Synthesis and biological activity research of bergenin derivative

Abstract

The invention relates to the field of chemical medicines, and particularly discloses synthesis and biological activity research of bergenin derivatives. The bergenin derivative is a compound as shown in a formula I, wherein R1, R2, R3, R4, R5 and R6 are defined in the specification. The bergenin derivative can be used as an inflammation inhibitor, compared with a fluorine-free compound, fluorine atoms introduced into the compound have higher activity, the anti-inflammation performance of the compound can be effectively improved, and the bergenin derivative can be used for effectively treating and / or preventing inflammatory diseases. In addition, the invention provides a scientific basis for discussing new application of bergenin, and has important significance for research and development of new drugs.

Description

Technical Field

[0001] This invention belongs to the field of chemical medicine, specifically involving several Bergenin derivatives, their preparation methods, and uses. Background Technology

[0002] Bergenin is a natural compound extracted from plants such as Bergenia spp. In the chapter on treating childhood colds in the Tibetan medicine classic *Supplement to Tibetan Medical Formulas*, it is mentioned that Bergenin should be added to stop coughs. It is also a component of the classic Tibetan medicine formula "Jiuxi Gengzhuo," which is completely identical to the formula of An'erning granules exclusively produced by Jinhe Tibetan Medicine, used for clearing heat, dispelling wind, resolving phlegm, and stopping coughs. Clinically, it is often used as an effective ingredient in antitussive and anti-inflammatory drugs to treat coughs, acute and chronic bronchitis, duodenal ulcers, and other conditions. Currently, Bergenin tablets are used as a prepared medicine for the treatment of chronic bronchitis. Recent pharmacological experiments have shown that Bergenin also has hepatoprotective, anti-ulcer, immune-enhancing, anti-lipid peroxidation, and free radical scavenging abilities.

[0003] Fluorine atoms have been shown to impart unique properties to fluorine-containing drug compounds, thus playing a crucial role in medicinal chemistry and new drug development. Currently, 20%-25% of drug molecules worldwide contain fluorine atoms, and commercially available fluorine-containing drugs are used to treat a variety of diseases. The introduction of fluorine atoms into drug molecules has been shown to modulate several key properties, including lipophilicity, acidity / basicity, conformation, ligand-receptor interactions, bioavailability, and metabolic stability.

[0004] The following are studies on the anti-inflammatory effects of synthesized bergenin derivatives: Nunomura et al. (J. Braz. Chem. Soc. 2009, 20(6), 1060–1064) reported that bergenin is a key target enzyme of COX-1 (IC50 = 107.2 μmol·L⁻¹) in the development of inflammation. -1 COX-2 (IC50 = 1.2 μmol·L⁻¹) -1 ) and phospholipase A2 (IC50 = 156.6 μmol·L) -1 The results showed that bergenin is a selective COX-2 inhibitor, which is of great significance for reducing gastrointestinal adverse reactions after drug development.

[0005] In 2011, Jung et al. (Chem Biol Drug Des 2011, 78 (4), 725–729) performed a total acylation modification of the hydroxyl groups of Bergenin and determined the inhibitory effect of the synthesized derivatives on LPS-induced NO production (the IC50 values ​​of the derivatives were in the range of 20–30 μmol·L⁻¹). -1(range) and anti-anesthetic effect (10–20 mg / kg) -1 That is, it produces a significant anti-anesthetic effect in morphine-dependent mice.

[0006]

[0007] In 2012, Shah et al. (Bioorganic & Medicinal Chemistry Letters 2012, 22 (8), 2744–2747) alkylated two phenolic hydroxyl groups of Bergenin and determined the inhibitory effects of these derivatives on the inflammatory mediators NO and TNF-α. The compound with the best activity had an IC50 value of 212.95 μmol·L⁻¹. -1 Compared with the bergenin prototype and the control indomethacin, the activity was improved.

[0008]

[0009] In 2014, Jain et al. (J Med Chem, 2014 (8), 7085–709) reported that a series of nitrogen-containing heterocyclic derivatives were obtained by modifying the benzene ring of Bergenin by the Mannich reaction, and the in vitro and in vivo anti-arthritis activity of these compounds was determined. The results showed that they exerted anti-inflammatory effects as potent IL-6 inhibitors.

[0010]

[0011] However, direct fluorination of the hydroxyl groups on the sugar and benzene rings of bergenin has not been reported. Furthermore, studies on the anti-inflammatory properties of fluorinated bergenin derivatives are also rare. Therefore, research on the synthesis and anti-inflammatory activity of fluorinated bergenin derivatives is of great significance. Summary of the Invention

[0012] The purpose of this invention is to provide methods for preparing and using several Bergenin derivatives.

[0013] This invention provides bergenin derivatives as shown in Formula I:

[0014] in, (1) When R4=H, R5=R6=OH, R1 is selected from COF, CF2H, CH2R7; R7, R2, and R3 may be the same or different, and each is independent of OH, F, F2, and OR8; R8 is selected from COR9, SO2R9, F-substituted C1~C8 alkyl, CF2-substituted C1~C8 alkyl, and CF3-substituted C1~C8 alkyl. R9 is selected from F-substituted C1-C8 alkyl groups, CF2-substituted C1-C8 alkyl groups, and CF3-substituted C1-C8 alkyl groups; R 10 Selected from 1 to 5 identical or different F, CF3, CF2H; (2) When R1=CH2OH, R2=R3=OH, and R4=H, R5 and R6 are the same or different, and each is independently OH, F, or OR. 11 ; R 11 Selected from substituted or unsubstituted benzyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C1-C8 acyl or sulfonyl; The substituents of the benzyl group are selected from OCH3, F, OH, CN, NO2, CF3, and CF2H; The substituents of the phenyl group are selected from OCH3, F, OH, CN, NO2, CF3, CF2H; The substituents of the alkyl group are selected from F, CF3, and CF2H; The substituents of the cycloalkyl group are selected from F, CF3, and CF2H; The acyl or sulfonyl substituent is selected from C1-C8 alkyl, F, CF3, CF2H, F or CF3-substituted phenyl groups; (3) When R1 = CH2OH, R2 = R3 = R5 = R6 = OH, R4 is F or COR. 12 SO2R 12 CF2H, CF3, NR 13 ; R 12 Selected from F or CF3-substituted C1~C8 alkyl or phenyl groups; R 13 Selected from C1-C8 alkyl or 3-6 membered cycloalkyl or alkyl groups substituted with F or CF3.

[0015] Furthermore, the application of bergenin derivatives shown in Formula I in terms of anti-inflammatory activity.

[0016] The beneficial effects of this invention are: This invention designs several novel fluorinated bergenin derivatives. The introduction of fluorine atoms significantly improves the anti-inflammatory properties and oral absorption of the entire compound. Compared with compounds without fluorine atoms, the compounds of this invention exhibit higher anti-inflammatory effects and can be used for the effective treatment and / or prevention of inflammatory diseases. Furthermore, this invention provides a scientific basis for exploring new uses of bergenin and is of great significance for the development of new drugs. Attached Figure Description

[0017] Figure 1 Compound 1 described in this invention 1 H-NMR spectrum; Figure 2 Compound 2 as described in this invention 1 H-NMR spectrum; Figure 3 Compound 3 as described in this invention 1 H-NMR spectrum; Figure 4 Compound 4 described in this invention 1 H-NMR spectrum; Figure 5 Compound 5 as described in this invention 1 H-NMR spectrum; Figure 6 Compound 6 described in this invention 1 H-NMR spectrum; Figure 7 Compound 7 described in this invention 1 H-NMR spectrum; Figure 8 This is the structure of the Bergenin derivative described in this invention. Detailed Implementation Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0018] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0019] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0020] Example 1: Preparation of (2S,3S,4S,4aR,10bS)-2-(fluoromethyl)-3,4,8,10-tetrahydroxy-9-methoxy-3,4,4a,10b-tetrahydropyrano[3,2-c]isochromene-6(2H)-one (Compound 1)

[0021] S1. Add bergenin (2 g), diethylaminosulfur trifluoride (4.9 g), and N,N-dimethylformamide (25 ml) to the reaction flask. oThe reaction was monitored by TLC below C; after the reaction was complete, saturated sodium bicarbonate was added to quench the reaction, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 1 (703 mg, yield 35%).

[0022] 1 H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.33 (s, 1H), 7.00 (s, 1H), 5.70 (d, J = 5.5 Hz, 1H), 5.65 (d, J = 5.9 Hz, 1H), 4.98 (d, J = 10.5 Hz,1H), 4.85 – 4.52 (m, 2H), 3.98 (t, J = 9.9 Hz, 1H), 3.84 – 3.55 (m, 6H). Example 2: Preparation of (2R,3R,4R,4aR,10bS)-3-fluoro-4,8,10-trihydroxy-2-(hydroxymethyl)-9-methoxy-3,4,4a,10b-tetrahydropyrano[3,2-c]isocyanene-6(2H)-one (compound 2)

[0023] S1. Bergenin (6.56 g), potassium carbonate (13.8 g), and N,N-dimethylformamide (100 ml) were added to the reaction flask and stirred at room temperature for 30 minutes. Benzyl bromide (8.5 g) was added, and stirring continued. The reaction was monitored by TLC. After the reaction was complete, water was added to quench the reaction. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2a (9.75 g, yield 89%).

[0024] 1H NMR (400 MHz, DMSO-d6) δ 7.56 – 7.46 (m, 5H), 7.45 – 7.27 (m, 6H), 5.57 (d, J = 5.4 Hz, 1H), 5.27 (d, J = 5.0 Hz, 1H), 5.22 (s, 2H), 5.09 – 4.96(m, 2H), 4.79 (d, J = 10.3 Hz, 1H), 4.50 (dd, J = 6.1, 4.6 Hz, 1H), 3.97 –3.91 (m, 1H), 3.81 (s, 3H), 3.66 (ddd, J = 9.7, 6.5, 4.6 Hz, 2H), 3.57 (ddd,J = 11.6, 6.1, 3.8 Hz, 1H), 3.42 – 3.35 (m, 2H). S2. Compound 2a (4.5 g), 2,2-dimethoxypropane (13.1 g), pyridinium p-toluenesulfonate (900 mg), and dichloromethane (200 ml) were added to the reaction flask, and the mixture was heated to 40 °C. o C, TLC monitoring of the reaction; after the reaction was complete, saturated sodium bicarbonate was added to quench the reaction, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2b (4.14 g, yield 85%).

[0025] 1 H NMR (400 MHz, DMSO-d6) δ 7.54 – 7.47 (m, 3H), 7.45 – 7.32 (m, 8H), 5.74 (d, J = 5.6 Hz, 1H), 5.22 (s, 2H), 4.98 (dd, J = 10.7, 6.5 Hz, 2H), 4.85(d, J = 11.0 Hz, 1H), 4.05 (dd, J = 10.4, 9.1 Hz, 1H), 3.86 (s, 3H), 3.79(td, J = 9.0, 5.7 Hz, 1H), 3.67 – 3.52 (m, 2H), 3.50 – 3.40 (m, 2H), 1.42 (s,3H), 1.32 (s, 3H). S3 Compound 2b (4.14 g), triethylamine (1.1 g), acetic anhydride (1.5 g), and dichloromethane (75 ml) were added to the reaction flask. The mixture was heated to room temperature, and the reaction was monitored by TLC. After the reaction was complete, saturated sodium bicarbonate was added to quench the reaction. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 2c (3.51 g, yield 79%).

[0026] 1 H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.49 – 7.44 (m, 2H), 7.43 –7.33 (m, 8H), 5.39 (t, J = 9.5 Hz, 1H), 5.17 (q, J = 11.7 Hz, 2H), 5.05 (d, J = 10.8 Hz, 1H), 4.95 (d, J = 10.8 Hz, 1H), 4.61 (d, J = 10.4 Hz, 1H), 4.21 (t, J = 10.0 Hz, 1H), 3.97 (s, 3H), 3.77 – 3.63 (m, 3H), 3.42 (td, J = 9.4,6.1 Hz, 1H), 2.14 (s, 3H), 1.44 (s, 3H), 1.39 (s, 3H). S4 Compound 2c (3.5 g), trifluoroacetic acid (5 g), and dichloromethane (50 ml) were added to the reaction flask and the mixture was heated to room temperature. The reaction was monitored by TLC. After the reaction was complete, saturated sodium bicarbonate was added to quench the reaction. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 2d (2.8 g, yield 88%).

[0027] 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.48 – 7.41 (m, 2H), 7.41 –7.31 (m, 8H), 5.25 – 5.12 (m, 3H), 5.09 – 5.00 (m, 2H), 4.44 (d, J = 10.4 Hz,1H), 4.16 (t, J = 10.1 Hz, 1H), 3.97 (s, 3H), 3.77 (dd, J = 12.1, 3.2 Hz,1H), 3.72 – 3.64 (m, 2H), 3.44 (ddd, J = 9.0, 5.1, 3.2 Hz, 1H), 3.23 (s, 1H), 2.18 (s, 3H). S5 Compound 2d (2.8 g), triethylamine (1 g), acetic anhydride (0.8 g), and dichloromethane (50 ml) were added to the reaction flask. The mixture was heated to room temperature, and the reaction was monitored by TLC. After the reaction was complete, saturated sodium bicarbonate was added to quench the reaction. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2e (1.92 g, yield 62%).

[0028] 1 H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.48 – 7.30 (m, 10H), 5.30 –5.24 (m, 1H), 5.17 (q, J = 11.7 Hz, 2H), 5.12 – 5.03 (m, 2H), 4.60 (d, J =10.4 Hz, 1H), 4.44 (dd, J = 12.2, 3.1 Hz, 1H), 4.22 (t, J = 10.1 Hz, 1H), 4.14 (dd, J = 12.4, 1.4 Hz, 1H), 3.96 (s, 3H), 3.60 (dt, J = 6.0, 2.8 Hz,2H), 3.24 (d, J = 3.8 Hz, 1H), 2.20 (s, 3H), 1.99 (s, 3H). S6 Using the synthesis method of compound 1 in Example 1, compound 2f (200 mg, yield 40%) was prepared by replacing the raw material Bergenin with compound 2e.

[0029] 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.48 – 7.32 (m, 10H), 5.24 –5.11 (m, 3H), 5.06 (s, 2H), 4.98 (dd, J = 49.5, 2.8 Hz, 1H), 4.61 (t, J =10.3 Hz, 1H), 4.51 (d, J = 10.3 Hz, 1H), 4.21 (d, J = 6.5 Hz, 2H), 3.96 (s,3H), 3.86 (dt, J = 28.1, 6.5 Hz, 1H), 2.21 (s, 3H), 1.94 (s, 3H). S7 Add compound 2f (200 mg), potassium carbonate (100 mg), and methanol (4 ml) to the reaction flask, raise the temperature to room temperature, and monitor the reaction by TLC. After the reaction is complete, quench with hydrochloric acid, extract the aqueous phase twice with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, and add directly to the reaction flask.

[0030] S8 Add 2g (200 mg) of compound, 40 mg of palladium on carbon, and 5 ml of methanol to the reaction flask, purge with hydrogen gas, and react at room temperature. Monitor the reaction by TLC. After the reaction is complete, filter with diatomaceous earth and concentrate under reduced pressure to obtain compound 2 (112 mg, yield 90%).

[0031] 1 H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.37 (s, 1H), 7.00 (s, 1H), 5.87 (d, J = 6.4 Hz, 1H), 5.12 (t, J = 5.5 Hz, 1H), 5.00 (d, J = 10.3 Hz,1H), 4.83 (dd, J = 49.4, 2.8 Hz, 1H), 4.26 (t, J = 10.1 Hz, 1H), 4.11 – 4.01(m, 1H), 3.95 (dt, J = 29.5, 6.7 Hz, 1H), 3.77 (s, 3H), 3.63 (t, J = 5.4 Hz, 2H). Example 3: Preparation of (2R,3R,4R,4aS,10bS)-4-fluoro-3,8,10-trihydroxy-2-(hydroxymethyl)-9-methoxy-3,4,4a,10b-tetrahydropyrano[3,2-c]isocyanene-6(2H)-one (compound 3)

[0032] S1. Using the synthesis method of compound 2b in Example 2, compound 3a (2.1 g, yield 85%) was obtained by replacing the starting material compound 2a with bergenin.

[0033] 1 H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.31 (s, 1H), 6.99 (s, 1H), 5.70 (d, J = 5.7 Hz, 1H), 4.99 (d, J = 10.4 Hz, 1H), 4.06 – 3.97 (m, 2H), 3.82 – 3.77 (m, 1H), 3.75 (s, 3H), 3.71 (d, J = 10.1 Hz, 1H), 3.62 – 3.51 (m, 2H), 1.44 (s, 3H), 1.34 (s, 3H). S2 The synthesis method of compound 1 in Example 1 was used, and compound 3b (500 mg, yield 47%) was obtained by replacing the raw material Bergenin with compound 3a.

[0034] 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.43 (s, 1H), 7.01 (s, 1H), 5.18 (d, J = 10.7 Hz, 1H), 5.16 (d, J = 56.2 Hz, 1H), 4.57 (ddd, J = 27.3,10.7, 1.7 Hz, 1H), 4.04 (dd, J = 9.6, 4.5 Hz, 1H), 3.95 (ddd, J = 28.1, 9.9,1.9 Hz, 1H), 3.82 (td, J = 9.7, 4.4 Hz, 1H), 3.78 – 3.72 (m, 4H), 1.47 (s, 3H), 1.35 (s, 3H). S3 was prepared by using the synthesis method of compound 2d in Example 2, replacing compound 2c with compound 3b to obtain compound 3 (410 mg, yield 92%).

[0035] 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.38 (s, 1H), 7.00 (s, 1H), 5.66 (d, J = 6.7 Hz, 1H), 5.16 (dd, J = 10.8, 1.1 Hz, 1H), 5.04 (dt, J =55.1, 2.0 Hz, 1H), 4.90 (s, 1H), 4.52 (ddd, J = 28.0, 10.9, 1.7 Hz, 1H), 3.83(d, J = 11.9 Hz, 1H), 3.78 (s, 3H), 3.77 – 3.72 (m, 1H), 3.68 – 3.54 (m, 1H), 3.53 – 3.45 (m, 1H). Example 4: Preparation of (2R,3R,4aS,10bS)-4,4-difluoro-3,8,10-trihydroxy-2-(hydroxymethyl)-9-methoxy-3,4,4a,10b-tetrahydropyrano[3,2-c]isocyanene-6(2H)-one (compound 4)

[0036] S1. Chromium trioxide (2.9 g), pyridine (4.6 g), and dichloromethane (70 ml) were added to the reaction flask. After stirring for 30 minutes, compound 2b (4 g) and acetic anhydride (3 g) were added. The mixture was heated to room temperature, and the reaction was monitored by TLC. After the reaction was complete, saturated sodium sulfite was added to quench the reaction. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 4a (3 g, 75% yield). This was then added directly to the reaction flask.

[0037] S2 The synthesis method of compound 1 in Example 1 was used, and compound 4b (2.5 g, yield 80%) was obtained by replacing the raw material Bergenin with compound 4a.

[0038] 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.48 – 7.34 (m, 10H), 5.18 (q,J = 11.7 Hz, 2H), 5.08 (d, J = 10.9 Hz, 1H), 4.94 (d, J = 10.8 Hz, 1H), 4.83(d, J = 10.6 Hz, 1H), 4.35 (ddd, J = 18.7, 10.6, 2.5 Hz, 1H), 3.98 (s, 3H), 3.85 (ddd, J = 19.2, 9.5, 3.5 Hz, 1H), 3.74 – 3.58 (m, 3H), 1.49 (d, J = 2.0Hz, 6H). S3 uses the synthesis method of compound 2d in Example 2, replacing the starting material compound 2c with compound 4b to obtain compound 4c (2 g, yield 90%).

[0039] 1 H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.47 – 7.34 (m, 10H), 5.17 (q,J = 11.6 Hz, 2H), 5.04 (d, J = 2.9 Hz, 2H), 4.60 (d, J = 9.8 Hz, 1H), 4.26(ddd, J = 19.9, 10.5, 2.1 Hz, 1H), 3.98 (s, 3H), 3.94 – 3.84 (m, 1H), 3.70(d, J = 3.5 Hz, 2H), 3.49 (dt, J = 10.8, 3.5 Hz, 1H), 3.17 (s, 1H). S4 The synthesis method of compound 2 in Example 2 was adopted, and compound 4 (1.2 g, yield 90%) was obtained by replacing the starting material compound 2 g with compound 4 c.

[0040] 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.35 (s, 1H), 7.02 (s, 1H), 6.18 (d, J = 7.1 Hz, 1H), 5.11 (dd, J = 10.8, 1.4 Hz, 1H), 4.98 (t, J = 5.3Hz, 1H), 4.78 (ddd, J = 20.9, 10.7, 2.1 Hz, 1H), 3.85 – 3.73 (m, 5H), 3.72 –3.65 (m, 1H), 3.61 – 3.52 (m, 1H). Example 5: Synthesis of (2R,3R,4S,4aS,10bS)-3,8,10-trihydroxy-2-(hydroxymethyl)-9-methoxy-6-oxo-2,3,4,4a,6,10b-hexahydropyrano[3,2-c]isocyanene-4-yl-4-fluorobenzoate (compound 7)

[0041] S1 Compound 2b (3 g), p-fluorobenzoyl chloride (1.9 g), triethylamine (1.5 g), and dichloromethane (55 ml) were added to the reaction flask. The mixture was heated to room temperature, and the reaction was monitored by TLC. After the reaction was complete, saturated sodium bicarbonate was added to quench the reaction. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 7a (3.1 g, yield 85%).

[0042] 1H NMR (400 MHz, CDCl3) δ 8.12 – 8.04 (m, 2H), 7.56 (s, 1H), 7.49 –7.42 (m, 2H), 7.45 – 7.32 (m, 8H), 7.12 (t, J = 8.6 Hz, 2H), 5.64 (t, J = 9.4Hz, 1H), 5.24 – 5.10 (m, 2H), 5.08 (d, J = 10.8 Hz, 1H), 4.97 (d, J = 10.8Hz, 1H), 4.71 (d, J = 10.4 Hz, 1H), 4.38 (t, J = 10.0 Hz, 1H), 3.99 (s, 3H), 3.87 (t, J = 9.5 Hz, 1H), 3.78 – 3.68 (m, 2H), 3.50 (td, J = 9.2, 6.4 Hz, 1H), 1.43 (s, 3H), 1.37 (s, 3H). S2 uses the synthesis method of compound 2d in Example 2, replacing the starting material compound 2c with compound 7a to obtain compound 7b (2.6 g, yield 90%), which is then directly added to the feed.

[0043] S3 uses the synthesis method of compound 2 in Example 2, replacing the starting material compound 2g with compound 7b to obtain compound 7 (1.4 g, yield 85%).

[0044] 1 H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.41 (s, 1H), 8.16 – 8.07(m, 2H), 7.40 (t, J = 8.8 Hz, 2H), 6.97 (s, 1H), 5.75 (d, J = 6.3 Hz, 1H),5.51 (t, J = 9.4 Hz, 1H), 5.24 (d, J = 10.5 Hz, 1H), 5.00 – 4.94 (m, 1H),4.49 (t, J = 10.1 Hz, 1H), 3.87 (ddd, J = 11.8, 4.9, 2.1 Hz, 1H), 3.80 – 3.74(m, 4H), 3.64 (td, J = 9.3, 6.4 Hz, 1H), 3.52 (dt, J = 12.3, 6.5 Hz, 1H). Example 6: Preparation of (2R,3S,4S,4aR,10bS)-3,4,10-trihydroxy-2-(hydroxymethyl)-9-methoxy-8-(2,2,2-trifluoroethoxy)-3,4,4a,10b-tetrahydropyrano[3,2-c]isocyanene-6(2H)-one (compound 17) and (2R,3S,4S,4aR,10bS)-3,4-dihydroxy-2-(hydroxymethyl)-9-methoxy-8,10-bis(2,2,2-trifluoroethoxy)-3,4,4a,10b-tetrahydropyrano[3,2-c]isocyanene-6(2H)-one (compound 18).

[0045] S1. Add bergenin (2 g), trifluoroiodoethane (1.6 g), potassium carbonate (3.4 g), and N,N-dimethylformamide (30 ml) to the reaction flask, and heat to 100°C. o C, TLC monitoring of the reaction; after the reaction was complete, water was added to quench it, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 17 (1 g, yield 40%) and compound 18 (0.5 g, yield 16.7%).

[0046] Compound 17: 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.24 (s, 1H), 5.69 (d, J = 5.4 Hz, 1H), 5.46 (d, J = 5.8 Hz, 1H), 5.06 (d, J = 10.5 Hz, 1H), 4.92 (t, J = 6.8 Hz, 1H), 4.85 (q, J = 8.8 Hz, 2H), 4.05 (t, J = 9.9 Hz, 1H), 3.90 – 3.82 (m, 1H), 3.80 (s, 3H), 3.67 (td, J = 8.9, 5.4 Hz, 1H), 3.58 ((td,J = 7.4, 2.1 Hz, 1H), 3.44 (t, J = 9.0 Hz, 1H), 3.21 (td, J = 9.0, 5.7 Hz, 1H). Compound 18: 1H NMR (400 MHz, DMSO-d6) δ 7.55 (s, 1H), 5.62 (d, J = 5.4Hz, 1H), 5.34 (d, J = 5.7 Hz, 1H), 4.99 – 4.88 (m, 3H), 4.77 – 4.59 (m, 3H), 3.95 (t, J = 9.9 Hz, 1H), 3.85 (s, 3H), 3.82 – 3.77 (m, 1H), 3.66 (td, J =9.0, 5.4 Hz, 1H), 3.52 (dt, J = 11.6, 6.0 Hz, 1H), 3.46 – 3.42 (m, 1H), 3.26(td, J = 9.0, 5.7 Hz, 1H). The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0047] Experimental Example 1: Determination of the anti-inflammatory activity of the compound of the present invention on RAW264.7 cells The experimental procedure is briefly described as follows: After cell culture, the toxicity of the compound of this invention to the cells was first tested. Then, a safe and non-toxic compound was selected for the NO inhibition test. After culturing the cells for 24 hours, compounds of various concentrations were added. One hour later, LPS was added. After incubation for 24 hours, the cells were centrifuged, and the supernatant was mixed with an equal volume of Griess reagent. The absorbance was measured at 540 nm using a microplate reader. The NO content of the compound was obtained by fitting the data with GraphPad Prism 8. The data are shown in Table 1.

[0048] Table 1. Inhibitory effect of the compounds of this invention on NO in RAW264.7 cells

[0049] As shown in Table 1, the compounds of this invention have a certain inhibitory effect on the inflammatory factor NO. The compounds with introduced fluorine atoms generally exhibit better inhibitory effects on NO than those without. Compounds 1, 3, and 4 show particularly excellent inhibitory effects.

[0050] In summary, this invention provides a novel compound with anti-inflammatory effects. The introduction of fluorine atoms into this compound results in higher activity compared to fluorine-free compounds, effectively enhancing its biological activity. Furthermore, the compound of this invention can be used to effectively treat and / or prevent inflammatory diseases.

Claims

1. Bergenin derivatives as shown in Formula I: in, (1) When R4=H, R5=R6=OH, R1 is selected from COF, CF2H, CH2R7; R7, R2, and R3 may be the same or different, and each is independent of OH, F, F2, and OR8; R8 is selected from COR9, SO2R9, F-substituted C1~C8 alkyl, CF2-substituted C1~C8 alkyl, and CF3-substituted C1~C8 alkyl. R9 is selected from F-substituted C1-C8 alkyl groups, CF2-substituted C1-C8 alkyl groups, and CF3-substituted C1-C8 alkyl groups; R 10 Selected from 1 to 5 identical or different F, CF3, CF2H; (2) When R1=CH2OH, R2=R3=OH, and R4=H, R5 and R6 are the same or different, and each is independently OH, F, or OR. 11 ; R 11 Selected from substituted or unsubstituted benzyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C1-C8 acyl or sulfonyl; The substituents of the benzyl group are selected from OCH3, F, OH, CN, NO2, CF3, and CF2H; The substituents of the phenyl group are selected from OCH3, F, OH, CN, NO2, CF3, CF2H; The substituents of the alkyl group are selected from F, CF3, and CF2H; The substituents of the cycloalkyl group are selected from F, CF3, and CF2H; The acyl or sulfonyl substituent is selected from C1-C8 alkyl, F, CF3, CF2H, F or CF3-substituted phenyl groups; (3) When R1 = CH2OH, R2 = R3 = R5 = R6 = OH, R4 is F or COR. 12 SO2R 12 CF2H, CF3, NR 13 ; R 12 Selected from F or CF3-substituted C1~C8 alkyl or phenyl groups; R 13 Selected from F or CF3-substituted C1~C8 alkyl or 3~6-membered cycloalkyl.

2. The Bergenin derivative according to claim 1, characterized in that: The compound has applications in the preparation of anti-inflammatory drugs.

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