Aromatic ether modified ginsenoside Rb1 derivative and application thereof in preparation of anti-flavivirus medicine with good stability

Abstract

The invention discloses an aromatic ether modified ginsenoside Rb1 derivative or a pharmaceutically acceptable salt thereof, wherein the structural formula of the aromatic ether modified ginsenoside Rb1 derivative is shown in the specification. According to the compound, high-selectivity etherification modification is carried out on a ginsenoside Rb1 sugar ring, an aromatic pharmacophore is introduced, the inhibitory activity on Zika virus and dengue virus is remarkably improved, and the compound has excellent metabolic stability and low cytotoxicity; the preparation method is realized through one-step reaction, is mild in condition and good in yield, and has an industrial production prospect; the derivative disclosed by the invention can be used for preparing medicines for resisting Zika virus and dengue virus, and dosage forms comprise tablets, injections and the like; .

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, specifically to an aromatic ether-modified ginsenoside Rb1 derivative or a pharmaceutically acceptable salt thereof, and its use in the preparation of stable drugs for the prevention and / or treatment of Zika virus and / or dengue virus infection. Background Technology

[0002] Dengue virus (DENV) and Zika virus (ZIKV) both belong to the Flaviviridae family and are primarily transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Reports indicate that DENV cases average 390 million annually, with a severe dengue mortality rate as high as 20%. ZIKV infection can lead to serious neurological complications such as microcephaly and Guillain-Barré syndrome in newborns. Currently, there are no specific antiviral drugs approved for these two viruses, and clinical treatment primarily relies on supportive therapy. Developing novel broad-spectrum antiviral drugs has become an urgent global public health need.

[0003] Ginsenoside Rb1, as a typical representative of protopanaxadiol-type tetracyclic triterpenoid saponins, has had its anti-inflammatory, antioxidant, and neuroprotective pharmacological activities fully verified. Recent studies have shown that its antiviral mechanism is gradually becoming a research hotspot (Zhang Y et al.). Journal of Ginseng Research , 2023, 47(2): 183-192.). Although previous studies have revealed the anti-hepatitis C virus (HCV) activity of ginsenoside Rb1 (CN201510695240.2), our research group found through systematic screening that the half-maximal inhibitory concentration (IC50) of natural Rb1 against ZIKV and DENV is 183-192. 50 The concentrations of all Rb1 molecules were greater than 120 μM, indicating that their direct antiviral activity was significantly insufficient. Further studies have shown that amino acid esterification modification of the Rb1 sugar ring structure can significantly enhance its anti-ZIKV and DENV activities (CN202210449816.7), but the existing technology still has the following key shortcomings: (1) Poor chemical stability: Ginsenoside Rb1 ester derivatives in the existing technology generally have obvious metabolic stability defects. Experiments show that after the ester bond is placed in simulated gastric juice (pH=1.2) at 37°C for 48 hours, the chemical residue rate is generally less than 65%, and the degradation intensifies with increasing temperature. This stability bottleneck seriously restricts its clinical application prospects; (2) Insufficient selectivity of modification sites: Rb1 molecules contain 15 modifiable hydroxyl groups, and conventional chemical modification often leads to the generation of multi-substituted byproducts, which makes purification difficult and the activity uncontrollable; (3) Limited structural diversity: Existing modification systems are mostly limited to the introduction of amino acid groups in the Rb1 sugar ring structure. Summary of the Invention

[0004] The present invention aims to overcome the shortcomings of the prior art and provide a class of aromatic ether modified ginsenoside Rb1 derivatives with novel structure, significant activity and high stability, as well as their preparation method and their application in the preparation of drugs with good stability against ZIKV and DENV.

[0005] This invention involves systematically modifying the sugar ring structure of ginsenoside Rb1 to introduce an aromatic amine pharmacophore, and designing and synthesizing derivatives or pharmaceutically acceptable salts of the following general formula I: ; Where: R1 and R2 are each independently selected from H or ; R1 is selected from H, halogen (F, Cl, Br, I), C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, hydroxyl, and the substitution site is one or more of the 2 to 6 positions of the aromatic ring; R1 and R2 cannot both be H.

[0006] The specific compounds of the aromatic ether-modified ginsenoside Rb1 derivatives are as follows: ; .

[0007] Another objective of this invention is to provide a method for preparing the above-mentioned aromatic ether-modified ginsenoside Rb1 derivative, namely, under the presence of a solvent and an alkaline catalyst, ginsenoside Rb1 and 2-bromo-N-phenylacetamide derivative are stirred and reacted at 20-25°C for 1-3 hours, followed by extraction, column chromatography purification, and drying to obtain the aromatic ether-modified ginsenoside Rb1 derivative. The molar ratio of ginsenoside Rb1 to 2-bromo-N-phenylacetamide derivative is 1:3~8; the alkaline catalyst is selected from one or more of sodium hydride (NaH), potassium iodide (KI), and tetra-n-butylammonium iodide (TBAI); the solvent is selected from one or more of N,N-dimethylformamide, tetrahydrofuran, and pyridine.

[0008] This method achieves specific etherification modification of Glc-2''' and Glc-2'' sites by precisely controlling reaction catalyst, raw material ratio, solvent, temperature and time, which significantly improves reaction selectivity and product purity.

[0009] This invention demonstrates through systematic stability studies that aromatic ether-modified ginsenoside Rb1 derivatives exhibit good chemical stability in simulated physiological environments. Experiments show that, within a wide pH range of 1.2 to 7.4, after being placed at 37°C for 48 hours, the chemical residue rate of aromatic ether-modified ginsenoside Rb1 derivatives remains above 90%, significantly better than ester derivatives (p<0.01). This characteristic provides an important guarantee for drug formulation development and clinical application.

[0010] Meanwhile, the aromatic ether-modified ginsenoside Rb1 derivative of this invention maintains low cytotoxicity (CC). 50 While exhibiting >200 μM, it also showed excellent inhibitory activity against ZIKV and DENV, with its EC50... 50 With values ​​reaching the micromolar or even nanomolar level, the therapeutic index (TI) is significantly higher than that of the positive control drug ribavirin. The aromatic ether-modified ginsenoside Rb1 derivative or its pharmaceutically acceptable salt can be used in the preparation of drugs with good stability for the prevention and / or treatment of Zika virus and / or dengue virus infection.

[0011] The components (or active ingredients) of the drug of the present invention are aromatic ether modified ginsenoside Rb1 derivatives or pharmaceutically acceptable salts thereof, and may also include one or more pharmaceutically acceptable excipients, or be compounded with other active ingredients to exert an inhibitory effect; in addition to being made into tablets, the preparations may also be made into various pharmaceutically acceptable forms such as pills, powders, capsules, granules, oral liquids and injections.

[0012] In summary, this invention provides a class of candidate compounds with good drug development prospects, good stability, and strong antiviral activity through rational structural design, highly selective synthesis methods, and systematic activity evaluation, offering a new solution for the development of anti-ZIKV and DENV drugs. Attached Figure Description

[0013] Figure 1 Stability test results of aromatic ether-modified ginsenoside Rb1 derivatives I-1 ~ I-14 and control compounds in artificial gastric fluid at 20°C; Figure 2 Stability test results of aromatic ether-modified ginsenoside Rb1 derivatives I-1 ~ I-14 and control compounds in artificial gastric fluid at 37°C; Figure 3 Stability test results of aromatic ether-modified ginsenoside Rb1 derivatives I-1 ~ I-14 and control compounds in artificial gastric fluid at 50°C; Figure 4Stability test results of aromatic ether-modified ginsenoside Rb1 derivatives I-1 ~ I-14 and control compounds in artificial intestinal fluid at 20°C; Figure 5 Stability test results of aromatic ether-modified ginsenoside Rb1 derivatives I-1 ~ I-14 and control compounds in artificial intestinal fluid at 37°C; Figure 6 Stability test results of aromatic ether-modified ginsenoside Rb1 derivatives I-1 ~ I-14 and control compounds in artificial intestinal fluid at 50°C; Figure 7 Stability test results of aromatic ether-modified ginsenoside Rb1 derivatives I-1 ~ I-14 and control compounds in phosphate buffer at 20°C; Figure 8 Stability test results of aromatic ether-modified ginsenoside Rb1 derivatives I-1 ~ I-14 and control compounds in phosphate buffer at 37°C; Figure 9 The results of stability tests of aromatic ether-modified ginsenoside Rb1 derivatives I-1 to I-14 and control compounds at 50°C in phosphate buffer. Detailed Implementation

[0014] The following examples further illustrate the content of the present invention, but these examples do not limit the scope of protection of the present invention. Unless otherwise specified, the methods in the examples are conventional methods, and unless otherwise specified, the reagents used are conventional commercial reagents or reagents prepared according to conventional methods. Example 1: Compound Synthesis Example 1: Preparation of ginsenoside Rb1-2-bromo-4-(trifluoromethyl)acetanilide derivative I-1 I-1:

[0015] Weigh out ginsenoside Rb1 (500 mg, 0.45 mmol) and 2-bromo-4-(trifluoromethyl)acetanilide (633.2 mg, 2.24 mmol) and place them in two 100 mL round-bottom flasks respectively; Add DMF (10 mL) to flask 1 containing ginsenoside Rb1, stir to dissolve, then add sodium hydride (180.25 mg, 7.51 mmol), and react at room temperature for 30 minutes; Add DMF (10 mL) to flask 2 containing 2-bromo-4-(trifluoromethyl)acetanilide, stir to dissolve, then add tetra-n-butylammonium iodide (150.1 mg, 0.45 mmol) and potassium iodide (374.1 mg, 2.25 mmol), and react at room temperature for 30 minutes; The reaction solutions from the two flasks were combined and stirred at room temperature for 1 hour (TLC monitoring of the reaction progress). After the reaction was completed, the mixture was extracted three times with n-butanol. The combined organic phases were collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The solution was then purified by silica gel column chromatography with elution conditions of dichloromethane:methanol = 5:1 (v / v). The target fraction was collected, concentrated, and dried to give a white solid compound I-1 (R). f =0.50), yield: 51%. 1 ¹H NMR (600 MHz, Pyridine-d5) δ 11.14 (s, 1H), 8.23 ​​(d, J = 6 Hz,2H), 7.58 (m, 2H), 5.59(s, 1H), 5.41(d, J = 12 Hz, 1H), 5.31 (m, 1H), 5.26 (m,1H), 5.13(d, J = 8.4 Hz, 1H), 5.10 (s, 1H), 5.09(d, J = 7.56 Hz, 1H), 4.88(d, J =7.38 Hz, 1H), 4.72(d, J = 11.28 Hz, 1H), 4.58-4.47 (m, 3H), 4.42-4.3(m, 7H), 4.22-4.17(m, 5H), 4.18-4.10(m, 3H), 4.08-4.03(m, 3H), 3.96-3.90(m, 3H), 3.28-3.24(m, 1H), 2.61-2.54(m, 2H), 2.42-2.35(m, 2H), 2.14-2.09(m, 1H), 2.02-1.94(m, 2H), 1.87-1.76(m, 3H), 1.65(s, 6H), 1.61(s, 3H), 1.52-1.49(m, 2H), 1.38-1.31(m, 5H), 1.24(s, 3H), 1.22-1.19(m, 1H), 1.07(s, 3H), 1.01-0.99(m, 1H),0.96(s, 3H), 0.95(s, 3H), 0.79(s, 3H), 0.75-0.71(m, 1H), 0.68(d, J= 11.7 Hz, 1H), overlapping of H on the parent nucleus and other H at 0.64–2.62, overlapping of H on the sugar ring and other H at 3.89–5.44, overlapping of active hydrogen at 5.56–11.14, blunt peak; ESI-MS 1332.6326 [M+H] + .

[0016] Example 2: Preparation of ginsenoside Rb1-2-bromo-4-(trifluoromethyl)acetanilide derivative I-2 I-2:

[0017] The preparation method is the same as in Example 1, except that the column chromatography elution conditions are dichloromethane:methanol = 4.5:1 (v / v), yielding a white solid compound I-2 (R). f = 0.25), yield: 45%. 1 ¹H NMR (600 MHz, Pyridine-d5) δ 11.44(s, 1H), 8.30(s, 1H), 8.29(s, 1H), 7.64(s, 1H), 7.63(s, 1H), 5.96(d, J = 8.76Hz, 1H), 5.57(s, 1H), 5,14-5.13(m, 1H), 5.12-5.09(m, 3H), 4.90(d, J = 3.60 Hz,1H), 4.85-4.82(m, 1H), 4.72(d, J = 10.68 Hz, 1H), 4.60-4.43(m, 1H), 4.36-4.30(m, 7H), 4.23-4.16(m, 5H), 4.16-4.07(m, 2H), 4.08-4.03(m, 3H), 3.95-3.87(m,3H), 3.83-3.79(m, 1H), 3.26-3.21(m, 1H), 2.61-2.54(m, 2H), 2.42-2.33(m, 2H),2.18-2.12(m, 1H), 1.98-1.92(m, 2H), 1.84-1.74(m, 3H), 1.63(s, 6H), 1.58(s,3H), 1.52-1.30(m, 8H), 1.26(s, 3H), 1.15(d, J= 10.2 Hz, 1H), 1.04 (s, 3H), 1.01-0.98 (m, 1H), 0.96 (s, 3H), 0.89 (s, 3H), 0.72 (s, 3H), 0.70-0.64 (m, 2H), with overlap between the parent nucleus and other H atoms at 0.64-2.62, overlap between the sugar ring and other H atoms at 3.78-5.32, and overlap between active hydrogen atoms at 5.56-11.44; blunt peaks; ESI-MS 1308.6376 [MH] - .

[0018] Example 3: Preparation of ginsenoside Rb1-2-bromo-N-phenylacetamide derivative I-3 I-3:

[0020] The preparation method is the same as in Example 1, except that 2-bromo-N-phenylacetamide is used instead of 2-bromo-4-(trifluoromethyl)acetanilide in Example 1. The elution conditions are dichloromethane:methanol = 5:1 (v / v), yielding a white solid compound I-3 (R f = 0.50), yield: 42%. 1 ¹H NMR (600 MHz, Pyridine-d5) δ10.95(s, 1H), 8.14-8.10(m, 2H), 7.32-7.29(m, 2H), 7.09-7.05(m, 2H), 5.60(s, 1H), 5.40-5.35(m, 1H), 5.31-5.29(m,1H), 5.22-5.21(m, 1H), 5.13-5.10(m, 1H), 5.09-5.07(m, 1H), 5.05-5.04(m, 1H),4.86-4.82(m, 1H), 4.73-4.69(m, 1H), 4.54-4.42(m, 3H), 4.37-4.25(m, 7H), 4.21-4.10(m, 8H), 4.07-4.05(m, 2H), 4.0-3.96(m, 1H), 3.93-3.90(m, 2H), 3.88-3.82(m, 1H), 3.26-3.22(m, 1H), 2.62-2.53(m, 2H), 2.40-2.34(m, 2H), 2.12-2.09(m,1H), 2.00-1.93(m, 2H), 1.86-1.76(m, 3H), 1.65(s, 6H), 1.61(s, 3H), 1.59-1.53(m, 2H), 1.50-1.47(m, 2H), 1.40-1.32 (m, 4H), 1.23 (s, 3H), 1.21-1.19 (m, 1H), 1.60 (s, 3H), 1.02-1.00 (m, 1H), 0.97-0.94 (m, 6H), 0.78 (s, 3H), 0.72-0.65 (m, 2H), with overlap between the parent nucleus and other H atoms at 0.64-2.62, overlap between the sugar ring and other H atoms at 3.81-5.40, and overlap between active hydrogen atoms at 5.60-10.95; blunt peaks; ESI-MS 1264.644 [M+H] + .

[0021] Example 4: Preparation of ginsenoside Rb1-2-bromo-N-phenylacetamide derivative I-4 I-4:

[0022] The preparation method is the same as in Example 1, except that 2-bromo-N-phenylacetamide is used instead of 2-bromo-4-(trifluoromethyl)acetanilide in Example 1. The elution conditions are dichloromethane:methanol = 4.5:1 (v / v), yielding a white solid compound I-4 (R f =0.25), yield: 30%. 1¹H NMR (600 MHz, Pyridine-d5) δ 11.18(s, 1H), 8.23(s, 1H), 8.22(s, 1H), 7.35-7.32(m, 2H), 7.11-7.08(m, 1H), 5.94(d, J = 7.14 Hz, 1H), 5.55(s,1H), 5.32-5.28(m, 1H), 5.12-5.07(m, 3H), 4.87(d, J = 7.98 Hz, 1H), 4.84-4.80(m,1H), 4.72(d, J = 11.52 Hz, 1H), 4.54-4.40(m, 3H), 4.37-4.27(m, 7H), 4.25-4.07(m, 8H), 4.05(s, 2H), 4.00-3.97(m, 1H), 3.94-3.83(m, 3H), 3.81-3.78(m, 1H),3.22(dd, J = 4.56, 4.8 Hz, 1H), 2.60-2.53(m, 2H), 2.42-2.32(m, 2H), 2.17-2.08(m, 1H), 2.00-1.92(m, 2H), 1.86-1.73(m, 3H), 1.64(s, 6H), 1.59(s, 3H), 1.53-1.42(m, 4H), 1.39-1.26(m, 4H), 1.23(s, 3H), 1.17(d, J = 12.12 Hz, 1H), 1.04(s,3H), 1.01-0.98(m, 1H), 0.97(s, 3H), 0.91(s, 3H), 0.74(s, 3H), 0.71-0.69(m,1H), 0.66(d, J = 12.12 Hz, 1H), overlapping of H on the parent nucleus and other H at 0.64–2.62, overlapping of H on the sugar ring and other H at 3.81–5.40, overlapping of active hydrogen at 5.60–11.18, blunt peak; ESI-MS 1264.6396 [M+Na] + .

[0023] Example 5: Preparation of ginsenoside Rb1-2-bromo-N-(4-fluorophenyl)acetamide derivative I-5 I-5:

[0025] The preparation method is the same as in Example 1, except that 2-bromo-N-(4-fluorophenyl)acetamide is used instead of 2-bromo-4-(trifluoromethyl)acetanilide in Example 1. The elution conditions are dichloromethane:methanol = 5:1 (v / v), yielding a white solid compound I-5 (R f =0.50), yield: 65%. 1 ¹H NMR (600 MHz, Pyridine-d5) δ 10.94(s, 1H), 8.11-8.05(m, 2H),7.08-7.05(m, 2H), 5.59(s, 1H), 5.39(d, J = 7.5 Hz, 1H), 5.33-5.29(m, 1H), 5.26-5.21(m, 1H), 5.12(d, J = 6.78 Hz, 1H), 5.09-5.07(m, 1H), 5.06(s, 1H), 4.86(d, J =7.92 Hz, 1H), 4.71(d, J = 11.4 Hz, 1H), 4.53-4.43(m, 3H), 4.40-4.25(m, 7H), 4.23-4.11(m, 8H), 4.08-4.02(m, 3H), 3.95-3.90(m, 3H), 3.25(dd, J = 4.74, 4.8Hz, 1H), 2.61-2.53(m, 2H), 2.42-2.32(m, 2H), 2.14-2.08(m, 1H), 2.01-1.93(m,2H), 1.86-1.77(m, 3H), 1.65(s, 6H), 1.60(s, 3H), 1.53-1.33(m, 8H), 1.23(s,3H), 1.21-1.18(m, 1H), 1.06(s, 3H), 1.03-1.00(m, 1H), 0.96(s, 3H), 0.95(s,3H), 0.78(s,3H), 0.75-0.70 (m, 1H), 0.67 (d, J = 12.06 Hz, 1H) Overlapping peaks of H on the parent nucleus and other H atoms at 0.64–2.62, overlapping peaks of H on the sugar ring and other H atoms at 3.81–5.40, overlapping peaks of active hydrogen atoms at 5.60–10.94, blunt peaks; ESI-MS 1282.6355 [M+Na] + .

[0026] Example 6: Preparation of ginsenoside Rb1-2-bromo-N-(4-fluorophenyl)acetamide derivative I-6 I-6:

[0027] The preparation method is the same as in Example 1, except that 2-bromo-N-(4-fluorophenyl)acetamide is used instead of 2-bromo-4-(trifluoromethyl)acetanilide in Example 1. The elution conditions are dichloromethane:methanol = 4.5:1 (v / v), yielding a white solid compound I-6 (R f = 0.25), yield: 38%. 1 ¹H NMR (600 MHz, Pyridine-d5) δ 11.24(s, 1H), 8.16(q, J =4.98 Hz, 2H), 7.11(t, J = 8.55 Hz, 1H), 5.95(d, J = 7.56 Hz, 1H), 5.56(s, 1H),5.30-5.28(m, 1H), 5.13-5.08(m, 3H), 4,88(d, J = 7.68 Hz, 1H), 4.84-4.80(m, 1H),4.72(d, J = 11.18 Hz, 1H), 4.56-4.40(m, 3H), 4.39-4.28(m, 7H), 4.28-4.08(m,7H), 4.08-4.02(m, 3H), 3.94-3.89(m, 2H), 3.88-3.85(m, 1H), 3.82-3.78(m, 1H),3.22(dd, J = 4.74, 4.92 Hz, 1H), 2.62-2.53(m, 2H), 2.42-2.31(m, 2H), 2.17-2.11(m, 1H), 1.98-1.93(m, 2H), 1.86-1.72(m, 3H), 1.63(s, 6H), 1.58(s, 3H), 1.54-1.29(m, 8H), 1.24(s, 3H), 1.15(d, J= 12.54 Hz (1H), 1.03 (s, 3H), 1.01-0.98 (m, 1H), 0.96 (s, 3H), 0.90 (s, 3H), 0.72 (s, 3H), 0.69-0.63 (m, 2H). Overlapping peaks are observed at 0.64-2.62 for the parent nucleus and other H atoms, at 3.81-5.40 for the sugar ring and other H atoms, and at 5.60-11.24 for active hydrogen atoms. Blunt peaks are observed. ESI-MS 1282.6357 [M+Na] + .

[0028] Example 7: Preparation of ginsenoside Rb1-2-bromo-N-(3-fluorophenyl)acetamide derivative I-7 I-7:

[0029] The preparation method is the same as in Example 1, except that 2-bromo-N-(3-fluorophenyl)acetamide is used instead of 2-bromo-4-(trifluoromethyl)acetanilide in Example 1. The elution conditions are dichloromethane:methanol = 5:1 (v / v), yielding a white solid compound I-7 (R f =0.50), yield: 36%. 1 ¹H NMR (600 MHz, Pyridine-d5) δ 11.09 (s, 1H), 8.16 (d, J = 11.34Hz, 1H), 7.75(d, J = 8.22 Hz, 1H), 7.25-7.23(m, 1H), 6.86-6.82(m, 1H), 5.60(s,1H), 5.38(d, J = 7.62 Hz, 1H), 5.32-5.30(m, 1H), 5.12(d, J = 7.8 Hz, 1H), 5.09-5.06(m, 2H), 4.86(d, J = 7.86 Hz, 1H), 4.71(d, J = 10.98 Hz, 1H), 4.55-4.42(m,3H), 4.40-4.25(m, 7H), 4.24-4.10(m, 8H), 4.07-3.90(m, 6H), 3,25(dd, J= 6, 4.36Hz, 1H), 2.62-2.52(m, 2H), 2.43-2.31(m, 2H), 2.14-2.07(m, 1H), 2.01-1.93(m,2H), 1.89-1.73(m, 3H), 1.66(s, 6H), 1.61(s, 3H), 1.53-1.31(m, 8H), 1.23(s,3H), 1.21-1.17(m, 1H), 1.06(s, 3H), 1.03-0.98(m, 1H), 0.96(s, 3H), 0.95(s,3H), 0.78(s, 3H), 0.74-0.64(m, 2H) Overlapping peaks of H on the parent nucleus and other H atoms at 0.64–2.62, overlapping peaks of H on the sugar ring and other H atoms at 3.81–5.40, overlapping peaks of active hydrogen atoms at 5.60–11.09, blunt peaks; ESI-MS 1282.6363 [M+Na] + .

[0030] Example 8: Preparation of ginsenoside Rb1-2-bromo-N-(3-fluorophenyl)acetamide derivative I-8 I-8:

[0032] The preparation method is the same as in Example 1, except that 2-bromo-N-(3-fluorophenyl)acetamide is used instead of 2-bromo-4-(trifluoromethyl)acetanilide in Example 1. The elution conditions are dichloromethane:methanol = 4.5:1 (v / v), yielding a white solid compound I-8 (R f = 0.25), yield: 30%. 1 ¹H NMR (600 MHz, Pyridine-d5) δ 11.38 (s, 1H), 8.22 (d, J =11.52 Hz, 1H), 7.87 (d, J = 8.34 Hz, 1H), 7.28-7.25(m, 1H), 6.88(t, J = 8.28 Hz, 1H), 5.96 (d, J = 7.62 Hz, 1H), 5.57(s, 1H), 5.28-5.26(m, 1H), 5.14-5.08(m, 3H),4.89(d, J = 7.74 Hz, 1H), 4.82-4.78(m, 1H), 4.72(d, J= 10.86 Hz, 1H), 4.57-4.40(m, 3H), 4.38-4.28(m, 7H), 4.28-4.09(m, 7H), 4.08-4.04(m, 3H), 3.95-3.85(m,3H), 3.80(t, J = 8.94 Hz, 1H), 3.23(dd, J = 3.78, 3.9 Hz, 1H), 2.62-2.52(m, 2H),2.42-2.32(m, 2H), 2.17-2.09(m, 1H), 1.99-1.91(m, 2H), 1.86-1.72(m, 3H), 1.63(s, 6H), 1.57(s, 3H), 1.53-1.28(m, 8H), 1.24(s, 3H), 1.14(d, J = 12.72 Hz, 1H), 1.03 (s, 3H), 1.00-0.97 (m, 1H), 0.96 (s, 3H), 0.89 (s, 3H), 0.71 (s, 3H), 0.68-0.62 (m, 1H). Overlapping peaks are observed at 0.64-2.62 for the parent nucleus and other H atoms, at 3.81-5.40 for the sugar ring and other H atoms, and at 5.60-11.38 for active hydrogen atoms; blunt peaks. ESI-MS 1282.6357 [M+Na] + .

[0033] Example 9: Preparation of ginsenoside Rb1-2-bromo-N-(3-methoxyphenyl)acetamide derivative I-9 I-9:

[0034] The preparation method is the same as in Example 1, except that 2-bromo-N-(3-methoxyphenyl)acetamide is used instead of 2-bromo-4-(trifluoromethyl)acetanilide in Example 1. The elution conditions are dichloromethane:methanol = 5:1 (v / v), yielding a white solid compound I-9 (R). f = 0.50), yield: 47%. 1 ¹H NMR (600 MHz, Pyridine-d5) δ 10.97 (s, 1H), 7.95 (t, J =1.98 Hz, 1H), 7.68 (d, J = 8.04 Hz, 1H), 7.24(t, J = 8.22 Hz, 1H), 6.73 (dd, J=2.34, 2.28 Hz, 1H), 5.57(s, 1H), 5.38(d, J = 7.62 Hz, 1H), 5.31(t, J = 7.08 Hz,1H), 5.27-5.23(m, 1H), 5.12(d, J = 7.8 Hz, 1H), 5.09-5.08(m, 1H), 5.05(s, 1H),4.84(d, J = 7.8 Hz, 1H), 4.72(d, J = 10.62 Hz, 1H), 4.54-4.41(m, 3H), 4.38-4.25(m, 7H), 4.22-4.09(m, 8H), 4.07-4.02(m, 3H), 3.94-3.89(m, 3H), 3.64(s, 3H),3.24(dd, J = 4.56, 4.5 Hz, 1H), 2.61-2.54(m, 2H), 2.43-2.32(m, 2H), 2.12-2.07(m, 1H), 2.01-1.93(m, 2H), 1.88-1.74(m, 3H), 1.65(s, 6H), 1.60(s, 3H), 1.52-1.46(m, 4H), 1.40-1.31(m, 4H), 1.23(s, 3H), 1.21-1.19(m, 1H), 1.06(s, 3H),1.03-0.98(m, 1H), 0.96(s, 3H), 0.95(s, 3H), 0.78 (s, 3H), 0.74-0.65 (m, 2H). Overlapping peaks are observed at 0.64-2.62 for the parent nucleus and other H atoms, 3.81-5.40 for the sugar ring and other H atoms, and 5.60-10.97 for active hydrogen atoms; blunt peaks. ESI-MS 1294.6556 [M+Na] + .

[0035] Example 10: Preparation of Ginsenoside Rb1-2-bromo-N-(3-methoxyphenyl)acetamide derivative I-10 I-10:

[0036] The preparation method is the same as in Example 1, except that 2-bromo-N-(3-methoxyphenyl)acetamide is used instead of 2-bromo-4-(trifluoromethyl)acetanilide in Example 1. The elution conditions are dichloromethane:methanol = 4.5:1 (v / v). The eluent is collected, concentrated, and dried to obtain a white solid compound I-10 (R).f = 0.25), yield: 36%. 1 ¹H NMR (600 MHz, Pyridine-d5) δ 11.25(s, 1H), 8.04(s, 1H), 7.82(d, J = 8.16 Hz, 1H), 7.30-7.25(m, 1H), 6.76(d, J = 7.26 Hz, 1H), 5.96 (d, J = 7.68 Hz, 1H), 5.56(s, 1H), 5.30-5.285(m, 1H), 5.14-5.085(m, 3H), 4.88(d, J = 7.8 Hz, 1H), 4.84-4.79(m, 1H), 4.72(d, J = 11.16 Hz,1H), 4.55-4.41(m, 3H), 4.39-4.28(m, 7H), 4.28-4.09(m, 7H), 4.08-4.04(m, 3H),3.96-3.85(m, 3H), 3.83-3.80(m, 1H), 3.61(s, 3H), 3.21(dd, J = 3.3, 6.42 Hz,1H), 2.63-2.53(m, 2H), 2.43-2.33(m, 2H), 2.16-2.09(m, 1H), 2.00-1.91(m, 2H),1.87-1.72(m, 3H), 1.63(s, 6H), 1.58(s, 3H), 1.51-1.40(m, 4H), 1.37-1.26(m,4H), 1.23(s, 3H), 1.15(d, J = 12.24 Hz, 1H), 1.03 (s, 3H), 1.00-0.99 (m, 1H), 0.96 (s, 3H), 0.90 (s, 3H), 0.72 (s, 3H), 0.69-0.62 (m, 2H). Overlapping peaks are observed at 0.64-2.62 for the parent nucleus and other H atoms, 3.81-5.40 for the sugar ring and other H atoms, and 5.60-11.25 for active hydrogen atoms. Blunt peaks are observed. ESI-MS 1270.6586 [MH] - .

[0037] Example 11: Preparation of ginsenoside Rb1-2-bromo-N-[3-(trifluoromethoxy)phenyl]acetamide derivative I-11 I-11:

[0038] The preparation method is the same as in Example 1, except that 2-bromo-N-[3-(trifluoromethoxy)phenyl]acetamide is used instead of 2-bromo-4-(trifluoromethyl)acetanilide in Example 1. The elution conditions are dichloromethane:methanol = 5:1 (v / v), yielding a white solid compound I-11 (R). f = 0.50), yield: 65%. 1 ¹H NMR (600 MHz, Pyridine-d5) δ 11.15(s, 1H), 8.31(s, 1H), 7.90(d, J = 8.16 Hz, 1H), 7.31-7.27(m, 1H), 6.98(d, J = 8.04 Hz, 1H),5.57(s, 1H), 5.39(d, J = 7.62 Hz, 1H), 5.31-5.27(m, 1H), 5.26(s, 1H), 5.11-5.04(m, 3H), 4.86(d, J = 7.92 Hz, 1H), 4.72 (d, J = 11.04 Hz, 1H), 4.53-4.40(m, 3H), 4.40-4.22(m, 7H), 4.22-4.06(m, 8H), 4.06-4.00(m, 3H), 3.96-3.86(m, 3H), 3.27-3.20(m, 1H), 2.62-2.52(m, 2H), 2.43-2.31(m, 2H), 2.13-2.06(m, 1H), 2.01-1.92(m, 2H), 1.86-1.74(m, 3H), 1.65(s, 6H), 1.60(s, 3H), 1.54-1.44(m, 4H), 1.40-1.30 (m, 4H), 1.23 (s, 3H), 1.21-1.16 (m, 1H), 1.06 (s, 3H), 1.03-0.98 (m, 1H), 0.95 (s, 6H), 0.78 (s, 3H), 0.74-0.64 (m, 2H). Overlapping peaks are observed at 0.64-2.62 for the parent nucleus and other H atoms, at 3.81-5.40 for the sugar ring and other H atoms, and at 5.60-11.15 for active hydrogen atoms. Blunt peaks are observed. ESI-MS 1324.6315 [MH] - .

[0039] Example 12: Preparation of ginsenoside Rb1-2-bromo-N-[3-(trifluoromethoxy)phenyl]acetamide derivative I-12 I-12:

[0040] The preparation method is the same as in Example 1, except that 2-bromo-N-[3-(trifluoromethoxy)phenyl]acetamide is used instead of 2-bromo-4-(trifluoromethyl)acetanilide in Example 1. The elution conditions are dichloromethane:methanol = 4.5:1 (v / v), yielding a white solid compound I-12 (R). f = 0.25), yield: 44%. 1 ¹H NMR (600 MHz, Pyridine-d5) δ 11.37(s, 1H),8.33(s, 1H), 8.00(d, J = 8.4 Hz, 1H), 7.33-7.30(m, 1H), 7.02(d, J = 8.4 Hz, 1H), 5.94(d, J = 7.62 Hz, 1H), 5.55(s, 1H), 5.30(t, J = 7.44 Hz, 1H), 5.12-5.08(m,3H), 4.89(d, J = 7.62 Hz, 1H), 4.83-4.79(m, 1H), 4.71(d, J = 11.22 Hz, 1H), 4.55-4.39(m, 3H), 4.38-4.27(m, 7H), 4.26-4.07(m, 7H), 4.06-4.02(m, 3H), 3.95-3.85(m, 3H), 3.79(t, J = 8.58 Hz, 1H), 3.24(dd, J = 3.6, 4.02 Hz, 1H), 2.62-2.53(m,2H), 2.42-2.32(m, 2H), 2.18-2.08(m, 1H), 2.00-1.91(m, 2H), 1.87-1.72(m, 3H),1.64(s, 6H), 1.59(s, 3H), 1.53-1.41(m, 4H), 1.41-1.28(m, 4H), 1.25(s, 3H),1.17(d, J= 12.9 Hz, 1H), 1.04(s, 3H), 1.02-0.98(m, 1H), 0.96(s, 3H), 0.91(s,3H), 0.74(s, 3H), 0.72-0.69(m, 1H), 0.67(d, J = 12.36 Hz, 1H) Overlapping peaks of H on the parent nucleus and other H atoms from 0.64 to 2.62, overlapping peaks of H on the sugar ring and other H atoms from 3.81 to 5.40, overlapping peaks of active hydrogen atoms from 5.60 to 11.37, blunt peaks; ESI-MS 1324.6304 [MH] - .

[0041] Example 13: Preparation of ginsenoside Rb1-2-bromo-N-(3,5-difluorophenyl)acetamide derivative I-13 I-13:

[0042] The preparation method is the same as in Example 1, except that 2-bromo-N-(3,5-difluorophenyl)acetamide is used instead of 2-bromo-4-(trifluoromethyl)acetanilide in Example 1. The elution conditions are dichloromethane:methanol = 5:1 (v / v), yielding a white solid compound I-13 (R f = 0.50), yield: 63%. 1 ¹H NMR (600 MHz, Pyridine-d5) δ 11.19(s, 1H), 7.79(dd, J =2.4, 2.58 Hz, 1H), 6.72(t, J = 9.12 Hz, 1H), 5.57(s, 1H), 5.38(d, J = 7.62 Hz, 1H), 5.31(t, J = 6.9 Hz, 1H), 5.29-5.25(m, 1H), 5.12(d, J = 7.8 Hz, 1H), 5.09(d, J = 7.8 Hz, 1H), 5.04(d, J = 16.68 Hz, 1H), 4.86(d, J = 7.8 Hz, 1H), 4.71(d, J=10.92 Hz, 1H), 4.54-4.42(m, 3H), 4.38-4.16(m, 12H), 4.16-4.06(m, 3H), 4.05-3.99(m, 3H), 3.97-3.87(m, 3H), 3.24(dd, J = 4.56, 4.62 Hz, 1H), 2.62(m, 2H),2.43-2.32(m, 2H), 2.12-2.06(m, 1H), 2.01-1.92(m, 2H), 1.87-1.74(m, 3H), 1.65(s, 6H), 1.60(s, 3H), 1.53-1.44(m, 4H), 1.42-1.26(m, 4H), 1.24(s, 3H), 1.22-1.19(m, 1H), 1.06(s, 3H), 1.03-0.98(m, 1H), 0.96(s, 3H), 0.95(s, 3H), 0.78(s,3H), 0.76-0.70(m, 1H), 0.67(d, J = 11.7 Hz, 1H) Overlapping peaks of H on the parent nucleus and other H atoms from 0.64 to 2.62, overlapping peaks of H on the sugar ring and other H atoms from 3.81 to 5.40, overlapping peaks of active hydrogen atoms from 5.60 to 11.19, blunt peaks; ESI-MS 1300.6259 [M+Na] + .

[0043] Example 14: Preparation of ginsenoside Rb1-2-bromo-N-(3,5-difluorophenyl)acetamide derivative I-14 I-14:

[0045] The preparation method is the same as in Example 1, except that 2-bromo-N-(3,5-difluorophenyl)acetamide is used instead of 2-bromo-4-(trifluoromethyl)acetanilide in Example 1. The elution conditions are dichloromethane:methanol = 4.5:1 (v / v), yielding a white solid compound I-14 (R f = 0.25), yield: 40%. 1 ¹H NMR (600 MHz, Pyridine-d5) δ 11.46 (s, 1H), 7.84 (d, J = 7.86 Hz, 1H), 6.77(t, J = 8.88 Hz, 1H), 5.95(d, J= 7.62 Hz, 1H), 5.55(s, 1H),5.29(t, J = 7.26 Hz, 1H), 5.13-5.08(m, 3H), 4.90(d, J = 7.68 Hz, 1H), 4.81-4.77(m, 1H), 4.72(d, J = 11.04 Hz, 1H), 4.54-4.40(m, 3H), 4.38-4.29(m, 7H), 4.28-4.12(m, 7H), 4.08-4.03(m, 3H), 3.94-3.85(m, 3H), 3.79(t, J = 7.98 Hz, 1H), 3.25 (dd, J = 4.62, 4.62 Hz, 1H), 2.62-2.53(m, 2H), 2.43-2.31(m, 2H), 2.19-2.09(m,1H), 2.01-1.92(m, 2H), 1.86-1.72(m, 3H), 1.63(s, 6H), 1.58(s, 3H), 1.52-1.41(m, 4H), 1.40-1.29(m, 4H), 1.27(s, 3H), 1.14(d, J = 12.84 Hz (1H), 1.04 (s, 3H), 1.01-0.97 (m, 1H), 0.96 (s, 3H), 0.90 (s, 3H), 0.73 (s, 3H), 0.71-0.64 (m, 2H). Overlapping peaks are observed at 0.64-2.62 for the parent nucleus and other H atoms, at 3.81-5.40 for the sugar ring and other H atoms, and at 5.60-11.46 for active hydrogen atoms. Blunt peaks are observed. ESI-MS 1276.6294 [MH] - .

[0046] Example 15: Compound Stability Test Stability is a core indicator for the clinical translation of drug candidates. In existing technologies, ester derivatives of ginsenoside Rb1 (such as 202210449816.7) are prone to rapid metabolism due to the ester bond's susceptibility to enzymatic degradation. This invention, however, by introducing ether bonds (such as compounds I-1 to I-14), achieves for the first time a synergistic enhancement of both inhibitory activity against flaviviruses and metabolic stability. This test simulates the human gastrointestinal tract and body fluid environment (acidic to neutral pH, physiological temperature) to focus on examining the metabolic stability advantages of ether bond modification compared to ester bond modification.

[0047] 1. Experimental instruments and reagents The system used an Agilent 1260 Infinity II high-performance liquid chromatograph; an XH-B type vortex mixer; a GENESPEED X1 high-speed centrifuge; an AE240 0.0001 g electronic balance; and a PHS-3C type precision pH meter.

[0048] The simulated body fluids were prepared strictly in accordance with the Chinese Pharmacopoeia (2020 edition): Artificial gastric fluid (pH 1.2): pepsin (10 g / L) in dilute hydrochloric acid system to simulate the gastric environment; artificial intestinal fluid (pH 6.8): trypsin (10 g / L) in phosphate buffer to simulate the intestinal environment; phosphate buffer (pH 7.4): simulates the neutral environment of blood.

[0049] The analytes were compounds (I-1 to I-14) obtained in Examples 1 to 14, and the solvent was chromatographic grade acetonitrile / ultrapure water. All operations were performed in the dark to eliminate interference from photodegradation.

[0050] Meanwhile, esterified compounds were used as controls, with the control compounds being compounds I-3 to I-6 in ZL202210449816.7 "A Ginsenoside Rb1 Derivative and Its Application"; 2. Preparation of test sample and setting of conditions Accurately weigh compounds I-1 to I-14 and the control compound, and add them to the artificial gastric fluid, artificial intestinal fluid, and phosphate buffer solution prepared in step 1, respectively. The concentration of each derivative is 2.5 × 10⁻⁶. -4 The concentration was mol / L, and incubated at 20℃, 37℃, and 50℃ respectively. After 48 hours, samples were taken, centrifuged at high speed for 10 min, and the supernatant was collected for residual content detection by HPLC (calculation formula: residual rate % = (Ct / C0) × 100%, where Ct is the concentration at time t, and C0 is the initial concentration). Chromatographic conditions: gradient elution (acetonitrile-water), flow rate 1.0 mL / min, detection wavelength 203 nm, column temperature 25℃; each experiment was repeated 3 times, and the data were taken as mean ± standard deviation.

[0051] 3. Test Results See results Figure 1-9 As shown, Figure 1-3 The results showed that the residual rate of aromatic ether-modified derivatives was higher than that of ester derivatives after 48 hours in a strong acid environment (pH 1.2), while the residual rate of ester derivatives decreased to below 65% at 50℃, indicating that the ether bond is significantly more resistant to acid hydrolysis than the ester bond.

[0052] Figure 4-6 The results showed that the aromatic ether-modified derivatives were still more stable than ester derivatives in a weakly acidic environment (pH 6.8), which verified the metabolic stability advantage of ether bonds in the intestinal environment.

[0053] Figure 7-9 The results showed that the residual rates of aromatic ether-modified derivatives were higher than those of ester derivatives under neutral conditions (pH 7.4), indicating that the degradation of derivatives was mainly driven by ester bond hydrolysis rather than pH specificity.

[0054] This stability test, through systematic verification under multiple environments and temperatures, proves that the aromatic ether-modified ginsenoside Rb1 derivative of this invention has good stability. The chemical inertness of the ether bond is higher than that of the ester bond, and the resistance to enzymatic hydrolysis is stronger. This invention achieves a balance between stability and activity through selective modification of the Glc-2"' and Glc-2'' sites.

[0055] Example 16: Anti-ZIKV and DENV Activity Tests Ribavirin (RBV) was used as the positive control drug, Vero cells as the experimental cells, and ZIKV SZ-WIV01 (GenBank: KU963796) and DENV-II D01090 (GenBank: KY882458) strains as experimental strains. Based on the results of cytotoxicity and plaque inhibition assays, the concentration of the compound that inhibited 50% viral replication (EC50) in the sample was calculated using the Read & Muench method. 50 The effective concentration of the sample that inhibits 50% cell growth (CC) 50 ), and through the formula TI=CC 50 / EC 50 The therapeutic index (TI) is calculated using the following method: 1. Cytotoxicity assay (MTT method): Vero cells were injected at a concentration of 1×10⁻⁶ cells / mL. 5 Cells were seeded per well in 96-well plates and cultured overnight at 37°C in a 5% CO2 incubator. Once a monolayer formed, the culture supernatant was discarded, and culture medium containing serially diluted compounds was added, with three replicates per concentration. A control group without the compound was also included. After 3 days of culture, 20 μL of 5 mg / mL MTT was added to each well, and the plates were incubated at 37°C for 4 hours. 100 μL of the supernatant was discarded, and 100 μL of 12% SDS-50% DMF solution was added. The plates were incubated overnight at 37°C until the formazan crystals were completely dissolved. The plates were then vortexed and the OD value was measured using a Bio-TEK microplate reader (measurement wavelength 570 nm, reference wavelength 630 nm). A dose-response curve was plotted based on the experimental results, and the half-maximal cytotoxic concentration (CC) was calculated. 50 (This refers to the drug concentration at which 50% of Vero cells become toxic).

[0056] 2. Anti-ZIKV / DENV activity assay (plutoid method): Vero cells were seeded into 12-well plates (3×10⁻⁶ cells / wells). 5Cells were cultured overnight at 37°C in a 5% CO2 incubator (number per well). After the cells formed a monolayer, the culture supernatant was discarded, and the cells were washed once with PBS. ZIKV / DENV (MOI = 0.5) was added for adsorption for 2-4 hours. Then, DMEM medium containing different drug concentrations, 1% low-melting-point agarose, and 2% FBS was added. After culturing at 37°C in a 5% CO2 incubator for 5 days, the cells were fixed with 4% paraformaldehyde for 15 minutes, the agar block was blown off, and 0.8% crystal violet was added for staining for 10 minutes. Images were acquired and plaques were counted using an ELISA reader (CTL, Immunospot S6 Universal). A dose-response curve was plotted based on the number of plaques, and the half-maximal effective concentration (EC50) was calculated. 50 This refers to the drug concentration at which plaque formation is inhibited by 50% after ZIKV / DENV infection of Vero cells.

[0057] 3. Anti-ZIKV / DENV Activity Assay (qRT-PCR): To further verify the antiviral activity of the compound, the inhibitory effect of the compound on progeny virus particles was detected by qRT-PCR. Vero cells were cultured at 3 × 10⁻⁶ cells / year. 5 Cells were seeded per well in 12-well plates and incubated overnight at 37°C with 5% CO2. Once the cells reached full adherence, ZIKV or DENV was added at an MOI of 0.5 and inoculated for 4 hours. After infection, the cells were washed three times with PBS to remove unadsorbed virus. Different concentrations of the compound (3.125 μM, 6.25 μM, 12.5 μM, 25 μM, 50 μM) were then added, and the cells were incubated for another 72 hours. The supernatant was collected, and RNA was extracted using the EasyPure® Viral DNA / RNA Kit (Beijing TransGen Biotech Co., Ltd.) according to the kit instructions. ZIKV viral load was then detected using the Evo M-MLV One Step RT-qPCR Kit Ⅲ (Probe), ROX dye, and TaqMan probe on a QuantStudio 5 Real-Time PCR system. The half-maximal effective concentration (EC50) was calculated based on the dose-response curve. 50 This refers to the drug concentration at which the progeny virus inhibition rate is 50% after ZIKV / DENV infection of Vero cells.

[0058] First, the concentration of the test compound was diluted to a concentration that was non-toxic to cells. Then, the compound was screened using the classic plaque assay. Compounds that showed an inhibition rate of more than 50% against ZIKV / DENV-induced plaque formation at a concentration of 25 μM were selected as compounds with anti-ZIKV / DENV activity.

[0059] Table 1 shows the drug cytotoxicity and in vitro anti-ZIKV / DENV activity of compounds I-1 to I-14. The compounds in the table exhibit significantly better inhibitory activity against DENV-II than the positive control ribavirin, with higher EC50 values. 50 The concentrations ranged from 2.553 to 25 μmol / L, and all showed low cytotoxicity. Their therapeutic index was 2 to 18 times higher than that of the positive control ribavirin, indicating their potential as anti-DENV drugs.

[0060] The compounds shown in Table 1 also exhibited significant inhibitory activity against ZIKV. Three compounds (I-2, I-12, and I-14) showed 50% inhibition of ZIKV at a concentration of 12.5 μM, with low cytotoxicity. The therapeutic index (TI) is the half-maximal toxic concentration (CMC) of a compound to cells. 50 and the half-maximal effective concentration (EC50) of the compound against the virus 50 The ratio represents the safety of the compound; the higher the value, the safer it is. The compounds in Table 1 all have significant inhibitory effects on ZIKV, and their therapeutic index is 1.3 to 3 times higher than that of the positive control ribavirin. They can be developed and applied as candidates for anti-ZIKV drugs.

[0061] Table 1

[0062] The results in the table show that compounds I-1 to I-14 exhibit strong inhibitory activity against both ZIKV and DENV, and their EC50 values ​​are [not specified]. 50 The value was better than that of the positive control ribavirin, and it can be further studied and developed as a drug candidate for anti-ZIKV / DENV infection.

[0063] The aromatic ether-modified derivatives I-1 to I-14 in Table 1 exhibit significantly better stability than ester derivatives, achieving synergistic optimization of stable drug release and prolonged in vivo action time. This demonstrates the irreplaceable nature of ether bond modification and provides technical support for subsequent structural modifications of these compounds.

[0064] Example 17: 1. Tablet preparation Compound I-1 (50 mg), microcrystalline cellulose (150 mg), crosporopyrrolidone (20 mg), and magnesium stearate (5 mg) were mixed evenly and directly compressed into tablets to obtain antiviral tablets containing 50 mg of active ingredients per tablet.

[0065] 2. Preparation of Injectable Formulation Take appropriate amounts of compound I-3 (100 mg), mannitol (50 mg), and phosphate buffer (pH 7.4), add water to 10 mL, filter to sterilize, and dispense into ampoules to obtain an injectable formulation.

Claims

1. An aromatic ether-modified ginsenoside Rb1 derivative of the following formula I or a pharmaceutically acceptable salt thereof: wherein R1 is selected from H, halogen, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, hydroxyl, and the substitution site is one or several of 2-6 positions of the aromatic ring. ； wherein: R 1 , R 2 each is independently selected from H or ; 2. An aromatic ether-modified ginsenoside Rb1 derivative of the following formula I or a pharmaceutically acceptable salt thereof: wherein R1 is selected from H, halogen, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, hydroxyl, and the substitution site is one or several of 2-6 positions of the aromatic ring. R 1 , R 2 are not simultaneously H. In a solvent, the ginsenoside Rb1 is stirred with a 2-bromo-N-phenylacetamide derivative in the presence of a basic catalyst at 20-25 °C for 1-3 hours, and then extracted, purified by column chromatography, and dried to obtain the aromatic ether-modified ginsenoside Rb1 derivative. ； ； 。 3. The method of preparing the aromatic ether-modified ginsenoside Rb1 derivative according to claim 1 or 2, characterized by: wherein R1 is selected from H, halogen, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, hydroxyl, and the substitution site is one or several of 2-6 positions of the aromatic ring. ； The molar ratio of the ginsenoside Rb1 to the 2-bromo-N-phenylacetamide derivative is 1:3-8.

4. The method of claim 3, wherein: The basic catalyst is selected from one or several of sodium hydride, potassium iodide, and tetra-n-butylammonium iodide.

5. The method of claim 3, wherein: The solvent is selected from one or several of N,N-dimethylformamide, tetrahydrofuran, and pyridine.

6. The method of claim 3, wherein:

7. Use of the aromatic ether-modified ginsenoside Rb1 derivative of claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating Zika virus and / or dengue virus infection with good stability. ​

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