), 2.31 (quint, J = 6.2 Hz, 2H). 13 C NMR (75 MHz, CDC13) 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] Example 27

[0133] 6f:

[0134] Synthetic procedure similar to Example 22, except that 1,2,3,4-tetrahydroisoquinoline was used instead of 5-methoxyindole and the product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to give the title compound 6f as a white solid in 94% yield.

[0135] (E)-2-[3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl]-1,2,3,4-tetrahydroisoquinoline (6f): white solid, yield 94%. 1 H NMR (300 MHz, CDC13) δ (ppm): 7.45 (d, J = 8.7 Hz, 2H), 7.16-7.12 (m, 3H), 7.08-7.03 (m, 2H), 6.94-6.89 (m, 3H), 6.67 (d, J = 2.3 Hz, 2H), 6.39 (t, J = 2.2 Hz, 1H), 4.10 (t, J = 6.4 Hz, 2H), 3.84 (s, 6H), 3.68 (s, 2H), 2.94 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 5.9 Hz, 2H), 2.72 (t, J = 7.2 Hz, 2H), 2.10 (quint, J = 7.5 Hz, 2H). 13C NMR (75 MHz, CDC13) δ (ppm): 161.0 (2C), 158.9, 139.7, 134.8, 134.3, 129.8, 128.8, 128.7, 127.8 (2C), 126.6, 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] Example 28

[0137] 6g:

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

[0139] (E)-N-(3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl)-4-methoxyaniline (6g): bright yellow solid, yield 83%. 1 H NMR (300 MHz, CDC13) δ (ppm): 7.45 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 16.3 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 16.3 Hz, 1H), 6.79 (d, J = 9.0 Hz, 2H), 6.66 (d, J = 2.4 Hz, 2H), 6.61 (d, J = 8.9 Hz, 2H), 6.38 (t, J = 2.2 Hz, 1H), 4.11 (t, J = 5.9 Hz, 2H), 3.83 (s, 6H), 3.75 (s, 3H), 3.32 (t, J = 6.7 Hz, 2H), 2.10 (quint, J = 6.2 Hz, 2H). 13 C NMR (75 MHz, CDC13) 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] Example 29

[0141] 6h:

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

[0143] (E)-N-(3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl)-4- methoxyaniline (6h): bright yellow oil liquid, yield 81%. 1 H NMR (300 MHz, CDC13) δ (ppm): 7.45 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 16.3 Hz, 1H), 6.94-6.87 (m, 5H), 6.66 (d, J = 2.3 Hz, 2H), 6.57 (d, J = 9.0 Hz, 1H), 6.56 (d, J = 9.0 Hz, 1H), 6.39 (t, J = 2.2 Hz, 1H), 4.11 (t, J = 5.8 Hz, 2H), 3.84 (s, 6H), 3.32 (t, J = 6.6 Hz, 2H), 2.10 (quint, J = 6.6 Hz, 2H). 13 C NMR (75 MHz, CDC13) 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] Example 30

[0145] 6i:

[0146] The synthetic method was the same as Example 22, except that 4- methoxyaniline was used instead of 5-methoxyindole, and the target product 6h was obtained by silica gel column chromatography elution (petroleum ether: ethyl acetate = 20: 1).

[0147] (E)-N-(3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl)-4- methoxyaniline (6h): bright yellow oil liquid, yield 81%. 1H NMR (300 MHz, CDC13) δ (ppm): 8.57 (d, J = 2.2 Hz, IH), 8.07 (dd, J = 9.2, 2.2 Hz, IH), 7.44 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 9.1 Hz, IH), 7.24 (d, J = 3.3 Hz, IH), 7.04 (d, J = 16.2 Hz, IH), 6.91 (d, J = 16.2 Hz, IH), 6.86 (d, J = 8.3 Hz, 2H), 6.66 (m, 3H), 6.39 (t, J = 2.2 Hz, IH), 4.43 (t, J = 6.6 Hz, 2H), 3.89 (t, J = 5.6 Hz, 2H), 3.83 (s, 6H), 2.31 (quint, J = 6.1 Hz, 2H). 13 C NMR (75 MHz, CDC13) 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] Example 31

[0149] 6j:

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

[0151] (E)-1-(3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl)-1H-pyrrole (6j): white crystal, yield 95%. 1 H NMR (300 MHz, CDC13) δ (ppm): 8.57 (d, J = 2.2 Hz, IH), 8.07 (dd, J = 9.2, 2.2 Hz, IH), 7.44 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 9.1 Hz, IH), 7.24 (d, J = 3.3 Hz, IH), 7.04 (d, J = 16.2 Hz, IH), 6.91 (d, J = 16.2 Hz, IH), 6.86 (d, J = 8.3 Hz, 2H), 6.66 (m, 3H), 6.39 (t, J = 2.2 Hz, IH), 4.43 (t, J = 6.6 Hz, 2H), 3.89 (t, J = 5.6 Hz, 2H), 3.83 (s, 6H), 2.31 (quint, J = 6.1 Hz, 2H). 13C NMR (75 MHz, CDC13) 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] Example 32

[0153] 6k:

[0154] The synthesis was carried out in the same manner as in Example 22, except that pyrazole was used instead of 5-methoxyindole, and the target product 6k was obtained by silica gel column chromatography elution (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 (300 MHz, CDC13) δ (ppm): 7.46 (s, 1H), 7.42 (d, J = 8.7 Hz, 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 = 2.2 Hz, 1H), 4.16 (t, J = 6.8 Hz, 2H), 3.89 (t, J = 5.7 Hz, 2H), 3.81 (s, 6H), 2.20 (quint, J = 6.2 Hz, 2H). 13 C NMR (75 MHz, CDC13) δ (ppm): 161.0 (2C), 158.2, 139.6, 137.3, 130.4, 129.6, 128.6, 127.9 (2C), 126.8, 119.0, 114.7 (2C), 104.4 (2C), 99.7, 63.8, 55.4 (2C), 43.4, 30.8.

[0156] Example 33

[0157] 6l:

[0158] The synthesis was carried out in the same manner as in Example 22, except that piperidine was used instead of 5-methoxyindole, and the target product 6l was obtained by silica gel column chromatography elution (petroleum ether: ethyl acetate = 1:3).

[0159] (E)-1-(3-(4-(3,5-dimethoxyphenyl)phenoxy)propyl)piperidine (6l): white solid, yield 93%.1 H NMR (300 MHz, CDC13) δ (ppm): 7.43 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 16.3 Hz, 1H), 6.90 (d, J = 16.3 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 2.2 Hz, 2H), 6.37 (t, J = 2.2 Hz, 1H), 4.02 (t, J = 6.4 Hz, 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 (75 MHz, CDC13) 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] Example 34

[0161] 6m:

[0162] Synthesis method is the same as Example 22, except that morpholine is used instead of 5-methoxyindole, and the target product 6m is obtained by silica gel column chromatography elution (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 (300 MHz, CDC13) δ (ppm): 7.43 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 16.3 Hz, 1H), 6.90 (d, J = 16.3 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 2.2 Hz, 2H), 6.37 (t, J = 2.2 Hz, 1H), 4.02 (t, J = 6.4 Hz, 2H), 3.82 (s, 6H), 2.54-2.34 (m, 6H), 1.98 (m, 2H), 1.60 (m, 4H), 1.45 (m, 2H). 13C NMR (75 MHz, CDC13) 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] Example 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, and the target product 6n is obtained by silica gel column chromatography elution (petroleum ether: ethyl acetate = 30:1).

[0167] (E)-1-(3-(4-(3-)dimethoxy styryl) phenoxy) propyl)-4-methylpiperazine (6n): white solid, yield 86%. 1 H NMR (300 MHz, CDC13) δ (ppm): 7.52 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 16.3 Hz, 1H), 7.02 (d, J = 16.3 Hz, 1H), 6.93 (d, J = 8.3 Hz, 2H), 6.74 (d, J = 2.2 Hz, 2H), 6.39 (t, J = 2.2 Hz, 1H), 4.01 (t, J = 6.4 Hz, 2H), 3.77 (s, 6H), 2.51 (m, 2H), 2.45-2.24 (m, 8H), 2.17 (s, 3H), 1.86 (quint, J = 6.8 Hz, 2H). 13 C NMR (75 MHz, CDC13) 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 tanshinone derivatives described in Examples 1-35, the present application uses vitamin C (Vc) as a positive control, uses DPPH free radical, superoxide anion free radical, ABTS free radical scavenging capacity and total reducing power as the determination index, and uses the enzyme marker method to evaluate the antioxidant activity of the tanshinone derivatives.

[0170] Test Example 1: DPPH radical scavenging capacity assay

[0171] 1. Experimental principle

[0172] 1,1-diphenyl-2-trinitrobenzene hydrazine (DPPH) is a stable free radical with three benzene rings around the nitrogen atom. DPPH· has a single electron, and the spectral scan has strong absorption at 517 nm, and its ethanol aqueous solution is dark purple, and the concentration has a linear relationship with the absorbance value. When there is a free radical scavenger in the solution, DPPH· can combine or replace with 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 discoloration is quantitatively related to the number of electrons accepted. Therefore, according to the absorbance value at this wavelength, the DPPH· scavenging rate of the compound can be calculated to evaluate the DPPH free radical scavenging capacity of the drug.

[0173] 2. Solution preparation

[0174] (1) A certain amount of sample to be tested was weighed and prepared into a mother liquor of a certain concentration. The mother liquor was taken and further diluted with DMSO to obtain a sample solution to be tested with an initial concentration of 600 μM.

[0175] (2) Ascorbic acid and pterostilbene were precisely weighed and dissolved in DMSO to obtain a 600 μM solution.

[0176] (3) DPPH solid was precisely weighed and dissolved in anhydrous ethanol to obtain a 0.2 mM DPPH solution for use.

[0177] 3. Experimental method

[0178] 50 μL of the sample solution to be tested with a concentration of 600 μM was added to a 96-well plate, and then 100 μL of the DPPH solution was added, and the total reaction volume was 150 μL. The control group was 50 μL of the sample solution to be tested added to 100 μL of anhydrous ethanol, and the blank group was 50 μL of the DMSO solution added to 100 μL of the DPPH solution. After being placed at room temperature in the dark for 30 min, the mixture was shaken and mixed, and after the reaction was completed, the absorbance value at 517 nm of each well was measured using an enzyme marker, and the DPPH free radical scavenging rate of the sample to be tested was calculated according to formula (1).

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

[0180] 4. Experimental results and analysis

[0181] According to the experimental results in Table 1, the DPPH radical scavenging rates of all the tested samples were between 1.53-55.09% at the maximum final concentration of 200 μM, which were obviously weaker than that of Vc (93.01%). The scavenging rates of derivatives 2b and 4e-4j were between 49.23-55.09%, indicating that their scavenging abilities were comparable to that of PTE (51.22%). Among the azido-type tanshinone derivatives (4a-4p), the introduction of aromatic sulfonyl group could improve the DPPH radical scavenging effect of the compounds (4e-4j vs. 3; 4e-4j vs. 4k-4p).

[0182] Table 1. DPPH radical scavenging abilities of the obtained tanshinone derivatives

[0183]

[0184] Test Example 2: Superoxide anion radical scavenging ability determination

[0185] 1. Experimental principle

[0186] Pyrogallol can undergo autoxidation under alkaline conditions to release O2 - ·, which in turn generates an orange-red intermediate product. The intermediate product has a strong absorption at 320 nm. When an O2 - · scavenger is present, it can rapidly react with O2 - ·, thereby preventing the accumulation of the intermediate product, resulting in a decrease in the absorption of the solution at a wavelength of 320 nm. That is, the amount of the intermediate product is positively correlated with the strength of the absorbance. Thus, the present application can determine the O2 - · scavenging effect of a compound by measuring the absorbance value.

[0187] 2. Solution preparation

[0188] (1) An appropriate amount of 20% hydrochloric acid solution was taken and distilled water was added to prepare a 10 mmol / L hydrochloric acid solution.

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

[0190] (3) Pyrogallol was precisely weighed, dissolved with a 10 mmol / L hydrochloric acid solution and diluted to volume to prepare a 3 mmol / L pyrogallol solution.

[0191] 3. Experimental method

[0192] Take 200 μM of the sample solution and Vc solution, 30 μL each, and add to a 96-well plate, then add 150 μL of Tris-HCl solution and mix well, and place in a 25°C air bath, incubate for 20 min, then take out. Add 30 μL of pyrogallol solution and mix well, and place in a 25°C air bath, incubate for 5 min, then take out. The control group is distilled water instead of pyrogallol solution in the system, and the blank group is DMSO solution instead of sample solution in the system.

[0193] Determine the absorbance value at 320 nm of each well by an enzyme marker. According to formula (2), calculate the scavenging rate of the sample on superoxide anion free radicals.

[0194] O2 - The scavenging rate (%) of O2 样品 · = [1-(OD 对照 -OD 空白 ) / OD - ] x 100% formula (2)

[0195] 4. Experimental results and analysis

[0196] Table 2. Scavenging rate of some tanshinone derivatives on superoxide anion

[0197]

[0198] The present application uses the pyrogallol autoxidation method to determine the scavenging rate of the sample on O2 - ·, and the results are shown in Table 2. At a maximum initial concentration of 200 μM, the scavenging rate of derivatives 2a, 4a, 4c, 4e, 4h, 4i and 4m-4p on superoxide anion free radicals is between 89.20-98.29%, and the scavenging effect is comparable to PTE (90.33%) or Vc (99.66%). It is worth noting that derivative 2a shows the best O2 - · scavenging ability, with a scavenging rate of 98.29%. For azide tanshinone derivatives, the introduction of electron-withdrawing groups (such as -CF3, -NO2 and -Cl) on the aromatic ring of aromatic sulfonyl and aromatic benzyl helps to improve the scavenging effect of the compound on superoxide anion (4c, 4e, 4h vs. 4d, 4f, 4g; 4m-4p vs. 4o).

[0199] Test Example 3: Total reducing capacity determination

[0200] 1. Experimental principle

[0201] When there is a reducing capacity in the system, Fe 3+ can be reduced to Fe 2+ , and then Fe 2+can generate purple red substance with ortho-phenanthroline, and has maximum absorption peak at wavelength of 510nm. On the contrary, Fe 3+ generate colorless substance with ortho-phenanthroline, and has no maximum characteristic peak at this wavelength. Therefore, absorbance value is closely related to sample reducing capacity, and the smaller the △OD value is, the stronger the reducing capacity of the sample is.

[0202] 2. Solution preparation

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

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

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

[0206] (4) mix equal volume of (1) and (2) solutions to obtain determination application liquid; mix equal volume of (1) and (3) solutions to obtain control application liquid.

[0207] 3. Experimental method

[0208] Add 180μL determination application liquid to 96-well plate, and then add 20μL 200μM sample and Vc solution to be detected, and incubate at room temperature for 30min in dark. The control group is reacted in the system by replacing the determination application liquid with 180μL control application liquid. Finally, the absorbance value OD at 510nm wavelength of each well is determined by using an enzyme marker.

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

[0210] 4. Experimental results and analysis

[0211] Table 3. Total reducing capacity of part of sirtinol derivatives

[0212]

[0213]

[0214] The total reducing capacity of the derivative is detected by the ortho-phenanthroline-Fe 2+ reduction method. As shown in Table 3, the total reducing capacity of most derivatives is equivalent to PTE (△OD = 1.7832), and the △OD value floats between 1.7-1.9. Especially, the total reducing capacity of derivatives 2b, 4i, 4j and 6g (△OD = 1.5456-1.5801) is slightly stronger than PTE.

[0215] Test Example 4: ABTS radical cation scavenging capacity assay

[0216] 1. Experimental principle

[0217] Under the action of oxidants such as K2S2O8, H2O2, 2,2'-azobis(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 734 nm. When the antioxidant in the system reacts with ABTS + ·, the system will become colorless ABTS, and the content of ABTS + · in the system is linearly related to the absorbance value. Therefore, according to the determined absorbance value, the scavenging effect of the compound on ABTS + · free radicals is determined.

[0218] 2. Solution preparation

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

[0220] (2) Precisely weigh ABTS solid, add an appropriate amount of ultrapure water to prepare a 7.4 mM ABTS solution;

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

[0222] (4) Accurately pipette the ABTS stock solution, and dilute with ultrapure water to obtain an ABTS + · assay solution.

[0223] 3. Experimental method

[0224] Pipette 20 μL of 600 μM of the sample solution to be tested 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 to be tested added to 200 μL of ultrapure water, and the blank group is 20 μL of DMSO solution added to 200 μL of ABTS + · assay solution. Place at room temperature in the dark for 10 min, shake well, and after the reaction is complete, measure the absorbance value at 734 nm of each well using an enzyme marker, and calculate the ABTS free radical scavenging rate of the sample according to formula (4).

[0225] ABTS + · scavenging rate = [1-(OD 样品 - OD 对照 ) / OD 空白 ] x 100% formula (4)

[0226] 4. Experimental Results and Analysis

[0227] Table 4. Scavenging rates of some pterostilbene derivatives against ABTS free radicals

[0228]

[0229]

[0230] This invention uses the ABTS method to detect the derivative's effect on ABTS. + • Free radical scavenging ability. Table 4 shows that most derivatives exhibited weak ABTS free radical scavenging ability, with scavenging rates ranging from 1.63% to 22.99%. At a maximum initial concentration of 600 μM, only derivatives 2a (77.19%) and 2b (94.39%) showed stronger ABTS free radical scavenging efficacy than the parent drug PTE (62.25%). Furthermore, the scavenging effect of derivative 2b on ABTS free radicals was similar to that of Vc (94.68%).

[0231] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A class of derivatives of pterostilbene, characterized in that: The chemical structure of the derivative is as follows: ; Wherein, R1 is one of the following structural formula: 。 2. Use of the derivative of pterostilbene or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating and / or preventing diseases caused by oxidative stress.

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

4. Use according to claim 3, characterized in that: The dosage form of the medicament is powder, granules, tablets, capsules, pills or injection.

5. A pharmaceutical composition, characterized by, The derivative of claim 1, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient or carrier.

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