CN110433152A - Application of the plain derivative of a kind of grapevine penta in preparation treatment liver related disease drug - Google Patents

Application of the plain derivative of a kind of grapevine penta in preparation treatment liver related disease drug Download PDF

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CN110433152A
CN110433152A CN201810413390.3A CN201810413390A CN110433152A CN 110433152 A CN110433152 A CN 110433152A CN 201810413390 A CN201810413390 A CN 201810413390A CN 110433152 A CN110433152 A CN 110433152A
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glu
compound
alkyl
group
acyl
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姚春所
孙华
王先分
刘威
李梅
滕彬豪
张凡
商昌辉
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Institute of Materia Medica of CAMS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention discloses the application of plain (Amurensin H) derivative of grapevine penta shown in a kind of formula (I), (II) and (III) 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

The plain derivative of a kind of grapevine penta is in preparation treatment liver related disease drug Using
Technical field
The present invention relates to biomedicine fields, and in particular to arrives the plain derivative of a kind of grapevine penta or its is medically acceptable Salt, the Pharmaceutical composition containing these derivatives preparation treatment and/or prevention liver related disease drug in terms of application.
Background technique
New drug is researched and developed based on bioactive natural product, is one of the important channel of modern medicines research and development.Natural products tool The features such as having from a wealth of sources, toxicity low and Small side effects.The natural guideization of remarkable activity is found to have from Chinese traditional herbs Object is closed, by structural modification, In vitro and in vivo activity test and druggability overall merit in conjunction with system are therefrom found safe and efficient Candidate compound as clinically useful proto-drug, be the important directions of drug development research.Oligomerization stilbene compound Be it is a kind of be polymerized that structure is complicated, the natural products with multiple biological activities in different ways by talan monomer, It is distributed mainly in the plants such as grape, Gnetaceae, Dipterocarpaceae, pulse family, Cyperaceae, Paeoniaceae.The hexichol second of different structure Alkene monomer polymerization methods and degree of polymerization difference, are formed by oligomeric Stilbene class natural products and show rich and varied structure type, It is adapted with this, presently found oligomerization stilbene compound also shows diversified bioactivity, including anti-oxidant, anti- The activity of inflammation, antibacterial, antitumor, antiviral and anti-senile dementia etc..In the past 10 years, due to separation and Structural Identification skill The continuous development of art, more and more complicated, with significant bioactivity oligomerization stilbene compounds are isolated and identified, So that the research of oligomerization stilbene compound is got a larger development in terms of structure and activity.Especially in bioactivity research Aspect not only has found more complicated compounds with different activities, but also finds such compound more multi-party Face shows significant bioactivity, such as beta-secretase inhibitory activity, anti-influenza virus activity, anti-herpesvirus (HSV) activity Deng.The new activity constantly discovered shows that such compound has great potentiality in drug development use aspects, so that Oligomerization stilbene compound receives more extensive concern, has been developed as one of the hot spot of Natural products research at present.Especially It is wherein dimer class compound, and activity is generally better than monomer diphenylethylene compounds, molecular weight between 400-600 it Between, have exploitation at the great potential of drug.In recent years, the fully synthetic of talan dimer class compound has evolved into work One of the hot spot of property Natural products research, and greater advance is achieved, main dimeric structure skeleton, including benzofuran knot The fully synthetic research of structure, indenes type structure and diaryl [3.2.1] octane structure achieves breakthrough, is dimer class The research and development of compound provide guarantee.But other than separation is identified and obtains natural products, to reactive oligomer class The structural modification and structure activity study for closing object (especially dimer class) progress system are still a completely new research field, So far, correlative study report is less in document.Benzofuran type and coumaran type talan dimerization syntaxy Object is the natural products that quantity is most in dimer class compound, and wherein activity a kind of compound the most significant.From mountain In grape (Vitis amurensis) isolated resveratrol dimer grapevine penta plain (Amurensin H) have compared with Strong anti-inflammatory, antioxidant activity is the lead compound for having researching value.In recent years, it based on the compound, originally grinds Study carefully the structure activity study of group synthesis for having carried out system, structure of modification and anti-inflammatory activity.It is found in activity research, The Derivatives In Mice hepatic injury of Amurensin H has significant inhibitory activity, by the synthesis, the liver that further go deep into system Protection activity screening and structure activity study, obtain a series of stronger talan dimer derivate of liver protective effects. Present invention firstly discloses the liver protective effects of such compound to be of great significance to deeply developing using such compound.
Summary of the invention
The technical problem to be solved by the present invention is to provide one kind 3,4- diphenylisobenzofuran or 3,4- diphenyl benzo two Hydrogen furfuran compound or combinations thereof object is preparing answering in the drug for preventing, treating or assisting in the treatment of liver related disease With.
The first aspect of technical solution of the present invention provide it is a kind of such as logical formula (I), (IA), (IAa), (IB), (IBa), (II), (IIA), (IIAa), (IIB), (IIBa) and (III), (IIIA), 3,4- diphenylisobenzofuran or 3,4- shown in (IIIAa) Diphenyl coumaran class compound and its pharmaceutically acceptable salt, in preparation for preventing, treating or assisting in the treatment of Application in the drug of liver related disease.
The second aspect of technical solution of the present invention provides a kind of pharmaceutical composition, including at least one as logical formula (I), (IA), (IAa), (IB), (IBa), (II), (IIA), (IIAa), (IIB), (IIBa) and (III), (IIIA), (IIIAa) institute 3, the 4- diphenylisobenzofuran shown or 3,4- diphenyl coumaran class compound and its pharmaceutically acceptable salt, In Prepare the application in the drug for preventing, treating or assisting in the treatment of liver related disease.
The third aspect of technical solution of the present invention provides the preparation method of derivative described in first aspect.
It is described that have related disorders with liver include hepatitis A, hepatitis B, hepatitis, drug-induced liver disease, alcoholic liver disease, non-alcoholic Hepatopathy, autoimmune liver disease, the liver fibrosis of liver disease progression, cirrhosis or hepatic failure.Compound of the present invention includes Acceptable salt on its derivative and pharmacodynamics.
Specifically, the present invention relates to plain (Amurensin H) derivatives of a kind of grapevine penta and its pharmaceutically acceptable Salt preparation treatment and/or prevention liver related disease drug in application, which is characterized in that the compound such as general formula (I), shown in (II) and (III):
Wherein, R1、R6、R11It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamine Base, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturated alkyl, C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R5、R10、R15For monosubstituted or polysubstituted group, monosubstituted singly taken selected from ortho position, meta position, contraposition wherein described Generation；It is described it is polysubstituted be selected from two substitutions, three replace, four replace；Substituent group is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxylic Base, methylamino, dimethylamino, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturated alkyl, C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R2、R3、R4、R7、R8、R9、R12、R13、R14It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to logical formula (I) shown in the plain derivative of grapevine penta including but not limited to general formula (IA) The application of compound represented and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IA):
Wherein, R5To be monosubstituted or polysubstituted, described is monosubstituted monosubstituted selected from ortho position, meta position, contraposition；Described is more Replace selected from two substitutions, three replace, four replace；Substituent group is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, two Methylamino, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturation Alkyl, C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to general formula (IA) shown in the plain derivative of grapevine penta including but not limited to general formula (IAa) application of compound represented and its pharmaceutically acceptable salt, which is characterized in that the compound such as general formula (IAa) It is shown:
Wherein, R2、R3、R4、R16、R17It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、 PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to logical formula (I) shown in the plain derivative of grapevine penta including but not limited to general formula (IB) The application of compound represented and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IB):
Wherein, R5To be monosubstituted or polysubstituted, described is monosubstituted monosubstituted selected from ortho position, meta position, contraposition；Described is more Replace selected from two substitutions, three replace, four replace；Substituent group is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, two Methylamino, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturation Alkyl, C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to general formula (IB) shown in the plain derivative of grapevine penta including but not limited to general formula (IBa) application of compound represented and its pharmaceutically acceptable salt, which is characterized in that the compound such as general formula (IBa) It is shown:
Wherein, R2、R3、R4、R18、R19It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、 PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to logical formula (II) shown in the plain derivative of grapevine penta including but not limited to general formula (IIA) application of compound represented and its pharmaceutically acceptable salt, which is characterized in that the compound such as general formula (IIA) It is shown:
Wherein, R10To be monosubstituted or polysubstituted, described is monosubstituted monosubstituted selected from ortho position, meta position, contraposition；Described is more Replace selected from two substitutions, three replace, four replace；Substituent group is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, two Methylamino, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturation Alkyl, C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R7、R8、R9It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy 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) shown in the plain derivative of grapevine penta including but not limited to general formula (IIAa) application of compound represented and its pharmaceutically acceptable salt, which is characterized in that the compound such as general formula (IIAa) shown in:
Wherein, R7、R8、R9、R20、R21It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alcoxyl 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) shown in the plain derivative of grapevine penta including but not limited to general formula (IIB) application of compound represented and its pharmaceutically acceptable salt, which is characterized in that the compound such as general formula (IIB) It is shown:
Wherein, R10To be monosubstituted or polysubstituted, described is monosubstituted monosubstituted selected from ortho position, meta position, contraposition；Described is more Replace selected from two substitutions, three replace, four replace；Substituent group is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, two Methylamino, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturated hydrocarbons Base, C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R7、R8、R9It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu, SO3H、 PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to general formula (IIB) shown in the plain derivative of grapevine penta including but not limited to general formula (IIBa) application of compound represented and its pharmaceutically acceptable salt, which is characterized in that the compound such as general formula (IIBa) shown in:
R7、R8、R9、R22、R23It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to logical formula (III) shown in the plain derivative of grapevine penta including but not limited to general formula (IIIA) application of compound represented and its pharmaceutically acceptable salt, which is characterized in that the compound such as general formula (IIIA) shown in:
Wherein, R15To be monosubstituted or polysubstituted, described is monosubstituted monosubstituted selected from ortho position, meta position, contraposition；Described is more Replace selected from two substitutions, three replace, four replace；Substituent group is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, two Methylamino, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturation Alkyl, C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R12、R13、R14、R24It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to general formula (IIIA) shown in the plain derivative of grapevine penta including but not limited to general formula (IIIAa) application of compound represented and its pharmaceutically acceptable salt, which is characterized in that the compound such as general formula (IIIAa) shown in:
Wherein, R12、R13、R14、R24、R25It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alcoxyl acyl Base, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
Specifically, logical formula (I), (IA), (IAa), (IB), (IBa), (II), (IIA), (IIAa), (IIB), (IIBa) And (III), (IIIA), the plain derivative of grapevine penta shown in (IIIAa) and its pharmaceutically acceptable salt, which is characterized in that The compound is selected from following group (compound numbers correspond to the compound numbers in embodiment):
The second aspect of technical solution of the present invention there is provided a kind of containing medicine effective dose as logical formula (I), (IA), (IAa), (IB), (IBa), (II), (IIA), (IIAa), (IIB), (IIBa) and (III), (IIIA), (IIIAa) each situation institute The pharmaceutical composition of the compound and pharmaceutically acceptable carrier stated is in preparation treatment and/or prevention liver related disease drug In application.
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.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be enteron aisle Or non-bowel, such as oral, muscle, subcutaneous, nasal cavity, mucous membrane of mouth, skin, peritonaeum or rectum.The compounds of this invention contains The administration route of its pharmaceutical composition can be drug administration by injection.Injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal 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, particle Dosage form, emulsion dosage form, mixed suspension form.Other dosage forms such as tablet, dripping pill, aerosol, pill, pulvis, solution, mixes capsule Suspension, emulsion, granule, suppository, freeze drying powder injection etc..
Ordinary preparation can be made in the compounds of this invention, be also possible to sustained release preparation, controlled release preparation, targeting preparation and various Particulate delivery system.
Such as 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 The example of carrier, 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, as water, glycerol, polyethylene glycol, Ethyl alcohol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, 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, lauryl sodium 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.
Such as in order to which pill is made in administration unit, carrier 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, Glycerin monostearate, 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 etc..
Such as in order to which capsule is made in administration unit, the compounds of this invention is mixed with above-mentioned various carriers, and will be by This obtained mixture is placed in hard gelatine capsule or soft capsule.Micro-capsule can also be made in effective component the compounds of this invention Agent is suspended in aqueous medium and forms suspension, also can be fitted into hard capsule or be made injection application.
For example, injection preparation is made in the compounds of this invention, such as solution, suspension solution, emulsion, freeze-dried powder Agent, this preparation can be aqueous or non-aqueous, can contain acceptable carrier in a kind of and/or a variety of pharmacodynamics, diluent, viscous Mixture, lubricant, preservative, surfactant or dispersing agent.As diluent can be selected from water, ethyl alcohol, polyethylene glycol, 1,3- the third two Alcohol, the isooctadecanol of ethoxylation, polyoxygenated isooctadecanol, polyoxyethylene sorbitan ester, fatty acid 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.
In addition, if desired, can also be added into pharmaceutical preparation colorant, preservative, fragrance, corrigent, sweetener or Other materials.
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any The administration of prescription method.
The dosage of the compounds of this invention pharmaceutical composition depends on many factors, such as to be prevented or be treated disease Property and severity, gender, age, weight, personality and the individual reaction of patient or animal, administration route, administration number of times, Therapeutic purposes, therefore therapeutic dose of the invention can have large-scale variation.In general, making for part is studied in the present invention It is well known to those skilled in the art with dosage.It can be according to the present invention contained in preparation last in compound composition Actual drug quantity is subject to adjustment appropriate, to reach the requirement of its therapeutically effective amount, completes prevention or treatment mesh of the invention 's.The daily Suitable dosage ranges of the compounds of this invention: the dosage of the compound of the present invention is 0.001~100mg/kg body Weight, preferably 0.1~60mg/kg weight, more preferably 1~30mg/kg weight, most preferably 2~15mg/kg weight.It is adult The compounds of this invention that patient takes is 10~500mg daily, preferably 10~100mg, can once take or divide 2~3 clothes With；The dosage of children taking is according to 5~30mg of every kg weight, preferably 10~20mg/kg weight.Above-mentioned dosage can be single dose Amount form is divided into several, such as two, three or four dosage forms for administration, this is limited to the clinical experience of administration doctor and controls The dosage regimen for the treatment of means.The compound of the present invention or composition can individually be taken, or with other therapeutic agents or symptomatic drugs Merge and uses.
The third aspect of technical solution 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, such as 3,5- methyl dihydroxy benzoate, vanillic aldehyde, resveratrol can lead to Commercially available acquisition is crossed, isorhapontigenin can be according to document [J.Asian Nat.Prod.Res., 2014,16 (5): 511- 521] method prepares.
The basic synthetic method of key reaction midbody compound 1c in the present invention includes the following steps:
Step 1: dimerization reaction is carried out as raw material using resveratrol and synthesizes the coumaran type containing styrene double bond Resveratrol dimer derivative.
Resveratrol is in methyl alcohol with FeCl3·6H2O is that catalyst carries out polymerization reaction, and reaction product is concentrated under reduced pressure, institute It obtains solid and obtains penta element (1a) of target product grapevine through chromatographic separation and purification.
Step 2: the acetylating coumaran of the acetylating synthesis phenolic hydroxyl group of the phenolic hydroxyl group of step 1 products therefrom Type resveratrol dimer derivative.
Step 1 products therefrom carries out acetylization reaction with aceticanhydride in dry pyridine, after reaction solution removes pyridine, decompression It is plain (1b) to be concentrated to give target product acetylation grapevine penta.
Step 3: step 2 products therefrom carries out dehydrogenation reaction and synthesizes full acetylated benzofuran type resveratrol dimerization Syntaxy object.
Step 2 products therefrom is in ethyl acetate, in a hydrogen atmosphere, carries out reduction reaction, reaction with Pd/C (10%) The full acetylated benzofuran type resveratrol dimer derivative of target product is concentrated under reduced pressure to obtain after being filtered to remove Pd/C in mixture Object (1c).
The basic synthetic method of key reaction midbody compound 2b, 3b, 2c and 3c in the present invention include 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.
The synthesis of resveratrol dimer: resveratrol is in anhydrous propanone with Ag2O is that oxidant progress oxidative coupling is anti- It answers, reaction solution filtering is concentrated to dryness to obtain crude product.Crude product obtains target product through chromatographic separation and purification and contains styrene pair The coumaran type talan dimer (2a) of key.
The synthesis of isorhapontigenin dimer: isorhapontigenin monomer is in the mixed solution of acetone and water with horseradish Enzyme (HRP) and H2O2Oxidative coupling reaction is carried out for oxidant, reaction mixture is concentrated under reduced pressure after being further processed, and gained slightly produces Object obtains the coumaran type talan dimer (3a) that target product contains styrene double bond through chromatographic separation and purification
Step 2: using 2a and 3a as raw material, the method for key intermediate 2b and 3b referring to step 2 in intermediate 1c synthesis Synthesis.
Step 3: using 2b and 3b as raw material, the method for key intermediate 2c and 3c referring to step 3 in intermediate 1c synthesis Synthesis.
The basic synthetic method of compound of the present invention includes the following steps:
Step 1: the coumaran derivative and benzofuran derivatives of the double bond containing styrene are closed by hydro-reduction At corresponding double bond hydrogenated derivatives.
The talan dimer derivate of the double bond containing styrene is catalysis with Pd/C (10%) in ethyl acetate solvent Agent carries out double bond reduction reaction in a hydrogen atmosphere.Reaction mixture is filtered to remove Pd/C, and it is double that filtrate decompression is concentrated to give styrene The benzofuran or coumaran derivative of key hydrogenation.
Step 2: it is derivative that full acetylated talan dimer derivate removing acetyl group synthesizes corresponding phenolic hydroxyl group Object.
Full acetylated talan dimer derivate in the mixed solution of methylene chloride and methanol with NH4OAc into Row reaction.Reaction product is added water and is extracted with ethyl acetate, and organic phase evaporated under reduced pressure obtains corresponding phenolic hydroxyl group talan dimerization Syntaxy object.
Step 3: phenolic hydroxyl group talan dimer derivate carries out methylation reaction and synthesizes permethylated talan Dimer derivate.
The anhydrous propanone solution of phenolic hydroxyl group talan dimer derivate is in K2CO3In the presence of, with CH3I methylates Reaction, reaction product obtain permethylated talan dimer derivate through recrystallization or chromatographic isolation.
Advantageous effects
The present inventor anti-inflammatory antioxidant activity natural products 7,8- dehydrogenation Portugal isolated in V. amurensis During the synthesis of grape rattan penta plain (Amurensin H), structural modification and activity research, it is aobvious to find that such compound has for the first time The liver protective effect of work, and liver protective effect evaluation is carried out as the derivative to obtained by, confirm the activity of such compound.It is real It tests and shows that such compound has significant protection to make the damage of human liver cell caused by paracetamol (APAP) under 10 μM of concentration With compound is to CCl4Caused acute liver has significant inhibitory activity, has the potential valence further developed Value.
Currently, to 7b, the benzofuran of 8b- double bond reduction hydrogenation or the talan dimer of coumaran structure The liver protective effect of class compound and the structure activity study of system are there is not yet document report.Pass is had no in existing literature and technology In 7b, the benzofuran or coumaran type talan dimer derivate of the reduction hydrogenation of 8b- double bond or its medically Acceptable salt and such compound are used to treat the report of liver related disease；It has no about the substitution of 4- phenethyl or 5- benzene The benzofuran or coumaran type talan dimer derivate class novel compound or its medicine that ethyl replaces Upper acceptable salt and such compound are used to treat the report of liver related 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.
The definition of the various groups of the compounds of this invention presented below, in addition to separately defining, they are wanted in specification and right Ask unified use in book.
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 to3-6Naphthenic base " refer to carbon atom number be 3,4,5,6 substituted or unsubstituted cycloalkanes Base may include C3-5Naphthenic base, C3-4Naphthenic base, C4-6Naphthenic base, C4-5Naphthenic base, C5-6Naphthenic base etc. indicate Subrange group, and preferred specific group, such as cyclopropyl alkyl, pentamethylene base and cyclohexyl.
Term " C mentioned by the present invention1-6Alkyl " refer to carbon atom number be 1,2,3,4,5,6 linear chain or branched chain hydrocarbon Base may include C1-5Alkyl, C1-4Alkyl, C2-5Alkyl, C2-4Alkyl, C2-3Alkyl, C3-5Alkyl 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 invention1-6Alkoxy " refers to that carbon atom number is 1,2,3,4,5,6 alkoxy, including C1-5Alkoxy, C1-2Alkoxy, C2-4Alkoxy, C2-3Alkoxy, C3-4The 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 invention2-6Unsaturated alkyl " refers to that carbon atom number is 2,3,4,5,6 unsaturated alkyl, It may include C2-5Unsaturated alkyl, C2-4Unsaturated alkyl, C2-5Unsaturated alkyl, C2-4Unsaturated alkyl etc. indicate Subrange group, and preferred specific group, such as vinyl, acetenyl, isopropenyl, isopropynyl, isobutene Base, isopentene group, 1,4- dibutene base etc..
Term " C mentioned by the present invention1-6Acyl group " refer to carbon atom number be 1,2,3,4,5,6 acyl group, may include C1-5Acyl group, C1-3Acyl group, C2-5Acyl group, C2-3Acyl group, C3-4The 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 invention1-6Acyloxy " refer to carbon atom number be 1,2,3,4,5,6 linear chain or branched chain acyl-oxygen Base may include C1-5Acyloxy, C1-3Acyloxy, C2-5Acyloxy, C2-3Acyloxy, C3-4Acyloxy etc. indicate The group, and preferred specific group, such as formyloxy, acetoxyl group, propionyloxy of subrange etc..
" C mentioned by the present invention1-6Alkoxy acyl " refer to that carbon atom number is 1,2,3,4,5,6 alkoxy acyl, can be with Including C1-5Alkoxy acyl, C1-3Alkoxy acyl, C2-5Alkoxy acyl, C2-3Alkoxy acyl, C3-4The 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 invention1-6Alkylthio group " refer to carbon atom number be 1,2,3,4,5,6 linear chain or branched chain Alkylthio group may include C1-5Alkylthio group, C1-3Alkylthio group, C2-5Alkylthio group, C2-3Alkylthio group, C3-4Alkylthio 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, and (compound numbers correspond in embodiment Compound numbers), these embodiments be entirely it is illustrative, they are only used to that the present invention is specifically described, and should not manage Solution is limitation of the present invention.
The synthetic route of midbody compound 1c in embodiment:
The synthetic route of midbody compound 2b, 3b, 2c and 3c in embodiment:
Embodiment 1:
5- [6- acetoxyl group -2- [4- acetoxyl group phenyl] -4- [2- (4- acetoxyl group phenyl) ethyl] -3- benzo furan Mutter base] -1,3- benzenediol -1,3- diacetate esters (1)
The synthetic route of compound 1:
100mg compound 1c is added 7.11mg Pd/C (10%), is pressurizeed in a hydrogen atmosphere with the dissolution of 6ml ethyl acetate 1h is reacted, is filtered to remove Pd/C, filtrate decompression is concentrated to give 1 93.8mg of compound as white solid (0.140mmol), yield 93.5%, m.p.79-81 DEG C.
Compound 1:UV λmax(MeOH,logε):307.4(4.43)nm；1H NMR(CD3COCD3,500MHz)δ:7.55 (2H, d, J=8.5Hz, H-2a, 6a), 7.31 (1H, d, J=1.5Hz, H-14b), 7.26 (2H, d, J=2.0Hz, H-10a, 14a), 7.12 (1H, t, J=2.0Hz, H-12a), 7.09 (2H, d, J=8.5Hz, H-3a, 5a), 6.89 (1H, J=1.5Hz, H-12b),6.87-6.88(4H,m,H-2b,6b,3b,5b),2.79-2.83(2H,m,H2-7b),2.61-2.65(2H,m,H2- 8b),2.29(3H,s,OCOCH3),2.24(6H,s,OCOCH3),2.21(3H,s,OCOCH3)；13C NMR(CD3COCD3, 125MHz)δ:169.8(OCOCH3),169.6(OCOCH3),169.44(OCOCH3),169.35(2×C,OCOCH3),154.7, 152.8(2×C),152.0,151.7,150.0,149.7,139.4,137.4,136.7,130.1(2×C),128.4(2× C),126.0,122.9(2×C),122.5(2×C),122.2(2×C),119.5,117.1,116.8,103.9,38.0, 34.9,21.0(5×C,OCOCH3)；ESI-MS m/z:687.2[M+Na]+,703.2[M+K]+,653.4[M-H]-；HR-ESI- MS m/z:687.1849[M+Na]+(calcd.for C38H32NaO11,687.1837).
Embodiment 2:
5- [6- hydroxyl -2- (4- hydroxy phenyl) -4- [2- (4- hydroxy phenyl) ethyl] -3- benzofuranyl] -1,3- benzene Diphenol (2)
The synthetic route of compound 2:
100mg compound 1 (0.154mmol) is dissolved in 3ml methylene chloride, and 3ml methanol dilution is added, adds 1855mg NH4OAc (24.096mmol), is stirred at room temperature 4d.Water and ethyl acetate extraction are added after fully reacting, organic phase merges, decompression It is concentrated to dryness to obtain 62mg (0.137mmol) yellow solid compound 2, yield 90.4%, m.p.240-242 DEG C.
Compound 2:UV λmax(MeOH,logε):284.6(4.34),319.2(4.54)nm；1H NMR(CD3COCD3, 500MHz) δ: 8.18-8.62 (br s, H-OH), 7.41 (2H, d, J=8.5Hz, H-2a, 6a), 6.85 7.31 (1H, d, J= 2.0Hz, H-14b), 6.78 (2H, d, J=8.5Hz, H-2b, 6b), 6.77 (2H, d, J=8.5Hz, H-3a, 5a), 6.64 (2H, D, J=8.5Hz, H-3b, 5b), 6.62 (1H, J=2.0Hz, H-12b), 6.51 (1H, t, J=1.5Hz, H-12a), 6.49 (2H, d, J=1.5Hz, H-10a, 14a), 2.68-2.71 (2H, m, H2-7b),2.52-2.56(2H,m,H2-8b)；13C NMR (CD3COCD3,125MHz)δ:160.0(2×C),158.0,156.22,156.18,155.7,149.9,137.9,137.6, 133.6,130.1(2×C),128.3(2×C),123.6,121.7,117.0,116.1(2×C),115.7(2×C), 114.0,110.0(2×C),103.2,96.1,38.7,36.0；ESI-MS m/z:455.2[M+H]+,453.2[M-H]-；HR- ESI-MS m/z:477.1314[M+Na]+(calcd.for C28H22NaO6,477.1309).
Embodiment 3:
3- (3,5- Dimethoxyphenyl) -6- methoxyl group -2- (4- methoxyphenyl) -4- [2- (4- methoxybenzene) second Base]-benzofuran (3)
The synthetic route of compound 3:
761mg K is added portionwise with the dissolution of 10ml anhydrous propanone in 250mg compound 2 (0.551mmol)2CO3 (5.507mmol) instills 1955mg CH after stirring 30min3I (13.775mmol), is stirred at room temperature 52h.It is added after fully reacting Water is extracted with ethyl acetate, and organic phase merges, saturated common salt water washing, anhydrous Na2SO4It is dry, be concentrated to dryness 231.9mg is shallow Yellow solid compound 3 (0.443mmol), yield 80.3%, m.p.57-58 DEG C.
Compound 3:UV λmax(MeOH,logε):230.6(3.98),284.6(4.00),319.2(4.33),332(sh, 4.29)nm；1H NMR(CD3COCD3, 500MHz) and δ: 7.46 (2H, d, J=8.5Hz, H-2a, 6a), 7.03 (1H, d, J= 2.0Hz, H-14b), 6.86 (2H, d, J=8.5Hz, H-3a, 5a), 6.79 (2H, d, J=9.0Hz, H-2b, 6b), 6.74 (2H, D, J=9.0Hz, H-3b, 5b), 6.72 (1H, t, J=1.5Hz, H-12a), 6.68 (2H, brs, H-10a, 14a), 6.67 (1H, D, J=2.0Hz, H-12b), 3.86 (3H, s, OCH3),3.80(6H,s,OCH3),3.77(3H,s,OCH3),3.73(3H,s, OCH3),2.66-2.69(2H,m,H-8b),2.55-2.59(2H,m,H-7b)；13C NMR(CD3COCD3,125MHz)δ:162.4 (2×C),160.4,159.1,158.8,155.7,150.1,137.8,137.5,134.5(C),129.9(2×C),128.1(2 ×C),124.3,122.4,117.2,114.7(2×C),114.2(2×C),113.7,109.6(2×C),100.7,94.2, 55.9(OCH3),55.8(2×OCH3),55.5(OCH3),55.4(OCH3),38.4,35.6；ESI-MS m/z:525.3[M+H ]+,547.3[M+Na]+,563.2[M+K]+；HR-ESI-MS m/z:547.2078[M+Na]+(calcd.for C33H32NaO6, 547.2091).
Embodiment 4:
5- [2- [2- (4- acetoxyl group phenyl) -3- (3,5- diacetoxy phenyl) -5- benzofuranyl] ethyl -1, 3- benzenediol -1,3- diacetate esters (4)
The synthetic route of compound 4:
238mg compound 2c (0.360mmol) is added 15.3mg Pd/C (10%), with the dissolution of 15ml ethyl acetate in hydrogen 4h is reacted at room temperature under gas atmosphere, is filtered to remove Pd/C, filtrate decompression concentration obtains 4 231mg of compound as white solid (0.348mmol), yield 96.6%, m.p.130-132 DEG C.
Compound 4:UV λmax((MeOH,logε):311.6(4.39)nm；1H NMR(CD3COCD3,500MHz)δ:7.72 (2H, d, J=8.0Hz, H-2a, 6a), 7.51 (1H, d, J=8.5Hz, H-5b), 7.39 (1H, brs, H-2b), 7.29 (1H, Dd, J=8.5Hz, 1.5Hz, H-6b), 7.18 (2H, d, J=2.0Hz, H-10b, 14b), 7.16 (1H, d, J=8.0Hz, H- 3a, 5a), 7.06 (1H, t, J=2.0Hz, H-12b), 6.91 (2H, d, J=2.0Hz, H-10a, 14a), 6.78 (1H, t, J= 2.0Hz,H-12a),3.01-3.04(2H,m,H-7b),2.95-2.98(2H,m,H-8b),2.27(12H,s,OCOCH3), 2.22(3H,s,OCOCH3)；13C NMR(CD3COCD3,125MHz)δ:169.5(OCOCH3),169.4(2×C,OCOCH3), 169.3(2×C,OCOCH3),153.5,152.9(2×C),152.3,152.2(2×C),151.2,145.1,137.8, 135.1,130.5,128.8(2×C),128.4,127.0,123.1(2×C),121.3(2×C),120.1,120.0(2× C),116.7,116.1,114.2,111.7,38.7,38.1,20.9(5×C,OCOCH3)；ESI-MS m/z:687.2[M+Na ]+,703.2[M+K]+；HR-ESI-MS m/z:665.2022[M+H]+(cacld.for C38H33O11,665.2017).
Embodiment 5:
5- [2- [3- (3,5- dihydroxy phenyl) -2- (4- hydroxy phenyl) -5- benzofuranyl] ethyl] -1,3- benzenediol (5)
The synthetic route of compound 5:
2.5ml methanol dilution is added with the dissolution of 2.5ml methylene chloride in 18.5mg Compound Compound 4 (0.028mmol), Add 343mg NH4OAc (4.458mmol), is stirred at room temperature 4d.Water dilution is added in reaction mixture, and ethyl acetate extraction has For machine mutually respectively with saturated salt solution and water washing, anhydrous sodium sulfate is dry, is concentrated to dryness to obtain yellow solid compound 5 10.6mg (0.023mmol), yield 83.7%, m.p.77-79 DEG C.
Compound 5: yellow solid.UVλmax(MeOH,logε):284.2(4.07),311.4(4.15)nm；1H NMR (CD3COCD3, 500MHz) and δ: 7.55 (2H, d, J=8.0Hz, H-2a, 6a), 7.42 (1H, d, J=8.0Hz, H-5b), 7.33 (1H, brs, H-2b), 7.17 (1H, dd, J=8.0Hz, 1.0Hz, H-6b), 6.85 (2H, d, J=8.0Hz, H-3a, 5a), 6.47 (2H, d, J=2.0Hz, H-10b, 14b), 6.42 (1H, t, J=2.0Hz, H-12b), 6.23 (2H, d, J=2.0Hz, H- 10b, 14b), 6.1 (1H, t, J=2.0Hz, H-12a), 2.93-2.96 (2H, m, H-7b), 2.76-2.79 (2H, m, H-8b)；13C NMR(CD3COCD3,125MHz)δ:159.9(2×C),159.2(2×C),158.7,153.2,151.8,145.0, 137.6,135.7,131.1,129.4(2×C),125.9,123.0,119.9,116.5,116.2(2×C),111.1,108.8 (2×C),107.8(2×C),102.8,101.4,39.3,38.4；ESI-MS m/z:477.2[M+Na]+,493.2[M+K]+； HR-ESI-MS m/z:455.1501[M+H]+(cacld.for C28H23O6,455.1489).
Embodiment 6:
3- (3,5- Dimethoxyphenyl) -2- (4- methoxyphenyl) -5- [2- (4- methoxybenzene) ethyl] benzofuran (6)
The synthetic route of compound 6:
381mg K is added portionwise with the dissolution of 20ml anhydrous propanone in 5 125mg of compound (0.275mmol)2CO3 (2.754mmol) instills 976mg CH after stirring 30min3I (6.875mmol), is stirred at room temperature 52h.Water is added in reaction mixture Dilution, is extracted with ethyl acetate, and organic phase merges, saturated common salt water washing, anhydrous Na2SO4It is dry, it is concentrated to dryness white Sticky 6 115.8mg of shape compound (0.221mmol), yield 80.3%.
Compound 6:UV λmax(MeOH,logε):281.6(4.22),312.4(4.15)nm；1H NMR(CD3COCD3, 500MHz) δ: 7.61 (2H, d, J=9.0Hz, H-2a, 6a), 7.47 (1H, d, J=8.5Hz, H-5b), 7.29 (1H, brs, H- 2b), 7.24 (1H, dd, J=8.5Hz, 2.0Hz, H-6b), 6.94 (2H, d, J=9.0Hz, H-3a, 5a), 6.60 (2H, d, J= 2.5Hz, H-10b, 14b), 6.56 (1H, t, J=2.5Hz, H-12b), 6.39 (2H, d, J=2.0Hz, H-10a, 14a), 6.28 (1H, t, J=2.0Hz, H-12a), 3.82 (3H, s, OCH3),3.78(6H,s,OCH3),3.71(6H,s,OCH3).2.98- 3.02(2H,m,H-7b),2.85-2.88(2H,m,H-8b)；13C NMR(CD3COCD3,125MHz)δ:162.4(2×C), 161.8(2×C),161.0,153.3,151.6,145.0,137.7,135.7,131.0,129.2(2×C),126.1, 123.9,120.1,116.8,114.8(2×C),111.3,108.4(2×C),107.4(2×C),100.4,98.6,55.7 (OCH3),55.6(2×OCH3),55.4(2×OCH3),39.5,38.4；ESI-MS m/z:547.2[M+Na]+,563.2[M+ K]+；HR-ESI-MS m/z:525.2272[M+H]+(cacld.for C33H33O6,525.2272).
Embodiment 7:
5- [2- [4- acetoxy-3-methoxyphenyl]-5- [2- [3,5- diacetoxy phenyl] ethyl]-7- methoxy Base -3- benzofuranyl] -1,3- benzenediol-diacetate esters (7)
The synthetic route of compound 7:
102mg compound 3c (0.141mmol) is added 6.0mg Pd/C (10%), with the dissolution of 10ml ethyl acetate in hydrogen React at room temperature 4h under gas atmosphere, be filtered to remove Pd/C, filtrate decompression concentration, obtain compound as white solid 7 (99mg, 0.137mmol), yield 96.9%, m.p.173-174 DEG C.
Compound 7:UV λmax(MeOH,logε):281.4(4.18)nm；1H NMR(CD3COCD3,500MHz)δ:7.35 (1H, dd, J=8.5Hz, 2.0Hz, H-6a), 7.16-7.17 (3H, m, H-2a, 10b, 14b), 7.10 (1H, d, J=8.5Hz, ), H-5a 7.05 (1H, t, J=2.5Hz, H-12b), 6.900-6.904 (3H, m, H-10a, 14a, 2b), 6.87 (1H, br s, ), H-5b 6.77 (1H, t, J=2.5Hz, H-12a), 4.00 (3H, s, OCH3),3.64(3H,s,OCH3),2.97-2.99(4H, m,H-7b,8b),2.27(6H,s,OCOCH3),2.24(3H,s,OCOCH3),2.23(6H,s,OCOCH3)；13C NMR (CD3COCD3,125MHz)δ:169.5(2×C,OCOCH3),169.4(2×C,OCOCH3),168.8(OCOCH3),152.9(2 ×C),152.3,152.2(2×C),151.1,145.9,145.1,142.7,141.3,138.9,135.6,132.1,129.5, 124.1,121.5(2×C),120.1(2×C),119.8,117.2,116.4,114.2,111.9,111.6,109.7,56.4 (OCH3),56.0(OCH3),38.6,38.5,20.9(4×C,OCOCH3),20.5(OCOCH3)；ESI-MS m/z:747.3[M+ Na]+,763.2[M+K]+；HR-ESI-MS m/z:725.2238[M+H]+(calcd.for C40H37O13,725.2229).
Embodiment 8:
5- [3- (3,5- dihydroxy phenyl) -2- (4- hydroxy 3-methoxybenzene base) -7- methoxyl group -5- benzofuranyl] Ethyl] -1,3- benzenediol (8)
The synthetic route of compound 8:
271mg is added with the dissolution of 2.5ml methylene chloride, 2.5ml methanol dilution in 16mg compound 7 (0.022mmol) NH4OAc solid (3.52mmol), is stirred at room temperature 3d.It is diluted with water, ethyl acetate extraction, organic phase merges, saturated salt solution It washes, washes, anhydrous sodium sulfate is dry, is concentrated to dryness to obtain gray solid compound 8 (9.3mg, 0.018mmol), yield 82.3%, m.p.84-85 DEG C.
Compound 8:UV λmax(MeOH,logε):221.6(sh,5.32),260.4(4.71),333.4(4.13)nm；1H NMR(CD3COCD3,500MHz)δ:7.23-7.24(2H,m,H-2a,6a),6.92(1H,brs,H-2b),6.85(1H,d, 9.0Hz, H-5a), 6.80 (1H, br s, H-6b), 6.49 (2H, d, J=2.0Hz, H-10b, 14b), 6.41 (1H, t, J= 2.0Hz, H-12b), 6.24 (2H, d, J=2.0Hz, H-10a, 14a), 6.18 (1H, t, J=2.0Hz, H-12a), 3.40 (3H, s,OCH3),3.70(3H,s,OCH3),2.91-2.94(2H,m,H-8b),2.77-2.82(2H,m,H-7b)；13C NMR (CD3COCD3,125MHz)δ:160.0(2×C),159.3(2×C),151.6,1489.0,145.7,145.1,142.3, 138.8,135.8,132.6,123.2,121.1,117.0,116.0,112.0,111.3(2×C),107.9(2×C), 102.8,101.1,56.4(OCH3),56.0(OCH3),39.2,38.8；ESI-MS m/z:537.2[M+Na]+,553.1[M+K ]+；HR-ESI-MS m/z:515.1703[M+H]+(calcd.for C30H27O8,515.1700).
Embodiment 9:
2- (3,4- Dimethoxyphenyl) -3- (3,5- Dimethoxyphenyl) -7- methoxyl group -5- [2- (3,4- dimethoxy Phenyl) ethyl] benzofuran (9)
The synthetic route of compound 9:
203mg K is added portionwise with the dissolution of 10ml anhydrous propanone in 75.8mg compound 8 (0.147mmol)2CO3 (1.47mmol) instills 521mg CH after stirring 30min3I (3.675mmol), is stirred at room temperature 52h.Water is added after fully reacting, It is extracted with ethyl acetate, organic phase merges, saturated common salt water washing, anhydrous Na2SO4It is dry, it is concentrated to dryness to obtain light yellow solid It closes object 9 (73.2mg, 0.443mmol), yield 85%, m.p.94-96 DEG C.
Compound 9:UV λmax(MeOH,logε):280(sh,4.49),315.4(4.41)nm；1H NMR(CD3COCD3, 500MHz) δ: 7.28 (1H, dd, J=8.5Hz, 2.0Hz, H-6a), 7.19 (1H, d, J=2.0Hz, H-2a), 6.96 (1H, d, J =8.5Hz, H-5a), 6.87 (1H, brs, H-2b), 6.95 (1H, brs, H-6b), 6.61 (2H, d, J=2.5Hz, H-10b, 14b), 6.57 (1H, t, J=2.5Hz, H-12b), 6.40 (2H, d, J=2.0Hz, H-10a, 14a), 6.29 (1H, t, J= 2.0Hz,H-12a),4.02(3H,s,OCH3),3.82(3H,s,OCH3),3.79(6H,s,OCH3),3.72(6H,s,OCH3), 3.64(3H,s,OCH3),2.96-2.99(2H,m,H-8b),2.86-2.90(2H,m,H-8b)；13C NMR(CD3COCD3, 125MHz)δ:162.4(2×C),161.8(2×C),151.6,150.9,150.0,145.8,145.0,142.4,138.9, 135.9,132.6,124.0,120.6,117.3,112.5,112.1,111.3,109.1,108.6(2×C),107.4(2× C),100.4,98.6,56.4(OCH3),56.0(OCH3),56.8(2×OCH3),55.7(OCH3),55.4(2×OCH3), 39.4,38.8；ESI-MS m/z:607.3[M+Na]+,623.2[M+K]+；HR-ESI-MS m/z:585.2482[M+H]+ (calcd.for C35H37O8,585.2483).
Embodiment 10:
5- [2- [4- (acetoxyl group phenyl] -5- [2- [3,4- diacetoxy phenyl] ethyl] -2,3- dihydro -3- benzo Furyl] -1,3- benzenediol -1,3- diacetate esters (10)
The synthetic route of compound 10:
514mg compound 2b (0.774mmol) is dissolved in 30ml ethyl acetate, is added 31.0mg Pd/C (10%), is passed through 4h is stirred at room temperature in hydrogen, is filtered to remove Pd/C, filtrate decompression concentration, obtain compound as white solid 10 (509.8mg, 0.765mmol), yield 98.9%, m.p.77-78 DEG C.
Compound 10:UV λmax(MeOH,logε):284.4(4.18),349.4(4.12)nm；1H NMR(CD3COCD3, 500MHz) δ: 7.40 (2H, d, J=8.0Hz, H-2a, 6a), 7.13 (2H, d, J=8.0Hz, H-3a, 5a), 7.12 (1H, dd, J =8.5Hz, 1.5Hz, H-6b), 6.93 (1H, t, J=2.0Hz, H-12b), 6.91 (1H, brs, H-2b), 6.90 (2H, d, J= 2.0Hz, H-10b, 14b), 6.87 (2H, d, J=2.0Hz, H-10a, 14a), 6.85 (1H, d, J=8.5Hz, H-5b), 6.75 (1H, t, J=2.0Hz, H-12a), 5.60 (1H, d, J=8.0Hz, H-7a), 4.65 (1H, d, J=8.0Hz, H-8a), 2.81- 2.86(4H,m,H-7b,8b),2.25(3H,s,OCOCH3),2.23(6H,s,OCOCH3),2.22(6H,s,OCOCH3)；13C NMR(CD3COCD3,125MHz)δ:169.6(OCOCH3),169.35(2×C,OCOCH3),169.30(2×C,OCOCH3), 158.9,152.5(2×C),152.1(2×C),151.8,145.3,145.1,139.0,135.5,130.5,130.0,127.8 (2×C),126.1,122.8(2×C),119.9(2×C),119.6(2×C),115.6,114.1,110.0,92.5,57.8, 38.7,37.6,20.9(5×C,COCOCH3)；ESI-MS m/z:689.2[M+Na]+,705.2[M+K]+；HR-ESI-MS m/ z:667.2180[M+H]+(cacld.for C38H35O11,667.2174).
Embodiment 11:
5- [2,3- dihydro -2- (4- hydroxy phenyl) -4- [2- (3,4- dihydroxy phenyl) ethyl] -3- benzofuranyl] - 1,3- benzenediol (11)
The synthetic route of compound 11:
1035mg is added with the dissolution of 5ml methylene chloride, 5ml methanol dilution in 56mg compound 10 (0.084mmol) NH4OAc solid (13.44mmol), is stirred at room temperature 3d.It is diluted with water, ethyl acetate extraction, organic phase merges, saturated salt solution It washes, washes, anhydrous sodium sulfate is dry, is concentrated to dryness to obtain faint yellow solid compound 11 (32.1mg, 0.071mmol), receives Rate is 84.5%, m.p.77-79 DEG C.
Compound 11:UV λmax(MeOH,logε):230.2(sh,4.52),279.8(4.21),315.4(3.92)nm；1H NMR(CD3COCD3, 500MHz) and δ: 7.21 (2H, d, J=8.5Hz, H-2a, 6a), 7.06 (1H, brd, J=9.0Hz, H-6b), 6.87 (1H, brs, H-2b), 6.83 (2H, d, J=8.5Hz, H-3a, 5a), 8.76 (1H, d, J=9.0Hz, H-5b), 6.26 (1H, t, J=1.5Hz, H-12b), 6.26 (2H, d, J=1.5Hz), 6.17 (3H, d, J=2.0Hz, H-10a, 12a, 14a), 5.37 (1H, d, J=8.5Hz, H-7a), 4.40 (1H, d, J=8.5Hz, H-8a), 2.76-2.79 (2H, m, H-8b), 2.67- 2.71(2H,m,H-7b)；13C NMR(CD3COCD3,125MHz)δ:159.6(2×C),159.1(2×C),159.0,158.3, 145.4,145.1,135.3,132.8,131.2,129.4,128.5(2×C),126.0,116.1(2×C),109.6,107.8 (2×C),107.4(2×C),102.2,101.1,93.6,58.2,39.2,38.0；ESI-MS m/z:455.2[M+H]+, 491.8[M+Cl]-；HR-ESI-MS m/z:457.1649[M+H]+(calcd.for C28H25O6,457.1646).
Embodiment 12:
3- (3,5- Dimethoxyphenyl) -2,3- dihydro -2- (4- methoxyphenyl) -5- [2- (3,5- dimethoxy benzene Base) ethyl] benzofuran (12)
The synthetic route of compound 12:
304mg K is added portionwise with the dissolution of 10ml anhydrous propanone in 100mg compound 11 (0.220mmol)2CO3 (2.20mmol) instills 780mg CH after stirring 30min3I (5.50mmol), is stirred at room temperature 52h.Water is added after fully reacting, It is extracted with ethyl acetate, organic phase merges, saturated common salt water washing, anhydrous Na2SO4It is dry, it is concentrated to dryness to obtain light yellow solid It closes object 12 (94.6mg, 0.1798mmol), yield 82%.
Compound 12:UV λmax(MeOH,logε):229(4.63,279.4(4.20),355.2(4.90)nm；1H NMR (CD3COCD3, 500MHz) and δ: 7.30 (2H, d, J=9.0Hz, H-2a, 6a), 7.07 (1h, brd, J=8.0Hz, H-6b), 6.92 (2H, d, J=9.0Hz, H-3a, 5a), 6.88 (1H, br s, H-2b), 6.79 (1h, d, J=8.0Hz, H-5b), 6.42 (1H, T, J=2.0Hz, H-12b), 6.37 (4H, br s, H-10a, 14a, 10b, 14b), 5.52 (1H, d, J=8.5Hz, H-7a), 4.50 (1H, d, J=8.5Hz, H-8a), 3.79 (3H, s, OCH3),3.73(6H,s,OCH3),3.71(6H,s,OCH3),3.77- 3.83(4H,m,H-7b,8b)；13C NMR(CD3COCD3,125MHz)δ:162.1(2×C),161.7(2×C),160.6, 158.9,145.14,145.05,135.4,133.8,131.3,129.6,128.3(2×C),125.8,114.7(2×C), 109.7,107.2(2×C),107.1(2×C),99.4,98.6,93.1,58.4,55.5(3C,OCH3),55.4(2×OCH3), 39.4,37.9；ESI-MS m/z:549.2[M+Na]+,565.2[M+K]+；HR-ESI-MS m/z:527.2432[M+H]+ (cacld.for C33H35O6,527.2428).
Embodiment 13:
5- [2- (4- acetoxy-3-methoxyl group)]-5- [2- [3,5- and acetoxyl group phenyl] ethyl]-2,3- dihydro- 7- methoxyl group -3- benzofuranyl] -1,3- benzenediol diethylester (13)
The synthetic route of compound 13:
132mg compound 3b (0.182mmol) is dissolved in 15ml ethyl acetate, is added 8.23mg Pd/C (10%), is passed through 4h is stirred at room temperature in hydrogen, is filtered to remove Pd/C, filtrate decompression concentration, obtain shallow compound as white solid 13 (130.2mg, 0.179mmol), yield 98.5%, m.p.83-85 DEG C.
Compound 13:UV λmax(MeOH,logε):256(4.88)nm；1H NMR(CD3COCD3,500MHz)δ:7.12 (1H, d, J=1.5Hz, H-2a), 7.04 (1H, d, J=8.0Hz, H-5a), 6.94 (1H, dd, J=8.0Hz, 1.5Hz, H- 6a), 6.93 (3H, brs, H-10b, 12b, 14b), 6.87 (2H, d, J=2.0Hz, H-10a, 14a), 6.81 (1H, br s, H- 2b), 6.75 (1H, t, J=2.0Hz, H-12a), 6.49 (1H, brs, H-6b), 5.58 (1H, d, J=8.0Hz, H-7a), 6.68 (1H, d, J=8.0Hz, H-8a), 3.85 (3H, s, OCH3),3.78(3H,s,OCH3),2.80-2.86(4H,m,H-7b,8b), 2.233(6H,s,OCOCH3),2.225(9H,s,OCOCH3)；169.4(2×C,OCOCH3),169.3(2×C,OCOCH3), 168.9(OCOCH3),152.5(2×C),152.4,152.1(2×C),147.3,145.2,145.1,140.8,140.1, 136.5(2×C),131.6,123.7,120.0(2×C),119.7(2×C),118.7,117.6,115.6,114.2, 114.1,111.1,93.0,58.1,56.4(OCH3),56.2(OCH3),38.6,37.9,20.9(4×C,OCOCH3),20.5 (OCOCH3)；ESI-MS m/z:749.2[M+Na]+,765.2[M+K]+；HR-ESI-MS m/z:727.2391[M+H]+ (calcd for C40H39O13,727.2385).
Embodiment 14:
5- [3- (3,5- dihydroxy phenyl) -2,3- dihydro -2- (4- hydroxy 3-methoxybenzene base) -7- methoxyl group -5- benzene And furyl] ethyl] -1,3- benzenediol (14)
The synthetic route of compound 14:
30.6mg compound 3a (0.060mmol) is dissolved in 5ml ethyl acetate, is added 2.4mg Pd/C (10%), is passed through Hydrogen, atmospheric pressure at room stir 4h, are filtered to remove Pd/C, filtrate decompression concentration, obtain faint yellow solid compound 14 (30.1mg, 0.058mmol), yield 98.0%, m.p.111-112 DEG C.
Compound 14:UV λmax(MeOH,logε):220.6(sh,5.3),272(4.47)nm；1H NMR(CD3COCD3, 500MHz)δ:8.14(2H,s,OH),8.03(2H,s,OH),7.62(1H,s,OH),7.02(1H,brs,H-2b),6.80- 6.81 (2H, m, H-5a, 6a), 6.77 (1H, brs, H-2a), 6.46 (1H, brs, H-6b), 6.26 (1H, t, J=2.0Hz, H- 12b), 6.21 (2H, d, J=2.0Hz, H-10b, 14b), 6.18-6.21 (3H, m, H-10a, 12a, 14a), 5.37 (1H, d, J =9.0Hz, H-7a), 4.45 (1H, d, J=9.0Hz, H-8a), 3.84 (3H, s, OCH3),3.82(3H,s,OCH3),2.76- 2.84(2H,m,H-8b),2.69-2.72(2H,m,H-7b)；13C NMR(CD3COCD3,125MHz)δ:159.6(2×C), 159.2(2×C),148.3,147.51,147.45,145.1(2×C),144.9,136.3,132.9,132.2,120.2, 117.8,115.6,113.7,110.8,107.8(2×C),107.6(2×C),102.3,101.1,94.2,58.5,56.34(3 ×OCH3),56.25(2×OCH3),39.1,38.2；ESI-MS m/z:539.2[M+Na]+,555.1[M+K]+；HR-ESI-MS m/z:517.1866[M+H]+(calcd.for C28H22O6,517.1857).
Embodiment 15:
2- (3,4- Dimethoxyphenyl) -3- (3,5- Dimethoxyphenyl) -2,3- dihydro -7- methoxyl group -5- [2- (3, 5- Dimethoxyphenyl) ethyl] benzofuran (15)
The synthetic route of compound 15:
134mg K is added portionwise with the dissolution of 10ml anhydrous propanone in 50mg compound 14 (0.0969mmol)2CO3 (0.969mmol) instills 345mg CH after stirring 30min3I (2.43mmol), is stirred at room temperature 52h.Water is added after fully reacting, It is extracted with ethyl acetate, organic phase merges, saturated common salt water washing, anhydrous Na2SO4It is dry, it is concentrated to dryness to obtain light yellow solid It closes object 15 (47.30mg, 0.081mmol), yield 83.3%, m.p.121-123 DEG C.
Compound 15:UV λmax(MeOH,logε):231.4(sh,4.48),280.4(4.28),352(4.02)nm；1H NMR(CD3COCD3,500MHz)δ:7.23-7.24(2H,m,H-2a,6a),6.92(1H,brs,H-2b),6.85(1H,d, 9.0Hz, H-5a), 6.80 (1H, br s, H-6b), 6.49 (2H, d, J=2.0Hz, H-10b, 14b), 6.41 (1H, t, J= 2.0Hz H-12b), 6.24 (2H, d, J=2.0Hz, H-10a, 14a), 6.18 (1H, t, J=2.0Hz, H-12a), 3.40 (3H, s,OCH3),3.70(3H,s,OCH3),2.91-2.94(2H,m,H-8b),2.77-2.82(2H,m,H-7b)；13C NMR (CD3COCD3,125MHz)δ:162.1(2×C),161.8(2×C),150.4(2C),147.4,145.1,145.01, 144.97,136.4,134.0,132.3,119.6,117.6,113.9,112.5,110.9,107.3(2×C),107.2(2× C),99.5,98.6,93.7,58.7,56.4(OCH3),56.1(OCH3),55.6(2×OCH3),55.4(3×OCH3),38.3, 38.2；ESI-MS m/z:609.3[M+Na]+,625.2[M+K]+；HR-ESI-MS m/z:587.2648[M+H]+ (calcd.for C35H39O8,587.2639).
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
One, experimental method:
1) cytotoxicity of the compound to human liver cell 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.
Two, experimental result:
1) cytotoxicity: Amurenin H derivative acts on HepG2 cell 48h in 10 μM of concentration, right under the concentration For HepG2 cell without overt toxicity, cell survival rate is greater than 90% (data are not shown).10 μM of concentration of untested compound are selected to use In subsequent experimental.
2) protective effect for causing human liver cell to damage APAP: it the results are shown in Table 1, APAP 8mM effect HepG2 cell 48h generates significant damage, cell survival rate 43.84% to HepG2 cell.Under current experimental program, Amurensin H Derivative 2,3,4,5,11 and 13 is shared in 10 μM of concentration with APAP, has significant protection to HepG2 cellular damage caused by the latter Effect, there is statistical difference compared with model group, and cell survival rate is respectively increased 20.59%, 12.66%, 14.15%, 17.11%, 13.36% and 15.24%.10 μM of concentration of positive control drug bicyclic alcohols (bicyclol) are to liver cell caused by APAP Damage also has 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, with APAP model group
Compare；10 μM of concentration.
Experimental example 2:Amurensin H derivative is to carbon tetrachloride (CCl4) caused by chmice acute toxic liver injury It influences
One, 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, 200 mg/kg group of bicyclic alcohols, 2 50 mg/kg group of compound, 5 50 mg/kg group of compound and compound 11 50 Mg/kg group.The afternoon of each compound dosage group and 200 mg/kg group of bicyclic alcohols on the day before modeling, the upper and lower noon on the same day respectively fill Stomach is administered once, and blank control group and model group animal give the same dose of physiological saline.After last dose 2h, blank pair is removed According to group, each group mouse peritoneal injects 0.15%CCl410ml/kg is primary, and Isodose peanut oil is injected intraperitoneally in blank control group. After mouse is 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 Content.
Two, 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 animal resistance under dosage used to 2,5 and 11 50 mg/kg of compound By good.
Compound is to CCl4The result of acute liver protective effect is caused to see Table 3.0.15%CCl4It can cause The significant hepatic injury of mouse, model group animal blood serum ALT, AST, LDH content are significantly increased compared with blank control group.3 compounds pair CCl4Caused acute liver shows certain inhibitory activity, and wherein compound 2 is in 50 mg/kg dosage Shi Nengxian Write attenuating serum transaminase and LDH content, Serum ALT, AST, LDH content has statistical difference, chemical combination compared with model group Object 2 is better than bicyclic alcohols to the reduction effect of AST and LDH.Compound 11 shows certain liver injury protection activity in 50 mg/kg, 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=9- in mice serum 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: ig.；Dosage: mg/kg.

Claims (16)

1. the plain derivative of a kind of grapevine penta and its pharmaceutically acceptable salt are in preparation treatment and/or prevention liver related disease Application in drug, which is characterized in that such as logical formula (I) of the compound, (II) and (III) it is shown:
Wherein, R1、R6、R11It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C1-6 Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturated alkyl, C3-6's Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R5、R10、R15For monosubstituted or polysubstituted group, wherein described is monosubstituted monosubstituted selected from ortho position, meta position, contraposition；Institute State it is polysubstituted be selected from two substitutions, three replace, four replace；Substituent group is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamine Base, dimethylamino, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6No Saturated hydrocarbyl, C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R2、R3、R4、R7、R8、R9、R12、R13、R14It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、 PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
2. the application of the plain derivative of grapevine penta according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that institute It states shown in compound such as general formula (IA):
Wherein, R5To be monosubstituted or polysubstituted, described is monosubstituted monosubstituted selected from ortho position, meta position, contraposition；Described is polysubstituted Selected from two substitutions, three replace, four replace；Substituent group is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamine Base, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturated alkyl, C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
3. the application of the plain derivative of grapevine penta according to claim 2 and its pharmaceutically acceptable salt, which is characterized in that institute It states shown in compound such as general formula (IAa):
Wherein, R2、R3、R4、R16、R17It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
4. the application of the plain derivative of grapevine penta according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that institute It states shown in compound such as general formula (IB):
Wherein, R5To be monosubstituted or polysubstituted, described is monosubstituted monosubstituted selected from ortho position, meta position, contraposition；Described is polysubstituted Selected from two substitutions, three replace, four replace；Substituent group is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamine Base, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturated alkyl, C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
5. the application of the plain derivative of grapevine penta according to claim 4 and its pharmaceutically acceptable salt, which is characterized in that institute It states shown in compound such as general formula (IBa):
Wherein, R2、R3、R4、R18、R19It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
6. the application of the plain derivative of grapevine penta according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that institute It states shown in compound such as general formula (IIA):
Wherein, R10To be monosubstituted or polysubstituted, described is monosubstituted monosubstituted selected from ortho position, meta position, contraposition；Described is polysubstituted Selected from two substitutions, three replace, four replace；Substituent group is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamine Base, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturated alkyl, C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R7、R8、R9It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
7. the application of the plain derivative of grapevine penta according to claim 6 and its pharmaceutically acceptable salt, which is characterized in that institute It states shown in compound such as general formula (IIAa):
Wherein, R7、R8、R9、R20、R21It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
8. the application of the plain derivative of grapevine penta according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that institute It states shown in compound such as general formula (IIB):
Wherein, R10To be monosubstituted or polysubstituted, described is monosubstituted monosubstituted selected from ortho position, meta position, contraposition；Described is polysubstituted Selected from two substitutions, three replace, four replace；Substituent group is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamine Base, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturated alkyl, C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R7、R8、R9It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
9. the application of the plain derivative of grapevine penta according to claim 8 and its pharmaceutically acceptable salt, which is characterized in that institute It states shown in compound such as general formula (IIBa):
Wherein, R7、R8、R9、R22、R23It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
10. the application of the plain derivative of grapevine penta according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that Shown in the compound such as general formula (IIIA):
Wherein, R15To be monosubstituted or polysubstituted, described is monosubstituted monosubstituted selected from ortho position, meta position, contraposition；Described is polysubstituted Selected from two substitutions, three replace, four replace；Substituent group is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamine Base, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturated alkyl, C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R12、R13、R14、R24It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu, SO3H、 PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
11. the application of the plain derivative of grapevine penta according to claim 10 and its pharmaceutically acceptable salt, which is characterized in that Shown in the compound such as general formula (IIIAa):
Wherein, R12、R13、R14、R24、R25It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu、SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
12. the application of the plain derivative of any one of -11 grapevine penta and its pharmaceutically acceptable salt according to claim 1, It is characterized in that, the compound is selected from following group:
13. application of a kind of pharmaceutical composition in preparation treatment and/or prevention liver related disease drug, by effective dose The plain derivative of the described in any item grapevines of claim 1-12 penta and its pharmaceutically acceptable salt and pharmaceutically acceptable Carrier or auxiliary material composition.
14. application according to claim 13, which is characterized in that the pharmaceutical composition is selected from tablet, capsule, pill, note Penetrate agent.
15. application according to claim 13, which is characterized in that described pharmaceutical composition be selected from sustained release preparation, controlled release preparation and Various particulate delivery systems.
16. application according to claim 1, 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.
CN201810413390.3A 2018-05-03 2018-05-03 Application of the plain derivative of a kind of grapevine penta in preparation treatment liver related disease drug Pending CN110433152A (en)

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CN115246802A (en) * 2021-04-26 2022-10-28 中国医学科学院药物研究所 Vitis vinifera derivatives, preparation method thereof, pharmaceutical composition and application thereof

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Cited By (4)

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CN114073688A (en) * 2020-08-19 2022-02-22 中国医学科学院药物研究所 Application of 2, 3-diaryl derivative in preparation of medicine for treating liver-related diseases
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CN115246802A (en) * 2021-04-26 2022-10-28 中国医学科学院药物研究所 Vitis vinifera derivatives, preparation method thereof, pharmaceutical composition and application thereof
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Application publication date: 20191112