Galactorhamnoside compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of chemical medicines, and particularly relates to a galactorhamnoside compound as well as a preparation method and application thereof. The structural formula of the compound is selected from any one of the following formulas; ; or; in the formula, R1 ', R1 '', R1''' and R2 'are independently selected from-H, fluorine-substituted benzoyl, fluorine-substituted benzyl, nitro-substituted benzoyl or nitro-substituted benzyl. The galactorhamnoside compound is used as a galectin-3 inhibitor to be applied to preparation of anti-pulmonary fibrosis drugs and anti-chronic / acute myelogenous leukemia drugs. Particularly, the TGF-beta-induced A549 (human lung epithelial cell) fibrosis can be obviously inhibited; the obvious lethality is realized on NB4 and K562 cells.

Description

Technical Field

[0001] This invention belongs to the technical field of chemical drugs, specifically relating to a galactor rhamnoside compound, its preparation method, and its application. Background Technology

[0002] Lectins are a class of proteins widely distributed in animals and plants that specifically recognize and bind to glycodomains. Gallectin-3 (Gal-3) is an important member of the galectin family. It specifically recognizes galactosides and binds to galactose monosaccharide or oligosaccharide ligands, thus playing a crucial role in many pathophysiological processes such as inflammation, fibrosis, cell proliferation and apoptosis, angiogenesis, and immune responses. As a multifunctional protein, Gal-3 participates in the occurrence and development of various diseases, including liver fibrosis and tumors. In-depth research on this protein can provide more evidence for the clinical diagnosis of related diseases, while research on Gal-3 inhibitors can provide new methods for clinical treatment.

[0003] In recent years, researchers have developed various inhibitors targeting Gal-3, which can be categorized structurally into polysaccharides, antibodies, and small-molecule sugars. The application of polysaccharide macromolecular inhibitors is largely limited due to drawbacks such as difficulty in extraction and separation, poor stability, low bioavailability, and interference with the expression of galactolectin proteins. In contrast, fully synthetic small-molecule sugar inhibitors have become the most promising galactolectin inhibitors due to their advantages of chemical synthesis, high stability, and easy absorption by the body. Currently, most small-molecule sugar inhibitors use D-galactose as the core backbone structure and undergo related modifications; Gal-3 inhibitors with galactorhamnetose as the core backbone have not yet been reported. Summary of the Invention

[0004] The purpose of this invention is to provide a galactor rhamnoside compound, its preparation method, and its application, in order to address the aforementioned deficiencies.

[0005] The technical solution of this invention is as follows: A galactor rhamnoside compound, the structural formula of which is selected from any of the following formulas: , , or ; In the formula, R1 ＇ R1 ＂ R1 ＇＇＇ R2 ＇ It is independently selected from -H, fluorinated benzoyl, fluorinated benzyl, nitro-substituted benzoyl, or nitro-substituted benzyl. Me represents methyl-CH3.

[0006] In this invention, the fluorinated benzoyl group in the galactor rhamnoside compound is selected from... o -F-Ph-CO- (o-fluorobenzoyl) m -F-Ph-CO- (m-fluorobenzoyl) p -F-Ph-CO- (p-fluorobenzoyl) or p -F- o- Any one of NO2-Ph-CO- (p-fluoro-o-nitrobenzoyl).

[0007] The fluorinated benzyl group is selected from... o -F-Ph-CH2- (o-fluorobenzyl) m -F-Ph-CH2- (m-Fluorobenzyl) p -F-Ph-CH2- (p-fluorobenzyl) or p -F- o- Any one of NO2-Ph-CH2- (p-fluoro-o-nitrobenzyl).

[0008] The nitro-substituted benzoyl group is selected from... o -NO2-Ph-CO-(o-nitrobenzoyl) m -NO2-Ph-CO-(m-nitrobenzoyl) p -NO2-Ph-CO- (p-nitrobenzoyl) or p -F- o- Any one of NO2-Ph-CO- (p-fluoro-o-nitrobenzoyl).

[0009] The nitro-substituted benzyl group is selected from... o -NO2-Ph-CH2-(o-nitrobenzyl) m -NO2-Ph-CH2-(m-nitrobenzyl) p -NO2-Ph-CH2- (p-nitrobenzyl) or p -F- o- Any one of NO2-Ph-CH2- (p-fluoro-o-nitrobenzyl).

[0010] In this invention, the galactor rhamnoside compounds have structural formulas selected from any one of the formulas RG1 to RG12: ; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or pAny of the following: -F-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph-、 p -F-Ph- or p -F- o- Any one of NO2-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or p Any of the following: -F-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or p Any of the following: -F-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or p Any of the following: -F-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph-、 p -F-Ph- or p -F- o- Any one of NO2-Ph-; ; In the formula, R is selected from... o -NO2-Ph-、 m-NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or p Any of the following: -F-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or p Any of the following: -F-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or p Any of the following: -F-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or p Any of -F-Ph-.

[0011] Preferably, the galactor rhamnoside compound has a structural formula selected from any of the following formulas: In the formula, R is p -F-Ph-; In the formula, R is m -NO2-Ph-; In the formula, R is m -F-Ph-; In the formula, R is o -F-Ph-.

[0012] More preferably, the structural formula of the compound is selected from any of the following formulas: In the formula, R is m -NO2-Ph-; or In the formula, R iso -F-Ph-.

[0013] The preparation method of the above-mentioned galactor rhamnoside compounds includes the following steps: First, glycosylation is performed: using rhamnosulosin as the donor and galactosylmethyl glycoside as the acceptor; or using galactosulosin as the donor and rhamnosylmethyl glycoside as the acceptor, the mixture is dissolved in dichloromethane and glycosylated under the catalysis of iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH); the details are as follows: The donor and acceptor were dissolved in dry dichloromethane at a molar ratio of 1.5–3.0:1, and 4A molecular sieves were added. The mixture was stirred at room temperature for 0.5 h and then placed in an ice bath at 0 °C. Iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH) were then added sequentially, and the reaction was catalyzed for 4 h. The molar ratio of iodosuccinimide to donor was 2.5:1, and the molar ratio of trifluoromethanesulfonic acid to donor was 0.2:1.

[0014] After the reaction was completed, the solution was neutralized with triethylamine, filtered, washed with dichloromethane, the residue was concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain unprotected galactor rhamnoside compounds.

[0015] Then, deprotection was performed to obtain the galactor rhamnoside compound.

[0016] In this invention, the method for preparing the galactor rhamnoside compound includes rhamnosulosin as the donor, comprising any one of the following compounds: compound 1, compounds 4a-f, or compounds 5a-g: , or ; In the structural formulas of compounds 4a and 5a, R= o -NO2-Ph-; In the structural formulas of compounds 4b and 5b, R= m -NO2-Ph-; R= in the 4c ​​and 5c structures of compounds p -NO2-Ph-; R= in the 4d and 5d structures of compounds o -F-Ph-; In the structural formulas of compounds 4e and 5e, R= m -F-Ph-; R= in the structural formulas of compounds 4f and 5f p -F-Ph-; In the structural formula of compound 5g, R= p -F- o- NO2-Ph-.

[0017] The rhamnosinogen donor compounds 4a-f were prepared by the following steps: (1) Synthesis of intermediate compound 2 Compound 1 (4-methylphenyl 2,3,4-tri-O-acetyl-1-thio-α-L-rhamnoside) was dissolved in methanol, and the pH of the solution was adjusted to 10 by adding a methanol solution of 1 mol / L sodium methoxide. The reaction was stirred at room temperature for 3 h.

[0018] After the reaction is complete, acidic resin is added to the solution to adjust the pH to 7. The insoluble matter is filtered off, and the solution is concentrated under reduced pressure until the solvent is completely removed to obtain the concentrate. Commercially available Amberlite IR120 or Dowex 50WX acidic resins can be used.

[0019] The concentrate was dissolved in acetone, and 2,2-dimethoxypropane was added to the reaction system; wherein the molar ratio of 2,2-dimethoxypropane to compound 1 was 1:5~10; p-toluenesulfonic acid was added to adjust the pH of the solution to 4, and the reaction was carried out at room temperature for 2 h, and the reaction progress was monitored by TLC.

[0020] After the reaction was completed, triethylamine was added to neutralize the solution, and the solvent was removed by concentration under reduced pressure. The concentrated crude product was separated by silica gel column chromatography to obtain intermediate compound 2.

[0021] The structural formula of intermediate compound 2 is shown below: .

[0022] (2) Synthesis of intermediate compounds 3a~f Intermediate compound 2 was dissolved in N,N-dimethylformamide, and sodium hydride and benzyl bromide reagent were added sequentially in an ice bath at 0°C, and the mixture was stirred for 3 h. The molar ratio of sodium hydride to intermediate compound 2 was 1:1.5~2.5, and the molar ratio of benzyl bromide reagent to intermediate compound 2 was 1:1.5~2.5.

[0023] After the reaction was complete, ice water was added to the solution to quench it, and the solution was extracted with ethyl acetate. The organic phase was then concentrated to obtain the crude intermediate compounds 3a~f.

[0024] The benzyl bromide reagent is selected from any one of o-nitrobenzyl bromide, m-nitrobenzyl bromide, p-nitrobenzyl bromide, o-fluorobenzyl bromide, m-fluorobenzyl bromide, or p-fluorobenzyl bromide.

[0025] The general structural formulas of the intermediate compounds 3a~f are shown below: ; In the general formula of intermediate compound 3a, R= o -NO2-Ph-; In the general formula of intermediate compound 3b, R= m -NO2-Ph-; In the general formula of the 3c structure of intermediate compounds, R= p -NO2-Ph-; In the general formula of the 3d structure of intermediate compounds, R= o -F-Ph-; In the general formula of the intermediate compound 3e, R= m -F-Ph-; In the general formula of the intermediate compound 3f, R= p -F-Ph-.

[0026] (3) Synthesis of rhamnosinogen donor compound 4a~f The crude intermediate compounds 3a-f were dissolved in dichloromethane. A 5% trifluoroacetic acid solution in dichloromethane was added to the reaction system at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, an equal volume of toluene was added to dilute the product and then concentrated to remove all solvent, thus obtaining the concentrate.

[0027] The concentrate was dissolved in sufficient pyridine, acetic anhydride was added, and the mixture was stirred at room temperature for 3 h; wherein the molar ratio of acetic anhydride to intermediate compound 2 was 1:3~4.

[0028] After the reaction was completed, the crude products of compounds 4a~f were obtained by concentration, and the rhamnosyl thioglycoside donor compounds 4a~f were obtained by silica gel column chromatography.

[0029] The general structural formulas of the rhamnosinogen donor compounds 4a~f are shown below: ; In the general formula of donor compound 4a, R= o -NO2-Ph-; In the general formula of donor compound 4b, R= m -NO2-Ph-; In the general formula of the 4c ​​structure of the donor compound, R= p -NO2-Ph-; In the general formula of the 4d structure of the donor compound, R= o -F-Ph-; In the general formula of the donor compound 4e, R= m -F-Ph-; In the general formula of the donor compound 4f, R= p -F-Ph-.

[0030] The synthetic routes for the above rhamnosinogen donor compounds 4a~f are shown below: .

[0031] The rhamnosinogen donor compounds 5a-f were prepared by the following steps: The intermediate compound 2 obtained above was dissolved in pyridine, and an acyl chloride reagent was added. The mixture was stirred at room temperature for 3 h. The molar ratio of the acyl chloride reagent to the intermediate compound 2 was 1:3~4.

[0032] After the reaction was completed, the crude products of donor compounds 5a~f were obtained by concentration; the donor compounds 5a~f were then separated by silica gel column chromatography.

[0033] The acyl chloride reagent is selected from any one of o-nitrobenzoyl chloride, m-nitrobenzoyl chloride, p-nitrobenzoyl chloride, o-fluorobenzoyl chloride, m-fluorobenzoyl chloride, or p-fluorobenzoyl chloride.

[0034] The general structural formulas of the rhamnosinogen donor compounds 5a-f are shown below: ; In the general formula of donor compound 5a, R= o -NO2-Ph-; In the general formula of donor compound 5b, R= m -NO2-Ph-; In the general formula of the donor compound 5c, R= p -NO2-Ph-; In the general formula of the 5d structure of the donor compound, R= o -F-Ph-; In the general formula of the donor compound 5e, R= m -F-Ph-; In the general formula of the donor compound 5f, R= p -F-Ph-.

[0035] The 5g rhamnosinogen donor compound was prepared by the following steps: The intermediate compound 2 obtained above was dissolved in pyridine, and p-fluoroo-nitrobenzoic acid, N,N'-dicyclohexylcarbodiimide, and 4-dimethylaminopyridine were added sequentially. The mixture was stirred at room temperature for 3 h. The molar ratio of p-fluoroo-nitrobenzoic acid: N,N'-dicyclohexylcarbodiimide: 4-dimethylaminopyridine: intermediate compound 2 was 1:2~3:3~4:1.

[0036] After the reaction was complete, the product was diluted with dichloromethane, extracted with saturated ammonium chloride solution to obtain the organic phase, dried with anhydrous sodium sulfate, concentrated to obtain 5g of crude donor compound, and then separated by silica gel column chromatography to obtain 5g of donor compound.

[0037] The general structural formula of the rhamnosinogen donor compound 5g is shown below: ; In the general formula of the donor compound 5g, R= p -F- o- NO2-Ph-.

[0038] The synthetic routes for the above-mentioned rhamnosinogen donor compounds 5a~g are shown below: .

[0039] In this invention, the method for preparing the galactor rhamnoside compound uses galactosyl glycosides as donors, which include any one of compounds 6, 8a-f, or 10a-g as shown in the following structural formulas: , or ; In the structural formulas of compounds 8a and 10a, R= o -NO2-Ph-; In the structural formulas of compounds 8b and 10b, R= m -NO2-Ph-; R= in the structural formulas of compounds 8c and 10c p -NO2-Ph-; R= in the 8d and 10d structures of compounds o -F-Ph-; In the structural formulas of compounds 8e and 10e, R= m -F-Ph-; R= in the structural formulas of compounds 8f and 10f p -F-Ph-; In the structural formula of compound 10g, R= p -F- o- NO2-Ph-.

[0040] The galactosidoside donor compounds 8a-f were prepared by the following steps: (1) Synthesis of intermediate compound 7 Compound 6 (4-methylphenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactoside) was dissolved in methanol, and the pH of the solution was adjusted to 10 by adding a methanol solution of 1 mol / L sodium methoxide. The mixture was stirred at room temperature for 3 h.

[0041] After the reaction is complete, acidic resin is added to the solution to adjust the pH to 7. The insoluble matter is then filtered off, and the solution is concentrated under reduced pressure to obtain the concentrate. Commercially available Amberlite IR120 or Dowex 50WX acidic resins can be used.

[0042] The concentrate was dissolved in acetonitrile, and benzaldehyde dimethyl acetal was added to the reaction system; wherein the molar ratio of benzaldehyde dimethyl acetal to compound 6 was 1:2~3; p-toluenesulfonic acid was added to adjust the pH of the solution to 4, and the reaction was carried out at room temperature for 2 h, and the reaction progress was monitored by TLC.

[0043] After the reaction was completed, triethylamine was added to neutralize the solution, and the solvent was removed by concentration under reduced pressure. The concentrated crude product was separated by silica gel column chromatography to obtain intermediate compound 7.

[0044] The structural formula of intermediate compound 7 is shown below: .

[0045] (2) Synthesis of galactosinolate donor compounds 8a~f Intermediate compound 7 was dissolved in N,N-dimethylformamide, and sodium hydride and benzyl bromide reagent were added sequentially in an ice bath at 0°C, and the mixture was stirred for 3 h. The molar ratio of sodium hydride to intermediate compound 7 was 1:3~5, and the molar ratio of benzyl bromide reagent to intermediate compound 7 was 1:3~5.

[0046] After the reaction was complete, ice water was added to the solution to quench it, and the solution was extracted with ethyl acetate. The organic phase was concentrated to obtain crude products of galactosodium donor compounds 8a-f. The concentrated crude products were separated by silica gel column chromatography to obtain galactosodium donor compounds 8a-f.

[0047] The benzyl bromide reagent is selected from any one of o-nitrobenzyl bromide, m-nitrobenzyl bromide, p-nitrobenzyl bromide, o-fluorobenzyl bromide, m-fluorobenzyl bromide, or p-fluorobenzyl bromide.

[0048] The general structural formulas of the galactosidoside donor compounds 8a~f are shown below: ; In the general formula of donor compound 8a, R= o -NO2-Ph-; In the general formula of donor compound 8b, R= m -NO2-Ph-; In the general formula of the donor compound 8c, R= p -NO2-Ph-; In the general formula of the 8d structure of the donor compound, R= o -F-Ph-; In the general formula of the donor compound 8e, R= m -F-Ph-; In the general formula of the donor compound 8f, R= p -F-Ph-.

[0049] The synthetic routes for the above galactosinolate donor compounds 8a~f are shown below: .

[0050] The galactosidoside donor compound 10a~g was prepared by the following steps: (1) Synthesis of intermediate compound 9 Compound 6 (4-methylphenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactoside) was dissolved in methanol, and the pH of the solution was adjusted to 10 by adding a methanol solution of 1 mol / L sodium methoxide. The mixture was stirred at room temperature for 3 h.

[0051] After the reaction is complete, acidic resin is added to the solution to adjust the pH to 7. The insoluble matter is then filtered off, and the solution is concentrated under reduced pressure to obtain the concentrate. Commercially available Amberlite IR120 or Dowex 50WX acidic resins can be used.

[0052] The concentrate was dissolved in acetone, and 2,2-dimethoxypropane was added to the reaction system; wherein the molar ratio of 2,2-dimethoxypropane to compound 6 was 1:5~10; p-toluenesulfonic acid was added to adjust the pH of the solution to 4, and the reaction was carried out at room temperature for 2 h, and the reaction progress was monitored by TLC.

[0053] After the reaction was completed, triethylamine was added to neutralize the solution, and the solvent was removed by concentration under reduced pressure. The concentrated crude product was separated by silica gel column chromatography to obtain intermediate compound 9.

[0054] The structural formula of intermediate compound 9 is shown below: .

[0055] (2) Synthesis of galactosidoside donor compound 10a~f Compound 9 was dissolved in pyridine, and an acyl chloride reagent was added. The mixture was stirred at room temperature for 3 h. The molar ratio of acyl chloride reagent to compound 9 was 1:3~4.

[0056] After the reaction was completed, the crude products of donor compounds 10a~f were obtained by concentration; the donor compounds 10a~f were then separated by silica gel column chromatography.

[0057] The acyl chloride reagent is selected from any one of o-nitrobenzoyl chloride, m-nitrobenzoyl chloride, p-nitrobenzoyl chloride, o-fluorobenzoyl chloride, m-fluorobenzoyl chloride, or p-fluorobenzoyl chloride.

[0058] The general structural formulas of the galactosidoside donor compounds 10a-f are shown below: ; In the general formula of donor compound 10a, R= o -NO2-Ph-; In the general formula of donor compound 10b, R= m -NO2-Ph-; In the general formula of donor compound 10c, R= p -NO2-Ph-; In the 10d structural formula of the donor compound, R= o -F-Ph-; In the general formula of donor compound 10e, R= m -F-Ph-; In the general formula of donor compound 10f, R= p -F-Ph-.

[0059] Synthesize 10g of galactosidoside donor compound: Intermediate compound 9 was dissolved in pyridine, and p-fluoroo-nitrobenzoic acid, N,N'-dicyclohexylcarbodiimide, and 4-dimethylaminopyridine were added sequentially. The mixture was stirred at room temperature for 3 h. The molar ratio of p-fluoroo-nitrobenzoic acid: N,N'-dicyclohexylcarbodiimide: 4-dimethylaminopyridine: intermediate compound 9 was 1:2~3:3~4:1.

[0060] After the reaction was complete, the product was diluted with dichloromethane, extracted with saturated ammonium chloride solution to obtain the organic phase, dried with anhydrous sodium sulfate, concentrated to obtain 10g of crude product of donor compound, and then separated by silica gel column chromatography to obtain 10g of donor compound.

[0061] The general structural formula of 10g of the galactosidoside donor compound is shown below: ; In the general formula of the donor compound 10g, R= p -F- o- NO2-Ph-.

[0062] The synthetic route for the above-mentioned galactosidoside donor compound 10a~g is shown below: .

[0063] In this invention, the method for preparing the galactor rhamnoside compound includes, as the acceptor, any one of compounds 16a-h, 19a-f, or 20a-g, as shown in the following structural formulas: , or ; In the structural formulas of compounds 16a, 19a, and 20a, R= o -NO2-Ph-; In the structural formulas of compounds 16b, 19b, and 20b, R=m -NO2-Ph-; In the structural formulas of compounds 16c, 19c, and 20c, R= p -NO2-Ph-; In the structural formulas of compounds 16d, 19d, and 20d, R= o -F-Ph-; In the structural formulas of compounds 16e, 19e, and 20e, R= m -F-Ph-; In the structural formulas of compounds 16f, 19f, and 20f, R= p -F-Ph-; In the structural formulas of compounds 16g and 20g, R= p -F- o- NO2-Ph-; In the structural formula of compound 16h, R = Ac.

[0064] In the formula, TBDMS- represents tert-butyldimethylsilyl.

[0065] The galactosyl methyl glycoside receptor compound 16a~h was prepared by the following steps: (1) Synthesis of intermediate compound 12 Compound 11 (methyl α-D-galactopyranoside) was dissolved in acetonitrile, and benzaldehyde dimethyl acetal was added to the reaction system, wherein the molar ratio of benzaldehyde dimethyl acetal to compound 11 was 1:2~3. The pH of the solution was adjusted to 4 by adding p-toluenesulfonic acid, and the reaction was carried out at room temperature for 2 h. The reaction progress was monitored by TLC.

[0066] After the reaction was complete, triethylamine was added to neutralize the solution, and the solvent was removed by concentration under reduced pressure. The concentrated crude product was then separated by silica gel column chromatography to obtain intermediate compound 12.

[0067] The structural formula of intermediate compound 12 is shown below: .

[0068] (2) Synthesis of intermediate compound 14a~h Synthesize intermediate compounds 14a~f: Dissolve intermediate compound 12 in pyridine, add acyl chloride reagent, and stir the reaction at room temperature for 3 h; wherein the molar ratio of acyl chloride reagent to intermediate compound 12 is 1:3~4.

[0069] After the reaction was completed, the product was concentrated to obtain a concentrated crude product, which was then separated by silica gel column chromatography to obtain compounds 14a~f.

[0070] The acyl chloride reagent is selected from any one of o-nitrobenzoyl chloride, m-nitrobenzoyl chloride, p-nitrobenzoyl chloride, o-fluorobenzoyl chloride, m-fluorobenzoyl chloride, or p-fluorobenzoyl chloride.

[0071] The general structural formulas of the intermediate compounds 14a~f are shown below: ; In the general formula of intermediate compound 14a, R= o -NO2-Ph-; In the general formula of intermediate compound 14b, R= m -NO2-Ph-; In the general formula of intermediate compound 14c, R= p -NO2-Ph-; In the general formula of the 14d structure of the intermediate compound, R= o -F-Ph-; In the general formula of intermediate compound 14e, R= m -F-Ph-; In the general formula of intermediate compound 14f, R= p -F-Ph-.

[0072] Synthesize intermediate compound 14g: Dissolve intermediate compound 12 in pyridine, and add p-fluoroo-nitrobenzoic acid, N,N'-dicyclohexylcarbodiimide, and 4-dimethylaminopyridine in sequence. Stir the reaction at room temperature for 3 h; wherein the molar ratio of p-fluoroo-nitrobenzoic acid: N,N'-dicyclohexylcarbodiimide: 4-dimethylaminopyridine: intermediate compound 12 is 3~4:4~6:5~7:1.

[0073] After the reaction was complete, the product was diluted with dichloromethane, extracted with saturated ammonium chloride solution to obtain the organic phase, dried over anhydrous sodium sulfate, concentrated to obtain a concentrated crude product, and then separated by silica gel column chromatography to obtain 14g of intermediate compound.

[0074] The general structural formula of intermediate compound 14g is shown below:

[0075] In the general formula of intermediate compound 14g, R= p -F- o- NO2-Ph-.

[0076] Synthesize intermediate compound 14h: Intermediate compound 12 was dissolved in pyridine, and acetic anhydride was added. The mixture was stirred at room temperature for 3 h. The molar ratio of acetic anhydride to intermediate compound 12 was 1:3~4.

[0077] After the reaction was completed, the product was concentrated to obtain a concentrated crude product, which was then separated by silica gel column chromatography for 14 hours to obtain the intermediate compound.

[0078] The general structural formula of the intermediate compound 14h is shown below: .

[0079] In the general formula of intermediate compound 14h, R=Ac.

[0080] (3) Synthesis of intermediate compound 15a~h Intermediate compound 14a~h was dissolved in dichloromethane, and a 5% trifluoroacetic acid solution in dichloromethane was added to the reaction system. The reaction was carried out at room temperature, and the reaction progress was monitored by TLC.

[0081] After the reaction was completed, toluene of equal volume to the solvent was added for dilution and then concentrated to remove all solvent, obtaining a concentrated crude product, which was then separated by silica gel column chromatography to obtain intermediate compound 15a~h.

[0082] The general structural formula of the intermediate compounds 15a~h is shown below: ; In the general formula of intermediate compound 15a, R= o -NO2-Ph-; In the general formula of intermediate compound 15b, R= m -NO2-Ph-; In the general formula of intermediate compound 15c, R= p -NO2-Ph-; In the general formula of the 15d structure of the intermediate compound, R= o -F-Ph-; In the general structural formula of intermediate compound 15e, R= m -F-Ph-; In the general formula of intermediate compound 15f, R= p -F-Ph-; In the general formula of intermediate compound 15g, R= p -F- o- NO2-Ph-; In the general formula of intermediate compound 15h, R = Ac.

[0083] (4) Synthesis of galactosyl methyl glycoside receptor compound 16a~h Intermediate compound 15a~h was dissolved in pyridine, and tert-butyldimethylchlorosilane was added. The mixture was stirred at room temperature for 12 h. The molar ratio of tert-butyldimethylchlorosilane to intermediate compound 15a~h was 1:1.5~2.

[0084] After the reaction was completed, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography to obtain galactosyl methyl glycoside receptor compound 16a~h.

[0085] The general structural formula of the galactosyl methyl glycoside receptor compound 16a~h is shown below: ; In the general formula of receptor compound 16a, R= o -NO2-Ph-; In the general formula of receptor compound 16b, R= m -NO2-Ph-; In the general formula of receptor compound 16c, R= p -NO2-Ph-; In the general formula of the 16d structure of receptor compounds, R= o -F-Ph-; In the general formula of receptor compound 16e, R= m -F-Ph-; In the general formula of receptor compound 16f, R= p -F-Ph-; In the general formula of receptor compound 16g, R= p -F- o- NO2-Ph-; In the general formula of receptor compound 16h, R=Ac.

[0086] The synthetic route of the above-mentioned galactosyl methyl glycoside receptor compound 16a~h is shown below: .

[0087] The compounds 19a-f were prepared by the following steps: (1) Synthesis of intermediate compounds 17a~f Intermediate compound 12 was dissolved in N,N-dimethylformamide, and sodium hydride and benzyl bromide reagent were added sequentially in an ice bath at 0°C, and the mixture was stirred for 3 h. The molar ratio of sodium hydride to intermediate compound 12 was 1:3~5, and the molar ratio of benzyl bromide reagent to intermediate compound 12 was 1:3~5.

[0088] After the reaction was complete, the solution was quenched with 0°C ice water, extracted with ethyl acetate, and the organic phase was concentrated to obtain the crude intermediate compound 17a~f.

[0089] The benzyl bromide reagent is selected from any one of o-nitrobenzyl bromide, m-nitrobenzyl bromide, p-nitrobenzyl bromide, o-fluorobenzyl bromide, m-fluorobenzyl bromide, or p-fluorobenzyl bromide.

[0090] The general structural formulas of the intermediate compounds 17a~f are shown below: ; In the general formula of intermediate compound 17a, R= o -NO2-Ph-; In the general structural formula of intermediate compound 17b, R= m -NO2-Ph-; In the general formula of intermediate compound 17c, R= p -NO2-Ph-; In the general formula of the 17d structure of the intermediate compound, R= o -F-Ph-; In the general structural formula of intermediate compound 17e, R= m -F-Ph-; In the general formula of intermediate compound 17f, R= p -F-Ph-.

[0091] (2) Synthesis of intermediate compounds 18a~f Intermediate compounds 17a-f were dissolved in dichloromethane, and a 5% trifluoroacetic acid solution in dichloromethane was added to the reaction system. The reaction was carried out at room temperature, and the reaction progress was monitored by TLC.

[0092] After the reaction was completed, toluene of equal volume to the solvent was added for dilution and then concentrated to remove all solvent, obtaining a concentrated crude product, which was then separated by silica gel column chromatography to obtain intermediate compounds 18a~f.

[0093] The general structural formulas of the intermediate compounds 18a~f are shown below: ; In the general formula of intermediate compound 18a, R= o -NO2-Ph-; In the general structural formula of intermediate compound 18b, R= m -NO2-Ph-; In the general formula of the intermediate compound 18c, R= p -NO2-Ph-; In the general formula of the 18d structure of intermediate compound, R= o -F-Ph-; In the general structural formula of intermediate compound 18e, R= m -F-Ph-; In the general formula of intermediate compound 18f, R= p -F-Ph-.

[0094] (3) Synthesis of galactosyl methyl glycoside receptor compound 19a~f Intermediate compounds 18a-f were dissolved in pyridine, and tert-butyldimethylchlorosilane was added; wherein the molar ratio of tert-butyldimethylchlorosilane to intermediate compounds 18a-f was 1:1.5-2, and the reaction was stirred at room temperature for 12 h.

[0095] After the reaction was completed, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography to obtain galactosyl methyl glycoside receptor compounds 19a~f.

[0096] The general structural formulas of the galactosyl methyl glycoside receptor compounds 19a-f are shown below: ; In the general formula of receptor compound 19a, R= o -NO2-Ph-; In the general formula of receptor compound 19b, R= m -NO2-Ph-; In the general formula of receptor compound 19c, R= p -NO2-Ph-; In the general formula of receptor compound 19d, R= o -F-Ph-; In the general structural formula of receptor compound 19e, R= m -F-Ph-; In the general formula of receptor compound 19f, R= p -F-Ph-.

[0097] The synthetic routes for the above-mentioned galactosyl methyl glycoside receptor compounds 19a~f are shown below: .

[0098] The galactosyl methyl glycoside receptor compound 20a~g was prepared by the following steps: (1) Synthesis of intermediate compound 13 Compound 11 was dissolved in acetone, and 2,2-dimethoxypropane was added to the reaction system, wherein the molar ratio of 2,2-dimethoxypropane to compound 11 was 1:3~5; p-toluenesulfonic acid was added to adjust the pH of the solution to 4, and the reaction was carried out at room temperature for 2 h. The reaction progress was monitored by TLC.

[0099] After the reaction was completed, triethylamine was added to neutralize the solution, and the solvent was removed by concentration under reduced pressure. The concentrated crude product was separated by silica gel column chromatography to obtain intermediate compound 13.

[0100] The general structural formula of the intermediate compound 13 is shown below: .

[0101] (2) Synthesis of galactosyl glycoside receptor compound 20a~g Intermediate compound 13 was dissolved in N,N-dimethylformamide, and sodium hydride and benzyl bromide reagent were added sequentially in an ice bath at 0°C, and the mixture was stirred for 3 h. The molar ratio of sodium hydride to intermediate compound 13 was 1:1.2~1.5, and the molar ratio of benzyl bromide reagent to intermediate compound 13 was 1:1.2~1.5.

[0102] After the reaction was complete, the solution was quenched with 0°C ice water, extracted with ethyl acetate, and the organic phase was concentrated to obtain 20a~g of galactosyl methyl glycoside receptor compound.

[0103] The benzyl bromide reagent is selected from any one of o-nitrobenzyl bromide, m-nitrobenzyl bromide, p-nitrobenzyl bromide, o-fluorobenzyl bromide, m-fluorobenzyl bromide, p-fluorobenzyl bromide, or 4-fluoro-2-nitrobenzyl bromide.

[0104] The general structural formula of the galactosyl methyl glycoside receptor compound 20a~g is shown below: ; In the general formula of galactosyl methyl glycoside receptor compound 20a, R= o -NO2-Ph-; In the general structural formula of galactosyl methyl glycoside receptor compound 20b, R= m -NO2-Ph-; In the general structural formula of galactosyl methyl glycoside receptor compound 20c, R= p -NO2-Ph-; In the general structural formula of galactosyl methyl glycoside receptor compound 20d, R= o -F-Ph-; In the general structural formula of galactosyl methyl glycoside receptor compound 20e, R= m -F-Ph-; In the general structural formula of galactosyl methyl glycoside receptor compound 20f, R= p -F-Ph-; In the general structural formula of 20g galactosyl glycoside receptor compound, R= p -F- o- NO2-Ph-.

[0105] The synthetic route for the above-mentioned galactosyl methyl glycoside receptor compound 20a~g is shown below: .

[0106] In this invention, the method for preparing the galactor rhamnoside compound includes rhamnosulosin as the acceptor, comprising any one of compound 22 or compounds 24a-f as shown in the following structural formulas: or ; In the structural formula of compound 24a, R= o -NO2-Ph-; In the structural formula of compound 24b, R= m -NO2-Ph-; In the structural formula of compound 24c, R= p -NO2-Ph-; In the structural formula of compound 24d, R= o -F-Ph-; In the structural formula of compound 24e, R= m -F-Ph-; In the structural formula of compound 24f, R= p -F-Ph-.

[0107] The rhamnosyl methyl glycoside receptor compound 22 was prepared by the following steps: Compound 21 (methyl α-L-rhamnoside) was dissolved in acetone, and 2,2-dimethoxypropane was added to the reaction system, wherein the molar ratio of 2,2-dimethoxypropane to compound 21 was 1:5~10. The pH of the solution was adjusted to 4 by adding p-toluenesulfonic acid, and the reaction was carried out at room temperature for 2 h. The reaction progress was monitored by TLC.

[0108] After the reaction was completed, triethylamine was added to neutralize the solution, and the solvent was removed by concentration under reduced pressure. The concentrated crude product was separated by silica gel column chromatography to obtain rhamnosyl methyl glycoside receptor compound 22.

[0109] The structural formula of the rhamnomethyl glycoside receptor compound 22 is shown below: .

[0110] The rhamnosyl methyl glycoside receptor compound 24a~f was prepared by the following steps: (1) Synthesis of intermediate compounds 23a~f Compound 22 was dissolved in N,N-dimethylformamide, and sodium hydride and benzyl bromide reagent were added sequentially in an ice bath at 0°C, and the mixture was stirred for 3 h. The molar ratio of sodium hydride to compound 22 was 1:1.5~2.5, and the molar ratio of benzyl bromide reagent to compound 22 was 1:1.5~2.5.

[0111] After the reaction was complete, the solution was quenched with 0°C ice water, extracted with ethyl acetate, and the organic phase was concentrated to obtain a concentrated crude product.

[0112] The concentrated crude product was dissolved in dichloromethane, and a 5% trifluoroacetic acid solution in dichloromethane was added to the reaction system. The reaction progress was monitored by TLC.

[0113] After the reaction was completed, sufficient toluene was added for concentration to obtain a concentrated crude product, which was then separated by silica gel column chromatography to obtain intermediate compounds 23a~f.

[0114] The benzyl bromide reagent is selected from any one of o-nitrobenzyl bromide, m-nitrobenzyl bromide, p-nitrobenzyl bromide, o-fluorobenzyl bromide, m-fluorobenzyl bromide, or p-fluorobenzyl bromide.

[0115] The general structural formulas of the intermediate compounds 23a~f are shown below: ; In the general formula of intermediate compound 23a, R= o -NO2-Ph-; In the general formula of intermediate compound 23b, R= m -NO2-Ph-; In the general formula of intermediate compound 23c, R= p -NO2-Ph-; In the general formula of the intermediate compound 23d, R= o -F-Ph-; In the general formula of intermediate compound 23e, R= m -F-Ph-; In the general formula of intermediate compound 23f, R= p -F-Ph-.

[0116] (2) Synthesis of rhamnosyl methyl glycoside receptor compound 24a~f Intermediate compounds 23a~f were dissolved in dichloromethane, and trimethyl orthoacetate was added under an ice bath at 0°C, wherein the molar ratio of trimethyl orthoacetate to intermediate compounds 23a~f was 1:2~3; after reacting for 1 hour, p-toluenesulfonic acid was added as a catalyst.

[0117] After the reaction was completed, triethylamine was added to neutralize the solution, followed by dilution with dichloromethane and extraction with water. The organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the concentrated crude product was then separated by silica gel column chromatography to obtain rhamnose methyl glycoside receptor compounds 24a~f.

[0118] The general structural formulas of the rhamnosyl methyl glycoside receptor compounds 24a~f are shown below: ; In the general formula of receptor compound 24a, R= o -NO2-Ph-; In the general formula of receptor compound 24b, R= m -NO2-Ph-; In the general formula of receptor compound 24c, R= p -NO2-Ph-; In the general formula of receptor compound 24d, R= o -F-Ph-; In the general formula of receptor compound 24e, R= m -F-Ph-; In the general formula of receptor compound 24f, R= p -F-Ph-.

[0119] The synthetic routes for the above-mentioned rhamnosyl methyl glycoside receptor compounds 24a~f are shown below: .

[0120] The aforementioned galactorranoside compounds, as inhibitors of galactolectin-3, have been used in the preparation of drugs for treating pulmonary fibrosis and chronic / acute myeloid leukemia. They exhibit particularly significant inhibitory activity against TGF-β-induced A549 (human lung epithelial cells) fibrosis and significant killing activity against NB4 and K562 cells.

[0121] The beneficial effects of this invention are as follows: This invention uses galactorhamnetose (a derivative of galactose and rhamnose) as its core framework, representing a novel small-molecule carbohydrate inhibitor core framework. Compared to polysaccharide macromolecular inhibitors, the galactorhamnetose framework of this invention is a fully synthetic small-molecule inhibitor, possessing advantages such as simple chemical synthesis, high stability, and easy absorption by the body. It overcomes the limitations of polysaccharide inhibitors, such as difficult extraction and separation, poor stability, low bioavailability, and potential interference with galactose lectin protein expression, making it a more promising Gal-3 inhibitor.

[0122] The galactor rhamnoside compounds of this invention enhance target binding affinity: the carbohydrate recognition domain (CRD) of Gal-3 preferentially binds to β-galactosides, but the hydrophobic region and hydrogen bond network of its binding pocket are crucial for affinity. The introduction of rhamnose into the galactor rhamnosose backbone (with a deoxy group at C6) significantly enhances hydrophobic interactions, enabling more effective filling of the hydrophobic pocket of Gal-3, thereby improving inhibitory efficacy; while in the prior art, the C6 hydroxyl group of the D-galactose backbone may introduce unnecessary hydrophilicity, limiting binding optimization.

[0123] This invention, through the innovative design of the galactor rhamnose core framework, demonstrates significant advantages in formulation development and target binding, providing a new technical route for developing highly efficient and selective Gal-3 inhibitors, and has important clinical and application value. Attached Figure Description

[0124] Figure 1 To detect the in vitro affinity of compounds RG1-RG12 for Gal-3 using SPR.

[0125] Figure 2 The compound's ability to inhibit TGF-β-induced fibrosis in A549 cells was demonstrated. Detailed Implementation

[0126] The technical solution of the present invention will now be described in detail with reference to the accompanying drawings.

[0127] Example 1 The galactor rhamnoside compound RG1 has the following structural formula: .

[0128] The galactor rhamnoside compounds are prepared by the following steps: (1) Glycosylation First, the compound uses rhamnosinogen as the donor and galactosyl glycoside as the acceptor; specifically, compound 1 is used as the donor and compound 16h is used as the acceptor.

[0129] ; In the formula, R = Ac.

[0130] Then, the donor and acceptor were dissolved in dry dichloromethane at a molar ratio of 2:1, and 4A molecular sieves were added. The mixture was stirred at room temperature for 0.5 h and then placed in an ice bath at 0 °C. Subsequently, iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH) were added sequentially, and the reaction was catalyzed for 4 h. The molar ratio of iodosuccinimide to donor was 2.5:1, and the molar ratio of trifluoromethanesulfonic acid to donor was 0.2:1.

[0131] After the reaction was completed, the solution was neutralized with triethylamine, filtered, washed with dichloromethane, the residue was concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain unprotected galactor rhamnoside compounds.

[0132] (2) Perform deprotection Deprotection of tert-butyldiphenylsilyl group: The unprotected galactor rhamnoside compound obtained in step (1) was dissolved in dichloromethane, 3 equivalents of tetrabutylammonium fluoride were added, the reaction was concentrated after completion, and silica gel column chromatography was performed to obtain the product with the tert-butyldiphenylsilyl group removed.

[0133] Deacetyl protection was performed: the compound de-tert-butyldiphenylsilyl protected was dissolved in methanol, 1M sodium methoxide in methanol was added, the pH was adjusted to 10, after the reaction was completed, acidic resin was added to neutralize, the insoluble matter was filtered off, and the organic phase was concentrated.

[0134] Gel column purification: The deacetylated compound was dissolved in water and purified using a dextran gel column with water as the mobile phase. The final galactor rhamnoside compound RG1 was obtained by lyophilization.

[0135] Example 2 The galactor rhamnoside compound RG2a~f has the following structural formula: ; In the general formula of compound RG2a, R= o -NO2-Ph-;RG2a uses compound 1 as the donor and compound 19a as the acceptor.

[0136] In the general structural formula of compound RG2b, R= m -NO2-Ph-;RG2b uses compound 1 as the donor and compound 19b as the acceptor.

[0137] In the general structural formula of compound RG2c, R= p -NO2-Ph-;RG2c uses compound 1 as the donor and compound 19c as the acceptor.

[0138] In the general structural formula of compound RG2d, R= o -F-Ph-;RG2d uses compound 1 as the donor and compound 19d as the acceptor.

[0139] In the general structural formula of compound RG2e, R= m -F-Ph-;RG2e means that compound 1 is the donor and compound 19e is the acceptor.

[0140] In the general structural formula of compound RG2f, R= p -F-Ph-. RG2f uses compound 1 as the donor and compound 19f as the acceptor.

[0141] The galactor rhamnoside compounds are prepared by the following steps: (1) Glycosylation First, the compound uses rhamnosinogen as the donor and galactosyl glycoside as the acceptor; specifically, compound 1 is used as the donor and compounds 19a~f are used as acceptors.

[0142] ; ; In the general formula of receptor compound 19a, R= o -NO2-Ph-; In the general formula of receptor compound 19b, R= m -NO2-Ph-; In the general formula of receptor compound 19c, R= p -NO2-Ph-; In the general formula of receptor compound 19d, R= o -F-Ph-; In the general structural formula of receptor compound 19e, R= m -F-Ph-; In the general formula of receptor compound 19f, R= p -F-Ph-.

[0143] Then, the donor and acceptor were dissolved in dry dichloromethane at a molar ratio of 2:1, and 4A molecular sieves were added. The mixture was stirred at room temperature for 0.5 h and then placed in an ice bath at 0 °C. Subsequently, iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH) were added sequentially, and the reaction was catalyzed for 4 h. The molar ratio of iodosuccinimide to donor was 2.5:1, and the molar ratio of trifluoromethanesulfonic acid to donor was 0.2:1.

[0144] After the reaction was completed, the solution was neutralized with triethylamine, filtered, washed with dichloromethane, the residue was concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain unprotected galactor rhamnoside compounds.

[0145] (2) Perform deprotection Deprotection of tert-butyldiphenylsilyl group: The unprotected galactor rhamnoside compound obtained in step (1) was dissolved in dichloromethane, 3 equivalents of tetrabutylammonium fluoride were added, the reaction was concentrated after completion, and silica gel column chromatography was performed to obtain the product with the tert-butyldiphenylsilyl group removed.

[0146] Deacetyl protection was performed: the compound after detert-butyldiphenylsilyl protection was dissolved in methanol, 1M sodium methoxide in methanol was added, the pH was adjusted to 10, after the reaction was completed, acidic resin was added to neutralize, the insoluble matter was filtered off, and the organic phase was concentrated.

[0147] Gel column purification: The deacetylated compound was dissolved in water and purified using a dextran gel column with water as the mobile phase. The final galactor rhamnoside compound RG2a~f was obtained by lyophilization.

[0148] Example 3 The galactor rhamnoside compound RG3a~g has the following structural formula: ; In the general formula of compound RG3a, R= o -NO2-Ph-; Compound RG3a uses compound 1 as the donor and compound 20a as the acceptor.

[0149] In the general structural formula of compound RG3b, R= m -NO2-Ph-; Compound RG3b uses compound 1 as the donor and compound 20b as the acceptor.

[0150] In the general structural formula of compound RG3c, R= p-NO2-Ph-; Compound RG3c uses compound 1 as the donor and compound 20c as the acceptor.

[0151] In the general structural formula of compound RG3d, R= o -F-Ph-; Compound RG3d uses compound 1 as the donor and compound 20d as the acceptor.

[0152] In the general structural formula of compound RG3e, R= m -F-Ph-; Compound RG3e uses compound 1 as the donor and compound 20e as the acceptor.

[0153] In the general structural formula of compound RG3f, R= p -F-Ph-; Compound RG3f uses compound 1 as the donor and compound 20f as the acceptor.

[0154] In the general structural formula of compound RG3g, R= p -F- o- NO2-Ph-. Compound RG3a uses compound 1 as the donor and compound 20g as the acceptor.

[0155] The galactor rhamnoside compounds are prepared by the following steps: (1) Glycosylation First, the compound uses rhamnosinogen as the donor and galactosyl glycoside as the acceptor; specifically, compound 1 is used as the donor and compounds 20a~g are used as the acceptors.

[0156] ; ; In the general formula of receptor compound 20a, R= o -NO2-Ph-; In the general formula of receptor compound 20b, R= m -NO2-Ph-; In the general formula of receptor compound 20c, R= p -NO2-Ph-; In the general formula of receptor compound 20d, R= o -F-Ph-; In the general formula of receptor compound 20e, R= m -F-Ph-; In the general formula of receptor compound 20f, R= p -F-Ph-; In the general structural formula of receptor compound 20g, R= p -F- o- NO2-Ph-.

[0157] Then, the donor and acceptor were dissolved in dry dichloromethane at a molar ratio of 2:1, and 4A molecular sieves were added. The mixture was stirred at room temperature for 0.5 h and then placed in an ice bath at 0 °C. Subsequently, iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH) were added sequentially, and the reaction was catalyzed for 4 h. The molar ratio of iodosuccinimide to donor was 2.5:1, and the molar ratio of trifluoromethanesulfonic acid to donor was 0.2:1.

[0158] After the reaction was completed, the solution was neutralized with triethylamine, filtered, washed with dichloromethane, the residue was concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain unprotected galactor rhamnoside compounds.

[0159] (2) Perform deprotection Deprotection with isopropylidene or benzylidene: Dissolve the unprotected galactorlaminoid obtained in step (1) in dichloromethane, add a dichloromethane solution of 5% trifluoroacetic acid, and after the reaction is complete, add sufficient toluene to concentrate and obtain the crude product.

[0160] Acetyl protection was performed: the compound after the removal of isopropylidene and benzylidene groups was dissolved in methanol, a 1M sodium methoxide methanol solution was added, the pH was adjusted to 10, after the reaction was completed, acidic resin was added to neutralize, the insoluble matter was filtered off, and the organic phase was concentrated.

[0161] Gel column purification: The deacetyl-protected compound was dissolved in water and purified using a dextran gel column with water as the mobile phase. The final product RG3a~g was obtained by lyophilization.

[0162] Among them, compound RG3c: 1 H NMR (400 MHz, D2O) δ 8.33 (d, J = 8.9 Hz, 2H), 8.26(d, J = 8.9 Hz, 2H), 5.12 (d, J = 3.6 Hz, 1H), 4.80-4.75 (m, 3H), 4.15 – 3.85 (m,4H), 3.82 (dd, J = 3.4, 1.7 Hz, 1H), 3.75 – 3.47 (m, 2H), 3.32 (dd, J = 9.6, 5.1Hz, 1H), 3.28 (s, 3H), 1.17 (d, J = 6.3 Hz, 3H). Example 4 The galactor rhamnoside compound RG4a~f has the following structural formula: ; In the general formula of compound RG4a, R= o -NO2-Ph-;RG4a uses compound 4a as the donor and compound 16h as the acceptor.

[0163] In the general structural formula of compound RG4b, R= m -NO2-Ph-;RG4b uses compound 4b as the donor and compound 16h as the acceptor.

[0164] In the general structural formula of compound RG4c, R= p -NO2-Ph-;RG4c uses compound 4c as the donor and compound 16h as the acceptor.

[0165] In the general structural formula of compound RG4d, R= o -F-Ph-;RG4d means that compound 4d is used as the donor and compound 16h is used as the acceptor.

[0166] In the general structural formula of compound RG4e, R= m -F-Ph-;RG4e uses compound 4e as the donor and compound 16h as the acceptor.

[0167] In the general structural formula of compound RG4f, R= p -F-Ph-. RG4f uses compound 4f as the donor and compound 16h as the acceptor.

[0168] The galactor rhamnoside compounds are prepared by the following steps: (1) Glycosylation First, the compound uses rhamnosinogen as the donor and galactosyl glycoside as the acceptor; specifically, compounds 4a~f are used as donors and compound 16h is used as acceptor.

[0169] ; In the general formula of donor compound 4a, R= o -NO2-Ph-; In the general formula of donor compound 4b, R= m -NO2-Ph-; In the general formula of the 4c ​​structure of the donor compound, R= p -NO2-Ph-; In the general formula of the 4d structure of the donor compound, R= o -F-Ph-; In the general formula of the donor compound 4e, R= m -F-Ph-; In the general formula of the donor compound 4f, R= p -F-Ph-.

[0170] ; In the structural formula of receptor compound 16h, R=Ac.

[0171] Then, the donor and acceptor were dissolved in dry dichloromethane at a molar ratio of 2:1, and 4A molecular sieves were added. The mixture was stirred at room temperature for 0.5 h and then placed in an ice bath at 0 °C. Subsequently, iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH) were added sequentially, and the reaction was catalyzed for 4 h. The molar ratio of iodosuccinimide to donor was 2.5:1, and the molar ratio of trifluoromethanesulfonic acid to donor was 0.2:1.

[0172] After the reaction was completed, the solution was neutralized with triethylamine, filtered, washed with dichloromethane, the residue was concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain unprotected galactor rhamnoside compounds.

[0173] (2) Perform deprotection Deprotection of tert-butyldiphenylsilyl group: The unprotected galactor rhamnoside compound obtained in step (1) was dissolved in dichloromethane, 3 equivalents of tetrabutylammonium fluoride were added, the reaction was concentrated after completion, and silica gel column chromatography was performed to obtain the product with the tert-butyldiphenylsilyl group removed.

[0174] Deacetyl protection was performed: the compound after detert-butyldiphenylsilyl protection was dissolved in methanol, 1M sodium methoxide in methanol was added, the pH was adjusted to 10, after the reaction was completed, acidic resin was added to neutralize, the insoluble matter was filtered off, and the organic phase was concentrated.

[0175] Gel column purification: The deacetylated compound was dissolved in water and purified using a dextran gel column with water as the mobile phase. The final galactor rhamnoside compound RG4a~f was obtained by freeze-drying.

[0176] Among them, compound RG4c: 1 H NMR (400 MHz, D2O) δ 8.38 (d, J = 8.6 Hz, 2H), 8.30(d, J = 8.7 Hz, 2H), 5.00 (d, J = 3.6 Hz, 1H), 4.90-4.65 (m, 3H), 4.50-4.25 (m,2H), 4.05 – 3.55 (m, 5H), 3.32 (dd, J = 8.0, 3.5 Hz, 1H), 3.30 (s, 3H), 1.15(d, J = 6.4 Hz, 3H). Example 5 The galactor rhamnoside compound RG5a~f has the following structural formula: ; In the general formula of compound RG5a, R= o -NO2-Ph-;RG5a uses compound 4a as the donor and compound 19a as the acceptor.

[0177] In the general structural formula of compound RG5b, R= m -NO2-Ph-;RG5b uses compound 4b as the donor and compound 19b as the acceptor.

[0178] In the general structural formula of compound RG5c, R= p -NO2-Ph-;RG5c uses compound 4c as the donor and compound 19c as the acceptor.

[0179] In the general structural formula of compound RG5d, R= o -F-Ph-;RG5d uses compound 4d as the donor and compound 19d as the acceptor.

[0180] In the general structural formula of compound RG5e, R= m -F-Ph-;RG5e uses compound 4e as the donor and compound 19e as the acceptor.

[0181] In the general structural formula of compound RG5f, R= p -F-Ph-. RG5f uses compound 4f as the donor and compound 19f as the acceptor.

[0182] The galactor rhamnoside compounds are prepared by the following steps: (1) Glycosylation First, the compound uses rhamnosinogen as the donor and galactosyl glycoside as the acceptor; specifically, compounds 4a~f are used as donors and compounds 19a~f are used as acceptors.

[0183] ; In the general formula of donor compound 4a, R= o -NO2-Ph-; In the general formula of donor compound 4b, R= m -NO2-Ph-; In the general formula of the 4c ​​structure of the donor compound, R= p -NO2-Ph-; In the general formula of the 4d structure of the donor compound, R= o -F-Ph-; In the general formula of the donor compound 4e, R= m -F-Ph-; In the general formula of the donor compound 4f, R= p -F-Ph-.

[0184] ; In the general formula of receptor compound 19a, R= o -NO2-Ph-; In the general formula of receptor compound 19b, R= m -NO2-Ph-; In the general formula of receptor compound 19c, R= p -NO2-Ph-; In the general formula of receptor compound 19d, R= o -F-Ph-; In the general structural formula of receptor compound 19e, R= m -F-Ph-; In the general formula of receptor compound 19f, R= p -F-Ph-.

[0185] Then, the donor and acceptor were dissolved in dry dichloromethane at a molar ratio of 2:1, and 4A molecular sieves were added. The mixture was stirred at room temperature for 0.5 h and then placed in an ice bath at 0 °C. Subsequently, iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH) were added sequentially, and the reaction was catalyzed for 4 h. The molar ratio of iodosuccinimide to donor was 2.5:1, and the molar ratio of trifluoromethanesulfonic acid to donor was 0.2:1.

[0186] After the reaction was completed, the solution was neutralized with triethylamine, filtered, washed with dichloromethane, the residue was concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain unprotected galactor rhamnoside compounds.

[0187] (2) Perform deprotection Deprotection of tert-butyldiphenylsilyl group: The unprotected galactor rhamnoside compound obtained in step (1) was dissolved in dichloromethane, 3 equivalents of tetrabutylammonium fluoride were added, the reaction was concentrated after completion, and silica gel column chromatography was performed to obtain the product with the tert-butyldiphenylsilyl group removed.

[0188] Deacetyl protection was performed: the compound after detert-butyldiphenylsilyl protection was dissolved in methanol, 1M sodium methoxide in methanol was added, the pH was adjusted to 10, after the reaction was completed, acidic resin was added to neutralize, the insoluble matter was filtered off, and the organic phase was concentrated.

[0189] Gel column purification: The deacetylated compound was dissolved in water and purified using a dextran gel column with water as the mobile phase. The final galactor rhamnoside compound RG5a~f was obtained by freeze-drying.

[0190] Example 6 The galactor rhamnoside compound RG6a~f has the following structural formula: ; In the general formula of compound RG6a, R= o -NO2-Ph-;RG6a uses compound 4a as the donor and compound 20a as the acceptor.

[0191] In the general structural formula of compound RG6b, R= m -NO2-Ph-;RG6b uses compound 4b as the donor and compound 20b as the acceptor.

[0192] In the general structural formula of compound RG6c, R= p -NO2-Ph-;RG6c uses compound 4c as the donor and compound 20c as the acceptor.

[0193] In the general structural formula of compound RG6d, R= o -F-Ph-;RG6d uses compound 4d as the donor and compound 20d as the acceptor.

[0194] In the general structural formula of compound RG6e, R= m -F-Ph-;RG6e uses compound 4e as the donor and compound 20e as the acceptor.

[0195] In the general structural formula of compound RG6f, R= p -F-Ph-. RG6f uses compound 4f as the donor and compound 20f as the acceptor.

[0196] The galactor rhamnoside compounds are prepared by the following steps: (1) Glycosylation First, the compound uses rhamnosinogen as the donor and galactosyl glycoside as the acceptor; specifically, it uses compounds 4a~f as the donor and compounds 20a~f as the acceptor.

[0197] ; In the general formula of donor compound 4a, R= o -NO2-Ph-; In the general formula of donor compound 4b, R= m -NO2-Ph-; In the general formula of the 4c ​​structure of the donor compound, R= p -NO2-Ph-; In the general formula of the 4d structure of the donor compound, R= o -F-Ph-; In the general formula of the donor compound 4e, R= m-F-Ph-; In the general formula of the donor compound 4f, R= p -F-Ph-.

[0198] ; In the general formula of receptor compound 20a, R= o -NO2-Ph-; In the general formula of receptor compound 20b, R= m -NO2-Ph-; In the general formula of receptor compound 20c, R= p -NO2-Ph-; In the general formula of receptor compound 20d, R= o -F-Ph-; In the general formula of receptor compound 20e, R= m -F-Ph-; In the general formula of receptor compound 20f, R= p -F-Ph-.

[0199] Then, the donor and acceptor were dissolved in dry dichloromethane at a molar ratio of 2:1, and 4A molecular sieves were added. The mixture was stirred at room temperature for 0.5 h and then placed in an ice bath at 0 °C. Subsequently, iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH) were added sequentially, and the reaction was catalyzed for 4 h. The molar ratio of iodosuccinimide to donor was 2.5:1, and the molar ratio of trifluoromethanesulfonic acid to donor was 0.2:1.

[0200] After the reaction was completed, the solution was neutralized with triethylamine, filtered, washed with dichloromethane, the residue was concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain unprotected galactor rhamnoside compounds.

[0201] (2) Perform deprotection Deprotection with isopropylidene or benzylidene: Dissolve the unprotected galactorlaminoid obtained in step (1) in dichloromethane, add a dichloromethane solution of 5% trifluoroacetic acid, and after the reaction is complete, add sufficient toluene to concentrate and obtain the crude product.

[0202] Deacetyl protection: The compound protected by deacetylation or debenzylation is dissolved in methanol, 1M sodium methoxide in methanol is added, the pH is adjusted to 10, after the reaction is complete, acidic resin is added to neutralize, insoluble matter is filtered off, and the organic phase is concentrated.

[0203] Gel column purification: The deacetylated compound was dissolved in water and purified using a dextran gel column with water as the mobile phase. The final product RG6a~f was obtained by lyophilization.

[0204] Example 7 The galactor rhamnoside compound RG7a~g has the following structural formula: ; In the general formula of compound RG7a, R= o -NO2-Ph-;RG7a uses compound 5a as the donor and compound 16a as the acceptor.

[0205] In the general structural formula of compound RG7b, R= m -NO2-Ph-;RG7b uses compound 5b as the donor and compound 16b as the acceptor.

[0206] In the general structural formula of compound RG7c, R= p -NO2-Ph-;RG7c uses compound 5c as the donor and compound 16c as the acceptor.

[0207] In the general structural formula of compound RG7d, R= o -F-Ph-;RG7d uses compound 5d as the donor and compound 16d as the acceptor.

[0208] In the general structural formula of compound RG7e, R= m -F-Ph-;RG7e uses compound 5e as the donor and compound 16e as the acceptor.

[0209] In the general structural formula of compound RG7f, R= p -F-Ph-. RG7f uses compound 5f as the donor and compound 16f as the acceptor.

[0210] In the general structural formula of compound RG7g, R= p -F- o- NO2-Ph-. RG7g uses compound 5g as the donor and compound 16g as the acceptor.

[0211] The galactor rhamnoside compounds are prepared by the following steps: (1) Glycosylation First, the compound uses rhamnosinogen as the donor and galactosyl glycoside as the acceptor; specifically, it uses compounds 5a~g as the donor and compounds 16a~g as the acceptor.

[0212] ; In the general formula of donor compound 5a, R= o -NO2-Ph-; In the general formula of donor compound 5b, R= m -NO2-Ph-; In the general formula of the donor compound 5c, R= p-NO2-Ph-; In the general formula of the 5d structure of the donor compound, R= o -F-Ph-; In the general formula of the donor compound 5e, R= m -F-Ph-; In the general formula of the donor compound 5f, R= p -F-Ph-; In the general formula of the donor compound 5g, R= p -F- o- NO2-Ph- ; In the general formula of receptor compound 16a, R= o -NO2-Ph-; In the general formula of receptor compound 16b, R= m -NO2-Ph-; In the general formula of receptor compound 16c, R= p -NO2-Ph-; In the general formula of the 16d structure of receptor compounds, R= o -F-Ph-; In the general formula of receptor compound 16e, R= m -F-Ph-; In the general formula of receptor compound 16f, R= p -F-Ph-; In the general formula of receptor compound 16g, R= p -F- o- NO2-Ph-.

[0213] Then, the donor and acceptor were dissolved in dry dichloromethane at a molar ratio of 2:1, and 4A molecular sieves were added. The mixture was stirred at room temperature for 0.5 h and then placed in an ice bath at 0 °C. Subsequently, iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH) were added sequentially, and the reaction was catalyzed for 4 h. The molar ratio of iodosuccinimide to donor was 2.5:1, and the molar ratio of trifluoromethanesulfonic acid to donor was 0.2:1.

[0214] After the reaction was completed, the solution was neutralized with triethylamine, filtered, washed with dichloromethane, the residue was concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain unprotected galactor rhamnoside compounds.

[0215] (2) Perform deprotection Deprotection with isopropylidene or benzylidene: Dissolve the unprotected galactorlaminoid obtained in step (1) in dichloromethane, add a dichloromethane solution of 5% trifluoroacetic acid, and after the reaction is complete, add sufficient toluene to concentrate and obtain the crude product.

[0216] Detert-butyldiphenylsilyl protection: The detert-isopropylidene or benzylidene-protected compound is dissolved in dichloromethane, and 3 equivalents of tetrabutylammonium fluoride are added. After the reaction is complete, the mixture is concentrated and subjected to silica gel column chromatography to obtain the product with the detert-butyldiphenylsilyl group removed.

[0217] Gel column purification: The detert-butyldiphenylsilyl-protected compound was dissolved in water and purified using a dextran gel column with water as the mobile phase. The final product RG7a~g was obtained by lyophilization.

[0218] Example 8 The galactor rhamnoside compound RG8 has the following structural formula: .

[0219] The galactor rhamnoside compounds are prepared by the following steps: (1) Glycosylation First, the compound uses galactosyl glycoside as the donor and rhamnosyl thioglycoside as the acceptor; specifically, compound 6 is the donor and compound 22 is the acceptor.

[0220] ; .

[0221] Then, the donor and acceptor were dissolved in dry dichloromethane at a molar ratio of 2:1, 4A molecular sieve was added, and the reaction was stirred at room temperature for 0.5 h and then placed in an ice bath at 0 °C. Subsequently, iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH) were added sequentially, and the reaction was catalyzed for 4 h. The molar ratio of iodosuccinimide to donor was 2.5:1, and the molar ratio of trifluoromethanesulfonic acid to donor was 0.2:1.

[0222] After the reaction was completed, the solution was neutralized with triethylamine, filtered, washed with dichloromethane, the residue was concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain unprotected galactor rhamnoside compounds.

[0223] (2) Perform deprotection Deprotection with isopropylidene or benzylidene: Dissolve the unprotected galactorlaminoid obtained in step (1) in dichloromethane, add a dichloromethane solution of 5% trifluoroacetic acid, and after the reaction is complete, add sufficient toluene to concentrate and obtain the crude product.

[0224] Deacetyl protection: The compound deacetylated or benzylidene-protected is dissolved in methanol, 1M sodium methoxide in methanol is added, the pH is adjusted to 10, after the reaction is complete, acidic resin is added to neutralize, insoluble matter is filtered off, and the organic phase is concentrated.

[0225] Gel column purification: The deacetyl-protected compound was dissolved in water and purified using a dextran gel column with water as the mobile phase. The final product RG8 was obtained by lyophilization.

[0226] Example 9 The galactor rhamnoside compound RG9a~f has the following structural formula: ; In the general formula of compound RG9a, R= o -NO2-Ph-;RG9a uses compound 6 as the donor and compound 24a as the acceptor.

[0227] In the general structural formula of compound RG9b, R= m -NO2-Ph-;RG9b uses compound 6 as the donor and compound 24b as the acceptor.

[0228] In the general structural formula of compound RG9c, R= p -NO2-Ph-;RG9c uses compound 6 as the donor and compound 24c as the acceptor.

[0229] In the general structural formula of compound RG9d, R= o -F-Ph-;RG9d uses compound 6 as the donor and compound 24d as the acceptor.

[0230] In the general structural formula of compound RG9e, R= m -F-Ph-;RG9e uses compound 6 as the donor and compound 24e as the acceptor.

[0231] In the general structural formula of compound RG9f, R= p -F-Ph-. RG9f uses compound 6 as the donor and compound 24f as the acceptor.

[0232] The galactor rhamnoside compounds are prepared by the following steps: (1) Glycosylation First, the compound uses galactosyl glycoside as the donor and rhamnosyl thioglycoside as the acceptor; specifically, compound 6 is used as the donor and compounds 24a~f are used as acceptors.

[0233] ; ; In the general formula of receptor compound 24a, R= o -NO2-Ph-; In the general formula of receptor compound 24b, R= m -NO2-Ph-; In the general formula of receptor compound 24c, R= p-NO2-Ph-; In the general formula of receptor compound 24d, R= o -F-Ph-; In the general formula of receptor compound 24e, R= m -F-Ph-; In the general formula of receptor compound 24f, R= p -F-Ph-.

[0234] Then, the donor and acceptor were dissolved in dry dichloromethane at a molar ratio of 2:1, 4A molecular sieve was added, and the reaction was stirred at room temperature for 0.5 h and then placed in an ice bath at 0 °C. Subsequently, iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH) were added sequentially, and the reaction was catalyzed for 4 h. The molar ratio of iodosuccinimide to donor was 2.5:1, and the molar ratio of trifluoromethanesulfonic acid to donor was 0.2:1.

[0235] After the reaction was completed, the solution was neutralized with triethylamine, filtered, washed with dichloromethane, the residue was concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain unprotected galactor rhamnoside compounds.

[0236] (2) Perform deprotection Deacetyl protection: Dissolve the unprotected galactor rhamnoside obtained in step (1) in methanol, add 1M sodium methoxide in methanol, adjust the pH to 10, after the reaction is complete, add acidic resin to neutralize, filter out the insoluble matter, and concentrate the organic phase.

[0237] Gel column purification: The deacetyl-protected compound was dissolved in water and purified using a dextran gel column with water as the mobile phase. The final product RG9a~f was obtained by lyophilization.

[0238] Among them, compound RG9c: 1 H NMR (400 MHz, Chloroform-d) δ 8.38 (d, J = 8.9 Hz, 2H), 8.34 (d, J = 8.9 Hz, 2H), 5.12 (d, J = 1.8 Hz, 1H), 4.80 – 4.60 (m, 2H), 3.90 – 3.50 (m, 7H), 3.40 – 3.30 (m, 2H), 3.32 (s, 3H), 1.23 (d, J = 6.0 Hz, 3H).

[0239] Example 10 The galactor rhamnoside compound RG10a~f has the following structural formula: ; In the general formula of compound RG10a, R= o -NO2-Ph-;RG10a uses compound 8a as the donor and compound 22 as the acceptor.

[0240] In the general structural formula of compound RG10b, R= m -NO2-Ph-;RG10b uses compound 8b as the donor and compound 22 as the acceptor.

[0241] In the general structural formula of compound RG10c, R= p -NO2-Ph-;RG10c uses compound 8c as the donor and compound 22 as the acceptor.

[0242] In the general structural formula of compound RG10d, R= o -F-Ph-;RG10d uses compound 8d as the donor and compound 22 as the acceptor.

[0243] In the general structural formula of compound RG10e, R= m -F-Ph-;RG10e uses compound 8e as the donor and compound 22 as the acceptor.

[0244] In the general structural formula of compound RG10f, R= p -F-Ph-. RG10f uses compound 8f as the donor and compound 22 as the acceptor.

[0245] The galactor rhamnoside compounds are prepared by the following steps: (1) Glycosylation First, the compound uses galactosyl glycoside as the donor and rhamnosyl thioglycoside as the acceptor; specifically, it uses compounds 8a~f as the donor and compound 22 as the acceptor.

[0246] ; In the general formula of donor compound 8a, R= o -NO2-Ph-; In the general formula of donor compound 8b, R= m -NO2-Ph-; In the general formula of the donor compound 8c, R= p -NO2-Ph-; In the general formula of the 8d structure of the donor compound, R= o -F-Ph-; In the general formula of the donor compound 8e, R= m -F-Ph-; In the general formula of the donor compound 8f, R= p-F-Ph-.

[0247] .

[0248] Then, the donor and acceptor were dissolved in dry dichloromethane at a molar ratio of 2:1, 4A molecular sieve was added, and the reaction was stirred at room temperature for 0.5 h and then placed in an ice bath at 0 °C. Subsequently, iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH) were added sequentially, and the reaction was catalyzed for 4 h. The molar ratio of iodosuccinimide to donor was 2.5:1, and the molar ratio of trifluoromethanesulfonic acid to donor was 0.2:1.

[0249] After the reaction was completed, the solution was neutralized with triethylamine, filtered, washed with dichloromethane, the residue was concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain unprotected galactor rhamnoside compounds.

[0250] (2) Perform deprotection Deprotection with isopropylidene or benzylidene: Dissolve the unprotected galactorlaminoid obtained in step (1) in dichloromethane, add a dichloromethane solution of 5% trifluoroacetic acid, and after the reaction is complete, add sufficient toluene to concentrate and obtain the crude product.

[0251] Gel column purification: The compound after the removal of isopropylidene and benzylidene groups was dissolved in water and purified by dextran gel column using water as the mobile phase. The final product RG10a~f was obtained by lyophilization.

[0252] Example 11 The galactor rhamnoside compound RG11a~f has the following structural formula: ; In the general formula of compound RG11a, R= o -NO2-Ph-;RG11a uses compound 8a as the donor and compound 24a as the acceptor.

[0253] In the general structural formula of compound RG11b, R= m -NO2-Ph-;RG11b uses compound 8b as the donor and compound 24b as the acceptor.

[0254] In the general structural formula of compound RG11c, R= p -NO2-Ph-;RG11c uses compound 8c as the donor and compound 24c as the acceptor.

[0255] In the general structural formula of compound RG11d, R= o -F-Ph-;RG11d uses compound 8d as the donor and compound 24d as the acceptor.

[0256] In the general structural formula of compound RG11e, R=m -F-Ph-;RG11e uses compound 8e as the donor and compound 24e as the acceptor.

[0257] In the general structural formula of compound RG11f, R= p -F-Ph-. RG11f uses compound 8f as the donor and compound 24f as the acceptor.

[0258] The galactor rhamnoside compounds are prepared by the following steps: (1) Glycosylation First, the compound uses galactosyl glycoside as the donor and rhamnosyl thioglycoside as the acceptor; specifically, it uses compounds 8a~f as the donor and compounds 24a~f as the acceptor.

[0259] ; In the general formula of donor compound 8a, R= o -NO2-Ph-; In the general formula of donor compound 8b, R= m -NO2-Ph-; In the general formula of the donor compound 8c, R= p -NO2-Ph-; In the general formula of the 8d structure of the donor compound, R= o -F-Ph-; In the general formula of the donor compound 8e, R= m -F-Ph-; In the general formula of the donor compound 8f, R= p -F-Ph-.

[0260] ; In the general formula of receptor compound 24a, R= o -NO2-Ph-; In the general formula of receptor compound 24b, R= m -NO2-Ph-; In the general formula of receptor compound 24c, R= p -NO2-Ph-; In the general formula of receptor compound 24d, R= o -F-Ph-; In the general formula of receptor compound 24e, R= m -F-Ph-; In the general formula of receptor compound 24f, R= p -F-Ph-.

[0261] Then, the donor and acceptor were dissolved in dry dichloromethane at a molar ratio of 2:1, 4A molecular sieve was added, and the reaction was stirred at room temperature for 0.5 h and then placed in an ice bath at 0 °C. Subsequently, iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH) were added sequentially, and the reaction was catalyzed for 4 h. The molar ratio of iodosuccinimide to donor was 2.5:1, and the molar ratio of trifluoromethanesulfonic acid to donor was 0.2:1.

[0262] After the reaction was completed, the solution was neutralized with triethylamine, filtered, washed with dichloromethane, the residue was concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain unprotected galactor rhamnoside compounds.

[0263] (2) Perform deprotection Deprotection with isopropylidene or benzylidene: Dissolve the unprotected galactorlaminoid obtained in step (1) in dichloromethane, add a dichloromethane solution of 5% trifluoroacetic acid, and after the reaction is complete, add sufficient toluene to concentrate and obtain the crude product.

[0264] Acetyl protection was performed: the compound after the removal of isopropylidene and benzylidene groups was dissolved in methanol, a 1M sodium methoxide methanol solution was added, the pH was adjusted to 10, after the reaction was completed, acidic resin was added to neutralize, the insoluble matter was filtered off, and the organic phase was concentrated.

[0265] Gel column purification: The deacetyl-protected compound was dissolved in water and purified using a dextran gel column with water as the mobile phase. The final product RG11a~f was obtained by lyophilization.

[0266] Example 12 The galactor rhamnoside compound RG12a~g has the following structural formula: ; In the general formula of compound RG12a, R= o -NO2-Ph-;RG12a uses compound 10a as the donor and compound 22 as the acceptor.

[0267] In the general structural formula of compound RG12b, R= m -NO2-Ph-;RG12b uses compound 10b as the donor and compound 22 as the acceptor.

[0268] In the general structural formula of compound RG12c, R= p -NO2-Ph-;RG12c uses compound 10c as the donor and compound 22 as the acceptor.

[0269] In the general structural formula of compound RG12d, R= o -F-Ph-;RG12d uses compound 10d as the donor and compound 22 as the acceptor.

[0270] In the general structural formula of compound RG12e, R= m -F-Ph-;RG12e uses compound 10e as the donor and compound 22 as the acceptor.

[0271] In the general structural formula of compound RG12f, R= p -F-Ph-. RG12f uses compound 10f as the donor and compound 22 as the acceptor.

[0272] In the general structural formula of compound RG12g, R= p -F- o- NO2-Ph-.RG12g uses compound 10g as the donor and compound 22 as the acceptor.

[0273] The galactor rhamnoside compounds are prepared by the following steps: (1) Glycosylation First, the compound uses galactosyl glycoside as the donor and rhamnosyl thioglycoside as the acceptor; specifically, it uses compound 10a~g as the donor and compound 22 as the acceptor.

[0274] ; In the general formula of donor compound 10a, R= o -NO2-Ph-; In the general formula of donor compound 10b, R= m -NO2-Ph-; In the general formula of donor compound 10c, R= p -NO2-Ph-; In the 10d structural formula of the donor compound, R= o -F-Ph-; In the general formula of donor compound 10e, R= m -F-Ph-; In the general formula of donor compound 10f, R= p -F-Ph- In the general formula of the donor compound 10g, R= p -F- o- NO2-Ph-.

[0275] .

[0276] Then, the donor and acceptor were dissolved in dry dichloromethane at a molar ratio of 2:1, 4A molecular sieve was added, and the reaction was stirred at room temperature for 0.5 h and then placed in an ice bath at 0 °C. Subsequently, iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH) were added sequentially, and the reaction was catalyzed for 4 h. The molar ratio of iodosuccinimide to donor was 2.5:1, and the molar ratio of trifluoromethanesulfonic acid to donor was 0.2:1.

[0277] After the reaction was completed, the solution was neutralized with triethylamine, filtered, washed with dichloromethane, the residue was concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain unprotected galactor rhamnoside compounds.

[0278] (2) Perform deprotection Deprotection with isopropylidene or benzylidene: Dissolve the unprotected galactorlaminoid obtained in step (1) in dichloromethane, add a dichloromethane solution of 5% trifluoroacetic acid, and after the reaction is complete, add sufficient toluene to concentrate and obtain the crude product.

[0279] Gel column purification: The compound after the removal of isopropylidene and benzylidene groups was dissolved in water and purified by dextran gel column using water as the mobile phase. The final product RG12a~g was obtained by lyophilization.

[0280] Among them, compound RG12c: ¹H NMR (400 MHz, Chloroform-d) δ 8.37 (d, J = 8.9 Hz, 2H), 8.34 (d, J = 8.8 Hz, 2H), 8.28 (d, J = 8.9 Hz, 2H), 8.26 (d, J = 8.9 Hz, 2H), 4.60 (d, J = 1.7 Hz, 1H), 4.57 (d, J = 7.8 Hz, 1H), 4.05 – 3.83 (m, 4H), 3.80 –3.55 (m, 5H), 3.49 (t, J = 9.5 Hz, 1H), 3.31 (s, 3H), 1.28 (d, J = 6.0 Hz, 3H).

[0281] Application Example 1 In vitro affinity determination of compounds RG1~RG12 with Gal-3.

[0282] The inventors used compounds RG1~12 synthesized in the above embodiments as test compounds and tested their affinity for Gal-3 using SPR. The specific experimental results are as follows: a. Place the running buffer (200 mL 1 × PBS Buffer), water bottle, and waste bottle in the left and right trays respectively, and insert the corresponding inlet tubes. b. Hold the CM5 chip with the labeled side facing up. Gently push the chip into the slot according to the arrow on the chip, and finally close the chip compartment door. c. Activate channel 2 of the chip with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC GE Healthcare) and N-hydroxysuccinimide at a flow rate of 10 μL / min. d. Dilute the ligand protein to 50 μg / mL with sodium acetate at pH 4.5, and immobilize the protein in channel 2 of the chip at a flow rate of 10 μL / min. e. Block the channel with ethanolamine at a flow rate of 10 μL / min. f. Repeat step (ce) for channel 1 as a reference, except that step d uses acetate buffer without protein. g. Take a 96-well plate, dilute the small molecule to be used for single-concentration screening with PBS solution to an initial concentration of 100 μM, and flow at a rate of 10 μL / min for 150 s in each run. At the end of each flow, regenerate the chip with 10 mM glycine hydrochloride (pH 2.0) solution for 5 minutes, and repeat this process until all compounds have been analyzed.

[0283] The test results are as follows Figure 1 As shown, the rhamnoside compounds RG3f, RG4b, RG5e and RG9d of the present invention exhibit strong binding ability to Gal-3 and can be used to prepare Gal-3 inhibitors.

[0284] Application Example 2 Application of rhamnoside compounds as Gal-3 inhibitors in pulmonary fibrosis according to this invention The inventors used the compounds RG3f, RG4b, RG5e, and RG9d synthesized in the above embodiments as test compounds and tested their ability to inhibit A549 (human lung epithelial cells) fibrosis in vitro and in vivo. The specific experimental results are as follows: A549 cells with a confluence of approximately 80% were harvested, digested with trypsin, and added to 12-well plates at a density of 5E5 cells / well, and cultured for 6 h. In the experimental group, 2 ng / mL TGF-β and compounds RG3f, RG4b, RG5e, and RG9d were added to each well, respectively. The positive control group received 2 ng / mL TGF-β, and the negative control group received an equal volume of culture medium. The culture was incubated at 37°C. o Cells were cultured in a C24 incubator for 24 h. Cells from each well were collected, and total RNA was extracted using the Trizol method and reverse transcribed into cDNA. qPCR was used to detect the different treatment groups. α-SMA and COL1A1 mRNA expression levels were used to evaluate the fibrosis level of A549 cells.

[0285] The test results are as follows Figure 2 As shown, the rhamnoside compounds RG4b and RG9d of the present invention can significantly inhibit TGF-β-induced pulmonary epithelial cell fibrosis and can be used to prepare drugs that inhibit pulmonary fibrosis.

[0286] Application Example 3 The application of rhamnoside compounds of this invention as Gal-3 inhibitors in the treatment of chronic and acute myeloid leukemia (CML and AML). The inventors used the compounds RG3f, RG4b, RG5e, and RG9d synthesized in the above embodiments as test compounds and tested their ability to kill CML and AML cells in vitro and in vivo. The specific experimental results are as follows: Logarithmically growing K562 and NB4 cells were added to 96-well plates at a density of 5E3 cells / well and cultured for 4 h. The experimental groups were treated with serially diluted compounds RG3f, RG4b, RG5e, and RG9d (final concentrations of 10, 5, 2.5, 1.25, 0.625, 0.3125, and 0.15625 μM), while the control group was treated with an equal volume of DMSO. All wells were incubated at 37 ℃ for 72 h. OD450 was measured using the CCK-8 assay kit, and cell viability was calculated based on the OD value: Cell viability = [(OD sample - OD blank) / (OD negative - OD blank)] × 100%. The IC50 value of each compound was calculated based on the correlation between cell viability and concentration.

[0287] The experimental results are shown in Table 1. It can be seen that the rhamnoside compounds RG4b and RG9d of the present invention can significantly kill NB4 and K562 cells and can be used to prepare drugs for the treatment of CML and AML.

[0288] Table 1

[0289] Note: The unit in the table is μg / ml, and N represents exceeding the detection limit, i.e., >10 μg / ml.

Claims

1. A galactorlaminoid compound, characterized in that, The structural formula of the compound is selected from any of the following formulas: ; ; or ; In the formula, R1 ＇ R1 ＂ R1 ＇＇＇ R2 ＇ It is independently selected from -H, fluorinated benzoyl, fluorinated benzyl, nitro-substituted benzoyl or nitro-substituted benzyl.

2. The galactorlaminoid compound according to claim 1, characterized in that, The fluorinated substituted benzoyl group is selected from... o -F-Ph-CO-、 m -F-Ph-CO-、 p -F-Ph-CO- or p -F- o- Any one of NO2-, Ph-, or CO-; The fluorinated benzyl group is selected from... o -F-Ph-CH2-、 m -F-Ph-CH2-、 p -F-Ph-CH2- or p -F- o- Any one of NO2-Ph-CH2-; The nitro-substituted benzoyl group is selected from... o -NO2-Ph-CO-、 m -NO2-Ph-CO-、 p -NO2-Ph-CO- or p -F- o- Any one of NO2-, Ph-, or CO-; The nitro-substituted benzyl group is selected from... o -NO2-Ph-CH2-、 m -NO2-Ph-CH2-、 p -NO2-Ph-CH2- or p -F- o- Any of NO2-Ph-CH2-.

3. The galactorlaminoid compound according to claim 1, characterized in that, The structural formula of this compound is selected from any one of the formulas RG1 to RG12: ； In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or p Any of the following: -F-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph-、 p -F-Ph- or p -F- o- Any one of NO2-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or p Any of the following: -F-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or p Any of the following: -F-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or p Any of the following: -F-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph-、 p -F-Ph- or p -F- o- Any one of NO2-Ph-; ； In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or p Any of the following: -F-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or p Any of the following: -F-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or p Any of the following: -F-Ph-; In the formula, R is selected from... o -NO2-Ph-、 m -NO2-Ph-、 p -NO2-Ph-、 o -F-Ph-、 m -F-Ph- or p Any of -F-Ph-.

4. The galactorlaminoid compound according to claim 3, characterized in that, The structural formula of the compound is selected from any of the following formulas: In the formula, R is p -F-Ph-; In the formula, R is m -NO2-Ph-; In the formula, R is m -F-Ph-; In the formula, R is o -F-Ph-; Preferably, the structural formula of the compound is selected from any of the following formulas: In the formula, R is m -NO2-Ph-; or In the formula, R is o -F-Ph-.

5. A method for preparing the galactor rhamnoside compound as described in claim 1, characterized in that, Includes the following steps: First, glycosylation is performed: using rhamnosulosin as the donor and galactosylmethyl glycoside as the acceptor; or using galactosulosin as the donor and rhamnosylmethyl glycoside as the acceptor; dissolved in dichloromethane, the glycosylation reaction is carried out under the catalysis of iodosuccinimide and trifluoromethanesulfonic acid; the details are as follows: The donor and acceptor were dissolved in dry dichloromethane at a molar ratio of 1.5–3.0:1, and 4A molecular sieves were added. The mixture was stirred at room temperature for 0.5 h and then placed in an ice bath at 0 °C. Iodosuccinimide and trifluoromethanesulfonic acid were then added sequentially, and the reaction was catalyzed for 4 h. The molar ratio of iodosuccinimide to donor was 2.5:1, and the molar ratio of trifluoromethanesulfonic acid to donor was 0.2:

1. After the reaction was completed, the solution was neutralized with triethylamine, filtered, washed with dichloromethane, the residue was concentrated under reduced pressure, and silica gel column chromatography was performed to obtain unprotected galactor rhamnoside compounds. Then, deprotection was performed to obtain the galactor rhamnoside compound.

6. The method for preparing galactor rhamnoside compounds according to claim 5, characterized in that, The rhamnosulosin used as the donor includes any one of the following compounds: compound 1, compounds 4a-f, or compounds 5a-g, as shown in the following structural formulas: , or ; In the structural formulas of compounds 4a and 5a, R= o -NO2-Ph-; In the structural formulas of compounds 4b and 5b, R= m -NO2-Ph-; R= in the 4c ​​and 5c structures of compounds p -NO2-Ph-; R= in the 4d and 5d structures of compounds o -F-Ph-; In the structural formulas of compounds 4e and 5e, R= m -F-Ph-; R= in the structural formulas of compounds 4f and 5f p -F-Ph-; In the structural formula of compound 5g, R= p -F- o- NO2-Ph-.

7. The method for preparing galactor rhamnoside compounds according to claim 5, characterized in that, The galactosyl glycoside used as the donor includes any one of the following compounds 6, 8a-f, or 10a-g: , or ; In the structural formulas of compounds 8a and 10a, R= o -NO2-Ph-; In the structural formulas of compounds 8b and 10b, R= m -NO2-Ph-; R= in the structural formulas of compounds 8c and 10c p -NO2-Ph-; R= in the 8d and 10d structures of compounds o -F-Ph-; In the structural formulas of compounds 8e and 10e, R= m -F-Ph-; R= in the structural formulas of compounds 8f and 10f p -F-Ph-; In the structural formula of compound 10g, R= p -F- o- NO2-Ph-.

8. The method for preparing galactor rhamnoside compounds according to claim 5, characterized in that, The galactosyl glycoside acting as the acceptor includes any one of compounds 16a-h, 19a-f, or 20a-g, as shown in the following structural formulas: , or ; In the structural formulas of compounds 16a, 19a, and 20a, R= o -NO2-Ph-; In the structural formulas of compounds 16b, 19b, and 20b, R= m -NO2-Ph-; In the structural formulas of compounds 16c, 19c, and 20c, R= p -NO2-Ph-; In the structural formulas of compounds 16d, 19d, and 20d, R= o -F-Ph-; In the structural formulas of compounds 16e, 19e, and 20e, R= m -F-Ph-; In the structural formulas of compounds 16f, 19f, and 20f, R= p -F-Ph-; In the structural formulas of compounds 16g and 20g, R= p -F- o- NO2-Ph-; In the structural formula of compound 16h, R = Ac.

9. The method for preparing galactor rhamnoside compounds according to claim 5, characterized in that, The rhamnosinogenase acting as the receptor includes any one of compound 22 or compounds 24a-f shown in the following structural formulas: or ; In the structural formula of compound 24a, R= o -NO2-Ph-; In the structural formula of compound 24b, R= m -NO2-Ph-; In the structural formula of compound 24c, R= p -NO2-Ph-; In the structural formula of compound 24d, R= o -F-Ph-; In the structural formula of compound 24e, R= m -F-Ph-; In the structural formula of compound 24f, R= p -F-Ph-。 .

10. The use of a galactorlaminoid compound as described in any one of claims 1-4 as a galactolectin-3 inhibitor in the preparation of anti-pulmonary fibrosis drugs and anti-chronic / acute myeloid leukemia drugs.

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