WO2005123711A1 - Bicyclol glycosides and the preparation method and uses thereof - Google Patents

Abstract

The present invention relates to pharmaceutics and organic chemistry. The invention discloses a new kind of bicyclol glycosides and the preparation method thereof. The method comprises bicyclol being reacted with trichloroimide ester of acylating sugar in the presence of a conventional solvent to carry out glycosidation, and the acylated glycosides being treated with sodium alkoxide to form the bicyclol glycosides. The present bicyclol glycosides is useful for the treatment of hepatopathy.

Description

 Bicyclic alcohol glycoside compound, preparation method and application thereof

 The present invention relates to pharmacy and organic chemistry, in particular, the present invention relates to a bicyclic alcohol glycoside compound, a preparation method thereof, and its clinical application. Background technique

 Bicyclol is a known compound. It is a synthetic anti-chronic viral hepatitis drug with significant liver-protective effect and certain anti-hepatitis virus activity. The results of various studies on the mechanism of the drug's action indicate that bicyclol is not a transaminase inhibitor Instead, it has the effect of scavenging free radicals to protect the cell membrane, and can protect nuclear DNA from damage and reduce the occurrence of apoptosis. Its structure can be expressed by the formula (II):

欧洲专利 EP0353358 公开了其制备方法， 反应路线如路线 1所示。

European patent EP0353358 discloses a preparation method thereof, and the reaction scheme is shown in Scheme 1.

 In the reaction scheme, a known compound biphenyl diester (Π-1) (the preparation method is disclosed in Japanese Patent JP60209582) is used as a raw material, and a dicarboxylic acid (11-2) is obtained by alkaline hydrolysis according to a general method of ester hydrolysis, and then The dicarboxylic acid is heated with acetic anhydride to obtain the acid anhydride (Π-3). The acid anhydride is reduced with sodium borohydride and heated with p-toluenesulfonic acid to obtain the lactone (Π-4). The lactone is then reacted with methanol in the carboxylic acid. It is reacted in the presence of a salt (sodium acetate), and then conventionally separated and purified to obtain bicyclic alcohol (Π).

Existing technology for the preparation of bicyclic alcohols: 1.

SUMMARY OF THE INVENTION The present invention relates to a novel bicyclic alcohol glycoside compound which can be applied to the treatment of liver diseases, a production method and clinical application thereof.

 Specifically, the present invention relates to a bicyclic alcohol glycoside compound, which is characterized by having the following structural formula:

Wherein, R, and respectively represent H, 0H or galactosyl. In the compound (I), wherein galactosyl is represented by the following formula, and R2 represents! "!.

 The present invention also relates to a method for preparing a bicyclic alcohol glycoside compound (I), which is characterized by:

 Make compound (Π)

With compound (ΠΙ)

 (III)

Reaction to obtain compound (IV),

(IV) Then, the protecting group is removed to obtain compound (I)

The invention also relates to a pharmaceutical composition containing a pharmaceutically effective dose of the compound (I) and a pharmaceutically acceptable carrier, and the use of the compound in the preparation of a pharmaceutical preparation for treating liver diseases.

 In other words, the bicyclic alcohol glycoside compound of the present invention is a novel compound, and it can be represented by the formula (I)

In the formula, R, and R2 represent groups of the following structure:

R ^ H, R ₂ = 0H

 = 0H, = H

The preparation route of the target compound of the present invention is shown in the following reaction scheme 2. The preparation method of the target compound of the present invention is detailed as follows-In the reaction scheme, a known carbohydrate compound (IIII-1) is used as a raw material; when galactosyl group and R ₂ = H, compound III-1 is lactose (III- la); when R, = H, R _a = 0H, compound III-1 is galactose (III-lb); when R, = 0H, R ₂ = H, compound III-1 is glucose (III-lc ). According to the general method of carbohydrate acylation, benzoyl chloride is used to obtain the fully benzoylated lactose (III-2), and then the fully acylated sugar 1-position protecting group is selectively removed in the presence of hydrazine acetate Compound Π1-2 is obtained, and then reacted with trichloroacetonitrile to obtain trichloroimide (III-3) of acylated sugar; trichloroimide (ΠΙ-3) and bicyclic alcohol glycosylation coupling reaction to obtain bicyclic alcohol benzyl Acylated glycoside (IV), acylated glycoside (IV) was treated with sodium alkoxide to deprotect it to give bicyclic alcohol glycoside (1).

Preparation of bicyclic alcohol glycoside compounds

糖的全酰化反应， 制备活性亚胺酯的反应以及糖苷化反应均需在非 活性溶剂中进行， 非活性溶剂有四氢呋喃、 二氧六环、 乙醚、 丙酮、 乙 酸乙酯、 甲苯、 氯仿、 二氯甲垸等醚类、 酮类,酯类，卤代烃类、 烃类溶 剂； 这些溶剂可单独使用，也可混合使用， 优选卤代烃类， 如氯仿、 二氯 甲垸等。 脱保护基反应通常在常规溶剂中进行， 所用溶剂的例子有乙 醇、 甲醇、 N， N-二甲基甲酰胺、 N， N-二甲基乙酰胺、 四氢呋喃等。 为 了加快反应速度或提高收率， 在一些反应步骤加入合适的催化剂是必要 的。 糖的全酰化反应可加入合适量的有机碱,如吡啶，三乙胺等,制备三氯 亚胺酯可加入合适量的碱催化剂如 DBU等,糖苷化反应可加入合适量的 路易斯酸如三氟甲磺酸三甲硅烷酯等。 反应通常是在常温的情况下进行 的，温度范围约- 20〜60°C，优选- 10- 40°C， 最好在 0°C〜35°C范围内进行 反应。 反应时间由反应的种类， 溶剂的种类,反应温度等因素决定， 反应 时间从 0. 5-72小时不等;具体地说， 酰化反应约 6- 12小时， 1-位脱保护 约 36- 72小时， 制备活性亚胺酯以及糖苷化反应约 0. 5- 2小时，酰化糖苷 脱保护约 2-6小时。 反应的后处理可按常规方法进行。 一般需采用提 取、 浓缩、 冲析、 大孔树脂层析、 硅胶层析、 结晶或冷冻干燥等方法得 到产物。

The total acylation of sugar, the reaction to prepare the active imide, and the glycosylation reaction need to be performed in an inactive solvent. The inactive solvents are tetrahydrofuran, dioxane, ether, acetone, ethyl acetate, toluene, chloroform, Ethers, ketones, esters, halogenated hydrocarbons, and hydrocarbon solvents such as dichloromethane; These solvents can be used alone or in combination. Halogenated hydrocarbons such as chloroform and dichloromethane are preferred. The deprotection reaction is usually performed in a conventional solvent. Examples of the solvent used are ethanol, methanol, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, and the like. In order to speed up the reaction or increase the yield, it is necessary to add a suitable catalyst in some reaction steps. A suitable amount of organic base such as pyridine, triethylamine, etc. can be added to the sugar acylation reaction, and a suitable amount of alkali catalyst such as DBU can be added to prepare the trichloroimide ester. Lewis acids such as trisilyl triflate and the like. The reaction is usually carried out at normal temperature, and the temperature range is about -20 to 60 ° C, preferably -10 to 40 ° C, and most preferably, the reaction is performed in the range of 0 ° C to 35 ° C. The reaction time is determined by the type of reaction, the type of solvent, the reaction temperature, and other factors. The reaction time ranges from 0.5 to 72 hours; specifically, the acylation reaction is about 6 to 12 hours, and the 1-position deprotection is about 36- In 72 hours, the preparation of the active imide and the glycosylation reaction takes about 0.5 to 2 hours, and the acylated glycoside is deprotected for about 2-6 hours. Post-treatment of the reaction can be carried out in a conventional manner. Generally, products are obtained by extraction, concentration, decantation, macroporous resin chromatography, silica gel chromatography, crystallization or freeze drying.

 The present invention also provides a pharmaceutical composition containing the bicyclic alcohol glycoside compound as an active ingredient and a pharmaceutically acceptable carrier, such as a pharmaceutical auxiliary such as an excipient or a diluent.

 The pharmaceutical composition is obtained by mixing the bicyclic alcohol glycoside compound prepared by the above method with a pharmaceutically acceptable pharmaceutical adjuvant, and then preparing the desired preparation form according to the conventional preparation method of the preparation. The composition can be in the form of tablets, capsules, granules, or liquid preparations such as oral solutions or sterile parenteral solutions; the route of administration, dose, and number of administrations can be adjusted appropriately according to the age, weight and disease of the patient.

 The composition may also be in the form of a large or small volume injection, a lyophilized powder injection, a sterile powder packaging and the like.

 Single-dose representations for oral administration may be tablets and capsules, and may contain conventional excipients such as binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, For example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants such as magnesium stearate; disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; Or a pharmaceutically acceptable wetting agent, such as sodium lauryl sulfate.

 Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. Repeated mixing operations can be used to distribute the active agent sufficiently into a composition using a large amount of filler. Such operations are of course routine in the art. The tablets can be made into coated or plain tablets according to a conventional method.

Oral liquid preparations can be in the form of, for example, emulsions, dragees, or can be used as a dry The product exists and is reconstituted with water or other suitable carrier before use. This liquid formulation may contain conventional additives such as suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated food fat; emulsification; Agents, such as lecithin, sorbitan monooleate, or gum arabic; anhydrous carriers (which may include edible oils), such as almond oil, distilled coconut oil, or oily esters, such oily esters include glycerides, propylene glycol Or ethanol; preservatives, such as methyl or propyl parabens, or sorbic acid; if desired, conventional flavoring or coloring agents can also be added.

 For parenteral administration, especially injections, the active ingredient can be dissolved in a sterile carrier to prepare a unit liquid dosage form. When preparing a solution, the active ingredient can be dissolved in water for injection and filtered for sterilization, and then poured into a vial or ampoule and sealed. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the carrier. To enhance stability, the composition can be frozen and filled into vials, and the water can be removed under vacuum. Or a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

 Another object of the present invention is to provide application of a bicyclic alcohol glycoside compound (I) and a composition thereof for preparing a medicament for treating liver diseases. ,

 The present invention has found through research that a new bicyclic alcohol glycoside compound prepared by glycosylation of a bicyclic alcohol and a saccharide compound has a strong liver injury protection effect, and thus constitutes the present invention. The purpose of the present invention is to prepare medicines with better curative effect for the treatment of liver diseases, and overcome the shortcomings of the clinical curative effect and treatment scope of the existing preparations. detailed description

 The present invention will be explained in more detail with reference to the following embodiments. The embodiments of the present invention are only used to explain the technical solution of the present invention, and not to limit the essence of the present invention. Experimental Section Reference Example 1. Preparation of biphenyldicarboxylic acid:

In a 3000 ml reaction flask, add a solution of 100 g (239 mmol) of biphenyl diester (Π-1), 1200 ml of acetone, and 50 g of sodium hydroxide dissolved in 800 ml of water. Stir and heat to reflux. 6 hour. After the acetone was removed by concentration under reduced pressure, the alkaline solution was acidified with concentrated hydrochloric acid to precipitate a solid. A white solid precipitate was obtained by filtration, washed with water and dried under vacuum to obtain 88.2 g of biphenyldicarboxylic acid (II-2), mp> 280. C, yield 94.6%. Reference Example 2. Preparation of biphenyl dicarboxylic anhydride:

 In a 1000 ml reaction flask, 88 g (225.5 mmol) of biphenyldicarboxylic acid (II-2) and 600 ml of acetic anhydride were added, and the mixture was stirred and refluxed for 4 hours. After the solvent was distilled off, 500 ml of toluene was added to the residue, and the mixture was filtered to obtain 78 g of the title compound biphenyldicarboxylic anhydride (II-3) as a yellow solid, m.p. 267 to 270 ° C, with a yield of 92.9%. Reference example 3. Preparation of biphenyl lactone (VII-4):

 In a 3000 ml reaction flask, put 78 g (209.5 mmol) of biphenyldicarboxylic anhydride and 2200 ml of tetrahydrofuran, stir and heat to dissolve, and add 32 g of sodium borohydride in portions under ice cooling, and stir for 1 hour. Then, the reaction mixture was heated under reflux for 4 hours, and the white solid was removed by filtration. To the reaction mixture was added dropwise 6N hydrochloric acid, followed by filtration, and the solvent was removed by concentration under reduced pressure, and chloroform was added to the residue. The obtained chloroform solution was washed with water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 84 g of a solid.

 A solution of 40 g of the solid obtained above and 20 g of p-toluenesulfonic acid in 2000 ml of benzene was refluxed for hours. The resulting solution was washed with water, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 26.3 g of a white solid compound, m.p. 218-220 ° C, with a yield of 73.5%. Reference example 4. Preparation of bicyclic alcohol (ID

In a 3000 ml reaction flask, a mixture of 26 g (72.6 mmol) of diphenyl lactone (II-4), 42 g of anhydrous sodium acetate and 2500 ml of methanol was heated under reflux for 7 hours with stirring. Allow to cool, remove insoluble solids (recover biphenyl lactone), evaporate the filtrate to dryness, dissolve the obtained white solid in water, and extract with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate. Concentrated, purified by silica gel column chromatography (eluent: chloroform / methanol = 96: 4), collected the positive components, concentrated to remove the solvent, and crystallized from ethyl acetate / petroleum ether to obtain the title compound as white crystals 10.3 g, mp l37 -139 ° C, yield 36.3%. Example 1. Preparation of Perbenzoylated Lactose (III-2a)

 In a 500 ml reaction flask, put 18.2 g (53.2 mmol) of lactose, 50 ml of anhydrous pyridine, and 100 ml of dichloromethane, stir, then add DMAPlOOmg to the reaction solution, and cool to 0 ° C in an ice bath. Slowly add 65ml of benzoyl chloride, and control the temperature of the reaction solution not to exceed 10 ° C during the dropwise addition. The reaction was stirred in an ice bath for 3 hours and at room temperature for 10 hours. TLC inspection (high-efficiency thin-layer board

MerckGF254; developing agent: ethyl acetate / petroleum ether = 1: 1; scorching after spraying with sulfuric acid ethanol solution), after the reaction, dilute the residue with dichloromethane, transfer to a separatory funnel, and then use 5 in turn % Dilute hydrochloric acid (150ml X 3), saturated sodium bicarbonate solution (150ml X 3), water

(150ml X 3) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to a pale yellow slurry. 52.2 g of white crystals were obtained by recrystallization from dichloromethane / methanol with a yield of 83.5%. Example 2.Preparation of 1-position deprotected acylated lactose iin-3a)

 In a 100ml reaction flask, put 9.4g (8mmol) of benzoyl lactose, 0.883g (9.6mmol) of hydrazine acetate, and 20ml of dimethylformamide. Dissolve by magnetic stirring. The reaction process is detected by TLC (high-efficiency thin-layer plate). MerckGF254; tincture: ethyl acetate / petroleum ether-1: 1; color development after burning sulfuric acid ethanol solution). After the reaction is completed (it usually takes two days), the DMF is removed by rotary evaporation to obtain an orange slurry. Purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether 3: 1-1: 1), collect the positive components, and concentrate to remove the solvent to obtain 6.74 g of white solid, yield

78.6%. Example 3. Preparation of acylated lactose trichloroimide (III-4a)

In a 100 ml reaction flask, 6.74 g (6.29 mmol) of 1-OH benzoylated lactose and 100 ml of dichloromethane were added, and the mixture was dissolved by stirring. Subsequently, 3.8 ml (37.8 mmol) of trichloroacetonitrile and 473 μ1 (3.145 mmol) of ϋΒυ were added, and the reaction solution immediately turned orange, and then the color gradually deepened to black. The reaction process was detected by TLC (high-efficiency thin-layer plate MerckGF254; developing agent: ethyl acetate / petroleum ether = 1: 1; sulfuric acid ethanol solution was burnt and developed color). After the reaction is completed (usually the reaction is completed within 40 minutes), the solvent is distilled off by concentrating at low temperature. Purify by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 5: 1-2: 1). Collect the positive components and concentrate to remove the solvent to obtain 6.80 g of a white solid with a yield of 88.9%. Example 4. Preparation of full benzoylated galactose mi-2b)

 According to the preparation process of Example 1, milk H (III-la) was replaced with 10 g (55.5 mmol) of galactose (Ill-lb) to obtain 31.2 g of a white solid (III-2b) in a yield of 80.2%. Example 5.Preparation of 1-position deprotected acylated galactose an-3b)

 According to the preparation process of Example 2, 31.2 g (44.5 mmol) of all benzoylated galactose (III-2b) was used in place of all benzoylated lactose (III-2a) to obtain a white solid 1-position hydroxyacylation Galactose (III-3b) 20.1 g, yield 75.6%. Example 6. Preparation of acylated galactosyltrichloroimide (III-4b)

 According to the preparation process of Example 3, 1-position hydroxyacylated galactose (III-3b) 20 g (33.5 mmol) was used instead of 1-position hydroxyacylated galactose (III-3a) to obtain a white solid (III-4b) 18.8 g, yield 75.9%. Example 7.Preparation of Fully Benzoyl Glucose (III-2C)

According to the preparation process of Example 1, 10 _g (55.5 mmol) of glucose (III-lc) was used instead of lactose (III-la) to obtain 31.9 g of a white solid (III-2c) with a yield of 82%. Example 8. Preparation of 1-position deprotected acylated glucose GII-3c)

 According to the preparation process of Example 2, 31. 9 g (45.5 mmol) of all benzoylated glucose (III-2C) was used instead of all benzoylated lactose (III-2a) to obtain a white solid 1-position hydroxyacylated glucose (III-3c) 19.1 g, yield 70.3%. Example 9. Preparation of acylated glucose trichloroimide (III-4C)

According to the preparation process of Example 3, 19g of 1-position hydroxyacylated glucose (m-3c)

(31.8 mmol) was used instead of the 1-position hydroxyacylated lactose (III-3a) to obtain 19 g of a white solid (III-4c) in a yield of 81.8%. Example 10. Preparation of acylated lactosides av _a ) of bicyclic alcohols

 In a 100 ml reaction flask, put 1.56 g (4 mmol) of bicyclic alcohol, 6.3 g (5.18 mmol) of lactose trichloroimide, 2 g of 4A molecular sieve, fill with nitrogen protection, cool with ice-salt bath, then add 50 ml of dichloroform , Stir to dissolve. Stir under ice bath for 10 minutes, add

TMSOTfi4.5 L (0.2mmol), stirring under ice bath for 30 minutes, the reaction process was detected by TLC (High-efficiency thin-layer plate MerckGF254; developing agent: ethyl acetate / petroleum ether = 1: 1; sulfuric acid ethanol solution was burnt after spraying Color). After the reaction is completed (usually the reaction is completed within 40 minutes), the solution is rotated under reduced pressure, and the solvent is distilled off. Purify by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 5: 1- 5: 4). Collect the positive components and concentrate to remove the solvent to obtain 5.47 g of a white solid. Yield: 94.9%.

'HNMR (600 MHZ, CDC1 ₃ ) (diastereomer) .:

 δ 8.02-7.15 (m, 70H, Bz-PhH, two-set), 7.20 (s, lH, 3 '-H), 7.09 (s, lH, 3'-

H), 6.56 (s, lH, 3-H), 6.50 (s, lH, 3-H), 5.95 (d, lH, J = UHz, 7 '-CH _2-

I), 5.91 (d, lh, J = l.lHz, 7 '-CH ₂ -2) .5.89-5.86 (m, 4H, 7' -CH ₂ -1, 7 '-CH ₂ -2, 7- CH ₂ -1, 7 '-CH ₂ -2), 5.78 (d, lH, J = 1h, 7-CH ₂ -2), 5.73-5.65 (m, 6-H, glu3-H, gal4-

H, gal2, two-test), 5.46 (dd, lH, J = 8.0,10.3Hz, glu2-H), 5.46 (dd, lH, J = 8.0,9.8Hz, glu2-H), 5.33 (dd, lH , J = 3.3,10.3Hz, gal3-H), 5.29 (dd, lH, J = 3.3,10.3Hz, glal3-H), 4.81 (d, lH, j = 8.0Hz, gall-H),

4.76 (d, lH, J = 8.0Hz, gall-H), 4.70 (d, lH, J = 8.0Hz, glul-H), 4.66 (d, lH, J = 8.0Hz, glul-H), 4.61 ( d, 1 H, J = 12.8Hz , 2-CH 2 - 1), 4.45-4.31 (m, 5H, 2-CH 2 -2, 2-CH 2 -l, glu6- CH 2 -2, glu6-CH _{2 -2, gal6-CH 2 -} 1), 4.27-4.19 (m, 3H, glu4-H, glu6-CH 2 -l, glu6- CH 2 -l), 3.83-3.78 (m, 2H, gal5-H , gal5-H), 3.82 ( s, 3H, 4 '-OCH 3), 3.81 (s, 3H, 4' - OCH 3), 3.70-3.62 (m, 4H, glu5-H, gal6-CH 2 - 1 _{, gal6-CH 2 -2, gal6} -CH 2 - 2), 3.61 (s, 3H, 4-OCH 3), 3.57 (s, 3H, 4-OCH 3), 3.53-3.51 (m, lH, glu5- H), 3.46 (s, 3H, COOCH ₃ ), 3.35 (s, 3H, COOCH ₃ ).

Example 11. Preparation of Lactose Bicyclic Alcohol (la)

In a 100 ml reaction flask, put 5.05 g (3.5 mmol) of bicycloalcohol acylated glycoside and 100 ml of anhydrous methanol, dissolve by magnetic stirring, and add 1.5 g of methanol / sodium methoxide (containing sodium methoxide). 50% g), the reaction was stirred at room temperature, and the reaction process was detected by TLC (high-efficiency thin-layer plate MerckGF254; developing agent: chloroform / methanol = 3: 1; the sulfuric acid ethanol solution was burnt to develop color after spraying). After the reaction is completed (usually completed in about 2 hours), a strong acid cation exchange resin (hydrogen type) is added to neutralize to neutrality. The solvent was removed by filtration, and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 5: 1). The positive components were collected and the solvent was concentrated to remove 2.45 g of a white solid with a yield of 98.0%.

'HNMR (600MHz, DMSO- D6) (diastereomers): 7.27 (s, 1H, 3'-H), 7.26 (s, 1H, 3 '-H), 7.01 (s, 1H, 3- H), 7.00 (s, 1H, 3-H), 6.08 (bs, 3H, 7 '-C — 1, 7' — CH plant 1, T-C¾- 2,), 6.05 (d, 1H, J = l.1Hz, 7 '— CH ₂ —

2), 5.90 (d, 1H , J-0.7Hz, 7- CH 2 - 1), 5.86 (d, 1H, J: l.2Hz, 7 - CH 2 - 1), 5.89 (d, 1H, J two 0.7Hz, 7-C -2), 5.86 (d, H, J = l.1 Hz, 7- CH 2 - 1), 5.29 (d, 1H, J = 5 ΙΗζΟΗ), 5.25 (d, 1H,. J = 4.7HzOH); 5.10 (d, 1H,

J = 4.4HzOH), 5.10 (d, 1H, J = 4.4HzOH); 4.80 (t, 2H, J = 5.5Hz, two

set), 4.69-4.65 (m, 4H, 2 * 0H, two set), 4.59 (t, 1H, J = 5.9Hz, OH), 4.53 (dd, 2H, OH two set), 4.50 (d, 1H, J = 13.5Hz, 2— C¾— 1), 4.31 (d, 1H, J = 13.6Hz, 2—CH ₂ — 1), 4.47 (t, 1H, J = 5.9Hz, OH), 4.4 (bs, 2H , 2— CH ₂ — 2, 2— C¾-2), 4.19-4.11 (m, 4H, gall— H, glul- H, two set),

3.90 (s, 6H, 4 '-OCH3, two set), 3.90 (s, 6H, 4- 0C, two set), 3.72- 3.68 (m, 1H, g6H), 3.59 (s, 3H, C00C), 3.59 (s, 3H, C00CH ₃ ),

"CNMR (150MHz, DMSO- D6): δ 165.7 (00), 166.0 (C = 0), 147.4 (6'-C), 147.2 (6'-C), 146.1 (6-C), 146.0

 (6-C), 142.2 (4-C), 142.5 (4-C), 142.2 (4'-0, 142.2 (4'-C), 137.9 (5'-C), 137, 8 (5 '-C), 133.1 (2-0, 133.1 (2-C), 130.7 (5- C), 130.6 (5- C), 124.1 (2'-C), 123.9 (2 '-C), 110.8 ( 3 '-C), 110.7 (3' -C), 109.7 (1 '-C), 109.7 (1'-C), 108.6 (1- C), 108.2 (1- C), 106.8 (3-C) , 106.5 (3- C), 103.8 (glul— C), 102.4 (7 '-C¾), 102.4 (7'-C), 101.5 (gall—

C), 100.8 (gal 1-C), 101.1 (7-C¾), 80. 7, 80. 5, 75. 5, 74. 8, 74. 8, 74. 6, 73. 2 (glu2— C),

73. 2 (gal2-C), 70. 5 (glu-4C), 68. 1 (gal4- C), 66. 7 (2-CH), 66. 1 (2- CH 2), 60. 4 ( gal6-C), 60. 2 (glu6- C) '56.4 (4'-0C), 56.1 (4- 0C), 51.9 (C00CH ₃ ).

 Due to the use of DMSO as the solvent, all the hydroxyl peaks appear and are coupled with the peaks on the sugar. The presence of two sets of peaks makes the spectrum more complicated. Example 12. Preparation of acylated galactoside (IVb) of bicyclic alcohol

 According to the preparation process of Example 10, 3.84 g (5.18 mmol) of acylated galactosyltrichloroimide (III-4b) was used instead of lactose trichloroimide (III-4a) to obtain the acylated half of the bicyclic alcohol. Lactose (IVb) 3.52g, yield 90.9%.

'HNMR (600 MHZ, CDC1 ₃ ) (diastereomer): δ 8.10-7.74 (m, 16H, ph-H, two set), 7.63-7.2 l (m, 26H, ph-H, 3' -H, two set), 6.66 (s, lH, 3-H), 6.56 (s, 3-H), 6.06 (d, lH, J = 1.4 Hz, 7 '-CH ₂ -1), 6.04 (d , lH, J = 1.41 Hz, 7 '-CH ₂ -1), 5.99 (d, lH, J = 1.4 Hz, 7' -CH ₂ -2), 5.97 (d, lH, J = l .l Hz, 7 '-CH ₂ -2), 5.95 (dd, lH, g4-H), 5.91 (dd, lH, g4-H), 5.93-5.89 (m, 4H, 7-CH ₂ , two set), 5.79 ( dd, lH, J = 8.0, 10.6 Hz, g2-H), 5.75 (dd, lH, J = 8.0, 10.63 Hz, g2-H), 5.55 (dd, lH, J = 3.7, 10.3 Hz, g3-H ), 5.50 (t, lH, J = 3.7, 10.6 Hz, g3-H), 4.82 (d, lH, J = 8.0 Hz, gl-H), 4.86 (d, lH, J = 8.1 Hz, gl-H ), 4.72 (d, lH, J = 12.8 Hz, 2-CH ₂ -1), 4.23 (d, lH, J = 12.1 Hz, 2-CH ₂ -1), 4.62 (d, lH, J = 12.5 Hz , 2-CH ₂ -2), 4.52 (d, lH, J = 12.4 Hz, 2-CH ₂ -2), 4.56 (dd, lH, J-6.2, 11.3 Hz, g6-CH _2-

1), 4.39 (dd, lH, J = 12.4Hz, 2-CH ₂ -l), 4.32 (dd, lH, J-7.7, l 1.4Hz, g6-CH _2-

2), 4.14 (dd, lH, J = 8.0, 11.4 Hz, g6-CH ₂ -2), 4.20-4.18 (m, lH, g5-H), 4.04- 4.02 (m, lH, g5-H), 3.95 (s, 3H, 4 '-OCH ₃ ), 3.86 (s, 3H, 4'-OCH ₃ ), 3.74 (s, 3H, 4-

OCH ₃ ), 3.67 (s, 3H, 4- OCH ₃ ), 3.55 (s, 3H, COO CH ₃ ), 3.37 (s, 3H, COOCH ₃ ). Example 13. Galactobicyclic alcohol (lb) Preparation According to the preparation process of Example 11, 3.5 g (3.61 mmol) of bicycloalcohol acylated galactoside (IVb) was used instead of bicycloalcohol acylated lactoside (IVa) to obtain 1.87 _{g of} galactobicyclic alcohol (lb), yield 94.6 %.

'HNMR (600MHz, DMS0-D6) (diastereomers): 7.26 (s, 1H, 3'-H), 7.26 (s, 1H, 3 '-H), 7.04 (s, 1H, 3- H), 7.01 (s, 1H , 3- H), 6.09 (s, 2H, 7 ' one _{CH 2), 6.07 (dd,} 2H, J two 1.1Hz, 7' - C), 5.89 (dd, 2H, J = 0.7Hz, 7 '-C¾), 5.85 (s, 2H, 7-CH ₂ ), 5.02 (d, 1H, J = 5.2Hz, g3—

OH), 4.98 (d, 1H, J = 4.7Hz, g2- OH); 4.74 (d, 1H, J = 5.5Hz, g3-

OH), 4.72 (d, 1H, J = 5.5Hz, g3-OH); 4.60

 (t, 1H, J = 5, 5Hz, g6- OH), 4.49 (t, 1H, J = 5.5Hz, g6-

OH), 4.49 (d, 1H, J = 13.2Hz, 2—CH ₂ — 1), 4.26 (d, 1H, J = 13.2Hz, 2— C —

1), 4.38 (s, 2H , 2- CH 2 - 2, 2- C - 2), 4.35 (t, 2H, g4- 0H, g4- OH), 4.05 (d, 1H, J = 7.7Hz, gl -H), 4.02 (d, 1H, J = 7.7Hz, gl-

H), 3.90 (s, 3H, 4 '-0C), 3.90 (s, 3H, 4'-0C), 3.85 (s, 3H, 4-OCH,), 3.85 (s, 3H, 4- 0C), 3.59 (s, 3H, C00CH _{: i} ), 3.58 (s, 3H, C00C¾), 3.61- 3.57 (m, 2H, g4- H, g4- H), 3.50-3.40 (m, 3H, g6- C-1 , G6- C-1, g6- C-

2), 3.37-3.27 (m, 3H, g2-H, g2-H, g6—C — 2), 3.26—3.20 (m, 2H, g3—H, g3—H), 3.18-3.15 (m, 2H , g5- H, g5- H). ^{1: 1} CNMR (150MHz, DMS0- D6): δ

165.7 (00),

147.5 (6 '-0, 147.2 (6' -C), 146.0 (6 ~ C), 146.0 (6-0, 142.6 (4- C), 142.2 (6 '-0,137.9 (5' -C), 137.9 ( 5 '-C), 133.1 (2-C), 133.0 (2- C), 131.0 (5-C), 130.8 (5-C), 124.0 (2' -C), 123.9 (2 '-C), 110.8 (3 '-C), 110.7 (3' -0,109.8 (1 '-C), 108.5 (C), 108.2 (1- C), 106.8 (3- 0,106.3 (3-0, 102.4

(7 '-CH,), 102.4 (gl-C), 102.0 (gl-C), 101.1 (7-CH ₂ ), 75.3 (g3- C), 73.3 (g3-3), 74.9 (g5- C) , 73.3 (g5- C), 70.7 (g2- C), 68.3 (g4- C), 67.9 (g4-C), 66.4 (2- C), 66.2 (2- C), 60.5 (g6-C), 60.1 (g6- 0,56.4 (4 '-0CH _{: i} ), 56.1 (4-OCH,), 51.9 (C00CH _{: i} ). Example 14. Preparation of acylated glucoside (IVc) of bicyclic alcohol

 According to the preparation process of Example 10, 3.84 g (5.18 mmol) of acylated glucose trichloroimide (III-4c) was used instead of lactose trichloroimide (III-4a) to obtain the acylated glucoside of bicyclic alcohol. (IVc)

3.58g, yield 92.4%.

'HNMR (600 MHz, CDCl _{: i} ) (diastereomer): δ 7.98-7.79 (m, 16H, ph-H, two set), 6.55 (s, 1H, 3-H), 6.04 (d , 1H, Jl.1Hz, 7 '— C —

l), 6.01 (d, 1H, J = 1.1 Hz, T — C — 2), 5.96 (bs, 2H, 7 '— C), 5.92 (d, 1H, J = 1.5 Hz, 7- CH-l), 5.91 (d, 1H, J = 1.5 Hz, 7-C -2), 5.90 (d, 1H, J = 1.5 Hz, 7-CH2-1), 5.89 (d, 1H , J = l.4 Hz, 7—CH factory 2), 5.83 (t, 1H, J 2 9.5

 Hz, g3-H), 5.80 (t, 1H, J = 9.9 Hz, g3-H), 5.66 (t, 1H, J = 9.5 Hz, g4-H), 5.65 (t, 1H, J = 9.9 Hz, g4- H), 5.52 (dd, 1H, J = 6.6, 8.0 Hz, g2— H),

5.51 (dd, 1H, J = 6.6, 7.7 Hz, g2-H), 4.85 (d, 1H, J = 8.0 Hz, gl— H),

4.84 (d, 1H, J = 8.0 Hz, gl-H), 4.70 (d, 1H, J = 12.5Hz, 2— C — 1),

4.70 (d, 1H, 12.5Hz, 2- CH 2 -1), 4.55 (d, 1H, J = 12.5Hz, 2-CH 2 - 2),

4.51 (d, 1H, J = 12.5Hz, 2— C -2), 4.53 (dd, 1H, J = 2.9, 12.1 Hz, g6- CH factory 1), 4.41 (dd, 1H, J = 4.7, 12.1 Hzg6 — C —2), 4.35—4.29 (m, 2H, g- 6-C), 4.01-3.96 (m, 1H, g5—H), 3.89—3.85 (m, 1H, g5—H), 3.93 (s , 3H, 4 '— 0CH _{: i} ), 3.85 (s, 3H, 4'-0C), 3.75 (s, 3H, 4- 0C), 3.68 (s, 3H, 4- 0C), 3.56 (s, 3H , C OOCH3), 3.37 (s, 3H, C00CH _{; i} ). ^{1 :,} CNMR (150 MHz, CDCl _{: i} ): δ 166.5- 165.0 (m, C = 0), 147.7 (6 '—C), 147.3 (6 '— C), 146.2 (6-0, 146.1 (6-0, 143.6 (4-0, 142.7 (4' — C), 138.3 (5 '— C), 138.1 (5' — C), 134.2 (2-0, 134.1 (2-0, 133.3-133.0 (m, ph- C), 129.7- 128.2 (m, ph-C), 124.4 (2 '-C), 124.0 (2' -C), 111.5 (3 '-C), 111.3 (3'-C), 110.3 (1 '-C), 110.1 (1' — 0, 110.0 (1-0, 1.9.4 (1-0, 1.7.5 (3- 0, 107.2 (3-C), 102.3 (7 '— C), 102.2 (7'-CH, 101.6 (7 '-C),

99. l (gl-C), 98.3 (gl- C), 72.9 (g3- C), 72.8 (g3-C), 71.9 (g2- C), 71.7 (g2-C), 71.7 (g5-C) , 71.6 (g5-C), 69.7 (g4-C), 68.1 (2-CH ₂ ), 66.9 (2-CH ₂ ), 63.0 (g6-C), 56.5 (4 '— 0CH :,), 56.4 ( 4 '— 0CH,), 55.8 (COOCH3), 55.6 (C00CH :,), 52.1 (4- OCH :,), 52.0 (4-0C).

Example 15.Preparation of glucose bicyclic alcohol (Ic)

 According to the preparation process of Example 11, the bicyclic alcohol acylated glucoside (IVc) 3.5 g (3.61 mmol) was used in place of the bicyclic alcohol acylated glucoside (IVa) to obtain the glucose bicyclic alcohol (Ic).

1.88g, yield 94.2%.

 'HNMR (600 MHz, DMSO- D6) (diastereomer): 7.26 (s, 1H, 3' -H),

7.26 (s, 1H, 3 '— H), 7.03 (s, IH, 3-H), 7.01 (s, 1H, 3— H), 6.09 (d, IH, J = 0.7 Hz, 7' -CH ₂ -1), 6.09 (d, lH, J = 0.7 Hz, 7 '— CH ₂ — 1), 6.08 (d, IH, J = 0.8 Hz, 7' — C — 2), 6.06 (d, IH, V 1 CH ₂ — 2), 5.89 (d, lH, J 2 0.7 Hz, 7 — CH ₂ — 1), 5.89 (d, IH, J = 0.7 Hz, 7 — C — 1), 5.85 (d, IH, J = 0.7 Hz, 7—CH ₂ — 2), 5.85 (d, IH, J = l.1 Hz, 7—CH ₂ — 2), 5.16 (d, IH, J = 4.7 Hz, g2-0H), 5.12 (d, 1H, J = 4.78Hz, g2-OH); 4.97 (d, 1H, J = 4.8 Hz, g3—

OH), 4.94 (d, IH, J = 4.8Hz, g3- OH); 4.90 (d, 1H, J = 5.2Hz, g4- OH), 4.86 (d, 1H, J = 5.2Hz, g4— OH) , 4.54 (t, IH, J = 5.5 Hz, g6— OH),

4.51 (d, 1H, J = 13.6 Hz, 2—C — 1), 4.40-4.38 (m, 3H, g6—0H, 2— C — 1, 2—CH ₂ — 2), 4.30 (d, IH, J = l 3.6Hz, 2— C-2), 4.09 (d, 1H, J = 7.7Hz, gl-H),

4.06 (d, IH, J = 7.7Hz, gl-H), 3.90 (s, 3H, 4 '-0CH,), 3.85 (s, 3H, 4'-0C,), 3.63-3.60 (m, IH, g6 _{- CH 2 - 1), 3.59} (s, 3H, 4- 0CH: i), 3.58 (s, 3H, 4- 0CH 3), 3.51-3.48 (m, 1H, g6- CH 2 -2), 3.41- 3.36 (m, 2H, g6- CH 2 - 1, g6- C - 2), 3.34 (s, 6H, C00C, C00C), 3.15-2.97 (m, 7H, g2- H, g2- H, g4- H , G4- H, g3- H, g3-H, g5-H), 2.90-2.88 (m, g5- H),

l ³ C MR (150MHz, DMS0-D6): δ 165.6 (m, C = 0), 147.4 (6 '-C), 147.2 (6 ¹ — C), 146.0 (6-C), 145.9 (6-C ), 142.6 (4-C), 142.5 (4-C),

142.2 (4 '-C), 137.9 (5' -C), 137.8 (5 '-C), 133.0 (2- C), 130.8 (5-C), 130.7 (5-0, 124.1 (2' — C ), 123.90 (2 '-C), 110.8 (3'-C), 109.7 (1 '-C), 108.5 (1-C), 108.2 (1-C), 106.7 (3- C), 106.4 (3 — C), 102.7 (7 '-C), 102.3 (7' -CH ₂ ), 101.7 (gl-C), 101.2 (gl-C), 101.1 (7- CH ₂ ), 77.0 (g3- C), 76.6 (g3-C, g5-C), 73.5 (g3-C), 70.1 (g4-C), 69.8 (g4-C), 66.5 (2-C¾), 66.1 (2-C¾), 61.0 ( g6-C), 60.7 (g6-C), 56.4 (4 '-OCH,), 56.1 (4- 0C), 51.9 (C00C). Example 16: Preparation of Lactose Bicyclic Alcohol Injection

 Lactose Bicyclo Alcohol 60g

 Sodium chloride 900g

 Water for injection to 10L

22 _μΐ Weigh the prescribed amount of lactose bicyclic alcohol, add about 85% of the total volume of water for injection, stir to dissolve, add sodium chloride, stir to dissolve, add water for injection to the total, stir well, and then use _{0.22 μΐ} η Microporous membrane filtration, nitrogen filling, potting, autoclaving at 115 ° C for 30 minutes, light inspection, inspection, packaging. Example 17: Preparation of lactose bicyclic alcohol tablets

 Lactose Bicyclo Alcohol 60g

 Pregelatinized starch 2g

 Hypromellose 4g

 Sodium carboxymethyl starch 3.5 g

 Microcrystalline cellulose lg

 Magnesium stearate 0.4 g

 Pass the 80-mesh sieve of lactose bicyclic alcohol into the above-mentioned auxiliary materials respectively, mix well, and use povidone to make a soft material, granulate with a 14-mesh nylon sieve, dry it at 50-60 ° C, adjust the granules with a 14-mesh sieve, mix and press the tablets. Example 18: Preparation of galactose bicyclic alcohol capsules

 Galactose Bicyclic Alcohol 50g

Microcrystalline cellulose 2 _g

 Starch 5g

 Magnesium stearate lg

Lactose bicyclic alcohol, microcrystalline cellulose, lactose, and magnesium stearate are sieved and mixed well, and divided into hard capsules to obtain. Example 19: Preparation of glucose bicyclic alcohol granules

 Glucose Bicyclo Alcohol 50g

 Cyclamate 8g

 8g lactose

 Flavor

 Add 50 g of glucose bicyclic alcohol, add 80 g of starch and 20 g of powdered sugar, add the appropriate amount of flavor, mix well, granulate with a 14-16 mesh sieve, dry below 60 ° C, and package. Experimental example 1

 In order to show the practicability of the target compound (I), the test efficacy data of the compound (I) of the present invention for the treatment of liver injury are given below.

Preventive and preventive effects of bicyclic alcohol glycosides on mouse CC1 ₄ injury caused by liver injury in mice. Test drug name: Lactose bicyclic alcohol: molecular weight 714.61, white powder; galactose bicyclic alcohol: molecular weight 552.47, white powder; : Molecular weight 552.47, white powder; positive control D: bicyclic alcohol, molecular weight 390.33, white particles. Dose design: Based on the results of the pharmacodynamic study of the positive control drug bicyclol on the CC1 ₄ injury model (effective dose is 100mg g ' ¹ ), it is proposed to set the test drugs VIII, B, and C to the mouse CC1 ₄ injury model. The doses were 183.1, 141.5, and 145.5 mg'kg ' ¹ , respectively, that is, the test drug and bicyclo alcohol were administered at a dose of 0.256 mg-kg ^ Dosage volume: 20ml-kg—' Group administered dose (mg'kg — ¹ ) Normal volume equal volume NS

 Model control group equal volume NS

 Positive drug control group 100.0

Lactose Bicyclol 183.1 Galactobiol

 Glucosyl alcohol

experimental method

Mice grouping: Mice were randomly divided into 6 groups, 10 in each group, half male and half male, weighing 25 to 2 g. They were set as normal control group, CC1 ₄ injury model control group, positive control drug bicyclol group, test drug lactobicyclol group, test drug galactose bicyclol group, and test drug glucobicyclol group. Treatment method: mice were ip 0.1% CC1 ₄ (10 ml-kg ¹ ) 24 hours before, except the normal control group and the model control group, the other groups were ig bicyclol, test lactose bicyclol group, test drug The galactose bicyclic alcohol group and the test drug glucobicyclic alcohol group were twice, spaced 6 hours before and after, and the doses were 100, 183.1, 141.5, and 141.5 mg.kg, respectively. The normal control group and the model control group were ig saline (NS). The volume of the drug is SO ml'kg '. Observation of the indicators: After 16 hours of intraperitoneal injection of CCl ₄ , blood is taken from the orbit, the serum is separated, and the alanine amino transfer is measured with a blood biochemical analyzer (BioSystems BTS-370 PlusAUTOMATIC ANAL YZER, produced in Spain). Enzyme (ALT), aspartate aminotransferase (AST). Animal deaths were recorded daily for a total of 96 hours. After the completion of the experimental records, the mice were sacrificed by common carotid bloodletting and tracheotomy. Statistical processing method: t test was used for comparison between groups. Experimental results

During the experiment, all test animals had no abnormal reaction, and no animal died. The measurement results of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are as follows: The other group is ALT AST normal control group 1342.96 + 277.92 2906.84 ± 1450.80 Model control group 10364.54 ± 4143.39 7733.77 ± 1343.98 Positive drug control group 2482.22 ± 1076.22 ^# 3485.11 ± 1457.01 Lactose bicyclo alcohol group 207.46% ± 901.03 * ^# 4014.75 ± 904.37 Galactosyl bicyclo alcohol group 2391.90 ± 1607.82 ^; 4040.28 ± 3468.21 Glucose bicyclo alcohol group 2127.08 ± 753.75 * 4176.51 ± 1399.57 '

Note: * is p <0.05 compared with the normal control group, ** is p <0.01 compared with the normal control group; # is p <0.05 compared with the model control group

 The biochemical index test results showed that the ALT and AST of the model control group were significantly higher than those of the normal control group. Combined with the pathological changes of the hepatocytes seen by pathological morphology examination, this experiment was successful. According to biochemical indicators, the ALT values of the test drug and the positive control group were significantly lower than those of the model control group, and there was no significant difference between the four groups; meanwhile, pathological morphological examination results showed that the liver The degree of cell damage was generally milder than that of the model control group.

Claims

Claim 1. A bicyclic alcohol glycoside compound (I), which is characterized by the following structural formula:

Where R, and R ₂ represent H, 0H, or galactosyl, respectively The compound according to claim 1, wherein  R, represents galactosyl having the structure shown below, and represents H.

 OH The compound according to claim 1, wherein H represents and R ₂ represents OH. The compound according to claim 1, wherein R, represents OH, and R ₂ represents H. 5. A method for preparing a bicyclic alcohol glycoside compound (I) according to claim 1, characterized in that: Make compound (Π)

 (ID and compound (III)

 (IV) Then, the protecting group is removed to obtain compound (I). 6. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 7. Use of a compound according to any one of claims 1-4 in the preparation of a pharmaceutical preparation for treating liver disease.