Glycyrrhetinic acid glucoside derivative as well as preparation method and application thereof

Abstract

The invention provides a glycyrrhetinic acid glucoside derivative as well as a preparation method and application thereof, and relates to the technical field of medicinal chemistry. The glycyrrhetinic acid glucoside derivative prepared by the invention has a relatively good inhibition effect on soluble epoxidase, can treat inflammation and relieve pain in vivo, and has a structure as shown in a formula I in the specification.

Description

Technical Field

[0001] This application relates to the field of medicinal chemistry, and in particular to a glycyrrhetinic acid glycoside derivative, its preparation method, and its application. Background Technology

[0002] Inflammation is a physiological process involving the intervention of the immune system. A key role of inflammation is to protect the organism from microbial infection; in some cases, it serves as a physiological defense mechanism against certain diseases, such as cancer. However, long-term or chronic inflammation can become harmful, leading to serious pathological conditions. Chronic inflammation is considered a component of the development of various diseases, including diabetes, heart disease, cancer, digestive disorders, autoimmune diseases, and neurodegenerative diseases. Therefore, suppressing inflammation is an effective therapeutic strategy for combating inflammation-related diseases.

[0003] Licorice is a traditional Chinese herbal medicine with a rich structural framework, including triterpenes, flavonoids, polysaccharides, coumarins, volatile oils, and amino acids. To date, more than 20 triterpenes (such as glycyrrhizic acid and methyl glycyrrhizate) and more than 300 flavonoids (such as flavonoids, rhizoma flavonoids, and stigmosiderin) have been isolated from licorice. In addition, licorice possesses various pharmacological activities, including anti-inflammatory, antioxidant, antiviral, antitumor, and hepatoprotective effects. Glycyrrhizic acid (GL) and glycyrrhetinic acid (GA) are abundant in the roots and stems of the licorice plant and are the main medicinal components; their structural formulas are shown in Formulas 2 and 3. Research on the anti-inflammatory properties of GA and GL has been ongoing for decades. Glycyrrhetinic acid exhibits multiple anti-inflammatory mechanisms, such as acting as an inhibitor of HMGB1 and a selective inhibitor of 11β-HSD; it also inhibits and regulates enzymes involved in various inflammation-related pathways (NF-Kappa B / MAPK / PI3K / COX), thereby suppressing the expression of related inflammatory factors (IL-6 / IL-10 / NO / TNF-α). Despite these studies demonstrating the diverse anti-inflammatory mechanisms of glycyrrhetinic acid, its limited target, low activity, and poor water solubility hinder further rational design and improvement in drug formulation. Research on its analgesic effects is limited; currently, no glycyrrhetinic acid-based derivatives have demonstrated in vivo analgesic effects.

[0004]

[0005] Soluble epoxide hydrolase (sEH) is an important hydrolytic enzyme in mammals. Recent studies have revealed its crucial role in the development of inflammation in humans, classifying it as a key enzyme regulating inflammation. SEH catalyzes the hydrolysis of arachidonic acid's lipid intermediate, epioxyeicosatrienoic acids (EETs), via the cytochrome P450 enzyme system (CYP450) cyclooxygenase pathway, converting EETs into dihydroxyeicosatrienoic acid. Endogenous EETs (ethyl acetate-containing acids, DHETs) are derived from arachidonic acid (AA) via cytochrome P450 oxidation. They are important signaling molecules in organisms, regulating ion transport and gene expression, vasodilation, and anti-inflammation. In animals, EETs are degraded through various pathways, with sEH (saturated EET-H) metabolism of EETs into DHETs being the most significant, leading to decreased EET concentration and physiological activity. Numerous studies have shown that inhibiting sEH to stabilize EETs can significantly reduce inflammation and pain; therefore, sEH inhibitors are an effective method for treating various types of inflammation and pain.

[0006] To date, AR9281, GSK2256294, and EC5026 have entered clinical trials, but no sEH inhibitor drugs are currently on the market, and research on sEH inhibitors based on natural scaffolds is also lacking. Natural products have the advantage of being drug-grade; for example, glycyrrhetinic acid and glycyrrhizic acid and their derivatives from licorice have good anti-inflammatory activity. However, currently, triterpenoid glycyrrhetinic acid and glycyrrhizic acid do not have significant sEH inhibitory activity.

[0007] Therefore, there is an urgent need for a soluble epoxide hydrolase inhibitory compound with good in vivo activity, targeting the anti-inflammatory target soluble epoxide hydrolase. Summary of the Invention

[0008] This application provides a glycyrrhetinic acid glycoside derivative, its preparation method, and its application, in order to address the problem of how to provide an inhibitor of soluble epoxide hydrolase to solve its poor in vivo activity.

[0009] The first aspect of this application provides a glycyrrhetinic acid glycoside derivative, which has the following general structural formula (Formula I):

[0010]

[0011] In Equation I, R 1Selected from any of the following groups:

[0012]

[0013] R 2 Selected from any of the following groups:

[0014]

[0015] The 18th hydrogen is selected from either the α-position or the β-position stereo configuration.

[0016] Optionally, the R 2 Selected from any of the following groups:

[0017]

[0018] Optionally, the R 1 Selected from any of the following groups:

[0019]

[0020] Optionally, the R 2 Selected from any of the following groups:

[0021]

[0022] The R 1 Selected from any of the following groups:

[0023]

[0024] Optionally, the glycyrrhetinic acid glycoside derivative according to any one of claims 1-4 has the following structure:

[0025]

[0026]

[0027]

[0028]

[0029] The second aspect of this application provides a method for preparing a glycyrrhetinic acid glycoside derivative as described in any one of the first aspects above, characterized in that the method includes the following steps: the compound of formula (1) undergoes glycosylation and reductive hydrogenation reactions to obtain the compound shown in formula I;

[0030]

[0031] Among them, R 1 and R 2As defined in any one of claims 1-3, the 18-position hydrogen is selected from the α-position or β-position stereoconfiguration.

[0032] Optionally, formula (1) is a compound having any of the following structures:

[0033]

[0034] Optionally, the preparation method includes reacting the compound shown in formula (1) with any one of the compounds in formula AE to obtain the compound shown in formula I;

[0035] The structure of the compound represented by formula AE is shown below:

[0036]

[0037] Optionally, a pharmaceutical composition comprising the glycyrrhetinic acid glycoside derivative as described in any one of the first aspects is characterized in that the pharmaceutical composition comprises at least one of the following: the glycyrrhetinic acid glycoside derivative, its isotopic label, solvate, polymorph, pharmaceutically acceptable salt, or its prodrug compound.

[0038] In a third aspect of this application, at least one of the following isotope-labeled, solvated, polymorphic, pharmaceutically acceptable salt, or prodrug compound as described in any of the first aspects above is provided for the preparation of an anti-inflammatory drug.

[0039] This application has the following advantages:

[0040] (1) The glycyrrhetinic acid glycoside derivative prepared in this application significantly improves the inhibition rate of sEH, with the highest inhibition rate reaching 96% and the IC50 value being less than 100 nM.

[0041] (2) The in vivo anti-inflammatory activity of the glycyrrhetinic acid glycoside derivative prepared in this application was significantly improved, with the highest inhibition rate significantly increased by 12-15% compared with its corresponding aglycone. The in vivo anti-inflammatory activity of the glycoside derivative was superior to that of the positive control drug TPPU (1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea; an sEH inhibitor).

[0042] (3) The glycyrrhetinic acid glycoside derivative prepared in this application has superior in vivo analgesic activity compared to the positive control drug celecoxib (a commonly used nonsteroidal anti-inflammatory drug in clinical practice) and EC5026 (N-[3-fluoro-4-(trifluoromethoxy)phenyl]-N'-[1-[(2S)-2-methyl-1-oxobutyl]-4-piperidinyl]urea; an sEH inhibitor that has entered clinical trials for the treatment of neuropathic pain). Detailed Implementation

[0043] The following embodiments are provided to better understand this application and are not limited to the preferred embodiments described herein. They do not constitute a limitation on the content and scope of protection of this application. Any product that is the same as or similar to this application, derived by anyone under the guidance of this application or by combining features of this application with other prior art, falls within the scope of protection of this application.

[0044] Specific experimental steps or conditions are not specified in the examples; however, they can be performed according to the conventional experimental steps or conditions described in the prior art. Reagents and other instruments used, unless otherwise specified, are all commercially available conventional reagent products. All chemicals used in this application are commercially available, and the nuclear magnetic resonance and mass spectrometry instruments used to determine the structures of the following compounds were provided by the Analysis and Testing Center of Beijing Institute of Technology.

[0045] The first aspect of this application provides a glycyrrhetinic acid glycoside derivative, which has the following general structural formula (Formula I):

[0046]

[0047] In Equation I, R 1 Selected from any of the following groups:

[0048]

[0049] R 2 Selected from any of the following groups:

[0050]

[0051] The 18th hydrogen is selected from either the α-position or the β-position stereo configuration.

[0052] The second aspect of this application provides a method for preparing a glycyrrhetinic acid glycoside derivative as described in any one of the first aspects above, characterized in that the method includes the following steps: the compound of formula (1) undergoes a glycosylation reaction and a reductive hydrogenation reaction to obtain the compound shown in formula I;

[0053]

[0054] Among them, R 1 and R 2 As defined in any one of claims 1-3, the 18-position hydrogen is selected from the α-position or β-position stereoconfiguration.

[0055] Optionally, formula (1) is a compound having any of the following structures:

[0056]

[0057] Optionally, the preparation method includes reacting the compound shown in formula (1) with any one of the compounds in formula AE to obtain the compound shown in formula I;

[0058] The structure of the compound represented by formula AE is shown below:

[0059]

[0060] Optionally, a pharmaceutical composition comprising the glycyrrhetinic acid glycoside derivative as described in any one of the first aspects is characterized in that the pharmaceutical composition comprises at least one of the following: the glycyrrhetinic acid glycoside derivative, its isotopic label, solvate, polymorph, pharmaceutically acceptable salt, or its prodrug compound.

[0061] In a third aspect of this application, at least one of the following isotope-labeled, solvated, polymorphic, pharmaceutically acceptable salt, or prodrug compound as described in any of the first aspects above is provided for the preparation of an anti-inflammatory drug.

[0062] To enable those skilled in the art to further understand the technical solution of this application, the following describes a glycyrrhetinic acid glycoside derivative, its preparation method, and its application through specific embodiments.

[0063] The following is a brief description of the synthetic methods for the compounds of this application. In the synthetic examples listed below, the synthesis of intermediates mainly involves glycosylation and hydrogenation reduction reactions.

[0064] Specifically, the following provides the synthetic methods for representative compounds of this application.

[0065] Synthesis Example 1 - Synthesis of Compound 1Aa and Compound 1Ae:

[0066]

[0067] Raw material 1 (500 mg, 0.84 mM) was dissolved in 30 mL of anhydrous dichloromethane. O-(2,3,4,6-tetra-O-benzyl-α-D-glucosyl)trichloroacetylimine ester A (860 mg, 1.5 eq) and... MS (100 mg) was added to the reaction system and stirred for 10 min in an ice-water bath. Then, trimethylsilyl trifluoromethanesulfonate (0.1 eq) was added dropwise, and the reaction continued in an ice-water bath. After the reaction was completed, the molecular sieve was removed by diatomaceous earth filtration, and the intermediate was purified by silica gel column chromatography (100-200 mesh, DCM / EtOH v / v 10 / 0.15). The intermediate was then dissolved in 5 mL of ethyl acetate and 15 mL of methanol. The reaction solution was placed in a reaction vessel, 10% Pd / C was added, and hydrogen was purged to 0.4 MPa. The reaction was carried out at 50 °C for 8 h. After the reaction was completed, the reaction solution was removed by diatomaceous earth filtration, concentrated, and then purified by silica gel column chromatography (200-300 mesh, EtOAc:EtOH:H2O v / v / v 7 / 2 / 1) to obtain compound 1Aa (80 mg, R f =0.54, yield 25.1%); compound 1Ae (80 mg, R f =0.56, yield 25.1%.

[0068] Compound 1Aa, melting point: 190-192℃.

[0069] HRMS(ESI)[M+H] + m / z calcd for C 43 H 71 N2O9:759.5154; found:759.5126.

[0070] 11H NMR (400 MHz, Methanol-d4) δ 5.53 (s, 1H), 4.85 (d, J = 3.9 Hz, 1H), 3.85 - 3.80 (m, 2H), 3.71 - 3.48 (m, 4H), 3.39 - 3.23 (m, 4H), 3.21 - 3.13 (m, 2H), 3.02 (dd, J = 13.7, 6.4 Hz, 1H), 2.86 (dd, J = 13.6, 6.8 Hz, 1H), 2.76 (dd, J = 13.6, 4.9 Hz, 1H), 2.67 (dt, J = 13.4, 3.6 Hz, 1H), 2.30 (d, J = 14.6 Hz, 2H), 2.06 (td, J = 13.6, 4.5 Hz, 1H), 1.78 (td, J = 13.6, 4.5 Hz, 1H), 1.70 - 1.56 (m, 4H), 1.52 (d, J = 14.1 Hz, 4H), 1.48 - 1.35 (m, 3H), 1.31 (s, 3H), 1.25 - 1.09 (m, 6H), 1.06 (d, J = 6.7 Hz, 6H), 0.97 (s, 3H), 0.93 - 0.84 (m, 2H), 0.81 (s, 3H), 0.79 (s, 3H), 0.76 (s, 3H), 0.71 (d, J = 10.7 Hz, 1H).

[0071] 13 13C NMR (175 MHz, Methanol-d4) δ 201.0, 171.9, 159.9, 127.5, 95.7, 83.3, 73.7, 72.7, 72.2, 70.4, 67.4 (2C), 61.7, 61.3, 55.1, 46.5, 45.4, 45.3, 43.5, 43.2, 40.3, 38.5, 38.5, 36.9, 35.8, 35.6, 34.8, 32.4, 31.9, 31.0, 30.3 (2C), 28.1, 27.7, 27.3, 26.2, 26.1, 22.7, 21.8, 18.0, 17.2, 而15.8, 15.6.

[0072] Compound 1Ae, melting point: 197-199 °C.

[0073] HRMS (ESI) [M + H] + m / z calcd for C 43 H 71 N2O9: 759.5154; found: 759.5129.

[0074] 1H NMR (400MHz, Methanol-d4) δ5.62(s,1H),4.31(d,J=7.7Hz,1H),3.95-3.89(m,2H),3.83(dd,J=11.9,2.3Hz,1H),3.66(dd,J=11.9,5.3Hz,1H),3.5 0-3.32(m,4H),3.30-3.16(m,4H),3.11(dd,J=13.6,6.4Hz,1H),2.96(dd, J=13.6,6.8Hz,1H),2.84(d,J=13.7Hz,1H),2.70(dt,J=13.4,3.6Hz,1H), 2.39(d,J=11.3Hz,2H),2.15(td,J=13.5,4.4Hz,1H),1.94-1.82(m,2H),1 .80-1.66(m,4H),1.62(d,J=13.4Hz,4H),1.57-1.50(m,1H),1.46(d,J=10 .8Hz,2H),1.41(s,3H),1.33-1.19(m,6H),1.14(s,6H),1.07(s,3H),1.02 -0.95(m,2H),0.90(s,3H),0.86(d,J=3.5Hz,6H),0.78(d,J=11.6Hz,1H).

[0075] 13 C NMR (175MHz, Methanol-d4) δ201.0,171.9,159.9,127.5,105.4,89.1,76.9,76.3,74.3,70.3,67.4(2C),61.8,61.4,55.1,46.5,45.4,45.3,43. 5,43.2,40.3,39.1,38.9,36.7,35.8,35.7,34.8,32.4,31.9,31.0,30. 4,30.3(2C),27.7,27.3,27.1,26.2,26.1,25.6,22.7,17.9,17.1,15.6.

[0076] Synthesis Example 2 - Synthesis of Compound 1Ca and Compound 1Ce

[0077]

[0078] Raw material 1 (500 mg, 0.84 mM) was dissolved in 30 mL of anhydrous dichloromethane. C (860 mg, 1.5 eq) and MS (100 mg) was added to the reaction system, and the subsequent reaction was the same as in Example 1. The final concentrated reaction solution was subjected to silica gel column chromatography (200-300 mesh, EtOAc:EtOH:H2O v / v / v 7 / 2 / 0.5) to obtain compound 1Ca (50 mg, R f =0.45, yield 15.7%), compound 1Ce (57mg, R f =0.43, yield 17.9%.

[0079] Compound 1Ca, melting point: 175-177℃.

[0080] HRMS(ESI)[M+H] + m / z calcd for C 43 H 71 N2O9:759.5154; found:759.5150.

[0081] 1 H NMR(400MHz, Methanol-d4)δ5.63(s,1H),4.94(d,J=1.6Hz,1H),3.92(dt,J=10.0,3.7Hz,2H),3.84-3.77(m,1H),3.75-3.5 9(m,5H),3.50-3.31(m,4H),3.11(dd,J=13.6,6.4Hz,1H),2.96(dd,J=13.6,6.7Hz,1H),2.87-2.74(m,2H),2.40(d,J=15.4 Hz,2H),2.16(td,J=13.6,4.4Hz,1H),1.88(td,J=13.7,4.6Hz,1H),1.81-1.59(m,7H),1.57-1.43(m,4H),1.41(s,3H),1.3 4-1.17(m,7H),1.15(d,J=2.8Hz,6H),1.05(s,3H),1.02-0.93(m,2H),0.90(s,3H),0.86(s,3H),0.83(s,3H),0.80(s,1H).

[0082] 1313C NMR(100MHz,MeOD)δ200.9,172.0,159.9,127.5,96.3,81.4,73.8,71.7,71.4,67.4(2C),67.2,61.7,61.6,54.9,46.5,45.4,45.3,43.5,43.3,40.3,38.4,38.3,36.9,35.8,35.6,34.8,32.4,31.9,31.0,30.4,30.3,28.0,27.7,27.2,26.2,26.1,22.7,21.2,17.9,17.1,15.7,15.6.

[0083] Compound 1Ce, melting point: 185 - 187 °C.

[0084] HRMS(ESI)[M+H] + m / z calcd for C 43 H 71 N2O9: 759.5154; found: 759.5114.

[0085] 1 1H NMR(400MHz,Methanol-d4)δ5.62(s,1H),4.53(d,J = 0.9Hz,1H),3.95 - 3.81(m,4H),3.71(dd,J = 11.7,5.4Hz,1H),3.57(t,J = 9.5Hz,1H),3.49 - 3.33(m,4H),3.24 - 3.08(m,3H),2.96(dd,J = 13.6,6.7Hz,1H),2.84(d,J = 13.7Hz,1H),2.71(dt,J = 13.4,3.5Hz,1H),2.40(d,J = 12.4Hz,2H),2.16(td,J = 13.3,4.3Hz,1H),1.87(td,J = 13.1,12.5,4.2Hz,2H),1.79 - 1.67(m,3H),1.62(d,J = 13.5Hz,4H),1.54 - 1.42(m,3H),1.41(s,3H),1.33 - 1.18(m,7H),1.14(d,J = 2.4Hz,6H),0.99(s,5H),0.90(s,3H),0.86(s,6H),0.79(d,J = 10.5Hz,1H).

[0086] 13C NMR(100MHz,MeOD)δ201.0,171.9,159.9,127.5,102.8,89.0,76.7,74.1,71.3,67.4(2C),67.1,61.8,61.4,54.9,46.5,45.4,45.3,43.5,4 3.2,40.3,39.0,38.9,36.7,35.8,35.6,34.8,32.4,31.9,31.0,30.3 (2C),27.7,27.3,27.2,26.1(2C),25.4,22.7,17.9,17.1,15.6,15.6.

[0087] Synthesis Example 3 - Synthesis of compounds 2Ca and 2Ce:

[0088]

[0089] Raw material 2 (547 mg, 0.84 mM) was dissolved in 30 mL of anhydrous dichloromethane. O-(2,3,4,6-tetra-O-benzyl-α-D-mannosyl)trichloroacetylimine ester C (860 mg, 1.5 eq) and... MS (100 mg) was added to the reaction system, and the subsequent reaction was the same as in Example 1. The concentrated reaction solution was subjected to silica gel column chromatography (200-300 mesh, EtOAc:EtOH:H2O v / v / v 10 / 2 / 1) to obtain compound 2Ca (65 mg, R f =0.50, yield 19%), compound 2Ce (80mg, R f =0.45, yield 23.4%.

[0090] Compound 2Ca, melting point: 182-184℃.

[0091] HRMS(ESI)[M+H] + m / z calcd for C 46 H 76 N3O9:814.5576; found:814.5571.

[0092] 11H NMR (400 MHz, Methanol-d4) δ 5.63 (d, J = 2.8 Hz, 1H), 4.94 (d, J = 1.6 Hz, 1H), 4.55 - 4.45 (m, 1H), 4.00 - 3.91 (m, 1H), 3.8 (d, J = 9.7 Hz, 1H), 3.74 - 3.50 (m, 6H), 3.36 - 3.31 (m, 1H), 3.23 - 2.86 (m, 3H), 2.81 - 2.52 (m, 3H), 2.48 - 2.33 (m, 4H), 2.16 (td, J = 13.6, 4.3 Hz, 1H), 1.87 (td, J = 13.5, 4.3 Hz, 1H), 1.81 - 1.68 (m, 5H), 1.67 - 1.48 (m, 5H), 1.44 (d, J = 14.0 Hz, 2H), 1.41 (s, 3H), 1.35 - 1.17 (m, 5H), 1.14 (d, J = 1.7 Hz, 5H), 1.10 (q, J = 7.3 Hz, 4H), 1.05 (s, 3H), 1.02 - 0.95 (m, 2H), 0.90 (s, 3H), 0.86 (s, 3H), 0.82 (d, J = 10.8 Hz, 4H).

[0093] 13 13C NMR (100 MHz, MeOD) δ 200.8, 173.3, 172.0, 159.8, 127.5, 96.3, 81.4, 73.8, 71.7, 71.4, 67.2, 61.6, 54.9, 46.5, 45.4, 45.4, 44.8, 43.6, 43.3, 41.6, 40.3, 38.4, 37.0, 36.9, 35.7, 34.9, 32.4, 31.9, 31.2, 30.1, 29.3, 28.0, 27.7, 27.3, 26.2, 26.1, 26.1, 22.8, 21.3, 18.0, 17.2, 15.7, 15.6, 8.8.

[0094] Compound 2Ce, melting point: 181 - 183 °C.

[0095] HRMS (ESI) [M + H] + m / z calcd for C 46 H 76 N3O9: 814.5576; found: 814.5565.

[0096] 1H NMR(400MHz, Methanol-d4)δ5.63(d,J=5.8Hz,1H),4.55-4.46(m,2H),4.00-3.91(m,1H),3.89-3.81(m,2H),3.71(dd,J=11.7,5.3Hz,1H),3.64 -3.49(m,2H),3.41(dd,J=9.4,3.2Hz,1H),3.24-3.14(m,3H),3.13-2.8 4(m,2H),2.81-2.51(m,3H),2.47-2.33(m,4H),2.16(td,J=13.6,4.3Hz ,1H),1.88(td,J=11.6,9.6,3.8Hz,2H),1.82-1.68(m,5H),1.66-1.48( m,4H),1.44(d,J=13.6Hz,2H),1.41(s,3H),1.33-1.18(m,5H),1.14(d, J=1.5Hz,5H),1.10(q,J=7.4Hz,5H),1.01(d,J=3.4Hz,1H),0.99(s,3H),0.95(d,J=3.3Hz,1H),0.90(s,3H),0.86(s,6H),0.79(d,J=9.8Hz,1H).

[0097] 13 C NMR(100MHz,MeOD)δ200.9,173.4,171.9,159.8,127.5,102.8,89.0,76. 7,74.1,71.3,67.1,61.8,61.5,54.9,46.5,45.4,45.4,44.8,44.7,43.5, 43.2,41.6,40.0,39.0,36.9,36.7,35.7,34.9,32.4,31.9,31.2,30.1,29 .2,27.7,27.3,26.2,26.1,26.1,25.4,22.7,17.9,17.2,15.6,15.6,8.8.

[0098] Synthesis Example 4 - Synthesis of compounds 3Aa and 3Ae:

[0099]

[0100] Raw material 3 (500 mg, 0.74 mM) was dissolved in 30 mL of anhydrous dichloromethane. O-(2,3,4,6-tetra-O-benzyl-α-D-glucosyl)trichloroacetylimine ester A (761 mg, 1.5 eq) and... MS (100 mg) was added to the reaction system, and the subsequent reaction was the same as in Example 1. Silica gel column chromatography (100-200 mesh, DCM / EtOH v / v 10 / 0.1) yielded an intermediate mixture. The final reaction concentrate was subjected to silica gel column chromatography (200-300 mesh, EtOAc:EtOH:H2O v / v / v 10 / 1 / 0.1) to obtain compound 3Aa (60 mg, R...). f =0.40, yield 19.4%), compound 3Ae (85 mg, R f =0.44, yield 27.5%.

[0101] Compound 3Aa, melting point: 162-164℃.

[0102] HRMS(ESI)[M+H] + m / z calcd for C 45 H 66 F3N2O9:835.4715; found:835.4692.

[0103] 1 H NMR (400MHz, Methanol-d4) δ7.38(d,J=8.6Hz,2H),7.19(d,J=7.7Hz,2H),5.63(s,1H),4.95(d,J=3.9Hz,1H),4.42-4.27(m,2H),3.81-3.59(m ,4H),3.48-3.33(m,2H),3.29-3.24(m,1H),2.93(dd,J=13.7,4.9Hz,1H),2.79(dt,J=13.4,3.6Hz,1H),2.43(s,1H),2.37(dd,J=13.3,4.3Hz, 1H),2.15(td,J=13.7,4.3Hz,1H),1.87(td,J=13.6,4.4Hz,1H),1.80- 1.70(m,2H),1.69-1.42(m,7H),1.40(s,3H),1.37-1.27(m,3H),1.23(d ,J=13.4Hz,2H),1.16(d,J=8.7Hz,6H),1.07(s,3H),0.99(dt,J=14.0,3.4Hz,2H),0.89(d,J=4.3Hz,6H),0.85(s,3H),0.81(d,J=11.0Hz,1H).

[0104] 1313C NMR (100 MHz, MeOD) δ 201.1, 172.0, 159.7, 148.0, 139.6, 128.5, 127.6, 121.8, 120.7, 119.3, 95.7, 83.5, 73.7, 72.7, 72.2, 70.5, 61.7, 61.3, 55.2, 46.6, 45.4, 43.7, 43.3, 42.7, 40.4, 38.6, 36.9, 35.6, 34.8, 32.4, 31.9, 30.9, 28.1, 27.7, 27.3, 26.2, 22.7, 21.9, 18.0, 17.2, 15.8, 15.6.

[0105] Compound 3Ae, melting point: 169 - 171 °C.

[0106] HRMS (ESI) [M + H] + m / z calcd for C 45 H 66 F3N2O9: 835.4715; found: 835.4683.

[0107] 1 1H NMR (400 MHz, Methanol - d4) δ 7.38 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 7.7 Hz, 2H), 5.62 (s, 1H), 4.38 - 4.28 (m, 3H), 3.84 (dd, J = 11.9, 2.4 Hz, 1H), 3.68 (dd, J = 11.8, 5.2 Hz, 1H), 3.47 - 3.32 (m, 2H), 3.30 - 3.16 (m, 3H), 2.94 (dd, J = 13.7, 5.0 Hz, 1H), 2.73 (dt, J = 13.4, 3.6 Hz, 1H), 2.43 (s, 1H), 2.36 (dd, J = 13.5, 4.4 Hz, 1H), 2.15 (td, J = 13.6, 4.4 Hz, 1H), 1.94 - 1.70 (m, 4H), 1.68 - 1.51 (m, 3H), 1.50 - 1.42 (m, 2H), 1.41 (s, 3H), 1.38 - 1.26 (m, 3H), 1.26 - 1.17 (m, 2H), 1.15 (d, J = 3.6 Hz, 6H), 1.08 (s, 3H), 1.02 (td, J = 13.8, 3.9 Hz, 2H), 0.93 - 0.83 (m, 9H), 0.79 (d, J = 10.7 Hz, 1H).

[0108] 13C NMR(100MHz,MeOD)δ201.2,171.9,159.7,148.0,139.6,128.5(3C),127. 6,121.8,120.7(2C),119.3,105.3,89.2,76.9,76.3,74.3,70.3,61.8,61 .4,55.2,46.6,45.4,43.7,43.3,42.7,40.5,39.1,39.0,36.7,35.6,34. 8,32.4,31.9,30.9,27.7,27.3,27.1,26.2,25.6,22.7,18.0,17.1,15.6.

[0109] Synthesis Example 5 - Synthesis of compounds 4Aa and 4Ae:

[0110]

[0111] Raw material 4 (500 mg, 0.84 mM) was dissolved in 30 mL of anhydrous dichloromethane. O-(2,3,4,6-tetra-O-benzyl-α-D-glucosyl)trichloroacetylimine ester A (860 mg, 1.5 eq) and... MS (100 mg) was added to the reaction system, and the subsequent reaction and post-treatment were the same as in Example 1, yielding compound 4Aa (85 mg, R). f =0.53, yield 26%); compound 4Ae (80 mg, R f =0.56, yield 25.1%.

[0112] Compound 4Aa: Melting point: 185-187℃.

[0113] HRMS(ESI)[M+H] + m / z calcd for C 43 H 71 N2O9:759.5154; found:759.5135.

[0114] 11H NMR (400 MHz, Methanol-d4) δ 5.42 (s, 1H), 4.85 (d, J = 3.9 Hz, 1H), 3.83 (dd, J = 11.5, 4.2 Hz, 2H), 3.71 - 3.61 (m, 2H), 3.61 - 3.48 (m, 2H), 3.33 - 3.22 (m, 4H), 3.19 - 3.14 (m, 1H), 2.97 - 2.82 (m, 4H), 2.62 - 2.52 (m, 1H), 2.27 (s, 1H), 2.25 - 2.18 (m, 1H), 1.93 (td, J = 13.9, 4.7 Hz, 1H), 1.72 - 1.57 (m, 3H), 1.53 (dt, J = 11.4, 5.2 Hz, 5H), 1.47 - 1.38 (m, 3H), 1.38 - 1.30 (m, 2H), 1.28 (s, 3H), 1.20 (q, J = 6.8, 5.1 Hz, 4H), 1.12 (s, 6H), 1.05 (s, 3H), 0.96 (s, 3H), 0.88 (dd, J = 13.5, 3.3 Hz, 1H), 0.82 (s, 3H), 0.79 (s, 3H), 0.71 (d, J = 11.4 Hz, 1H), 0.61 (s, 3H).

[0115] 13 13C NMR (175 MHz, MeOD) δ 200.8, 168.4, 160.1, 123.1, 95.7, 83.4, 73.7, 72.7, 72.2, 70.4, 67.4 (2C), 61.3, 60.6, 55.1, 52.2, 45.2, 44.9, 43.8, 40.6, 38.5 38.5, 37.3, 36.7, 36.0, 35.8, 35.6, 35.6, 33.5, 32.4, 30.3 (2C), 29.1, 28.1, 26.5, 21.8, 20.3, 19.8, 17.8, 17.3, 15.9, 15.8, 15.1.

[0116] [[ID=​​​​​​​​​​​​H NMR (400MHz, Methanol-d4) δ5.51(s,1H),4.31(d,J=7.7Hz,1H),3.92(dd,J=11.5,4.3Hz,2H),3.83(dd,J=11.9,2.2Hz,1H),3.66(dd,J=11 .9,5.2Hz,1H),3.43-3.32(m,3H),3.30-3.15(m,4H),3.09-2.91(m,4H),2.61(dt,J=13.8,3.7Hz,1H),2.35(s,1H),2.31(dd,J=11.0,4.1H z,1H),2.06-1.98(m,1H),1.91(dd,J=14.2,4.2Hz,1H),1.82-1.67(m,4H),1.61(dd,J=13.9,4.1Hz,4H),1.56-1.40(m,5H),1.38(s,3H),1 .35-1.21(m,6H),1.20(s,3H),1.14(s,3H),1.07(s,3H),1.04-0.95( m,1H),0.91(s,3H),0.87(s,3H),0.78(d,J=11.7Hz,1H),0.70(s,3H).

[0119] 13 C NMR(175MHz,MeOD)δ200.8,168.3,160.1,123.2,105.4,89.1,76.9,76.3,74.3,70.3,67.4(2C),61.4,60.6,55.2,52.3,45.3,44.9,43.8,4 0.6,39.1,38.9,37.3,36.5,36.1,35.8,35.6,35.6,33.5,32.4,30.3( 2C),29.1,27.1,26.5,25.6,20.3,19.8,17.8,17.2,15.9,15.7,15.1.

[0120] Synthesis Example 6 - Synthesis of compounds 4Ba and 4Be:

[0121]

[0122] Raw material 4 (500 mg, 0.84 mM) was dissolved in 30 mL of anhydrous dichloromethane. O-(2,3,4,6-tetra-O-benzyl-α-D-galactosyl)trichloroacetylimine ester B (860 mg, 1.5 eq) and... MS (100 mg) was added to the reaction system, and the subsequent reaction was the same as in Example 1. The final concentrated reaction solution was subjected to silica gel column chromatography (200-300 mesh, EtOAc:EtOH:H2O v / v / v7 / 1.8 / 0.2) to obtain compound 4Ba (85 mg, R). f =0.40, yield 26%); compound 4Be (80 mg, R f =0.44, yield 25.1%.

[0123] Compound 4Ba has a melting point of 197-199℃.

[0124] HRMS(ESI)[M+H] + m / z calcd for C 43 H 71 N2O9:759.5154; found:759.5124.

[0125] 1 H NMR (400MHz, Methanol-d4) δ5.51(d,J=1.8Hz,1H),4.97(d,J=3.9Hz,1H),4.00-3.88(m,4H),3.80-3.65(m,4H),3.38(tt,J=11.9,1.8Hz,2H ),3.27(dd,J=11.6,4.4Hz,1H),3.09-2.92(m,4H),2.66(dt,J=13.4,3.6Hz,1H),2.36(s,1H),2.31(ddd,J=10.8,4.6,1.9Hz,1H),2.02(td, J=13.8,4.8Hz,1H),1.80-1.67(m,3H),1.66-1.58(m,5H),1.56-1.49(m,3H),1.47-1.40(m,2H),1.37(s,3H),1.35-1.27(m,4H),1.26-1.24 (m,1H),1.22(s,4H),1.14(s,4H),1.05(s,3H),0.98(dd,J=13.5,3.6Hz,1H),0.91(s,3H),0.88(s,3H),0.81(d,J=10.8Hz,1H),0.70(s,3H).

[0126] 1313C NMR(175MHz,MeOD)δ200.8,168.4,160.1,123.1,95.9,83.3,71.3,70.3,69.6,68.8,67.4(2C),61.2,60.6,55.1,52.2,45.2,44.9,43.8,40.6,38.5,38.4,37.3,36.7,36.0,35.8,35.6,35.6,33.5,32.4,30.3(2C),29.1,28.0,26.4,21.8,20.3,19.7,17.7,17.3,15.9,15.8,15.1.

[0127] Compound 4Be, melting point: 199 - 202 °C.

[0128] HRMS(ESI)[M+H] + m / z calcd for C 43 H 71 N2O9: 759.5154; found: 759.5129.

[0129] 1 1H NMR(400MHz, Methanol - d4)δ5.51(d, J = 1.8Hz, 1H), 4.27(d, J = 7.6Hz, 1H), 3.96 - 3.88(m, 2H), 3.83(d, J = 3.4Hz, 1H), 3.71(dd, J = 6.2, 2.0Hz, 2H), 3.57 - 3.34(m, 5H), 3.19(dd, J = 11.7, 4.6Hz, 1H), 3.09 - 2.91(m, 4H), 2.60(dt, J = 13.3, 3.6Hz, 1H), 2.35(s, 1H), 2.34 - 2.28(m, 1H), 2.02(td, J = 13.6, 4.6Hz, 1H), 1.90(dt, J = 13.9, 3.4Hz, 1H), 1.81 - 1.67(m, 3H), 1.66 - 1.57(m, 4H), 1.55 - 1.40(m, 5H), 1.37(s, 3H), 1.34 - 1.27(m, 4H), 1.25(d, J = 5.0Hz, 1H), 1.19(s, 4H), 1.14(s, 4H), 1.07(s, 3H), 0.99(td, J = 13.6, 3.6Hz, 1H), 0.91(s, 3H), 0.87(s, 3H), 0.78(d, J = 11.5Hz, 1H), 0.70(s, 3H).

[0130] 13C NMR(175MHz,MeOD)δ200.8,168.3,160.1,123.2,106.0,89.0,74.9,73.8,71.7,68.8,67.4(2C),61.0,60.6,55.2,52.2,45.2,44.9,43.8,4 0.6,39.1,38.9,37.3,36.5,36.0,35.8,35.6,35.6,33.5,32.4,30.3( 2C),29.1,27.1,26.5,25.6,20.3,19.7,17.7,17.1,15.8,15.7,15.1.

[0131] Synthesis Example 7 - Synthesis of compounds 4Ca and 4Ce:

[0132]

[0133] Raw material 4 (500 mg, 0.84 mM) was dissolved in 30 mL of anhydrous dichloromethane. O-(2,3,4,6-tetra-O-benzyl-α-D-mannosyl)trichloroacetylimine ester C (860 mg, 1.5 eq) and... MS (100 mg) was added to the reaction system, and the subsequent reaction was the same as in Example 1. The final concentrated reaction solution was subjected to silica gel column chromatography (200-300 mesh, EtOAc:EtOH:H2O v / v / v 7 / 2 / 0.5) to obtain compound 4Ca (50 mg, R f =0.45, yield 15.7%), compound 4Ce (57mg, R f =0.43, yield 17.9%). J was calculated based on HSQC spectral analysis. C1'-H1' To identify glycosidic bonds, where 4Ca's J C1'-H1' The Hz is 167.5 Hz, and its glycosidic bond configuration is α-configuration, with 4Ce J. C1'-H1' The frequency is 157.3 Hz, and its glycosidic bond configuration is β-configuration.

[0134] Compound 4Ca, melting point: 192-194℃.

[0135] HRMS(ESI)[M+H] + m / z calcd for C 43 H 71 N2O9:759.5154; found:759.5138.

[0136] 11H NMR (400 MHz, Methanol-d4) δ 5.51 (d, J = 1.8 Hz, 1H), 4.94 (d, J = 1.6 Hz, 1H), 3.97 - 3.88 (m, 2H), 3.80 (d, J = 9.5 Hz, 1H), 3.74 - 3.62 (m, 5H), 3.42 - 3.33 (m, 3H), 3.09 - 2.92 (m, 4H), 2.67 (dt, J = 13.4, 3.5 Hz, 1H), 2.37 (s, 1H), 2.35 - 2.29 (m, 1H), 2.02 (m, 1H), 1.82 - 1.67 (m, 3H), 1.66 - 1.58 (m, 4H), 1.56 - 1.40 (m, 6H), 1.37 (s, 3H), 1.35 - 1.26 (m, 4H), 1.26 - 1.23 (m, 1H), 1.21 (s, 4H), 1.14 (s, 4H), 1.05 (s, 3H), 0.98 (ddd, J = 16.1, 12.3, 3.3 Hz, 1H), 0.91 (s, 3H), 0.83 (s, 3H), 0.82 - 0.79 (m, 1H), 0.70 (s, 3H).

[0137] 13 13C NMR (100 MHz, MeOD) δ 200.7, 168.4, 160.1, 123.2, 96.3, 81.5, 73.8, 71.7, 71.4, 67.4 (2C), 67.1, 61.6, 60.6, 55.0, 52.3, 45.3, 44.9, 43.8, 40.6, 38.3, 37.3, 36.7, 36.1, 35.9, 35.6, 35.6, 33.5, 32.4, 30.3 (2C), 29.1, 28.0, 26.5, 21.2, 20.3, 19.8, 17.8, 17.2, 15.9, 15.8, 15.1.

[0138] Compound 4Ce, melting point: 196 - 198 °C.

[0139] HRMS (ESI) [M + H] + m / z calcd for C 43 H 71 N2O9: 759.5154; found: 759.5141.

[0140] 1H NMR (400MHz, Methanol-d4) δ5.51(d,J=1.8Hz,1H),4.53(s,1H),3.96-3.80(m,4H),3.71(dd,J=11.8,5.4Hz,1H),3.57(t,J=9.5Hz,1H),3.45-3.34 (m,3H),3.26-3.15(m,2H),3.06-2.93(m,4H),2.61(dt,J=13.3,3.6Hz,1H ),2.37(s,1H),2.32(ddd,J=11.1,4.3,1.9Hz,1H),2.02(dt,J=13.8,7.0H z,1H),1.93-1.86(m,1H),1.85-1.76(m,1H),1.71(ddd,J=14.4,7.3,4.1H z,2H),1.66-1.58(m,4H),1.56-1.41(m,5H),1.38(s,3H),1.31(ddd,J=11 .9,5.7,3.3Hz,4H),1.27-1.23(m,1H),1.21(s,4H),1.14(s,4H),0.99(s, 4H),0.92(s,3H),0.86(s,3H),0.80(dd,J=11.7,1.8Hz,1H),0.71(s,3H).

[0141] 13 C NMR(100MHz,MeOD)δ200.8,168.3,160.1,123.2,102.8,89.0,76.7,74.1,71.3,67.4(2C),67.1,61.5,60.6,55.0,52.2,45.2,44.9,43.8,4 0.6,38.9,38.8,37.2,36.5,36.0,35.8,35.6,35.6,33.5,32.4,30.3( 2C),29.1,27.3,26.5,25.3,20.3,19.7,17.7,17.2,15.8,15.7,15.1.

[0142] Synthesis Example 8 - Synthesis of compounds 4Da and 4De:

[0143]

[0144] Raw material 4 (500 mg, 0.84 mM) was dissolved in 30 mL of anhydrous dichloromethane. O-(2,3,4-tris-O-benzyl-α-D-arabinose)trichloroacetylimine ester D (710 mg, 1.5 eq) and... MS (100 mg) was added to the reaction system, and the subsequent reaction was the same as in Example 1. The intermediate reaction was obtained by liquid crystal silica gel column chromatography (100-200 mesh, DCM / EtOH v / v 10 / 0.1). The final reaction concentrate was obtained by silica gel column chromatography (200-300 mesh, EtOAc:EtOH:H2O v / v / v 7 / 1.6 / 0.2) to give compound 4Da (43 mg, R). f =0.58, yield 13.5%), compound 4De (57 mg, R f =0.55, yield 17.9%.

[0145] Compound 4Da: Melting point: 150-152℃.

[0146] HRMS(ESI)[M+H] + m / z calcd for C 42 H 69 N2O8:729.5048; found:729.5051.

[0147] 1 H NMR (400MHz, Methanol-d4) δ5.51(d,J=1.8Hz,1H),3.98-3.88(m,3H),3.85(s,1H),3.78-3.75(m,2H),3.54(dd,J=12.2,2 .5Hz,1H),3.43-3.33(m,2H),3.14-2.90(m,5H),2.61(dt,J=13.3,3.5Hz,1H),2.39-2.28(m,2H),2.01(dt,J=13.8,7.2Hz ,1H),1.82-1.66(m,4H),1.66-1.57(m,4H),1.56-1.40(m,5H),1.38(s,3H),1.35-1.27(m,5H),1.26-1.22(m,1H),1.21(s ,4H),1.14(s,4H),1.06(s,3H),1.00(dt,J=13.6,8.4Hz,2H),0.90(d,J=13.6Hz,6H),0.79(d,J=12.5Hz,1H),0.70(s,3H).

[0148] 1313C NMR (100 MHz, MeOD) δ 200.8, 168.4, 160.1, 123.1, 102.1, 88.5, 69.6, 69.5, 69.3, 67.4 (2C), 63.0, 60.6, 55.1, 52.2, 45.2, 44.9, 43.8, 40.6, 39.2, 38.8, 37.3, 36.4, 36.0, 35.8, 35.6, 35.6, 33.4, 32.4, 30.3 (2C), 29.1, 27.1, 26.5, 25.2, 20.3, 19.8, 17.7, 17.2, 15.8, 15.6, 15.1.

[0149] Compound 4De: Melting point: 208 - 211 °C.

[0150] HRMS (ESI) [M + H] + m / z calcd for C 42 H 69 N2O8: 729.5048; found: 729.5024.

[0151] 1 1H NMR (400 MHz, Methanol - d4) δ 5.51 (d, J = 1.8 Hz, 1H), 4.28 - 4.23 (m, 1H), 3.95 - 3.88 (m, 2H), 3.84 (dd, J = 12.4, 3.0 Hz, 1H), 3.79 (s, 1H), 3.54 - 3.46 (m, 3H), 3.38 (tt, J = 11.4, 1.8 Hz, 2H), 3.26 (dd, J = 11.1, 5.1 Hz, 1H), 3.08 - 2.92 (m, 4H), 2.66 (dt, J = 13.3, 3.6 Hz, 1H), 2.33 (d, J = 18.9 Hz, 2H), 2.01 (dt, J = 13.6, 7.0 Hz, 1H), 1.70 (dq, J = 11.5, 4.2 Hz, 4H), 1.66 - 1.58 (m, 4H), 1.56 - 1.40 (m, 5H), 1.37 (s, 3H), 1.34 - 1.27 (m, 4H), 1.26 - 1.23 (m, 1H), 1.21 (s, 4H), 1.14 (s, 4H), 1.04 (s, 3H), 0.99 - 0.93 (m, 1H), 0.91 (s, 3H), 0.84 (s, 3H), 0.77 (d, J = 10.6 Hz, 1H), 0.70 (s, 3H).

[0152] 13C NMR(100MHz,MeOD)δ200.8,168.4,160.1,123.1,100.9,84.2,73.0,71.2,68.3,67.4(2C),65.4,60.6,55.5,52.2,45.2,44.9,43.8,40.6 ,38.6,38.1,37.3,36.6,36.0,35.8,35.6,35.6,33.5,32.4,30.3(2C),29.1,27.5,26.5,22.4,20.3,19.8,17.7,17.3,15.9,15.8,15.1.

[0153] Synthesis Example 9 - Synthesis of compounds 4Ea and 4Ee:

[0154]

[0155] Raw material 4 (500 mg, 0.84 mM) was dissolved in 30 mL of anhydrous dichloromethane. O-(2,3,4-tris-O-benzyl-α-D-axylose)trichloroacetylimine ester E (710 mg, 1.5 eq) and... MS (100 mg) was added to the reaction system, and the subsequent reaction was the same as in Example 1. The intermediate reaction solution was subjected to silica gel column chromatography (100-200 mesh, DCM / EtOH v / v 10 / 0.1) to obtain the intermediate; the final reaction concentrate was subjected to silica gel column chromatography (200-300 mesh, EtOAc:EtOH:H2O v / v / v 7 / 1.2 / 0.1) to obtain compound 4Ea (66 mg, R f =0.55, yield 21.5%), compound 4Ee (78mg, R f =0.6, yield 25.5%.

[0156] Compound 4Ea, melting point: 185-187℃.

[0157] HRMS(ESI)[M+H] + m / z calcd for C 42 H 69 N2O8:729.5048; found:729.5027.

[0158] 11H NMR (400 MHz, Methanol-d4) δ 5.51 (d, J = 1.8 Hz, 1H), 4.87 (d, J = 3.8 Hz, 1H), 3.94 - 3.90 (m, 2H), 3.68 - 3.33 (m, 7H), 3.19 (dd, J = 11.5, 4.5 Hz, 1H), 3.09 - 2.89 (m, 4H), 2.67 (dt, J = 13.4, 3.6 Hz, 1H), 2.39 - 2.26 (m, 2H), 2.02 (td, J = 13.9, 4.9 Hz, 1H), 1.78 - 1.58 (m, 8H), 1.56 - 1.40 (m, 5H), 1.38 (s, 3H), 1.34 - 1.24 (m, 4H), 1.22 (s, 5H), 1.14 (s, 4H), 1.06 (s, 3H), 0.96 (dd, J = 13.7, 3.8 Hz, 1H), 0.90 (d, J = 9.2 Hz, 6H), 0.79 (d, J = 11.0 Hz, 1H), 0.70 (s, 3H).

[0159] 13 13C NMR (100 MHz, MeOD) δ 200.8, 168.4, 160.1, 123.1, 96.2, 83.9, 73.8, 72.2, 70.2, 67.4 (2C), 62.3, 60.6, 55.2, 52.2, 45.2, 44.9, 43.8, 40.6, 38.5 (2C), 37.3, 36.7, 36.0, 35.8, 35.6, 35.6, 33.5, 32.4, 30.3 (2C), 29.1, 27.9, 26.5, 22.0, 20.3, 19.8, 17.7, 17.3, 15.9, 15.8, 15.1.

[0160] Compound 4Ee, melting point: 247 - 249 °C.

[0161] HRMS (ESI) [M + H] + m / z calcd for C 42 H 69 N2O8: 729.5048; found: 729.5024.

[0162] 1H NMR (400MHz, Methanol-d4) δ5.51(d,J=1.9Hz,1H),4.26(d,J=7.5Hz,1H),3.92(dd,J=11.3,4.4Hz,2H),3.81(dd,J=11.4,5.3Hz,1H),3.46(d dd,J=10.2,8.7,5.3Hz,1H),3.38(t,J=11.6Hz,2H),3.27(d,J=8.8Hz,1H),3.23-3.11(m,3H),3.09-2.91(m,4H),2.60(dt,J=13.4,3.5Hz,1H ),2.41-2.27(m,2H),2.02(td,J=13.8,4.8Hz,1H),1.77-1.68(m,4H), 1.66-1.57(m,4H),1.56-1.40(m,5H),1.38(s,3H),1.35-1.27(m,4H), 1.26-1.22(m,2H),1.19(s,4H),1.14(s,4H),1.06(s,3H),1.03-0.94( m,1H),0.91(s,3H),0.86(s,3H),0.78(d,J=11.0Hz,1H),0.70(s,3H).

[0163] 13 C NMR(100MHz,MeOD)δ200.8,168.3,160.1,123.2,106.1,89.0,76.6,74.1,69.9,67.4(2C),65.3,60.6,55.1,52.2,45.2,44.9,43.8,40.6 ,39.1,38.8,37.3,36.5,36.1,35.8,35.6,35.6,33.4,32.4,30.3(2C),29.1,27.0,26.5,25.7,20.3,19.8,17.7,17.1,15.8,15.6,15.1.

[0164] Synthesis Example 10 - Synthesis of compounds 5Ca and 5Ce:

[0165]

[0166] Raw material 5 (547 mg, 0.84 mM) was dissolved in 30 mL of anhydrous dichloromethane. O-(2,3,4,6-tetra-O-benzyl-α-D-mannosyl)trichloroacetylimine ester C (860 mg, 1.5 eq) and... MS (100 mg) was added to the reaction system, and the subsequent reaction was the same as in Example 1. The concentrated reaction solution was subjected to silica gel column chromatography (200-300 mesh, EtOAc:EtOH:H2O v / v / v 10 / 2 / 1) to obtain compound 5Ca (65 mg, R f =0.50, yield 19%), compound 5Ce (80mg, R f =0.45, yield 23.4%.

[0167] Compound 5Ca, melting point: 193-195℃.

[0168] HRMS(ESI)[M+H] + m / z calcd for C 46 H 76 N3O9:814.5576; found:814.5576.

[0169] 1 H NMR (400MHz, Methanol-d4) δ5.51(s,1H),4.94(d,J=1.6Hz,1H),4.53-4.47(m,1H),4.00-3.91(m,1H),3.83-3.59(m,6H),3.34( d,J=4.3Hz,1H),3.13-2.90(m,5H),2.71-2.55(m,2H),2.44-2.27(m,4H),2.02(td,J=13.1,12.5,4.3Hz,1H),1.75(td,J=14.6,7 .2Hz,5H),1.63(dd,J=14.1,4.9Hz,2H),1.57-1.40(m,6H),1.37(s,3H),1.34-1.23(m,3H),1.20(s,4H),1.16(d,J=7.0Hz,1H),1 .14(s,3H),1.10(td,J=7.5,1.8Hz,4H),1.05(s,3H),0.98(td,J=13.7,3.7Hz,2H),0.91(s,3H),0.83-0.80(m,4H),0.71(s,3H).

[0170] 1313C NMR (100 MHz, MeOD) δ 200.7, 173.3, 168.4, 160.1, 123.2, 96.3, 81.5, 73.8, 71.7, 71.4, 67.2, 61.6, 60.6, 55.0, 52.3, 45.4, 44.9, 44.8, 43.8, 41.6, 40.6, 38.3, 37.3, 37.0, 36.7, 36.1, 35.7, 35.6, 33.5, 32.4, 30.1, 29.3, 29.1, 28.0, 26.5, 26.1, 21.2, 20.4, 20.3, 19.8, 17.8, 17.3, 15.9, 15.8, 15.2, 8.8.

[0171] Compound 5Ce, melting point: 192 - 194 °C.

[0172] HRMS (ESI) [M + H] + m / z calcd for C 46 H 76 N3O9: 814.5576; found: 814.5575.

[0173] 1 1H NMR (400 MHz, Methanol-d4) δ 5.50 (s, 1H), 4.54 - 4.45 (m, 2H), 4.00 - 3.91 (m, 1H), 3.89 - 3.80 (m, 2H), 3.71 (dd, J = 11.7, 5.4 Hz, 1H), 3.57 (t, J = 9.4 Hz, 1H), 3.42 (dd, J = 9.4, 3.2 Hz, 1H), 3.25 - 3.15 (m, 2H), 3.13 - 2.90 (m, 5H), 2.60 (td, J = 12.7, 2.9 Hz, 2H), 2.45 - 2.27 (m, 4H), 2.02 (td, J = 13.0, 12.2, 4.1 Hz, 1H), 1.89 (dd, J = 13.7, 4.0 Hz, 1H), 1.74 (qt, J = 12.5, 5.7 Hz, 5H), 1.66 - 1.57 (m, 2H), 1.55 - 1.40 (m, 5H), 1.37 (s, 3H), 1.34 - 1.22 (m, 3H), 1.20 (s, 4H), 1.14 (s, 4H), 1.10 (td, J = 7.5, 2.0 Hz, 4H), 1.06 - 1.01 (m, 1H), 0.99 (s, 4H), 0.91 (s, 3H), 0.86 (s, 3H), 0.79 (d, J = 10.9 Hz, 1H), 0.70 (s, 3H).

[0174] 13C NMR(100MHz,MeOD)δ200.6,173.3,168.2,160.1,123.2,102.8,89.0,76.7, 74.1,71.3,67.1,61.5,60.6,55.0,52.3,45.4,44.9,44.7,43.8,41.6,40. 6,38.9,37.3,37.0,36.5,36.1,35.7,35.6,33.5,32.4,30.1,29.3,29.1,27.3,26.5,26.1,25.4,20.4,20.3,19.8,17.8,17.3,15.9,15.7,15.1,8.7.

[0175] Synthesis Example 11 - Synthesis of compounds 6Aa and 6Ae:

[0176]

[0177] Raw material 6 (500 mg, 0.74 mM) was dissolved in 30 mL of anhydrous dichloromethane. O-(2,3,4,6-tetra-O-benzyl-α-D-glucosyl)trichloroacetylimine ester A (761 mg, 1.5 eq) and... MS (100 mg) was added to the reaction system, and the subsequent reaction was the same as in Example 1. The intermediate reaction solution was subjected to silica gel column chromatography (100-200 mesh, DCM / EtOH v / v 10 / 0.1) to obtain the intermediate. The intermediate was dissolved in 5 mL of ethyl acetate and 15 mL of methanol and placed in a reaction vessel. 10% Pd / C was added, and hydrogen was purged to 0.4 MPa. The reaction was carried out at 50 °C for 6 h. After the reaction was complete, the reaction solution was filtered through diatomaceous earth to remove Pd / C. The concentrated reaction solution was subjected to silica gel column chromatography (200-300 mesh, EtOAc:EtOH:H2O v / v / v 10 / 1 / 0.1) to obtain compound 6Aa (60 mg, R f =0.40, yield 19.4%), compound 6Ae (85mg, R f =0.44, yield 27.5%.

[0178] The melting point of compound 6Aa is 176-178℃.

[0179] HRMS(ESI)[M+H] + m / z calcd for C 45 H 66 F3N2O9:835.4715; found:835.4684.

[0180] 11H NMR (400 MHz, Methanol-d4) δ 7.38 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 7.6 Hz, 2H), 5.51 (d, J = 1.8 Hz, 1H), 4.95 (d, J = 3.9 Hz, 1H), 4.34 (d, J = 3.0 Hz, 2H), 3.80 - 3.58 (m, 4H), 3.38 (dd, J = 9.8, 3.8 Hz, 1H), 3.30 - 3.24 (m, 2H), 3.00 (q, J = 13.6 Hz, 2H), 2.68 (dt, J = 13.4, 3.5 Hz, 1H), 2.37 (s, 1H), 2.33 - 2.27 (m, 1H), 2.01 (dt, J = 13.8, 7.0 Hz, 1H), 1.82 - 1.58 (m, 5H), 1.57 - 1.40 (m, 5H), 1.37 (s, 3H), 1.29 (td, J = 12.7, 11.3, ۷.۸ Hz, 3H), 1.23 (s, 3H), 1.20 - 1.18 (m, 1H), 1.15 (s, 4H), 1.06 (s, 3H), 0.96 (td, J = 13.5, 3.5 Hz, 1H), 0.90 (d, J = 4.7 Hz, 6H), 0.81 (d, J = 11.5 Hz, 1H), 0.68 (s, 3H).

[0181] 13 13C NMR (175 MHz, MeOD) δ 200.9, 168.4, 159.9, 148.0, 139.7, 128.4 (3C), 123.1, 121.3, 120.7, 119٫۸, 95.7, 83.4, 73.7, 72.7, 72.2, 70.4, 61.3, 60.6, 55.2, 44.9, 43.8, 42.6, 40.6, 38.5, 37.3, 36.7, 36.0, 35.6, 35.5, 33.5, 32.4, 29.1, 28.1, 26.5, 21.9, 20.3, 19.8, 17.8, 17.3, 15.9, 15.8, 15.1.

[0182] Melting point of Compound 6Ae: 178 - 180 °C.

[0183] HRMS (ESI) [M + H] + m / z calcd for C 45 H 66 F3N2O9: 835.4715; found: 835.4697.

[0184] 1H NMR (400MHz, Methanol-d4) δ7.37(d,J=8.6Hz,2H),7.19(d,J=7.7Hz,2H),5.51(d,J=1.8Hz,1H),4.40-4.27(m,3H),3.83(dd,J=11.9,2.3Hz,1H),3.67(d d,J=11.8,5.2Hz,1H),3.37-3.32(m,1H),3.28(s,1H),3.26-3.16(m,3H),3. 00(q,J=13.6Hz,2H),2.62(dt,J=13.3,3.5Hz,1H),2.36(s,1H),2.34-2.27(m ,1H),2.02(td,J=13.5,4.5Hz,1H),1.90(dt,J=12.2,4.1Hz,1H),1.82-1.70 (m,2H),1.62(dt,J=13.4,4.1Hz,2H),1.56-1.40(m,5H),1.37(s,3H),1.34-1 .22(m,3H),1.20(d,J=5.0Hz,4H),1.14(s,4H),1.07(s,3H),1.01(td,J=13. 5,3.7Hz,1H),0.90(s,3H),0.87(s,3H),0.78(d,J=10.8Hz,1H),0.68(s,3H).

[0185] 13 C NMR(175MHz,MeOD)δ200.9,168.3,159.9,148.0,139.7,128.4(3C),123. 2,121.3,120.7,119.8,105.4,89.2,76.9,76.3,74.3,70.2,61.4,60.6,5 5.2,44.9,43.8,42.6,40.6,39.1,38.9,37.3,36.5,36.0,35.6,35.6,33. 5,32.4,29.1,27.1,26.5,25.6,20.3,19.8,17.8,17.2,15.8,15.7,15.1.

[0186] The following demonstrates the technical effects and advantages of this application by applying the glycyrrhetinic acid glycoside derivative to inhibit soluble epoxide hydrolase (sEH).

[0187] Specifically, the verification method for the glycyrrhetinic acid glycoside derivative in this application embodiment involves co-incubating the glycyrrhetinic acid glycoside derivative prepared in this application with a sample containing soluble epoxide hydrolase and the endogenous hydrolysis substrate 14,15-EET of the hydrolase, detecting the content of the hydrolysis product 14,15-DHET, and using its relative amount to reflect the inhibitory effect of the compound on soluble epoxide hydrolase. The specific steps are as follows:

[0188] Add 1:10 (mg / μL) pre-cooled PBS (pH=7.4) to the collected brain tissue samples of adult (25-30g) male C57BL / 6JNifdc mice and homogenize for 30 seconds (4℃, 4500rpm) using a Bertin Precellys 24-Dual homogenizer. Then centrifuge at 9000g for 15 minutes at 4℃ using a small low-temperature centrifuge. Take the supernatant and dilute it 20 times. Add 160 μL of PBS (phosphate buffered saline) and 20 μL of tissue fluid diluted 20 times to an Eppendorf tube. Add 2 μL of a compound with concentration gradients of 2500, 10000, 5000, 1000, 500, 100, 50, 10, and 1 μg / mL (final concentrations of 250, 100, 50, 10, 5, 1, 0.5, 0.1, and 0.01 μg / mL). Incubate at room temperature for 15 minutes. The control is PBS without tissue dilution but with added solvent (180 μL PBS plus 2 μL DMSO). The positive control is the same concentration of sample dilution plus an equal volume of solvent (160 μL PBS plus 20 μL tissue fluid diluted 20 times plus 2 μL DMSO). After incubation at room temperature, all samples were placed on ice, and the enzyme substrate (10 μL of 14,15-EET (10 μg / mL)) was quickly added and mixed. The mixture was then incubated at 37°C in a shaker. After incubation, the samples were placed on ice, and 10 μL of 800 nM t-TUCB (No. 6757, Tocris Bioscience, UK, Bristol) was quickly added to terminate the reaction, resulting in a final reaction volume of 200 μL. To detect enzyme activity, the applicant used high-performance liquid chromatography-mass spectrometry (HPLC-MS) to determine the concentration of the reaction product 14,15-DHET. The pretreatment involved adding an equal volume (200 μL) of a 50 / 50, v / v mixture of methanol and acetonitrile, containing 0.4% acetic acid and the internal standard 14,15-EET-d. 11 and 14,15-DHET-d 11(20 ng / ml) was homogenized at 4500 rpm for 10 minutes and incubated at -20°C for 2 hours to precipitate the protein. Finally, the supernatant was collected after centrifugation at 14000 rpm (4°C) for 10 minutes for UPLC-MS / MS analysis. The sEH inhibition efficiency of each compound pair was calculated using the amount of 14,15-DHET produced and expressed as a percentage of the control.

[0189] Wherein, the inhibition rate % (5 μg / mL) is the inhibition rate of the tested compound against sEH at a concentration of 5 μg / mL. The verification results of the glycyrrhetinic acid glycoside derivatives prepared in this application are shown in Table 1:

[0190] Table 1. sEH inhibition results of glycyrrhetinic acid glycoside derivatives prepared in this application and GL and GA.

[0191]

[0192]

[0193]

[0194] The verification results of the C-20 ureoglycyrrhetinic acid derivative are shown in Table 2:

[0195] Table 2 shows the sEH inhibition results of the C-20 ureoglycyrrhetinic acid derivative as a control compound.

[0196]

[0197]

[0198] As shown in Table 1, glycyrrhizic acid and glycyrrhetinic acid had no inhibitory effect on soluble epoxide hydrolase (sEH) at a dose of 5 μg / mL. Except for compounds 3Aa, 3Ae, 6Aa, and 6Ae, the glycyrrhetinic acid glycoside derivatives prepared in this application significantly improved the inhibition rate of sEH, exceeding 80%, with the optimal compound 4De showing the best IC50. 50 The value is less than 100 nM. As shown in Table 2, the inhibition rates of sEH by the C-20 ureoglycyrrhetinic acid derivative control compounds (compounds a, b, c, and d) were 8.04%, 1.34%, 38.20%, and 43.74%, respectively. Compared with the C-20 ureoglycyrrhetinic acid derivative (control compound), the C-30 ureoglycyrrhetinic acid glycoside derivative prepared in this application showed a significantly higher inhibition rate against soluble epoxide hydrolase (sEH) at a concentration of 5 μg / mL. Except for compounds 3Aa, 3Ae, 6Aa, and 6Ae, the inhibition rates of the other compounds were all greater than 80%, and the corresponding IC50 values ​​were also significantly higher.50 The values ​​are all less than 500 nM. This is because the urea group of the urea compound at the C-30 position is attached at the C-30 position, where the steric hindrance of the triterpenoid skeleton formation is relatively small, thus utilizing the drug-like properties of the triterpenoid skeleton without impairing the interaction between the urea group and the enzyme.

[0199] Furthermore, to verify the in vivo anti-inflammatory activity of the glycyrrhetinic acid glycoside derivative prepared in this application, a mouse inflammation model was established, and its in vivo activity was evaluated by oral or injection administration. The positive control drug was TPPU (1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea; an sEH inhibitor), the structure of which is shown below:

[0200]

[0201] The specific in vivo activity testing methods are as follows:

[0202] Animal experiments were conducted using BALB / c mice aged 6–8 weeks. The animals were purchased from Peking University School of Medicine (Beijing, China). All experiments were approved by the Ethics Committee of Beijing Institute of Technology.

[0203] Male BALB / c mice (6-8 weeks old, 23-25g) were used to create a paw edema model. Before the experiment, the mice were fed for three days with free access to water and food, and the room temperature was maintained at 22±2℃. The mice were then randomly divided into a blank group, an experimental group, and a control group, with 10 mice in each group. After a 12-hour fast, the thickness of the right foot at 0 hours was measured first. Then, the blank group was given a solvent (5% DMSO + 95% (2-hydroxypropyl)-β-cyclodextrin aqueous solution (0.2 g / mL)), the control group was given the positive control drug TPPU (purity 98.9491%), and the experimental group was given the test compounds (compound 1 purity 99.0054%, compound 4 purity 95.5208%, compound 4Aa purity 98.1412%, compound 4Ae purity 99.4653%, compound 4Ca purity 98.0119%, compound 4Ce purity 97.9583%, compound 4Da purity 95.9114%, and compound 4De purity 95.7944%), administered intraperitoneally (5 mg / kg) or orally (20 mg / kg). One hour after drug administration, 50 μL of 1% carrageenan (prepared with sterile saline) was injected into the right paw of mice to induce inflammatory swelling. The thickness of the right paw was measured at 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, and 6 h after carrageenan administration to calculate the degree of swelling reduction.

[0204] The structural formulas of compounds 1 and 4 are shown below:

[0205]

[0206] Edema inhibition % = (swelling degree in blank group - swelling degree in treatment group) / swelling degree in blank group;

[0207] Swelling degree = Post-inflammatory foot thickness - Pre-inflammatory foot thickness. See Tables 3 and 4 for in vivo activity test results.

[0208] Table 3. In vivo activities of compounds 1, 4, 4Aa and 4Ae in a carrageenan-induced Balb / c mouse paw edema model (5 mg / kg, intraperitoneal injection).

[0209]

[0210] As shown in Table 3, for the carrageenan-induced paw edema model in Balb / c mice, compound 4Aa prepared in this application example achieved the highest swelling inhibition rate (40.3%) after 3 hours of induction, and compound 4Ae achieved the highest swelling inhibition rate (43.2%) after 2 hours of induction. Compared with the swelling inhibition rate of the sEH inhibitor TPPU, the glycyrrhetinic acid glycoside derivative prepared in this application example exhibits superior in vivo anti-inflammatory activity. Compound 1 achieved the highest swelling inhibition rate (27.2%) after 4 hours of induction, and compound 4 achieved the highest swelling inhibition rate (28.4%) after 4 hours of induction. It is evident that compared with aglycone compounds 1 and 4, the swelling inhibition rate of the glycyrrhetinic acid glycoside derivative prepared in this application example is significantly improved, with the highest inhibition rate significantly increased by 12-15%, and the in vivo anti-inflammatory activity of the glycoside derivative is superior to the positive control drug TPPU. Therefore, the glycyrrhetinic acid glycoside derivative prepared in the embodiments of this application can greatly improve its in vivo activity during intraperitoneal injection, indicating that its 3-OH glycoside group is crucial for further improving the in vivo activity of the glycyrrhetinic acid derivative.

[0211] Table 4. In vivo activities of compounds 4Ae, 4Ca, 4Ce, 4Da and 4De in a carrageenan-induced Balb / c mouse paw edema model (20 mg / kg, orally).

[0212]

[0213] After oral administration, the drug enters the gastrointestinal tract and, due to issues of drug stability in gastric acid, must pass through intestinal epithelial cells and undergo liver metabolism, resulting in a relatively low concentration of drug ultimately entering the bloodstream. In contrast, intraperitoneal injection delivers the drug directly into the peritoneal cavity, leading to faster absorption. Therefore, oral bioavailability is generally lower than that of intraperitoneal injection. Table 4 shows that, for the carrageenan-induced Balb / c mouse paw edema model, compound 4Ae (prepared in this application) achieved the highest swelling inhibition rate (29.3%) after 1 hour of induction, compound 4Ca (38.4%) after 1 hour, compound 4Ce (23.0%) after 5 hours, compound 4Da (37.4%) after 5 hours, compound 4De (22.8%) after 5 hours, and the positive control drug TPPU (27.5%) after 2 hours of oral administration. Therefore, the glycyrrhetinic acid glycoside derivatives prepared in the embodiments of this application are beneficial for maintaining high in vivo activity during oral administration.

[0214] Furthermore, to verify the in vivo analgesic activity of the glycyrrhetinic acid glycoside derivative prepared in this application, a mouse analgesia model was established, and its in vivo activity was evaluated by oral administration. The positive control drugs were celecoxib (a commonly used nonsteroidal anti-inflammatory drug) and EC5026 (N-[3-fluoro-4-(trifluoromethoxy)phenyl]-N'-[1-[(2S)-2-methyl-1-oxobutyl]-4-piperidinyl]urea; an sEH inhibitor that has entered clinical trials for the treatment of neuropathic pain), the structures of which are shown below:

[0215]

[0216] The specific methods for testing in vivo analgesic activity are as follows:

[0217] Male BALB / c mice (6-8 weeks old, 23-25g) were used for the acetic acid writhing test. Before the experiment, the mice were fed for three days with free access to water and food, and the room temperature was maintained at 22±2℃. The mice were randomly divided into a blank group (no medication), an experimental group (administered with compounds 4Ae (purity: 99.4653%), 4Ca (purity: 98.0119%), and 4Da (purity: 95.9114%)), and a control group (administered with celecoxib (purity: 98.3348%) and EC5026 (purity: 98.7269%)). After a 12-hour fast, celecoxib, EC5026, compound 4Ae, compound 4Ca, and compound 4Da were administered orally, while the blank group received only the solvent (5% DMSO + 95% 2-hydroxypropyl-β-cyclodextrin). One hour later, acetic acid solution (0.6% v / v, 0.01 mL / g) was injected intraperitoneally to induce pain, and the number of back arches, body extensions, and hind limb extensions were recorded over 30 minutes.

[0218] Inhibition rate % = (Number of writhing movements in the control group - Number of writhing movements in the experimental group) / Number of writhing movements in the control group. See Table 5 for the results.

[0219] Table 5. In vivo activities of compounds 4Ae, 4Ca and 4Da in an acetic acid-induced Balb / c mouse writhing model (20 mg / kg, orally).

[0220] Blank group Celecoxib EC5026 4Ae 4Ca 4Da Number of twists 32.88±2.72 18.75±2.83 17.13±2.41 15.63±1.45 13.13±1.88 14.25±2.45 Pain suppression rate % -- 42.97 47.91 52.47 60.08 56.65

[0221] EC5026 is a sEH inhibitor drug that has entered clinical trials for the treatment of neuropathic pain, while celecoxib is a commonly used nonsteroidal anti-inflammatory drug (NSAID). As shown in Table 5, EC5026 showed a pain inhibition rate of 47.91% in an acetic acid-induced Balb / c mouse writhing model, while celecoxib showed a pain inhibition rate of 42.97%. The compounds 4Ae, 4Ca, and 4Da prepared in this application showed pain inhibition rates of 52.47%, 60.08%, and 56.65% respectively in an acetic acid-induced Balb / c mouse writhing model. The in vivo analgesic activity of the glycyrrhetinic acid glycoside derivative compounds 4Ae, 4Ca, and 4Da prepared in this application is superior to that of celecoxib and EC5026, indicating that the glycyrrhetinic acid glycoside derivative compounds prepared in this application have the potential to become a novel sEH inhibitor based on the natural product glycyrrhetinic acid as a backbone.

[0222] The foregoing has provided a detailed description of a glycyrrhetinic acid glycoside derivative, its preparation method, and its application. Specific examples have been used to illustrate the principles and implementation methods of this application. The descriptions of the above embodiments are only for the purpose of helping to understand the method and core ideas of this application. At the same time, for those skilled in the art, there will be changes in the specific implementation methods and application scope based on the ideas of this application. Therefore, the content of this specification should not be construed as a limitation of this application.

Claims

1. A glycyrrhetinic acid glycoside derivative, characterized in that, The glycyrrhetinic acid glycoside derivative has the following general structural formula (Form I): In Equation I, R 1 Selected from any of the following groups: R 2 Selected from any of the following groups: The 18th hydrogen is selected from either the α-position or the β-position stereo configuration.

2. The glycyrrhetinic acid glycoside derivative according to claim 1, characterized in that, The R 2 Selected from any of the following groups:

3. The glycyrrhetinic acid glycoside derivative according to claim 1, characterized in that, The R 1 Selected from any of the following groups:

4. The glycyrrhetinic acid glycoside derivative according to claim 1, characterized in that, The R 2 Selected from any of the following groups: The R 1 Selected from any of the following groups:

5. The glycyrrhetinic acid glycoside derivative according to claim 1, characterized in that, The glycyrrhetinic acid glycoside derivative according to any one of claims 1-4 has the following structure:

6. A method for preparing a glycyrrhetinic acid glycoside derivative according to any one of claims 1-5, characterized in that, The method includes the following steps: glycosylation and reductive hydrogenation of compound (1) to obtain the compound shown in formula I; Among them, R 1 and R 2 As defined in any one of claims 1-3, the 18-position hydrogen is selected from the α-position or β-position stereoconfiguration.

7. The preparation method according to claim 6, characterized in that, Compounds of formula (1) are selected from any of the following structures:

8. The preparation method according to claim 6, characterized in that, The preparation method includes reacting the compound shown in formula (1) with any one of the compounds in formula AE to obtain the compound shown in formula I; The structure of the compound represented by formula AE is shown below:

9. A pharmaceutical composition comprising the glycyrrhetinic acid glycoside derivative according to any one of claims 1-5, characterized in that, The pharmaceutical composition comprises at least one of glycyrrhetinic acid glycoside derivatives, their isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts, or their prodrug compounds.

10. The use of at least one of the following as described in any one of claims 1-5: a glycyrrhetinic acid glycoside derivative, its isotope label, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, in the preparation of an anti-inflammatory drug.

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