CN110433153A - A kind of Amurensin H derivative is treating and preventing the application in liver related disease - Google Patents

Abstract

The invention discloses the application of plain (Amurensin H) derivative of grapevine penta shown in a kind of formula (I) and (II) and its pharmaceutically acceptable salt in preparation treatment and/or prevention liver related disease drug；And disclose the preparation method of such compound and application of the pharmaceutical composition in preparation treatment and/or prevention liver related disease drug containing such compound.

Description

A kind of Amurensin H derivative is in treating and preventing liver related disease Using

Technical field

The present invention relates to biomedicine fields, and in particular to a kind of Amurensin H (7,8- dehydrogenation grapevine, penta element) is spread out Biology or its medically acceptable salt, and the Pharmaceutical composition containing the derivative or its medically acceptable salt, are making It is standby to treat and/or prevent the application in liver related disease drug.

Background technique

Hepatopathy is worldwide disease, and China is hepatopathy big country.Hepatic injury caused by current China a variety of causes and liver are scorching Disease patient populations are huge, based on virus hepatitis, in recent years, drug-induced liver disease, Alcoholic and non-alcohol fatty liver, The disease incidence of autoimmune liver disease etc. is also in increase trend year by year.It is well known that hepatopathy is progressive disease, there are many cards According to prompt, liver inflammation sees hepatopathy caused by most all reasons, and often runs through hepatopathy disease course always.But for a long time, have Progress is undesirable in terms of closing liver inflammation study on prevention especially anti-inflammatory liver protection, causes clinical application means and method limited, and There are many different opinions.In view of the above-mentioned problems, " Chinese Medical Association infected sick credit meeting liver inflammation and its prevention and treatment is special in 2014 The common recognition Committee of Experts, family " delivers " liver inflammation and its prevention and treatment Consensus of experts " [1], and " common recognition " is pointed out: " liver inflammation and its institute Liver fibrosis due, cirrhosis and hepatic failure etc. are the dominant pathophysiology and histopathological basis of liver diseases progress；It is anti- Scorching liver protecting therapy is the important component of liver inflammation complex treatment, for liver inflammation, regardless of whether there is effective disease Because of therapy, it is considered as implementing anti-inflammatory liver protection treatment；Etiological treatment effective for shortage not can be carried out etiological treatment temporarily Some patientss are more considered as anti-inflammatory liver protection treatment ".Importance of the anti-inflammatory liver protection drug in liver disease is further agreed It is fixed.But it is as mentioned above, for a long time, the progress in terms of anti-inflammatory liver protection is unsatisfactory, clinical alternative anti-inflammatory liver protection medicine Object is limited, and original or with Chinese independent intellectual property right the kind of China is less.

Amurensin H (penta element of 7,8- dehydrogenation grapevine) is from folk medicinal plants V. amurensis (Vitis Amurensis) one isolated in the root resveratrol dimer compound with benzofuran ring.Pharmacological research hair Existing, the compound is with significant anti-inflammatory antioxidant activity, and natural products activity is strong, small toxicity, and being one has deeply Enter the active lead compound of researching value.For obtain it is safer effectively, the higher reactive compound of druggability, we with Amurensin H is lead compound, optimizes transformation to its structure, obtains a series of related derivatives.Pharmacological evaluation knot Fruit shows that the analog derivative has significant liver protective effect, has significant protection to make HepG2 cellular damage caused by APAP With to CCl₄Caused acute liver shows good protection activity.The analog derivative is in liver related disease Application study has no document report so far.This patent is related to such compound in preparation treatment and/or prevention liver related disease Application in drug.

Summary of the invention

For overcome the deficiencies in the prior art, the technical problem to be solved in the present invention is to provide a kind of Amurensin H to spread out Biology or combinations thereof object is preparing the application in the drug for preventing, treating or assisting in the treatment of liver related disease.

One of the objects of the present invention is to provide a kind of such as logical formula (I), (IA), (IAa), (IAb), (IB) and (II), (IIA), (IIAa), (IIAb), (IIB), acceptable salt on Amurensin H derivative shown in (IIC) and its pharmacodynamics, Preparing the application in the drug for preventing, treating or assisting in the treatment of liver related disease.

It is another object of the present invention to provide a kind of pharmaceutical compositions, including at least one as led to formula (I), (IA), (IAa), (IAb), (IB) and (II), (IIA), (IIAa), (IIAb), (IIB), Amurensin H shown in (IIC) Derivative and its pharmaceutically acceptable salt, in preparing the drug for preventing, treating or assisting in the treatment of liver related disease Application.

The third aspect of the present invention is to provide the preparation method of derivative described in first aspect.

The various liver related diseases include hepatitis A, hepatitis B, hepatitis, drug-induced liver disease, alcoholic liver disease, non-alcohol Property hepatopathy, autoimmune liver disease, the liver fibrosis of liver disease progression, cirrhosis or hepatic failure.Compound packet of the present invention Include acceptable salt in its derivative and pharmacodynamics.

Above-mentioned purpose to realize the present invention obtains the drug candidates of better pharmacodynamic profile and smaller toxicity, this Invention has been synthesized a series of using Amurensin H as lead compound by the semi-synthetic and structural modification method of synthesis Amurensin H derivative, and such compound is had studied in vivo and in vitro to the protection activity of liver.

Specifically, the present invention relates to a kind of Amurensin H derivatives in preparation treatment and/or prevention liver correlation disease Application in sick product, it is characterised in that: such as logical formula (I) of the structure and (II) are shown:

Wherein, R₁Selected from H,R₂、R₁₀Selected from H,

R₉Selected from H,

R₆、R₇、R₈、R₁₄、R₁₅、R₁₆、R₁₇、R₁₈、R₁₉、R₂₀It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alkoxy acyl, Glu, SO₃H、PO₃H₂；

R₃、R₄、R₅、R₁₁、R₁₂、R₁₃It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, phenyl, methylamine Base, dimethylamino, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, C_1-6Alkoxy acyl, C_2-6No Saturated hydrocarbyl, C_3-6Naphthenic base, C_1-6Alkylthio group, F, Cl, Br, I, Glu, SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

, according to the invention it is preferred to logical formula (I) compound represented including but not limited to chemical combination shown in general formula (IA) The application of object and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IA):

Wherein, R₄、R₅It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, phenyl, methylamino, dimethylamine Base, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, C_1-6Alkoxy acyl, C_2-6Unsaturated alkyl, C_3-6Naphthenic base, C_1-6Alkylthio group, F, Cl, Br, I, Glu, SO₃H、PO₃H₂；

R₆、R₇、R₈、R₁₇、R₁₈It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alkoxy acyl, Glu, SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

, according to the invention it is preferred to general formula (IA) compound represented including but not limited to shown in general formula (IAa) change Close the application of object and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IAa):

Wherein, R₆、R₇、R₈、R₁₇、R₁₈It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alcoxyl acyl Base, Glu, SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

, according to the invention it is preferred to general formula (IA) compound represented including but not limited to shown in general formula (IAb) change Close the application of object and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IAb):

Wherein, R₆、R₇、R₈、R₁₇、R₁₈It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alcoxyl acyl Base, Glu, SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

, according to the invention it is preferred to logical formula (I) compound represented including but not limited to chemical combination shown in general formula (IB) The application of object and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IB):

Wherein, R₆、R₇、R₈、R₁₉、R₂₁It is each independently selected from C_1-6Alkyl, C_1-6Acyl group, C_1-6Alkoxy acyl, Glu、SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

, according to the invention it is preferred to logical formula (II) compound represented including but not limited to shown in general formula (IIA) change Close the application of object and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IIA):

Wherein, R₁₂、R₁₃It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, phenyl, methylamino, diformazan Amido, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, C_1-6Alkoxy acyl, C_2-6Unsaturated hydrocarbons Base, C_3-6Naphthenic base, C_1-6Alkylthio group, F, Cl, Br, I, Glu, SO₃H、PO₃H₂；

R₁₄、R₁₅、R₁₆、R₁₇、R₁₈It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alkoxy acyl, Glu、SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

, according to the invention it is preferred to general formula (IIA) compound represented including but not limited to shown in general formula (IIAa) The application of compound and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IIAa):

R₁₄、R₁₅、R₁₆、R₁₇、R₁₈It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alkoxy acyl, Glu、SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

, according to the invention it is preferred to general formula (IIA) compound represented including but not limited to shown in general formula (IIAb) The application of compound and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IIAb):

R₁₄、R₁₅、R₁₆、R₁₇、R₁₈It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alkoxy acyl, Glu、SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

, according to the invention it is preferred to logical formula (II) compound represented including but not limited to shown in general formula (IIB) change Close the application of object and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IIB):

Wherein, R₁₄、R₁₅、R₁₆、R₁₉、R₂₂It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alcoxyl acyl Base, Glu, SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

, according to the invention it is preferred to logical formula (II) compound represented including but not limited to shown in general formula (IIC) change Close the application of object and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IIC):

Wherein, R₁₄、R₁₅、R₁₆、R₂₀、R₂₂It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alcoxyl acyl Base, Glu, SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

Specifically, logical formula (I), (IA), (IAa), (IAb), (IB) and (II), (IIA), (IIAa), (IIAb), (IIB), Amurensin H derivative and its pharmaceutically acceptable salt shown in (IIC), which is characterized in that the chemical combination Object is selected from following group (compound numbers correspond to the compound numbers in embodiment):

In order to complete the purpose of the present invention, that there is provided one kind is effective containing drug for the second aspect of technical solution of the present invention Dosage as lead to formula (I), (IA), (IAa), (IAb), (IB) and (II), (IIA), (IIAa), (IIAb), (IIB), (IIC) are each The pharmaceutical composition of compound described in situation and pharmaceutically acceptable carrier is in preparation for preventing, treating or assisting in the treatment of Application in the drug of liver related disease.

According to the present invention, the compounds of this invention can exist in the form of isomers, and usually described " of the present inventionization Conjunction object " includes the isomers of the compound.

According to an embodiment of the invention, the compounds of this invention further includes its pharmaceutically acceptable salt, salt Hydrate or pro-drug.

The invention further relates to containing as the compounds of this invention and customary pharmaceutical excipients of active constituent or the medicine of adjuvant Compositions.Usual pharmaceutical composition of the present invention contains the compounds of this invention of 0.1~95% weight.This hair in unit dosage form The bright general content of compound is 0.1~100mg, and preferred unit dosage form contains 4~50mg.

The pharmaceutical composition of the compounds of this invention can be prepared according to method well known in the art.When for this purpose, if It needs, can be by the compounds of this invention in conjunction with one or more solids or liquid pharmaceutical excipients and/or adjuvant, being made can be used as The administration form or dosage form appropriate that people's medicine or veterinary drug use.

Many reasons can cause hepar damnification.Paracetamol (APAP) is common analgesic-antipyretic, and being excessively used is state The main reason for outer acute liver damage.The present invention uses APAP to cause first, human liver cell damage model, preliminary assessment Amurensin H derivative hepatocellular injury protection activity.Result of study shows, 2,4,7,11 He of Amurensin H derivative 19 have significant protective effect to hepatocellular injury caused by APAP in 10 μM of concentration, and cell survival rate is distinguished compared with MODEL DAMAGE group Improve 24.9%, 23.2%, 20.2%, 31.7%, 16.0% and 19.4%.

Carbon tetrachloride (CCl₄) induction acute hepatic injury model, pathogenesis is mainly oxidisability hepatic injury, and is aoxidized Damage is almost that all Hepatoxic substances cause one of Common Mechanism of hepatic injury.The present invention further utilizes CCl₄What is induced is small Mouse acute hepatic injury model evaluates liver injury protection activity in Amurensin H derivative body.Result of study shows, 0.15% CCl₄Intraperitoneal injection is primary, causes the significant hepatic injury of mouse, mice serum glutamic-pyruvic transaminase ALT, glutamic-oxalacetic transaminease AST and cream Acidohydrogenase LDH content is significantly increased compared with normal mouse.Compound 2 50mg/kg, 7 50mg/kg and 11 50mg/kg, point Not in CCl₄Mouse continuous gavage is administered 3 times before damaging, in addition to compound 7, compound 2 and 11 pair CCl₄Caused serum turns ammonia Enzyme, which increases, certain reduction effect, shows significant liver injury protection activity, wherein 2 activity of compound is relatively preferable, rises High dose has more excellent activity.

The present invention has the advantages that (1) derivative of the present invention carries out structure optimization conjunction on the basis of Amurensin H structure At with better pharmacodynamic profile and relatively small toxic side effect；(2) present invention firstly discovers that Amurensin H is derivative Object has liver protecting activities, and the research and development for treating new drug for liver related disease provide new chemical entities, and (3) are of the invention Amurensin H derivative has significant liver protective effect, to CCl₄Caused acute liver has significant protect Shield effect；(4) this product raw material is easy to get, and preparation process is simple, and be easy to standardize production.

The invention further relates to the preparation methods of pharmaceutical composition.When for this purpose, if it is desired, can by active constituent with One or more solids or liquid pharmaceutical excipients and/or adjuvant combine, and are made and can be used as the appropriate administration form that people's medicine uses Or dosage form.

Pharmaceutical composition of the invention can be administered in a unit, and administration route can be enteron aisle or non-bowel, such as mouth Clothes, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc..

The administration route of pharmaceutical composition of the invention can be drug administration by injection.Injection includes intravenous injection, intramuscular injection, skin Lower injection, intracutaneous injection and acupoint injection therapy etc..Form of administration can be liquid dosage form, solid dosage forms.As liquid dosage form can be True solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other dosage forms for example tablet, capsule, dripping pill, aerosol, Pill, pulvis, solution, suspension, emulsion, granule, suppository, freeze drying powder injection etc..

Composition of the invention can be made ordinary preparation, be also possible to sustained release preparation, controlled release preparation, targeting preparation and each Kind particulate delivery system.

In order to which tablet is made in unit dosage forms for administration, various carriers well known in the art can be widely used.About carrier Example be such as diluent and absorbent, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, grape Sugar, urea, calcium carbonate, white bole, microcrystalline cellulose, alumina silicate etc.；Wetting agent and adhesive, Ru Shui, Gan Bo, polyethylene glycol, Ethyl alcohol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, carboxymethylcellulose sodium, Lac, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc.；Disintegrating agent, for example, dry starch, alginate, agar powder, Laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol aliphatic ester, dodecyl sodium sulfate, methyl Cellulose, ethyl cellulose etc.；Disintegration inhibitor, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil and fat etc.；It absorbs and promotees Into agent, such as quaternary ammonium salt, sodium lauryl sulfate etc.；Lubricant, such as talcum powder, silica, cornstarch, stearic acid Salt, boric acid, atoleine, polyethylene glycol etc..Tablet can also be further made to coating tablet, such as sugar coated tablet, film packet Garment piece, enteric coated tablets or double-layer tablets and multilayer tablet.

In order to which pill is made in administration unit, various carriers well known in the art can be widely used.Example about carrier Son is, such as diluent and absorbent, as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.；Adhesive, as Arabic gum, bassora gum, gelatin, ethyl alcohol, honey, liquid sugar, rice paste or Batter etc.；Disintegrating agent, such as agar powder, dry starch, alginate, dodecyl sodium sulfate, methylcellulose, ethyl cellulose Deng.

In order to which suppository is made in administration unit, various carriers well known in the art can be widely used.Example about carrier Son is, such as enzyme, gelatin, semi-synthetic glycerol enzyme of polyethylene glycol, lecithin, cocoa butter, higher alcohol, higher alcohol etc..

In order to which capsule is made in administration unit, effective component is mixed with above-mentioned various carriers, and will be thus obtained Mixture is placed in hard gelatine capsule or soft capsule.Microcapsules can also be made in effective component, be suspended in shape in aqueous medium At suspension, injection application also can be fitted into hard capsule or is made.

For example, injection preparation is made in composition of the invention, such as solution, suspension solution, emulsion, freeze-dried powder Injection, this preparation can be it is aqueous or non-aqueous, can contain acceptable carrier in a kind of and/or a variety of pharmacodynamics, diluent, Adhesive, lubricant, preservative, surfactant or dispersing agent.As diluent can be selected from water, ethyl alcohol, polyethylene glycol, 1,3- third Glycol, the isooctadecanol of ethoxylation, polyoxygenated isooctadecanol, polyoxy ethylene sorbitol fatty acid enzyme etc..In addition, in order to make Standby isotonic injection, can add suitable sodium chloride, glucose or glycerol, further, it is also possible to add into injection preparation Conventional cosolvent, buffer, pH adjusting agent etc..These auxiliary materials are commonly used in the art.

Furthermore if desired, can also be added into pharmaceutical preparation colorant, preservative, fragrance, corrigent, sweetener or its Its material.

The dosage of Pharmaceutical composition of the present invention depends on many factors, such as to be prevented or be treated the property of disease And severity, gender, age, weight, personality and the individual reaction of patient or animal, administration route, administration number of times etc., therefore Therapeutic dose of the invention can have large-scale variation.In general, the dosage of Chinese pharmacology ingredient of the present invention is ability Well known to field technique personnel.It can actually active drug number contained in preparation last in Pharmaceutical composition according to the present invention Amount, is subject to adjustment appropriate, to reach the requirement of its therapeutically effective amount, completes the purpose for the treatment of diseases associated with inflammation of the invention. Usually to about 75 kilogram patient of weight, the daily dose of given extract is 0.001mg/kg weight~500mg/kg weight, preferably 3mg/kg weight~30mg/kg weight.Above-mentioned dosage with single dose form or can be divided into several, such as two, three or four agent The administration of amount form, this is limited to the clinical experience and dosage regimen of administration doctor.

The third aspect of the present invention is to provide the preparation method of derivative described in first aspect.

It is used to prepare the raw material of the compounds of this invention, resveratrol can by commercially available acquisition, isorhapontigenin It is prepared according to the method for document [J.Asian Nat.Prod.Res., 2014,16 (5): 511-521].

The basic synthetic route of compound 1-8 in the present invention is as follows:

The basic synthetic route of compound 9-19 in the present invention is as follows:

The basic synthetic method of compound of the present invention includes the following steps:

Step 1: resveratrol (or isorhapontigenin) carries out dimerization reaction and synthesizes the benzo two containing styrene double bond Hydrogen furan type talan dimer derivate.

4- styrene substitution coumaran type resveratrol dimer synthesis: resveratrol in methyl alcohol with FeCl₃·6H₂O is that catalyst carries out polymerization reaction, and reaction product is concentrated under reduced pressure, and obtained solid obtains target through chromatographic separation and purification Product 4- styrene replaces coumaran type resveratrol dimer (such as compound 1).

5- styrene substitution coumaran type resveratrol dimer synthesis: resveratrol in anhydrous propanone with Ag₂O (or horseradish peroxidase) is that oxidant carries out oxidative coupling reaction, and reaction solution filtering is concentrated to dryness gained slightly Product obtains target product 5- styrene through chromatographic separation and purification and replaces coumaran type resveratrol dimer (such as compound 9)。

The synthesis of 5- styrene substitution coumaran type isorhapontigenin dimer: isorhapontigenin monomer exists With horseradish peroxidase (HRP) and H in the mixed solution of acetone and water₂O₂For oxidant (or Ag₂O is oxidant) carry out oxygen Change coupling reaction, reaction mixture is concentrated under reduced pressure after being further processed, and gained crude product obtains target product through chromatographic separation and purification 5- styrene replaces coumaran type isorhapontigenin dimer (such as compound 14).

Step 2: it is permethylated that phenolic hydroxyl group talan dimer derivate obtained by step 1 carries out methylation reaction synthesis Talan dimer derivate.

The anhydrous propanone solution of phenolic hydroxyl group talan dimer derivate is in K₂CO₃In the presence of, with CH₃I (or (CH₃)₂SO₄Or CH₂N₂) methylation reaction is carried out, reaction product obtains the permethylated hexichol second of phenolic hydroxyl group through recrystallization or chromatographic isolation Alkene dimer derivate.

Step 3: phenolic hydroxyl group talan dimer derivate obtained by step 1 carries out acetylating reaction and synthesizes full acetyl The talan dimer derivate of change.

Step 1 products therefrom carries out acetylization reaction with aceticanhydride in dry pyridine, after reaction solution removes pyridine, decompression It is concentrated to give the full acetylated talan dimer derivate of target product.

Step 4: permethylated or full acetylated dihydrofuran type talan dimer derivate is aoxidized by DDQ Synthesize furan type talan dimer derivate.

Permethylated or full acetylated dihydrofuran type talan dimer derivate obtained by step 2 and step 3 In anhydrous dioxane with DDQ carry out oxidative dehydrogenation, reaction product through recrystallization or chromatographic isolation obtain it is permethylated or Full acetylated furan type talan dimer derivate.

Step 5: the talan dimer derivate of the double bond containing styrene synthesizes corresponding double bond hydrogen by hydro-reduction Change derivative.

The talan dimer derivate of the double bond containing styrene obtained by above step is in ethyl acetate solvent, with Pd/C (10%) it is catalyst, carries out double bond reduction reaction in a hydrogen atmosphere.Reaction mixture is filtered to remove Pd/C, and filtrate decompression is dense Contract styrene double bond hydrogenation benzofuran or coumaran type talan dimer derivate.

Step 6: it is derivative that full acetylated talan dimer derivate removing acetyl group synthesizes corresponding phenolic hydroxyl group Object.

Mixed solution of the full acetylated talan dimer derivate in methylene chloride and methanol obtained by above step In with NH₄OAc is reacted.Reaction product is added water and is extracted with ethyl acetate, and organic phase evaporated under reduced pressure obtains corresponding phenolic hydroxyl group Talan dimer derivate.

Advantageous effects

The activity research process of the present inventor natural products Amurensin H isolated in V. amurensis In, it is found that the compound has stronger anti-oxidant and anti-inflammatory activity on animal model.On this basis, with Amurensin H is lead compound, and the method by synthesizing semi-synthetic integrated structure modification has synthesized a series of Amurensin H derivatives, Liver protective effect evaluation in inside and outside is carried out to obtained derivative, the structure effect for having studied such compound liver protective effect is closed System.The experimental results showed that Amurensin H derivative has significant protective effect to HepG2 cellular damage caused by APAP, it is right CCl₄Caused acute liver shows good protective effect, has the potential value further developed.

Currently, the Liver protection of the talan dimer class system of compounds to benzofuran or coumaran structure Activity research is there is not yet document report.It is had no in existing literature and technology about benzofuran or coumaran type hexichol second Alkene dimer derivate or its medically acceptable salt and such compound are used to prepare treatment and/or prevention liver is related The relevant report of disease.

Detailed description of the invention:

The various terms and phrase that the present invention uses have well known to a person skilled in the art general senses, nonetheless, The present invention remains desirable to that these terms and phrase are described in more detail and are explained at this, the term and phrase referred to if any with Common art-recognized meanings are inconsistent, the meaning that the present invention of being subject to is stated.Here is the definition of a variety of terms used in the present invention, these Definition is suitable for term used in the application the whole instruction, unless otherwise indicated in concrete condition.

Term mentioned by the present invention " alkyl " refers to specifying number the alkyl of carbon atom number, can for straight chain or The alkyl of branch, such as " C referred to_3-6Naphthenic base " refer to carbon atom number be 3,4,5,6 substituted or unsubstituted cycloalkanes Base may include C_3-5Naphthenic base, C_3-4Naphthenic base, C_4-6Naphthenic base, C_4-5Naphthenic base, C_5-6Naphthenic base etc. indicate Subrange group, and preferred specific group, such as cyclopropyl alkyl, pentamethylene base and cyclohexyl.

Term " C mentioned by the present invention_1-6Alkyl " refer to carbon atom number be 1,2,3,4,5,6 linear chain or branched chain hydrocarbon Base may include C_1-5Alkyl, C_1-4Alkyl, C_2-5Alkyl, C_2-4Alkyl, C_2-3Alkyl, C_3-5Alkyl etc. indicate Subrange group, and preferred specific group, for example, methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, Tert-butyl etc..

Term " C mentioned by the present invention_1-6Alkoxy " refer to carbon atom number be 1,2,3,4,5,6 alkoxy, including C_1-5Alkoxy, C_1-2Alkoxy, C_2-4Alkoxy, C_2-3Alkoxy, C_3-4The subrange of expressions such as alkoxy base Group, and preferred specific group such as methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup, normal-butyl oxygroup, Zhong Ding Base oxygroup, tert-butyl oxygroup etc..

Term " C mentioned by the present invention_2-6Unsaturated alkyl " refer to carbon atom number be 2,3,4,5,6 unsaturated hydrocarbons Base may include C_2-5Unsaturated alkyl, C_2-4The subrange of expressions such as unsaturated alkyl group, and it is preferred specific Group, such as vinyl, acetenyl, isopropenyl, isopropynyl, isobutenyl, isopentene group, Isosorbide-5-Nitrae-dibutene base.

Term " C mentioned by the present invention_1-6Acyl group " refer to carbon atom number be 1,2,3,4,5,6 acyl group, may include C_1-5Acyl group, C_1-3Acyl group, C_2-5Acyl group, C_2-3Acyl group, C_3-4The subrange of expressions such as acyl group group, Yi Jiyou The specific group, such as formoxyl, acetyl group, propiono etc. of choosing.

" C mentioned by the present invention_1-6Acyloxy " refer to carbon atom number be 1,2,3,4,5,6 linear chain or branched chain acyl-oxygen Base may include C_1-5Acyloxy, C_1-3Acyloxy, C_2-5Acyloxy, C_2-3Acyloxy, C_3-4Acyloxy etc. indicate The group, and preferred specific group, such as formyloxy, acetoxyl group, propionyloxy of subrange etc..

" C mentioned by the present invention_1-6Alkoxy acyl " refer to that carbon atom number is 1,2,3,4,5,6 alkoxy acyl, can be with Including C_1-5Alkoxy acyl, C_1-3Alkoxy acyl, C_2-5Alkoxy acyl, C_2-3Alkoxy acyl, C_3-4The tables such as alkoxy acyl Group of the subrange shown, and preferred specific group, such as methoxy acyl group, ethoxy acyl group etc.；

Term " C mentioned by the present invention_1-6Alkylthio group " refer to carbon atom number be 1,2,3,4,5,6 linear chain or branched chain Alkylthio group may include C_1-5Alkylthio group, C_1-3Alkylthio group, C_2-5Alkylthio group, C_2-3Alkylthio group, C_3-4Alkylthio group etc. Group of the subrange of expression, and preferred specific group, such as methyl mercapto, ethylmercapto group etc..

Specific embodiment

In order to which the present invention is furture elucidated, a series of embodiments are given below.These embodiments be entirely it is illustrative, it Only be used to the present invention is specifically described, be not construed as limitation of the present invention.

The basic synthetic route of compound 1-8 in the present invention is following, and (compound numbers correspond to the chemical combination in embodiment Object code name):

The basic synthetic route of compound 9-19 in the present invention is following, and (compound numbers correspond to the chemical combination in embodiment Object code name):

Embodiment 1:

5- [2- (4- hydroxy phenyl) -4- [2- (4- hydroxy phenyl) vinyl -6- hydroxyl] -2,3- dihydro -3- benzofuran Base] -1,3- benzenediol (1)

The synthetic route of compound 1:

100g resveratrol (438.6mmol) stirs lower dropwise addition FeCl with the dissolution of 1000mL anhydrous methanol₃Aqueous solution [116.7g FeCl₃·6H₂O (432.619mmol) is dissolved in 67mL water, and 100mL methanol dilution is added].Reaction solution is stirred at room temperature Stop reaction after 3d.Decompression boils off solvent and obtains black medicinal extract.The medicinal extract is with petroleum ether: acetone=6:3 carries out silica gel (100-200 Mesh) column chromatography for separation obtains 1 30.5g of gray solid compound (67.181mmol), yield 10.2%.

Compound 1,¹H NMR(CD₃COCD₃,500MHz)δ:8.41(OH),8.38(OH),8.33(OH),8.17(2H,2 × OH), 7.20 (2H, d, J=9.0Hz, H-2a, 6a), 7.16 (2H, d, J=8.5H, H-2b, 6b), 6.90 (1H, d, J= 16.0Hz, H-7b), 6.82 (2H, d, J=9.0Hz, H-3a, 5a), 6.73 (2H, d, J=8.5Hz, H-3b, 5b), 6.72 (2H, D, J=2.0Hz, H-10a, 14a), 6.70 (1H, d, J=16.0Hz, H-8b), 6.32 (1H, d, J J=2.0Hz, H-12b), 6.23 (2H, br s, H-12a, 14b), 5.41 (1H, d, J=5.5Hz, H-7a), 4.47 (1H, d, J=5.5Hz, H-8a).[α] 2_D ⁰0 (c=1.103, MeOH)；ESI-MS m/z:455.2[M+H]⁺,477.1[M+Na]⁺.

Embodiment 2:

2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -4- [2- (4- methoxyphenyl) vinyl] -6- first Oxygroup -2,3- Dihydro-benzofuran (2)

The synthetic route of compound 2:

1522mg K is added portionwise with the dissolution of 10ml anhydrous propanone in 500mg compound 1 (1.10mmol) under stirring₂CO₃Gu Body (11.013mmol) instills 3907mg CH after 30min is stirred at room temperature₃I (27.525mmol), continues to be stirred to react 48h.Instead Liquid is answered to dilute with water, ethyl acetate extraction, organic phase merges, and successively with saturated salt solution, water washing, anhydrous sodium sulfate is dry, It is concentrated to dryness to obtain white-yellowish solid compound 2 (489mg, 0.933mmol), yield 84.7%, m.p.58-59 DEG C.

Compound 2:¹H NMR(CD₃COCD₃, 500MHz) and δ: 7.31 (2H, d, J=9.0Hz, H-2a, 6a), 7.26 (2H, D, J=8.5Hz, H-2b, 6b), 7.03 (1H, d, J=16.5Hz, H-7a), 6.93 (2H, d, J=8.5Hz, H-3b, 5b), 6.82 (2H, d, J=9.0Hz, H-3a, 5a), 6.81 (1H, br s, H-14b), 6.78 (1H, d, J=16.5Hz, H-8a), 6.47 (2H, d, J=2.0Hz, H-10a, 14a), 6.45 (1H, d, J=1.5Hz, H-12b), 6.38 (1H, t, J=2.0Hz, H- 12a), 5.56 (1H, d, J=6.0Hz, H-7a), 4.66 (1H, d, J=6.0Hz, H-8a), 3.84 (3H, s, OCH₃),3.79 (3H,s,OCH₃),3.76(3H,s,OCH₃),3.71(6H,s,OCH₃)；¹³C NMR(CD₃COCD₃,125MHz)δ:162.3(4× C),160.58,160.51,147.2,136.2,134.7,130.9,130.2,128.6(2×C),127.8(2×C),123.9, 121.0,114.83(2×C),114.77(2×C),106.6(2×C),102.9,99.3,95.7,93.6,57.2,55.8 (OCH₃),55.5(4×OCH₃),36.4,35.9；ESI-MS m/z:547.3[M+Na]⁺.

Embodiment 3:

5- [2- (4- acetoxyl group phenyl)-4- [(1E)-2- (4- acetoxyl group phenyl) vinyl] acetoxyl group-2-6-, 3- dihydro -3- benzofuranyl] -1,3- diacetic ester (3)

The synthetic route of compound 2:

10g compound 1 (22.026mmol) is slowly added to aceticanhydride 56.2g with the dissolution of 150ml dry pyridine under stirring (550.980mmol), is stirred overnight at room temperature.After having reacted, 60ml water is slowly dropped under ice bath, reaction solution is transferred to 1000ml points In liquid funnel, with the dilution of 300ml water, ethyl acetate is extracted three times, merges organic phase, successively to be saturated CuSO₄Solution is washed, is saturated After saline solution, water washing, evaporated under reduced pressure obtains white-yellowish solid 3 (12.3g, 18.524mmol), yield 84.1%, m.p.147- 149℃。

Compound 3:¹H NMR(CD₃COCD₃, 500MHz) and δ: 7.43 (2H, d, J=8.5Hz, H-2a, 6a), 7.36 (2H, D, J=8.5Hz, H-2b, 6b), 7.15 (2H, d, J=8.5Hz, H-3a, 5a), 7.09 (1H, d, J=16.5Hz, H-7b), 7.07 (1H, d, J=2.0Hz, H-12b), 7.02 (2H, d, J=8.5Hz, H-3b, 5b), 7.01 (2H, d, J=2.0Hz, H- 10a, 14a), 6.91 (1H, t, J=2.0Hz, H-12a), 6.81 (1H, d, J=16.5Hz, H-8b), 6.70 (1H, d, J= 2.0Hz, H-14b), 5.71 (1H, d, J=6.0Hz, H-7a), 4.93 (1H, d, J=6.0Hz, H-8a), 2.29 (3H, s, OCOCH₃),2.28(3H,s,OCOCH₃),2.24(15H,s,OCOCH₃)；ESI-MS m/z:687.3[M+Na]⁺,703.2[M+ K]⁺.

Embodiment 4:

2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -4- [2- (4- methoxyphenyl) vinyl] -6- first Oxygroup-benzofuran (4)

The synthetic route of compound 4:

350mg compound 2 (0.668mmol) is added 227mg DDQ (1.00mmol), is added with the dissolution of 15ml dioxane Stop reaction after heat reflux 48h, reaction solution is concentrated under reduced pressure, and residue carries out silica gel (200-300 by eluant, eluent of methylene chloride Mesh) column chromatography for separation obtains light yellow solid 4 (277.5mg, 0.532mmol), yield 79.6%, and m.p.61-62 DEG C.

Compound 4:¹H NMR(CD₃COCD₃, 500MHz) and δ: 7.54 (2H, d, J=8.5Hz, H-2a, 6a), 7.18 (1H, D, J=2.0Hz, H-14b), 7.08 (1H, d, J=2.0Hz, H-12b), 7.06 (2H, d, J=8.5Hz, H-3a, 5a), 7.05 (1H, d, J=16.0Hz, H-7b), 6.89 (2H, d, J=9.0Hz, H-2b, 6b), 6.87 (1H, d, J=16.0Hz, H-8b), 6.84 (2H, d, J=9.0Hz, H-3b, 5b), 6.75 (1H, t, J=2.0Hz, H-12a), 6.67 (2H, d, J=2.0Hz, H- 10a,14a),3.91(3H,s,OCH₃),3.80(6H,s,OCH₃),3.794(3H,s,OCH₃),3.789(3H,s,OCH₃)；¹³C NMR(CD₃COCD₃,125MHz)δ:162.8(2×C),160.5,160.4,159.3,155.8,150.3,137.8,132.9, 131.0,129.4,128.4(2×C),128.2(2×C),124.1,123.2,122.6,117.3,114.8(4×C),109.5 (2×C),107.3,100.7,95.6,56.1(OCH₃),55.9(2×OCH₃),55.6(2×OCH₃)；m/z:545.3[M+Na ]⁺.

Embodiment 5:

5- [2- (4- acetoxyl group phenyl)-4- [(1E)-2- (4- acetoxyl group phenyl) vinyl]-6- acetoxy-3- Benzofuranyl] -1,3- diacetic ester (5)

The synthetic route of compound 5:

7.8g compound 3 (11.76mmol) is dissolved in the dry methylene chloride of 300ml, and 4.0g DDQ solid is added (17.621mmol) is heated to reflux 48h under stirring.Reaction solution evaporated under reduced pressure, remaining mixture are carried out by solvent of methylene chloride Silica gel column chromatography (200-300 mesh) separates to obtain yellowish crude product.Crude product with acetone recrystallization obtain light yellow crystal 5 (5.9g, 8.912mmol), yield 75.8%.

5:m.p.107-109 DEG C of compound；¹H NMR(CD₃COCD₃, 500MHz) and δ: 7.61 (2H, d, J=9.0Hz, H- 2a, 6a), 7.42 (1H, d, J=2.0Hz, H-14b), 7.36 (1H, d, J=2.0Hz, H-12b), 7.27 (2H, d, J= 2.0Hz, H-10a, 14a), 7.26 (1H, t, J=2.0Hz, H-12a), 7.23 (2H, d, J=9.0Hz, H-2b, 6b), 7.12 (2H, d, J=9.0Hz, H-3a, 5a), 7.15 (1H, d, J=17.0Hz, H-7b), 7.02 (2H, d, J=9.0Hz, H-3b, 5b), 6.98 (1H, d, J=17.0Hz, H-8b), 2.32 (3H, s, OCOCH₃),2.25(6H,s,OCOCH₃),2.24(6H,s, OCOCH₃)；ESI-MS m/z:685.3[M+Na]⁺,701.4[M+K]⁺.

Embodiment 6:

5- [2- (4- hydroxy phenyl) -4- [2- (4- hydroxy phenyl) ethyl] -2,3- dihydro -3- benzofuranyl] -1,3- Benzenediol (6)

The synthetic route of compound 6:

100mg compound 1 (0.220mmol) is dissolved in 7ml ethyl acetate, is added 8.8mg Pd/C (10%).In hydrogen Under atmosphere, atmospheric pressure at room stirs 4h, is filtered to remove Pd/C, and filtrate decompression is concentrated to give yellow solid 6 (98.0mg, 0.215mmol), Yield is 97.7%, m.p.107-109 DEG C.

Compound 6:UV λ_max(MeOH,logε):227(4.67),282.8(4.25),351(3.90)nm；¹H NMR (CD₃COCD₃, 500MHz) and δ: 8.15 (5H, br s, OH), 7.08 (2H, d, J=9.0Hz, H-2a, 6a), 6.78 (2H, d, J= 8.5Hz, H-2b, 6b), 6.76 (2H, d, J=9.0Hz, H-3a, 5a), 6.60 (2H, d, J=8.5Hz, H-3b, 5b), 6.23 (2H, d, J=2.0Hz, H-14b), 6.21 (1H, t, J=1.5Hz, H-12a), 6.20 (1H, d, J=1.5Hz, H-12b), 6.13 (2H, d, J=1.5Hz, H-10a, 12a), 5.28 (1H, d, J=6.0Hz, H-7a), 4.13 (1H, d, J=6.0Hz, H- 8a),2.46-2.50(1H,m,H-7b×1),2.35-2.39(3H,m,H-7b×1,8b×2)；¹³C NMR(CD₃COCD₃, 125MHz)δ:162.0,159.8(2×C),159.5,158.1,156.3,147.4,141.0,133.8,133.4,130.2(2 ×C),128.1(2×C),120.2,116.1(2×C),115.7(2×C),109.2,107.0(2×C),102.0,95.5, 94.0,57.1,36.5,36.1；ESI-MS m/z:457.3[M+H]⁺,479.2[M+Na]⁺,485.5[M+K]⁺；HR-ESI-MS m/z:457.1653[M+H]⁺(calcd.for C₂₈H₂₅O₆,457.1646).

Embodiment 7:

2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -4- [2- (4- methoxyphenyl) ethyl] -6- methoxy Base -2,3- Dihydrobenzofuranes (7)

The synthetic route of compound 7:

100mg compound 2 (0.191mmol) is dissolved in 6ml ethyl acetate, and 7.6mg Pd/C (10%) solid, In is added Under hydrogen atmosphere, 1h is stirred at room temperature in middle pressure, is filtered to remove Pd/C, and it is light yellow to obtain 98.1mg (0.187mmol) for filtrate decompression concentration Sticky shape compound 7, yield 97.6%.

Compound 7:¹H NMR(CD₃COCD₃, 500MHz) and δ: 7.20 (2H, d, J=9.0Hz, H-2a, 6a), 6.90 (2H, D, J=9.0Hz, H-3a, 5a), 6.85 (2H, d, J=8.5Hz, H-2b, 6b), 6.72 (2H, d, J=8.5Hz, H-3b, 5b), 6.42 (1H, br t, J=1.5Hz, H-12a), 6.36 (4H, br s, H-10a, 13a, 12b, 14b), 5.43 (1H, d, J= 6.0Hz, H-7a), 4.25 (1H, d, J=6.0Hz, H-8a), 3.79 (3H, s, OCH₃),3.74(6H,s,OCH₃),3.71(6H, s,OCH₃),2.58-2.61(1H,m,H-7b×1),2.43-2.48(3H,m,H-7b×1,8b×2)；¹³C NMR(CD₃COCD₃, 125MHz)δ:162.3(2×C),162.2,162.0,160.5,158.9,147.0,140.8,134.6,134.4,130.2(2 ×C),127.5(2×C)121.2,114.7(2×C),114.3(2×C),108.2,106.9(2×C),99.3,94.3, 93.7,57.3,55.6(3×OCH₃),55.4(2×OCH₃),36.4,35.9；ESI-MS m/z:527.3[M+H]⁺,549.3[M +Na]⁺,565.2[M+K]⁺.

Embodiment 8:

5- [2- (4- acetoxyl group phenyl)-4- [2- (4- acetoxyl group phenyl) ethyl]-6- acetoxy-3-benzo furan Mutter base] -1,3- diacetic ester (8)

The synthetic route of compound 8:

210mg compound 3 (0.316mmol) is dissolved in 10ml ethyl acetate, and 12.7mg Pd/C (10%) solid is added. In a hydrogen atmosphere, 2h is stirred at room temperature in middle pressure, is filtered to remove Pd/C, filtrate decompression concentration, obtain shallow white solid 8 (207mg, 0.206mmol), yield 98.2%, m.p.82-83 DEG C.

Compound 8:UV λ_max(MeOH,logε):279(4.22),348.8(4.02)nm；¹H NMR(CD₃COCD₃, 500MHz) δ: 7.33 (2H, d, J=8.5Hz, H-2a, 6a), 7.13 (2H, d, J=8.5Hz, H-3a, 5a), 6.96 (2H, d, J =8.5Hz, H-2b, 6b), 6.95 (1H, br s, H-12a), 6.92 (2H, d, J=2.0Hz, H-10a, 14a), 6.89 (2H, d, J=8.5Hz, H-3b, 5b), 6.63 (1H, d, J=1.5Hz, H-14b), 6.61 (1H, br s, H-12b), 5.58 (1H, d, J= 6.0Hz, H-7a), 4.48 (1H, d, J=6.0Hz, H-8a), 2.62-2.65 (1H, m, H-7b × 1), 2.51-2.56 (3H, m, H-7b×1,8b×2)；¹³C NMR(CD₃COCD₃,125MHz)δ:169.62(OCOCH₃),169.59(OCOCH₃),169.5 (OCOCH₃),169.5(2×C,OCOCH₃),161.3,153.2,152.7(2×C),151.9,150.1,146.0,140.0, 139.6,139.1,130.2(2×C),127.6(2×C),125.6,122.9(2×C),122.3(2×C),119.5(2× C),116.1,115.7,102.5,93.3,56.5,36.4,35.4,21.0(OCOCH₃),20.94(2×C,OCOCH₃),20.90 (2×C,OCOCH₃)；ESI-MS m/z:689.3[M+Na]⁺,705.2[M+K]⁺；HR-ESI-MS m/z:689.2004[M+Na ]⁺(calcd.for C₃₈H₃₄NaO₁₁,689.1993).

Embodiment 9:

5- [2- [4- hydroxy phenyl] -3- [3,5- dihydroxy phenyl] -2,3- dihydro -5- benzofuranyl] vinyl -1, 3- benzenediol (9)

The synthetic route of compound 9:

67.8g Ag is added with the dissolution of 1500ml anhydrous propanone in 60g resveratrol (263.158mmol)₂O is heated to reflux 3d, reaction solution are filtered with diatomite, and filtrate is evaporated to obtain reaction mixture.The mixture is with petroleum ether: acetone=3:2 carries out silica gel (200-300 mesh) column chromatography for separation, obtain yellow solid be compound 9 (6.7g, 14.758mmol), yield 11.2%, m.p.154-156℃。

Compound 9:¹H NMR(CD₃COCD₃,500MHz)δ:8.42(1H,s,OH),8.18(2H,s,OH),8.14(2H, S, OH), 7.42 (1H, br d, J=8.5Hz, H-6b), 7.26 (1H, br s, H-2b), 7.23 (2H, d, J=8.0Hz, H-2a, 6a), 7.05 (1H, d, J=16.0Hz, H-7b), 6.90 (1H, d, J=16.0Hz, H-8b), 6.86 (1H, d, 8.5Hz, H- 5b), 6.84 (2H, d, J=8.0Hz, H-3a, 5a), 6.53 (2H, d, J=2.0Hz, H-10b, 14b), 6.27 (1H, t, J= 2.0Hz, H-12b), 6.25 (1H, t, J=2.0Hz, H-12a), 6.18 (2H, d, J=2.0Hz, H-10a, 14a), 5.44 (1H, D, J=8.0Hz, H-7a), 4.46 (1H, d, J=8.0Hz, H-8a)；ESI-MS m/z:455.1[M+H]⁺,477.2[M+Na]⁺, 493.1[M+K]⁺；[α]² _D ⁰0 (c=1.018, MeOH)

Embodiment 10:

5- [2- (4- acetoxyl group phenyl) -3- (3,5- diacetoxy phenyl) -5- [(1E) -2- (4- acetyloxy phenyl Base) vinyl] -2,3- dihydro -3- benzofuranyl] -1,3- diacetic ester (10)

The synthetic route of compound 10:

4g compound 9 (8.810mmol) is added 22.5g aceticanhydride (220.564mmol) with the dissolution of 57.2ml dry pyridine, It is stirred overnight at room temperature, TLC detects fully reacting.Reaction solution is slowly dropped into ice water under ice bath, and it is dilute to continuously add 3 times of volume of water It releases, three times with ethyl acetate extraction, organic phase merges, successively to be saturated CuSO₄After solution, saturated salt solution, water washing, decompression Be evaporated to obtain crude product, the crude product is with petroleum ether: acetone=3:1 progress silica gel (200-300 mesh) column chromatography for separation obtains white solid Body be compound 10 (5.6g, 8.434mmol), yield 95.7%, m.p.182-183 DEG C.

Compound 10:¹H NMR(CD₃COCD₃, 500MHz) and δ: 7.53 (1H, br d, J=8.0Hz, H-6b), 7.43 (2H, D, J=8.5Hz, H-2a, 6a), 7.32 (1H, br s, H-2b), 7.25 (1H, d, J=16.5Hz, H-7b), 7.19 (2H, d, J =1.5Hz, H-10b, 14b), 7.15 (2H, d, J=8.5Hz, H-3a, 5a), 7.05 (1H, d, J=16.5H, H-8b), 6.97 (1H, d, J=8.0Hz, H-5b), 6.94 (1H, t, J=1.5Hz, H-12b), 6.93 (2H, d, J=2.0Hz, H-10a, 14a), 6.73 (1H, t, J=2.0Hz, H-12a), 5.67 (1H, d, J=8.0Hz, H-7a), 4.72 (1H, d, J=8.0Hz, H-8a), 2.252(6H,s,OCOCH₃),2.248(6H,s,OCOCH₃),2.23(3H,s,OCOCH₃)；¹³C NMR(CD₃COCD₃, 125MHz)δ:169.6(OCOCH₃),169.35(2×C,OCOCH₃),169.30(2×C,OCOCH₃),160.7,152.60(2 ×C),152.56(2×C),152.0,144.9,140.9,138.6,131.8,131.4,131.1,129.4,127.9(2× C),125.5,124.3,122.9(2×C),119.6(2×C),117.5(2×C),115.8.115.2,110.6,92.9, 57.4,20.9(5×C,OCOCH₃)；ESI-MS m/z:687.1[M-H]^-,703.1[M+Na]⁺.

Embodiment 11:

2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -5- [(1E) -2- (3,5- Dimethoxyphenyl) second Alkenyl]-benzofuran (11)

The synthetic route of compound 11:

250mg compound 9 (0.551mmol) is dissolved in 6ml anhydrous propanone, and 761mg K is added portionwise₂CO₃ (5.507mmol) instills 1955mg CH after stirring 30min₃52h, TLC detection is stirred at room temperature in I (13.775mmol), reaction solution End of reaction.Reaction solution filtering, filtrate are diluted with ethyl acetate, and saturated salt solution, water washing, organic phase evaporated under reduced pressure obtain pale yellow Color solid 231.9mg.It takes gained compound 150mg to be dissolved in the dry dioxane of 8ml, 97.3mg DDQ is added (0.429mmol) stops reaction after being heated to reflux 48h.Remove reaction solution under reduced pressure, gained medicinal extract using methylene chloride as eluant, eluent into It is compound 11 (122.9mg, 0.235mmol), yield that row silica gel (200-300 mesh) column chromatography for separation, which obtains shallow white solid, 82.3%, m.p.104-106 DEG C.

Compound 11:¹H NMR(CD₃COCD₃, 500MHz) and δ: 6.65 (1H, dd, J=9.0Hz, 1.5Hz, H-6b), 7.63 (2H, d, J=8.5Hz, H-2a, 6a), 7.62 (1H, br s, H-2b), 7.57 (1H, d, J=9.0Hz, H-5b), 7.38 (1H, D, J=17.0Hz, H-7b), 7.15 (1H, d, J=17.0Hz, H-8b), 6.96 (2H, d, J=8.5H, H-3a, 5a), 6.79 (2H, d, J=2.5Hz, H-10b, 14b), 6.66 (2H, d, 2.5Hz, H-10a, 14a), 6.60 (1H, t, J=2.5Hz, H- 12b), 6.39 (1H, t, J=2.5Hz, H-12a)；¹³C NMR(CD₃COCD₃,125MHz)δ:162.5(2×C),162.1(2× C),161.1,154.3,152.2,140.6,135.5,133.9,131.6,130.1,129.2(2×C),128.5,123.9, 123.6,118.9,116.9,114.9(2×C),111.9,108.4(2×C),105.2(2×C),100.6,100.5,55.7 (OCH₃),55.65(2×OCH₃),55.58(2×OCH₃)；ESI-MS m/z:523.2[M+H]⁺,545.1[M+Na]⁺.

Embodiment 12:

5- [2- (4- acetoxyl group phenyl) -5- [(1E) -2- (3,5- diacetoxy phenyl) vinyl] -3- benzo furan Mutter base] -1,3- diacetic ester (12)

The synthetic route of compound 12:

200mg compound 10 (0.301mmol) is dissolved in the dry dioxane of 8ml, and 102.5mg DDQ is added (0.452mmol), reaction solution stop reaction after being heated to reflux 48h, and evaporating solvent under reduced pressure carries out silicon by eluant, eluent of methylene chloride Glue (200-300 mesh) column chromatography for separation obtain shallow white solid be compound 12 (161.4mg, 0.244mmol), yield 81.1%, m.p.173-174℃。

Compound 12:UV λ_max(MeOH,logε):237.2(3.90),300.6(4.27)nm ¹H NMR(CD₃COCD₃, 500MHz) δ: 7.74 (2H, d, J=9.0Hz, H-2a, 6a), 7.70 (1H, dd, J=9.0Hz, 1.5Hz, H-6b), 7.61 (1H, D, J=9.0Hz, H-5b), 7.41 (1H, d, J=16.5Hz, H-7b), 7.26 (2H, d, J=2.0Hz, H-10b, 14b), 7.24 (2H, d, J=2.0Hz, H-10a, 14a), 7.19 (2H, d, J=16.5Hz, H-8b), 7.18 (2H, d, J=9.0Hz, H-3a, 5a), 7.08 (1H, t, J=2.0Hz, H-12b), 6.84 (1H, t, J=2.0Hz, H-12a), 2.27 (15H, s, OCOCH₃)；¹³C NMR(CD₃COCD₃,125MHz)δ:169.43(OCOCH₃),169.41(2×C,OCOCH₃),169.38(2×C,OCOCH₃), 154.7,152.9(2×C),152.6(2×C),152.4,151.7,140.7,134.8,133.8,131.4,131.0,128.8 (2×C),128.1,127.2,125.1,123.1(2×C),121.3(2×C),119.0,117.7,116.8(2×C), 116.3,115.5,112.3,20.92-20.95(5×C,OCOCH₃)；ESI-MS m/z:685.1[M+Na]⁺,701.1[M+K ]⁺；HR-ESI-MS m/z:685.1684[M+Na]⁺(calcd.for C₃₈H₃NaO₁₁,685.1680).

Embodiment 13:

2- (4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -5- [(1E) -2- (3,5- dihydroxy phenyl) vinyl] - Benzofuran (13)

The synthetic route of compound 13:

3ml methanol is added after dissolving with 3ml methylene chloride in 100mg compound 12 (0.151mmol), adds 1861mg NH₄OAc (24.169mmol), is stirred at room temperature 4d, and TLC detects end of reaction.Reaction solution is diluted with water, and ethyl acetate extraction has Machine mutually merges, and crude product is obtained after evaporated under reduced pressure.Crude product is with chloroform: methanol=15:1 carries out silica gel (200-300 mesh) column chromatography Separate yellow solid be compound 13 (57.1mg, 0.126mmol), yield 83.7%, m.p.97-99 DEG C.

Compound 13:UV λ_max(MeOH,logε):300.0(4.55)nm；¹H NMR(CD₃COCD₃,500MHz)δ:8.28 (5H, br s, H-OH), 7.63 (1H, brs, H-2b), 7.58 (1H, dd, J=8.5Hz, H-6b), 7.57 (2H, d, J= 9.0Hz, H-2a, 6a), 7.52 (1H, d, J=8.5Hz, H-5b), 7.22 (1H, d, J=16.0Hz, H-7b), 7.05 (1H, d, J =16.0Hz, H-8b), 6.86 (2H, d, J=9.0Hz, H-3a, 5a), 6.60 (2H, d, J=2.0Hz, H-10b, 14b), 6.51 (2H, d, J=2.0Hz, H-10b, 14b) .6.44 (1H, t, J=2.0Hz, H-12b), 6.29 (1H, t, J=2.0Hz, H- 12a)；¹³C NMR(CD₃COCD₃,125MHz)δ:160.06(2×C),159.96(2×C),158.9,154.3,152.3, 140.6,135.4,131.8,131.6,129.51,129.46(2×C),128.7,123.9,122.8,118.5,116.5, 116.28(2×C),111.8,108.9(2×C),105.9(2×C),103.0,102.9；ESI-MS m/z:453.2[M+H ]⁺；HR-ESI-MS m/z:453.1333[M+H]⁺(calcd.for C₂₈H₂₁O₆,453.1333).

Embodiment 14:

5- [2- (3- methoxyl group -4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -7- methoxyl group -2,3- dihydro -5- benzene And furyl] vinyl -1,3- benzenediol (14)

The synthetic route of compound 14:

Be added in the mixture of 900mg isorhapontigenin powder (3.48mmol) and 9.0mg HRP 54ml acetone with The mixed solvent of 18ml water instills 22.5ml 3%H in batches under stirring₂O₂1h is stirred at room temperature in aqueous solution, and reaction solution is with acetic acid second Ester extraction, with saturated salt solution, water washing after organic phase merging, anhydrous sodium sulfate is dry, and gained medicinal extract is concentrated under reduced pressure with chloroform: Acetone=3:1 be eluant, eluent carry out silica gel column chromatography separation, obtain sterling grey powder be compound 14 (490mg, 0.953mmol), yield 54.6%, m.p.161-163 DEG C.

Compound 14:¹H NMR(CD₃COCD₃,500MHz)δ:7.16(1H,br s,H-2b),7.04(1H,br s,H- 2a), 7.03 (1H, d, J=16.0Hz, H-8b), 6.92 (1H, d, J=16.0Hz, H-7b), 6.84 (1H, br d, J= 9.5Hz, H-6a), 6.82 (1H, br s, H-6b), 6.81 (1H, d, J=8.0Hz, H-5a), 6.52 (2H, d, J=1.5Hz, H- 10b, 14b), 6.27 (1H, t, J=1.5Hz, H-12b), 6.25 (1H, t, J=1.5Hz, H-12a), 6.19 (2H, d, J= 1.5Hz, H-10a, 14a), 5.44 (1H, d, J=8.5Hz, H-7a), 4.51 (1H, d, J=8.5Hz, H-8a), 3.96 (3H, s, OCH₃),3.92(3H,s,OCH₃)；ESI-MS m/z:515.2[M+H]⁺,537.2[M+Na]⁺,553.2[M+K]⁺；0 (c= 0.980,MeOH).

Embodiment 15:

2- (3,4- Dimethoxyphenyl) -3- (3,5- Dimethoxyphenyl) -5- [2- (3,4- Dimethoxyphenyl) ethylene Base] -7- methoxyl group -2,3- Dihydro-benzofuran (15)

The synthetic route of compound 15:

340.2mg K is added portionwise with the dissolution of 2.6ml anhydrous propanone in 130mg compound 14 (0.246mmol)₂CO₃Solid (2.462mmol) instills 873mg CH after stirring 30min₃I (6.150mmol), is stirred at room temperature 48h.Reaction solution is with ethyl acetate Dilution, successively with saturated salt solution, water washing, light yellow solid 15 (139mg, 0.238mmol) is concentrated under reduced pressure to obtain in organic phase, is received Rate 96.7%, m.p.105-107 DEG C.

Compound 15:UV λ_max(MeOH,logε):235.6(3.75),285(sh,3.35),334.2(3.79)nm；¹H NMR(CD₃COCD₃, 500MHz) and δ: 7.20 (1H, br s, H-2b), 7.18 (1H, d, 16.0Hz, H-8b), 7.05 (1H, d, J= 1.5Hz, H-2a), 7.00 (1H, d, J=16.0Hz, H-7b), 6.90-6.92 (2H, m, H-5a, 6a), 6.81 (1H, br s, H- 6b), 6.71 (1H, d, J=2.0Hz, H-10b, 14b), 6.43 (3H, br s, H-12b, 10a, 14a), 6.35 (1H, t, H- 12a), 5.59 (1H, d, J=8.5Hz, H-7a), 4.62 (1H, d, J=8.5Hz, H-8a), 3.94 (3H, s, OCH₃),3.80 (3H,s,OCH₃),3.78(9H,s,OCH₃),3.74(6H,s,OCH₃).¹³C NMR(CD₃COCD₃,125MHz)δ:162.2(2× C),162.0(2×C),150.54,150.47,149.2,145.5,144.7,140.8,133.6,133.0,132.6,130.0, 127.2,119.8,116.6,112.5,111.5,111.0,107.3(2×C),105.0(2×C),100.3,99.5,94.1, 58.4,56.4(OCH₃),56.10(OCH₃),56.06(2×OCH₃),55.6(2×OCH₃),55.5(OCH₃)；ESI-MS m/z: 607.1[M+Na]⁺,623.2[M+K]⁺；HR-ESI-MS m/z:607.2309[M+Na]⁺(calcd.for C₃₅H₃₆NaO₈, 607.2302).

Embodiment 16:

5- [2- (4- acetoxy-3-methoxyl group) phenyl-5- [2- (3,5- diacetoxy phenyl) vinyl]-7- first Oxygroup -2,3- dihydro -3- benzofuranyl] -1,3- diacetic ester (16)

The synthetic route of compound 16:

200mg compound 14 (0.389mmol) pyridinium dissolution dry with 5ml, instills 0.9ml dropwise under stirring (9.7mmol) aceticanhydride, is stirred overnight at room temperature.After having reacted, 3ml water is slowly dropped under ice bath, after completion of the reaction to extra aceticanhydride It is transferred in 50ml separatory funnel, with the dilution of 15ml water, ethyl acetate extraction, organic phase merges, successively to be saturated CuSO₄It is water-soluble Liquid, saturated salt solution, water washing, evaporated under reduced pressure obtain shallow white solid 16 (250mg, 0.345mmol), yield 88.9%, m.p.111-112℃。

Compound 16:¹H NMR(CD₃COCD₃, 500MHz) and δ: 7.26 (1H, br s, H-2b), 7.23 (1H, d, J= 16.0Hz, H-8b), 7.19 (2H, d, J=2.0Hz, H-10b, 14b), 7.15 (1H, d, J=2.0Hz, H-2a), 7.08 (1H, D, J=16.0Hz, H-7b), 7.05 (1H, d, J=8.0Hz, H-5a), 6.96 (1H, dd, J=8.0Hz, 2.0Hz, H-6a), 6.95 (2H, d, J=2.0Hz, H-10a, 14a), 6.94 (1H, t, J=2.0Hz, H-12b), 6.88 (1H, br s, H-6b), 6.80 (1H, t, J=2.0Hz, H-12a), 5.65 (1H, d, J=8.0Hz, H-7a), 4.76 (1h, d, J=8.0Hz, H-8a), 3.95(3H,s,OCH₃),3.79(3H,s,OCH₃),2.25(3H,s,OCOCH₃),2.23(12H,s,OCOCH₃)；¹³C NMR (CD₃COCD₃,125MHz)δ:169.3(4×C,OCOCH₃),168.9(OCOCH₃),152.6(4×C),152.4,149.4, 145.7,144.8,140.9(2×C),139.8,132.6,132.2,131.4,125.7,123.8,119.7(2×C), 118.9,117.5(2×C),,116.9,115.8,115.1,112.1,111.2,93.5,57.8,56.5(OCH₃),56.2 (OCH₃),20.9(4×C,OCOCH₃),20.6(OCOCH₃)；ESI-MS m/z:747.3[M+Na]⁺,763.2[M+K]⁺.

Embodiment 17:

2- (3,4- Dimethoxyphenyl) -3- (3,5- Dimethoxyphenyl) -7- methoxyl group -5- [2- (3,5- dimethoxy Phenyl) vinyl] benzofuran (17)

The synthetic route of compound 17:

80mg compound 15 (0.137mmol) the dioxane dissolution dry with 6ml, is added 46.6mg DDQ (0.206mmol) stops reaction after being heated to reflux 8h, and evaporating solvent under reduced pressure carries out silica gel (200- by eluant, eluent of methylene chloride 300 mesh) column chromatography for separation obtains crude product, and crude product is obtained white, needle-shaped crystals (50mg, 0.086mmol) with acetone recrystallization, is received Rate 62%, m.p.144-146 DEG C.

Compound 17:UV λ_max(MeOH,logε):222.4(4.38),278.8(3.69),312.4(3.84)nm；¹H NMR(CD₃COCD₃, 500MHz) and δ: 7.35 (1H, d, J=16.5Hz, H-7b), 7.30 (1H, dd, J=9.0Hz, 1.5Hz, H- 6a), 7.29 (1H, br s, H-2b), 7.20 (1H, d, J=1.5Hz, H-2a), 7.19 (1H, br s, H-6b), 7.17 (1H, d, J=16.5Hz, H-8b), 6.98 (1H, d, J=9.0Hz, H-5a), 6.78 (2H, d, J=2.0Hz, H-10b, 14b), 6.67 (2H, d, J=2.5Hz, H-10a, 14a), 6.60 (1H, t, J=2.0Hz, H-12b), 6.38 (1H, t, J=2.5Hz, H- 12a),4.11(3H,s,OCH₃),3.83(3H,s,OCH₃),3.81(6H,s,OCH₃),3.80(6H,s,OCH₃),3.65(3H, s,OCH₃)；162.5(2×C),162.1(2×C),152.0,151.0,150.0,146.4,143.6,140.6,135.1, 134.9,133.0,130.5,128.5,123.7,120.6,117.5,112.5,111.9,111.3,108.6(2×C), 105.8,105.2(2×C),100.6(2×C),56.5(OCH₃),56.0(OCH₃),55.8(3×OCH₃),55.6(2× OCH₃)；ESI-MS m/z:605.3[M+Na]⁺,520.9[M+K]⁺；HR-ESI-MS m/z:605.2163[M+Na]⁺ (calcd.for C₃₅H₃₄NaO₈,605.2146).

Embodiment 18:

5- [2- (3- methoxyl group -4- acetoxyl group) phenyl -5- [2- (3,5- diacetoxy phenyl) vinyl] -7- first Oxygroup -3- benzofuranyl] -1,3- diacetic ester (18)

The synthetic route of compound 18:

100mg compound 15 (0.138mmol) the dioxane dissolution dry with 5ml, is added 47.6mg DDQ (0.207mmol) stops reaction after being heated to reflux 32h, and evaporating solvent under reduced pressure carries out silica gel by eluant, eluent of methylene chloride (200-300 mesh) column chromatography for separation obtains shallow white solid 18 (83.3mg, 0.115mmol), yield 83.5%, m.p.223-224 ℃。

Compound 18:¹H NMR(CD₃COCD₃, 500MHz) and δ: 7.38 (1H, d, J=17.0Hz, H-7a), 7.37 (1H, Dd, J=8.5Hz, 1.5Hz, H-6a), 7.35 (1H, br s, H-2b), 7.25 (1H, d, J=17.0Hz, H-8a), 7.25 (3H, D, J=1.5Hz, H-2a, 10b, 14b), 7.22 (2H, d, J=2.0Hz, H-10a, 14a), 7.19 (1H, br s, H-6b), 7.12 (1H, d, J=8.5Hz, H-5a), 7.08 (1H, t, J=2.0Hz, H-12a), 6.83 (1H, t, J=2.0Hz, H-12b), 4.11(3H,s,OCH₃),3.65(3H,s,OCH₃),2.272(6H,s,OCOCH₃),2.266(6H,s,OCOCH₃),2.24(3H, s,OCOCH₃)；¹³C NMR(CD₃COCD₃,125MHz)δ:169.5(2×C,OCOCH₃),169.4(2×C,OCOCH₃),168.8 (OCOCH₃),153.0(2×C),152.6(2×C),152.3,151.6,146.5,144.0,141.4,140.7,135.2, 134.8,132.5,131.7,129.2,127.2,124.2,121.5(2×C),119.8,117.7(2×C),117.3, 116.6,115.4,111.8,111.6,106.8,56.6(OCH₃),56.0(OCH₃),20.9(4×C,OCOCH₃),20.5 (OCOCH₃)；ESI-MS m/z:745.2[M+Na]⁺,761.2[M+K]⁺.

Embodiment 19:

5- [2- (3- methoxyl group -4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -7- methoxyl group -2,3- dihydro -5- benzene And furyl] vinyl -1,3- benzenediol (19)

The synthetic route of compound 19:

46mg compound 18 (0.064mmol) is added 1.5ml methanol dilution, is added with the dissolution of 1.5ml methylene chloride 786mg NH₄OAc (6.116mmol), is stirred at room temperature 52h, stops upper reaction.The water of 4 times of amounts, ethyl acetate are added into reaction solution Extraction, organic phase washing, is concentrated under reduced pressure.Product is chromatographed through silica gel (200-300 mesh) column, and with chloroform: methanol=20:1 is eluted Pistac solid 19 (24mg, 0.047mmol), yield 74.1%, m.p.164-166 DEG C.

Compound 19:¹H NMR(CD₃COCD₃,500MHz)δ:7.25-7.26(2H,m,H-2a,6a),7.24(1H,br S, H-2b), 7.21 (1H, br s, H-6b), 7.19 (1H, d, J=16.5Hz, H-7b), 7.06 (1H, d, J=16.5Hz, H- 8b), 6.86 (1H, d, J=8.5Hz, H-5a), 6.59 (2H, d, J=1.5Hz, H-10b, 14b), 6.52 (1H, d, J= 1.5Hz,H-10a,14a),6.43(1H,br s,H-12a),6.28(1H,br s,H-12b),4.10(3H,s,3b-OCH₃), 3.71(3H,s,3a-OCH₃)；¹³C NMR(CD₃COCD₃,125MHz)δ:162.4(2×C),159.5(2×C),152.1, 148.2,148.1,146.3,143.6,140.6,135.5,134.8,132.9,129.8,128.8,122.9,121.2, 117.1,116.0,111.6,111.3,108.9(2×C),106.0,105.8(2×C),102.9,102.8,56.5(OCH₃), 56.0(OCH₃)；ESI-MS m/z:513.2[M+H]⁺,535.2[M+Na]⁺,551.1[M+K]⁺,511.6[M-H]^-.

Pharmacological evaluation

The present invention provides a kind of Amurensin H derivative and its pharmaceutically acceptable salts in preparation treatment and/or Prevention and the application in liver related disease drug, are set forth below experimental example and are further explained to the present invention, but not to appoint Where formula limitation is of the invention.

The liver protective effect pharmacological test procedures and result of the compounds of this invention following (the compound generation of pharmacological evaluation part Number correspond to experimental example in compound numbers):

Experimental example 1:Amurensin H derivative causes in vitro liver cell damage protective effect to be commented paracetamol (APAP) Valence

1. experimental method:

1) cytotoxicity of the compound to HepG2 cell

Using MTT method.After culture for 24 hours, various concentration is added in 96 porocyte culture plates in HepG2 cell inoculation Untested compound, while solvent control group is set, each drug concentration sets 3 parallel holes.After drug effect cell 48h, training is discarded 100 μ l of MTT (0.5mg/ml) liquid is added in nutrient solution, every hole, continues to cultivate 4h, discards MTT liquid, and 150 μ l of DMSO is added in every hole, mixes It is vibrated with oscillator, absorbance value is measured at microplate reader 570nm wavelength.Cell survival rate (%)=(administration cell OD is average Value/solvent control cell OD average value) × 100%.

2) compound causes the protective effect of in vitro liver cell damage to paracetamol (APAP)

Using MTT method.After culture for 24 hours, non-toxic concn is added in 96 porocyte culture plates in HepG2 cell inoculation Untested compound and paracetamol (APAP, final concentration 8mM), while setting positive drug control group (bicyclic alcohols, bicyclol), molten Agent blank control group and model group.Continue function cells 48h.Culture solution is discarded, 100 μ l of MTT (0.5mg/ml) liquid is added in every hole, Continue to cultivate 4h, discard MTT liquid, 150 μ l of DMSO is added in every hole, mixes oscillator oscillation, surveys at microplate reader 570nm wavelength Determine absorbance value.Cell survival rate (%)=100 × administration group OD average value/blank control group OD average value, cell survival mention High percent (%)=100 × (administration group cell survival rate-model group cell survival rate)/model group cell survival rate.2. real Test result:

1) cytotoxicity: the Amurenin H derivative of inspection acts on HepG2 cell 48h in 10 μM of concentration, in the concentration Under to HepG2 cell without overt toxicity, cell survival rate is greater than 90% (data are not shown).10 μM of untested compound of selection is dense Degree is used for subsequent experimental.

2) cause the protective effect of hepatocellular injury to APAP: the results are shown in Table 1, APAP 8mM effect HepG2 cell 48h, Significant damage, cell survival rate 43.84% are generated to HepG2 cell.Under current experimental program, Amurensin H is derivative Object 2,4,6,7,11 and 19 is shared in 10 μM of concentration with APAP, has significant protective effect to HepG2 cellular damage caused by the latter, Cell survival rate is respectively increased 24.9%, 23.2%, 19.5%, 20.2%, 31.7% compared with MODEL DAMAGE group, 16.0% He 19.4%, there is statistical difference compared with model group.10 μM of concentration of positive control drug bicyclic alcohols (bicyclol) cause APAP Hepatocellular injury also have significant protective effect.

Table 1.Amurensin H derivative causes the protective effect of HepG2 cellular damage to APAP

*^***P < 0.001, compared with blank control group；^#P < 0.05,^##P < 0.01, compared with APAP model group；It is dense

10 μM of degree.

Experimental example 2:Amurensin H derivative is to carbon tetrachloride (CCl₄) caused by chmice acute toxic liver injury It influences

1. experimental method

SPF grades of male ICR mouses (20~22g) are randomly divided into 6 groups after adapting to environment, blank control group, 0.15%CCl₄ Model group, bicyclic alcohols 200mg/kg group, 2 50mg/kg group of compound, 7 50mg/kg group of compound and 11 50mg/kg of compound Group.The afternoon of each compound dosage group and bicyclic alcohols 200mg/kg group on the day before modeling, each gastric infusion of upper and lower noon on the same day Once, blank control group and model group animal give the same dose of physiological saline.After last dose 2h, blank control group is removed, Each group mouse peritoneal injects 0.15%CCl₄10ml/kg is primary, and Isodose peanut oil is injected intraperitoneally in blank control group.Mouse After being deprived of food but not water 16h, mouse is put to death, blood is taken to prepare serum, automatic clinical chemistry analyzer detection detection ALT, AST, LDH contain Amount.

2. experimental result

Grouping and the original body mass of animal, terminal weight are shown in Table 2, each administration group successive administration 3 times, the weight of animals with Model group and blank group compare without being substantially reduced, and prompt without overt toxicity.

Compound is to CCl₄The result of acute liver protective effect is caused to see Table 3.0.15%CCl₄It can cause The significant acute liver damage of mouse, model group Serum ALT, AST, LDH content are significantly increased compared with blank control group.Except compound 7, Two compounds remaining to CCl₄Caused acute liver shows certain inhibitory activity, wherein 2 50mg/ of compound Kg is to CCl₄Caused hepatic injury shows good protective effect.Compound 11 shows certain liver injury protection in 50mg/kg Activity, but activity is not as good as compound 2.Positive control drug bicyclic alcohols are to CCl₄Caused Serum ALT raising has significant decrease effect.

The grouping of Table 2. and animal original body mass, terminal weight (n=9-12)

3. compound of Table is to 0.15%CCl₄Cause after hepatic injury ALT, AST, LDH changes of contents (n in mice serum =9-12)

^*P < 0.05,^**P < 0.01, compared with blank control group；^#P < 0.05,^##P < 0.01 is compared with model group；Administration Mode: i_g.。

Claims (15)

1. one kind Amurensin H derivative and its pharmaceutically acceptable salt are related to liver in preparation treatment and/or prevention Application in disease medicament, it is characterised in that: such as logical formula (I) of the derivative and (II) are shown:

Wherein, R₁Selected from H,R₂、R₁₀Selected from H,

R₉Selected from H,

R₆、R₇、R₈、R₁₄、R₁₅、R₁₆、R₁₇、R₁₈、R₁₉、R₂₀It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6's Alkoxy acyl, Glu, SO₃H、PO₃H₂；

R₃、R₄、R₅、R₁₁、R₁₂、R₁₃It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, phenyl, methylamino, two Methylamino, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, C_1-6Alkoxy acyl, C_2-6Unsaturation Alkyl, C_3-6Naphthenic base, C_1-6Alkylthio group, F, Cl, Br, I, Glu, SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

2. the application of Amurensin H derivative according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that Shown in the derivative such as general formula (IA):

Wherein, R₄、R₅Be each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, phenyl, methylamino, dimethylamino, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, C_1-6Alkoxy acyl, C_2-6Unsaturated alkyl, C_3-6 Naphthenic base, C_1-6Alkylthio group, F, Cl, Br, I, Glu, SO₃H、PO₃H₂；

R₆、R₇、R₈、R₁₇、R₁₈It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alkoxy acyl, Glu, SO₃H、 PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

3. the application of Amurensin H derivative according to claim 2 and its pharmaceutically acceptable salt, which is characterized in that Shown in the derivative such as general formula (IAa):

Wherein, R₆、R₇、R₈、R₁₇、R₁₈It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alkoxy acyl, Glu, SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

4. the application of Amurensin H derivative according to claim 2 and its pharmaceutically acceptable salt, which is characterized in that Shown in the derivative such as general formula (IAb):

Wherein, R₆、R₇、R₈、R₁₇、R₁₈It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alkoxy acyl, Glu, SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

5. the application of Amurensin H derivative according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that Shown in the derivative such as general formula (IB):

Wherein, R₆、R₇、R₈、R₁₉、R₂₁It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alkoxy acyl, Glu, SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

6. the application of Amurensin H derivative according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that Shown in the derivative such as general formula (IIA):

Wherein, R₁₂、R₁₃Be each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, phenyl, methylamino, dimethylamino, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, C_1-6Alkoxy acyl, C_2-6Unsaturated alkyl, C_3-6 Naphthenic base, C_1-6Alkylthio group, F, Cl, Br, I, Glu, SO₃H、PO₃H₂；

R₁₄、R₁₅、R₁₆、R₁₇、R₁₈It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alkoxy acyl, Glu, SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

7. the application of Amurensin H derivative according to claim 6 and its pharmaceutically acceptable salt, which is characterized in that Shown in the derivative such as general formula (IIAa):

R₁₄、R₁₅、R₁₆、R₁₇、R₁₈It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alkoxy acyl, Glu, SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

8. the application of Amurensin H derivative according to claim 6 and its pharmaceutically acceptable salt, which is characterized in that Shown in the derivative such as general formula (IIAb):

R₁₄、R₁₅、R₁₆、R₁₇、R₁₈It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alkoxy acyl, Glu, SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

9. the application of Amurensin H derivative according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that Shown in the derivative such as general formula (IIB):

Wherein, R₁₄、R₁₅、R₁₆、R₁₉、R₂₂It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alkoxy acyl, Glu、SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

10. the application of Amurensin H derivative according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that Shown in the derivative such as general formula (IIC):

Wherein, R₁₄、R₁₅、R₁₆、R₂₀、R₂₂It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, C_1-6Alkoxy acyl, Glu、SO₃H、PO₃H₂；

Glu indicates β-D glucopyranosyl；SO₃H indicates sulfonyl；PO₃H₂Indicate phosphoryl.

11. the application of Amurensin H derivative as claimed in one of claims 1-10 and its pharmaceutically acceptable salt, It is characterized in that, the derivative is selected from following group:

12. application of a kind of pharmaceutical composition in preparation treatment and/or prevention liver related disease drug, by effective dose The described in any item derivatives of claim 1-11 and its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or auxiliary material Composition.

13. application according to claim 12, wherein liver related disease includes: hepatitis A, hepatitis B, hepatitis, drug-induced liver disease, wine Essence hepatopathy, non-alcoholic hepatopathy, autoimmune liver disease, the liver fibrosis of liver disease progression, cirrhosis or hepatic failure.

14. application according to claim 12, which is characterized in that the pharmaceutical composition is selected from tablet, capsule, pill, note Penetrate agent.

15. application according to claim 12, which is characterized in that described pharmaceutical composition be selected from sustained release preparation, controlled release preparation and Various particulate delivery systems.