CN109721579A

CN109721579A - The plain derivative of 7,8- dehydrogenation grapevine penta, its preparation method and pharmaceutical composition and purposes

Info

Publication number: CN109721579A
Application number: CN201811265797.2A
Authority: CN
Inventors: 姚春所; 林明宝; 侯琦; 白金叶; 石建功; 张纪法; 杨慧; 滕彬豪
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2017-10-27
Filing date: 2018-10-29
Publication date: 2019-05-07
Anticipated expiration: 2038-10-29
Also published as: CN109721579B

Abstract

The invention discloses plain (Amurensin H) derivative of a kind of novel 7,8- dehydrogenation grapevine penta with anti-inflammatory activity and its anti-inflammatory activities.Replace benzofuran derivatives or its medically acceptable salt specifically related to a kind of new structural 2,3- diaryl -4- as shown in logical formula (I).The invention discloses the application of this kind of derivatives monomer or Pharmaceutical composition in the clinical treatment of inflammatory related disease.

Description

The plain derivative of 7,8- dehydrogenation grapevine penta, its preparation method and pharmaceutical composition and purposes

Technical field

The present invention relates to biomedicine fields, and in particular to one kind has 7, the 8- dehydrogenation grapevine penta of benzofuran structure Plain (Amurensin H) derivative or its medically acceptable salt, the Pharmaceutical composition containing these derivatives and its in inflammation Application in the clinical treatment of disease property related disease.

Background technique

Inflammation is the illness basis of human diseases, and numerous lesion reciprocal causations with disease are the pass of disease pathology process Key link.However, current anti-inflammatory drug, such as corticoid and non-steroid anti-inflammatory drug, there are still more in clinical application Problem such as easily causes alimentary canal discomfort, bleeding, increases the adverse reactions wind such as heart disease or the generation of whole body blood coagulation disorders disease Danger.Therefore, the vital task that safer effective anti-inflammatory drug is still current anti-inflammatory drug research and development is found.

Oligomerization stilbene compound is the new structural natural products of one kind to grow up for nearly 30 years, studies have shown that such Compound has a variety of pharmacological activity, the including [J.Asian such as antibacterial, anti-inflammatory, anti-oxidant, antiviral, anti-senile dementia Nat.Prod.Res., 2016,18 (4): 376-407], there is preferable research and development prospect.Currently, to such compound It extracts separation, Structural Identification and Preliminary activation screening and numerous studies has been carried out.However, naturally being produced since structure is complicated Universal content is less in object, fully synthetic often relatively difficult, and the exploitation that the shortage of sample size greatly limits such compound is ground Study carefully process.Therefore, based on activated oligomeric Stilbene class lead compound, pass through synthesis, structure optimization and structure activity study, hair Now new, the better drug of druggability is of great significance to such compound is developed and used.

Amurensin H is one isolated from folk medicinal plants V. amurensis (Vitis amurensis) root Resveratrol dimer compound [Chin.Chem.Lett., 1999,10 (10): 817-820] with benzofuran structure. Pharmacology activity research discovery, Amurensin H be one to the generation of a variety of inflammatory mediators have the natural activity of inhibiting effect at Divide [Acta.Pharmacol.Sin., 2006,27 (6): 735-740.], animal model test confirms that the compound can be supported significantly Chronic obstructive pulmonary disease (COPD) mouse lung tissue pathology damage is suffered from anti-chronic airway inflammation, alleviation.The pharmacology of further system Experiment display, natural products activity is strong, and toxicity is smaller, is an active lead compound with further investigation value. This study group of research of Amurensin H compound activity aspect itself has disclosed report, but the related system of compounds Structure optimization and anti-inflammatory activity in terms of structure activity study have no document report mistake so far.This patent is related to this compound Structure optimization and structure activity study are carried out to improve the work of its physicochemical property and interior anti-inflammatory activity

Summary of the invention

The technical problem to be solved by the present invention is to 3, the 4- diphenyl -4- for providing a kind of new construction replaces benzofurans Compound and its derivative, preparation method, pharmaceutical composition and purposes.

The first aspect of technical solution of the present invention provide it is a kind of as logical formula (I), (IA), (IAa), (IAb), (IAc), (IAd) and (IB), (IBa), (IBb), (IBc), new construction 2,3- diphenyl -4- shown in (IBd) replace benzofurans Close object and its derivative.

The second aspect of technical solution of the present invention provides a kind of pharmaceutical composition, including at least one such as general formula (I), (IA), (IAa), (IAb), (IAc), (IAd) and (IB), (IBa), (IBb), (IBc), 2,3- hexichol shown in (IBd) Base -4- replaces common carrier in benzofuran compounds and its pharmaceutically acceptable salt and pharmaceutical field.

The third aspect of technical solution of the present invention provides such as general formula ((I), (IA), (IAa), (IAb), (IAc), (IAd) And (IB), (IBa), (IBb), (IBc), 2,3- diphenyl -4- shown in (IBd) replace benzofuran compounds and its pharmacy Upper acceptable salt is preparing the application in the drug for preventing, treating and assisting in the treatment of various inflammatory diseases.

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

The various inflammatory diseases include: rheumatoid arthritis, osteoarthritis, rheumatic arthritis, gouty pass Save inflammation, lupus erythematosus syndrome, bronchitis, bursal synovitis, tenosynovitis, psoriasis, eczema, burn, dermatitis, inflammatory bowel disease, gram Labor grace disease, gastritis, irritable bowel syndrome, ulcerative colitis, multiple sclerosis, Autoimmune Encephalomyelitis, colon The carcinoma of the rectum, arteritis nodosa, thyroiditis, wind-heat be wet, gingivitis, periodontitis, canker sore, ephritis, occurs after damage Swelling, myocardial ischemia, various infectious pneumonias, physics and chemistry pneumonia and allergy pneumonia, Chronic Obstructive Pulmonary Disease, heavy breathing Asthma, proctalgia fugax and rectum split, liver and gallbladder capsulitis, cholangitis, sclerosing cholangitis, primary biliary cirrhosis and gall-bladder It is scorching.Compound of the present invention includes acceptable salt in its derivative and pharmacodynamics.

Specifically, the present invention relates to such as plain derivative (2, the 3- hexichol of 7,8- dehydrogenation grapevine penta shown in logical formula (I) Base -4- replaces benzofuran derivatives) and its pharmaceutically acceptable salt:

Wherein, X is selected from O, NR₆,S；

R₁Selected from H, substituted or unsubstituted C_3-8Naphthenic base, substituted or unsubstituted phenyl, substituted or unsubstituted Yin Diindyl base, substituted or unsubstituted furyl, substituted or unsubstituted naphthalene, substituted or unsubstituted quinolyl, substitution do not take The pyridyl group in generation；Wherein the substituent group of the naphthenic base, phenyl, indyl, furyl, naphthalene, quinolyl and pyridyl group is selected from Hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyl Oxygroup, C_1-6Alkylthio group, methylene-dioxy, carboxyl, F, Cl, Br, I, Glu, SO₃H、PO₃H₂；Replace type include it is monosubstituted, Two substitutions or three substitutions；

L₁Selected from substituted or unsubstituted C_0-16Linear or branched alkyl group, substituted or unsubstituted C_0-16Straight chain or branch Chain acyl, substituted or unsubstituted C_2-16Linear chain or branched chain alkenyl, C_2-6Alkynyl；The substituent group be selected from hydroxyl, nitro, Cyano, amino, methylamino, dimethylamino, phenyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, C_1-6Alkylthio group, F,Cl,Br,I；

R₆Independently selected from H, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Acyl group；Wherein, it takes Dai Ji is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C_1-6Alkoxy, phenyl, F, Cl, Br, I；

R₂、R₃、R₄、R₅It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl 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 7,8- dehydrogenation grapevine penta including but not limited to General formula (IA) compound represented and its pharmaceutically acceptable salt, which is characterized in that the compound is as shown in general formula IA:

Wherein, R₁Selected from H, substituted or unsubstituted C_3-8Naphthenic base, substituted or unsubstituted phenyl, substitution or do not take The indyl in generation, substituted or unsubstituted furyl, substituted or unsubstituted naphthalene, substituted or unsubstituted quinolyl, substitution Or unsubstituted pyridyl group；The wherein substitution of the naphthenic base, phenyl, indyl, furyl, naphthalene, quinolyl and pyridyl group Base is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6 Acyloxy, C_1-6Alkylthio group, methylene-dioxy, carboxyl, F, Cl, Br, I, Glu, SO₃H、PO₃H₂；Replacing type includes singly taking Generation, two substitutions or three substitutions；

, according to the invention it is preferred to general formula (IA) shown in the plain derivative of 7,8- dehydrogenation grapevine penta include but not limiting In general formula (IAa), (IAb), (IAc) compound represented and its pharmaceutically acceptable salt, which is characterized in that the chemical combination Object such as general formula (IAa), (IAb), (IAc) are shown:

Wherein, L₁Selected from substituted or unsubstituted C_0-16Linear or branched alkyl group, substituted or unsubstituted C_0-16Straight chain Or branched chain acyl, substituted or unsubstituted C_2-16Linear chain or branched chain alkenyl；The substituent group is selected from hydroxyl, nitro, cyano, ammonia Base, methylamino, dimethylamino, phenyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, F, Cl, Br, I；

R₇、R₈、R₉It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C_1-6Alkane Base, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, C_1-6Alkylthio group, methylene-dioxy, F, Cl, Br, I, Glu, SO₃H、PO₃H₂；

, according to the invention it is preferred to general formula (IAa), (IAb), the plain derivative of 7,8- dehydrogenation grapevine penta shown in (IAc), And its pharmaceutically acceptable salt, it is characterised in that:

The L₁Selected from C₀、C₁、C₂、C₃Straight chained alkyl；

R₆Independently selected from H, C₁、C₂、C₃Straight chained alkyl；

R₇、R₈、R₉It is each independently selected from hydrogen, hydroxyl, methoxyl group, acetyl group, Cl；

R₂、R₃、R₄、R₅It is each independently selected from hydrogen, methyl.

, according to the invention it is preferred to general formula (IA) shown in the plain derivative of 7,8- dehydrogenation grapevine penta include but not limiting In general formula (IAd) compound represented and its pharmaceutically acceptable salt, which is characterized in that the compound such as general formula (IAd) It is shown:

Wherein, R₁₀Independently selected from hydrogen, substituted or unsubstituted C_3-8Naphthenic base, substituted or unsubstituted C_1-16It is straight Chain or branched alkyl, substituted or unsubstituted C_1-16Linear chain or branched chain acyl group, substituted or unsubstituted C_2-16Linear chain or branched chain Alkenyl, C_2-6Alkynyl；Wherein, the substituent group be selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, F, Cl, Br, I；

R₆Independently selected from H, substituted or unsubstituted C_1-6Alkyl；Wherein, substituent group be selected from hydroxyl, nitro, cyano, Amino, methylamino, dimethylamino, C_1-6Alkoxy, phenyl, F, Cl, Br, I；

R₂、R₃、R₄、R₅It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, Glu, SO₃H、 PO₃H₂, preferably hydrogen, Methyl, acetyl group；

, according to the invention it is preferred to general formula (IAd) shown in the plain derivative of 7,8- dehydrogenation grapevine penta, and its pharmaceutically may be used The salt of receiving, it is characterised in that:

The R₁₀Selected from substituted or unsubstituted C_1-16Linear or branched alkyl group, substituted or unsubstituted C_3-8Ring Alkyl；Wherein, the substituent group is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, F, Cl, Br, I；

R₆Independently selected from hydrogen, C₁、C₂、C₃Straight chained alkyl；

R₂、R₃、R₄、R₅It is each independently selected from hydrogen, methyl, acetyl group；

The R₁₀Selected from substituted or unsubstituted C_3-12Linear or branched alkyl group, substituted or unsubstituted C_5-6Ring Alkyl；Wherein, the substituent group is selected from hydrogen, hydroxyl, methylamino, dimethylamino, methoxyl group, acetyl group, Cl；

, according to the invention it is preferred to logical formula (I) shown in the plain derivative of 7,8- dehydrogenation grapevine penta including but not limited to General formula (IB) compound represented and its pharmaceutically acceptable salt, which is characterized in that the compound such as general formula (IB) institute Show:

Wherein, R₁Selected from H, substituted or unsubstituted C_3-8Naphthenic base, substituted or unsubstituted phenyl, substitution or do not take The indyl in generation, substituted or unsubstituted furyl, substituted or unsubstituted naphthalene, substituted or unsubstituted quinolyl, substitution Or unsubstituted pyridyl group；The substituent group choosing of the naphthenic base, phenyl, indyl, furyl, naphthalene, quinolyl and pyridyl group From hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyl Oxygroup, C_1-6Alkylthio group, methylene-dioxy, carboxyl, F, Cl, Br, I, Glu, SO₃H、PO₃H₂；Replace type include it is monosubstituted, Two substitutions or three substitutions；

, according to the invention it is preferred to general formula (IB) shown in the plain derivative of 7,8- dehydrogenation grapevine penta include but not limiting In general formula (IBa), (IBb), (IBc) compound represented and its pharmaceutically acceptable salt, which is characterized in that the chemical combination Object such as general formula (IBa), (IBb), (IBc) are shown:

Wherein, L₁Selected from substituted or unsubstituted C_0-16Linear or branched alkyl group, substituted or unsubstituted C_0-16Straight chain Or branched chain acyl, substituted or unsubstituted C_2-16Linear chain or branched chain alkenyl；The substituent group is selected from hydroxyl, nitro, cyano, ammonia Base, methylamino, dimethylamino, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, F, Cl, Br, I；

R₁₁、R₁₂、R₁₃It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C_1-6Alkane Base, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, C_1-6Alkylthio group, methylene-dioxy, F, Cl, Br, I, Glu, SO₃H、PO₃H₂；

, according to the invention it is preferred to general formula (IBa), (IBb), the plain derivative of 7,8- dehydrogenation grapevine penta shown in (IBc), And its pharmaceutically acceptable salt, it is characterised in that:

The L₁Selected from C₁、C₂、C₃Straight chained alkyl；

R₁₁、R₁₂、R₁₃It is each independently selected from hydrogen, hydroxyl, methoxyl group, acetyl group, Cl；

R₂、R₃、R₄、R₅It is each independently selected from hydrogen, methyl, acetyl group.

, according to the invention it is preferred to general formula (IB) shown in the plain derivative of 7,8- dehydrogenation grapevine penta include but not limiting In general formula (IBd) compound represented and its pharmaceutically acceptable salt, which is characterized in that the compound such as general formula (IBd) It is shown:

Wherein, R₁₄Independently selected from hydrogen, substituted or unsubstituted C_3-8Naphthenic base, substituted or unsubstituted C_1-16It is straight Chain or branched alkyl, substituted or unsubstituted C_1-16Linear chain or branched chain acyl group, substituted or unsubstituted C_2-16Linear chain or branched chain Alkenyl, C_2-6Alkynyl；Wherein, the substituent group be selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, F, Cl, Br, I；

, according to the invention it is preferred to general formula (IBd) shown in the plain derivative of 7,8- dehydrogenation grapevine penta, and its pharmaceutically may be used The salt of receiving, it is characterised in that:

The R₁₄Selected from substituted or unsubstituted C_1-16Straight chain or straight chained alkyl, substituted or unsubstituted C_3-8Ring Alkyl；Wherein, the substituent group is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C_1-6Alkoxy, C_1-6Acyloxy, F, Cl, Br, I；

The R₁₄Selected from substituted or unsubstituted C_1-16Straight chain or straight chained alkyl, substituted or unsubstituted C_3-8Ring Alkyl；The substituent group is selected from hydrogen, hydroxyl, methylamino, dimethylamino, methoxyl group, acetyl group, Cl；

Specifically, lead to formula (I), (IA), (IAa), (IAb), (IAc), (IAd) and (IB), (IBa), (IBb), (IBc), the plain derivative of 7,8- dehydrogenation grapevine penta shown in (IBd) and its pharmaceutically acceptable salt, which is characterized in that described Compound be selected from following group (compound numbers correspond to embodiment in compound numbers):

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), (IAb), (IAc), (IAd) and (IB), (IBa), (IBb), (IBc), compound described in (IBd) each situation With the pharmaceutical composition of pharmaceutically acceptable carrier.

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.

Another object of the present invention is to provide a kind of benzofuran type talan dimer derivate or it medically may be used The salt of receiving, the hydrate of salt or pro-drug are preparing the application in anti-inflammatory and immunosupress and its related disease drug.

The diseases associated with inflammation includes rheumatoid arthritis, osteoarthritis, rheumatic arthritis, urarthritis Lupus erythematosus syndrome, bronchitis, bursal synovitis, tenosynovitis, psoriasis, eczema, burn, dermatitis, inflammatory bowel disease, Ke Laoen Disease, gastritis, irritable bowel syndrome, ulcerative colitis, multiple sclerosis, Autoimmune Encephalomyelitis, colorectum The swelling that occurs after cancer, arteritis nodosa, thyroiditis, rheumatic fever, gingivitis, periodontitis, canker sore, ephritis, damage, Myocardial ischemia, various infectious pneumonias, physics and chemistry pneumonia and allergy pneumonia, Chronic Obstructive Pulmonary Disease, asthma, convulsion Contraction proctalgia and rectum split, liver and gallbladder capsulitis, cholangitis, sclerosing cholangitis, primary biliary cirrhosis and cholecystitis etc.. The universals of this kind of disease on a cellular level show themselves in that macrophage overactivity, generate excessive NO.

The present invention has carried out the experiment that compound generates NO to the macrophage that inhibition is stimulated through LPS, from cellular level Illustrate that the benzofuran derivatives of invention have the activity for inhibiting macrophage to generate excessive NO.Meanwhile passing through research invention Shadow of the compound to croton oil inducing mouse otitis, the immune response of mouse Delayed onset and carrageenan inducing mouse foot swelling It rings, discovery benzofuran derivatives still have good anti-inflammatory and immunosuppressive activity in vivo.

The fourth 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, 1- (3,5- dimethoxy benzenes Base) -2- bromoacetophenone, alcohols, phenols and the aminated compounds of different structure can be by commercially available or according to prior art system It is standby to obtain.

The basic synthetic method of key reaction raw material compound 1d in the present invention includes the following steps:

Step 1: the preparation of 3- methoxyl group -5- methyl hydroxybenzoate.

3,5- methyl dihydroxy benzoate and iodomethane are in acetone in K₂CO₃It is reacted under solid catalysis, reaction mixing Object is filtered, and is concentrated under reduced pressure, and obtained solid obtains target product 3- methoxyl group -5- hydroxy benzenes first through recrystallization or chromatographic separation and purification Sour methyl esters.

Step 2: 3- methoxyl group -5- methyl hydroxybenzoate is reacted with 1- (3,5- Dimethoxyphenyl) -2- bromoacetophenone Synthesize 3- (2- (3,5- Dimethoxyphenyl) -2- oxygen ethyl) -5- methoxyl methyl benzoate (1a).

3- methoxyl group -5- methyl hydroxybenzoate and 1- (3,5- Dimethoxyphenyl) -2- bromoacetophenone are in anhydrous propanone In in K₂CO₃Heating reflux reaction is carried out under the catalysis of solid, reaction solution is concentrated under reduced pressure, and products therefrom is through recrystallization or chromatography point Target product 1a from purifying.

Step 3: compound 1a cyclization reaction generates compound 1b:

Step 2 products therefrom 1a in methylene chloride, is reacted, reaction solution is washed to by catalyst of Loprazolam Neutrality is concentrated to dryness, and obtained solid product obtains target product 1b through recrystallization or chromatographic separation and purification.In this reaction, urge Agent is Loprazolam (MSA), Bismuth triflate (Bi (OTf)₃), trifluoroacetic acid (TFA), ferric trichloride (FeCl₃), preferably Loprazolam and Bismuth triflate；Reaction temperature is 25-60 DEG C, preferably 40 DEG C.

Step 4: compound 1b reacts synthesis compound 1c with para-bromoanisole:

Compound 1b obtained by step 3 is in DMA solution, in KOAc solid, Pd (OAc)₂Under solid catalysis and to bromobenzene first Ether is in 120 DEG C of reaction 18h.Reaction solution is filtered with diatomite, organic phase removed under reduced pressure at 80-90 DEG C portion of ethyl acetate and DMA, the dilution of remaining mixture ethyl acetate, saturated common salt washing, anhydrous sodium sulfate is dry, evaporated under reduced pressure, residue obtained through weight Crystallization or chromatographic separation and purification obtain target compound compound 1c.

Step 5: compound 1c hydrolysis synthesizes compound 1d:

Compound 1c obtained by step 4 is dissolved in THF, MeOH and H₂In the mixed solution of O (1: 1: 1, v/v/v), with NaOH For catalyst heating reflux reaction, gained reaction solution removes most of solvent under reduced pressure, and 1mol/L is added dropwise into remaining reaction solution HCl solution to no white precipitate be precipitated until.Reaction mixture filters, and obtained solid is dried white to distill water washing The powdered solid chemical compound 1d of color.

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

First method includes the following steps:

Step 1: compound 1d and alcohols, phenols and aminated compounds pass through condensation reaction synthesizing methoxy ester or methoxy Yl amine derivatives.

Compound 1d and alcohols, phenols and aminated compounds are under the catalysis of HOBt and EDCI, in dry methylene chloride Middle carry out condensation reaction, for reaction solution through being concentrated under reduced pressure, products therefrom obtains methoxy base ester or first through recrystallization or chromatographic separation and purification Oxygroup amine target product.

Step 2: methoxy base ester or Methoxyamine derivative removing methyl synthesis phenolic hydroxyl group ester or phenolic hydroxyl group amine derivative.

Step 1 products therefrom in dry methylene chloride with BBr₃Reaction removing methyl is carried out, reaction solution is with water and satisfies It is concentrated under reduced pressure after washing away acid with saline solution, products therefrom obtains phenolic hydroxyl group ester or phenolic hydroxyl group amine through recrystallization or chromatographic separation and purification Target product.Specific reaction temperature is -50 DEG C -25 DEG C.

Second method includes the following steps:

Step 1: compound 1d and alcohols, phenols and aminated compounds carry out condensation reaction synthesizing methoxy ester or methoxy Yl amine derivatives.

Compound 1d and alcohols, phenols and aminated compounds are under the catalysis of DMAP and EDCI, in dry methylene chloride Middle carry out condensation reaction, for reaction solution through being concentrated under reduced pressure, products therefrom obtains methoxy base ester or first through recrystallization or chromatographic separation and purification Oxygroup amine target product.

The product that step 1 obtains in dry methylene chloride with BBr₃Carry out reaction removing methyl, reaction solution with water and After saturated salt solution washes away acid, products therefrom is concentrated under reduced pressure through recrystallization or chromatographic separation and purification and obtains phenolic hydroxyl group ester or phenolic hydroxyl group amine Class target product.Specific reaction temperature is -50 DEG C -25 DEG C.

Advantageous effects

Currently, although having had more document report to the anti-inflammatory activity of the compound with benzofuran structure, Up to the present, not yet to the structure activity study of the system of the talan dimer class compound with benzofuran structure See document report, had no in existing literature and technology about plain (Amurensin H) derivative of 7,8- dehydrogenation grapevine penta or its Medically acceptable salt and such compound are used to treat the report of diseases associated with inflammation；It has no and is taken about 2,3- diphenyl -4 For benzofurans novel compound or its medically acceptable salt and such compound for treating diseases associated with inflammation Report.

Detailed description of the invention:

C_3-8Naphthenic base refer to carbon atom number be 3,4,5,6,7,8 substituted or unsubstituted naphthenic base, C_2-6Alkynyl Refer to that carbon atom number is 2,3,4,5,6 linear chain or branched chain alkynyl, C_0-3Straight chained alkyl refer to that carbon atom number is 0,1,2,3 Straight chained alkyl；C_1-3Straight chained alkyl refer to carbon atom number be 1,2,3 straight chained alkyl, C_1-6Alkyl refer to that carbon atom number is 1,2,3,4,5,6 linear or branched alkyl group, C_1-6Alkoxy refer to carbon atom number be 1,2,3,4,5,6 linear chain or branched chain Alkoxy, C_1-6Acyl group refer to carbon atom number be 1,2,3,4,5,6 linear chain or branched chain acyl group, C_1-6Acyloxy refer to carbon original The linear chain or branched chain acyloxy that subnumber is 1,2,3,4,5,6, C_1-6Alkylthio group refer to carbon atom number be 1,2,3,4,5,6 it is straight Chain or branched alkylthio, C_0-16Linear or branched alkyl group refer to carbon atom number be 0,1,2,3,4,5,6,7,8,9,10,11, 12,13,14,15,16 linear or branched alkyl group, C_0-16Linear chain or branched chain acyl group refer to carbon atom number be 0,1,2,3,4, 5,6,7,8,9,10,11,12,13,14,15,16 linear chain or branched chain acyl group, C_2-16Linear chain or branched chain alkenyl refer to carbon original The linear chain or branched chain alkenyl that subnumber is 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16.

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 specifically describe, be not construed as limitation of the present invention.The synthesis road of intermediate 1d in embodiment Line:

The synthetic route of compound 1~9 in embodiment:

Synthesize final product (compound numbers correspond to the compound numbers in embodiment)

The synthetic method of compound 1~9 in embodiment:

Method A: compound 1d (100mg, 0.23mmol) is dissolved in the dry methylene chloride of 50mL, sequentially adds HOBt (37.6mg, 0.28mmol) and EDCI (53.0mg, 0.28mmol).After 20min is sufficiently stirred, alcohols or phenols chemical combination is added 4h is stirred at room temperature in object (1.2equiv), and TLC monitors raw material and disappears, and stops reaction.Reaction solution is concentrated under reduced pressure, and residue is with silica gel system Slave board preparative separation (selecting suitable solvent according to different compounds) obtains target product.

Method B: compound 1d (100mg, 0.23mmol) is dissolved in the dry methylene chloride of 50mL, sequentially adds DMAP (33.7mg, 0.28mmol) and EDCI (53.0mg, 0.28mmol), after 20min is sufficiently stirred, be added 1.2equiv alcohols or 4h is stirred at room temperature in phenolic compound, and TLC monitors reaction raw materials and disappears, and stops reaction.Reaction solution is concentrated under reduced pressure, and residue is with silica gel It prepares plate preparative separation (selecting suitable solvent according to different compounds) and obtains target product.

Embodiment 1:

2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid monooctyl ester (1)

It is synthesized according to method A, the alcohol compound of addition is n-octyl alcohol (1.2equiv), with petroleum ether: acetone (2: 1) For solvent, silica gel prepares plate preparative separation and obtains target product, yield 32.9%.The physical and chemical parameter of compound 1 is as follows:

Compound 1: faint yellow brown solid, yield=32.9%.¹H NMR(400MHz,acetone-d₆):δ 7.50 (d, J=8.8Hz, 2H), 7.37 (d, J=2.4Hz, 1H), 7.14 (d, J=2.4Hz, 1H), 6.91 (d, J=8.8Hz, 2H), 6.55 (t, J=2.4Hz, 1H), 6.50 (d, J=2.4Hz, 2H), 3.94 (s, 3H), 3.81 (s, 3H), 3.79 (s, 6H), 3.62 (t, J=6.8Hz, 2H), 1.43-1.11 (m, 12H), 0.86 (t, J=6.8Hz, 3H)；¹³C NMR(125MHz, acetone-d₆):δ167.73,162.22(2×C),160.90,158.36,156.13,152.22, 136.96,129.08(2 ×C),127.51,123.66,121.64,116.87,114.75(2×C),113.23,108.53 (2×C),100.51, 99.30,65.65,56.43,55.73(2×C),55.64,32.53,29.96,29.86,29.01, 26.60,23.27, 14.34.(+)-ESI-MS m/z:547.3[M+H]⁺,569.3[M+Na]⁺,585.2[M+K]⁺. HR-ESI-MS m/z: 547.2677[M+H]⁺(calcd.for C₃₃H₃₉O₇,547.2690).

Embodiment 2:

2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -2- furans Methyl ester (2)

It is synthesized according to method A, the alcohol compound of addition is 2- furancarbinol, with petroleum ether: ethyl acetate: methylene chloride It (5: 1: 2) is solvent, silica gel prepares plate preparative separation and obtains target product, yield 47.1%.The physical and chemical parameter of compound 2 is such as Under:

Compound 2: beige solid, yield=54.4%.¹H NMR(500MHz,acetone-d₆):δ7.51(d, J =9.0Hz, 2H), 7.48 (dd, J=2.0,1.0Hz, 1H), 7.37 (d, J=2.0Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 6.91 (d, J=9.0Hz, 2H), 6.59 (t, J=2.0Hz, 1H), 6.51 (d, J=2.0Hz, 2H), 6.36 (dd, J= 3.0,2.0Hz, 1H), 6.31 (d, J=3.0Hz, 1H), 4.58 (s, 2H), 3.93 (s, 3H), 3.81 (s, 3H), 3.80 (s, 6H)；¹³C NMR(125MHz,acetone-d₆):δ167.09,162.28(2×C),160.94, 158.36,156.11, 152.34,150.28,144.15,136.98,129.02(2×C),126.55,123.61,121.96, 116.82,114.77 (2×C),113.29,111.39,111.36,108.48(2×C),100.78,99.72,58.65, 56.47,55.75(2× C),55.64.(+)-ESI-MS m/z:515.0[M+H]⁺,537.2[M+Na]⁺,553.1 [M+K]⁺.HR-ESI-MS m/z: 515.1684[M+H]⁺(calcd.for C₃₀H₂₇O₈,515.1628).

Embodiment 3:

2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -2- phenyl Ethyl ester (3)

Synthesize according to method B, the alcohol compound of addition is benzyl carbinol, with petroleum ether: acetone (2: 1) is solvent, silicon Glue prepares plate preparative separation and obtains target product, yield 47.1%.The physical and chemical parameter of compound 3 is as follows:

Compound 3: beige solid, yield=73.5%.¹H NMR(600MHz,acetone-d₆) δ 7.51 (d, J= 9.0Hz, 2H), 7.36 (d, J=1.8Hz, 1H), 7.28~7.25 (m, 5H), 7.12 (d, J=1.8Hz, 1H), 6.91 (d, J =9.0Hz, 2H), 6.60 (t, J=1.8Hz, 1H), 6.54 (d, J=1.8Hz, 2H), 3.92 (s, 3H), 3.83 (t, J= 7.8Hz, 2H), 3.81 (s, 3H), 3.78 (s, 6H), 2.62 (t, J=7.8Hz, 2H)¹³C NMR (150MHz,acetone- d₆):δ167.60,162.20(2×C),160.84,158.25,156.07,152.24, 138.63,137.10,129.59(2 ×C),129.24(2×C),129.05(2×C),127.24,126.60,123.53, 121.63,116.73,114.71(2× C),113.22,108.47(2×C),100.57,99.46,66.11,56.38, 56.74(2×C),55.60,35.15.(+)- ESI-MS m/z:539.2[M+H]⁺,561.2[M+Na]⁺,577.2 [M+K]⁺.HR-ESI-MS m/z:539.2068[M+H]⁺ (calcd.for C₃₃H₃₁O₇,539.2064).

Embodiment 4:

2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -2- methyl Phenylester (4)

Synthesize according to method A, the alcohol compound of addition is ortho-methyl phenol, with petroleum ether: acetone (2: 1) is expansion Agent, silica gel prepare plate preparative separation and obtain target product, yield 41.6%.The physical and chemical parameter of compound 4 is as follows:

Compound 4: faint yellow brown solid, yield=41.6%.¹H NMR(500MHz,acetone-d₆):7.50 (d, J=9.5Hz, 2H), 7.49 (d, J=3.0Hz, 1H), 7.48 (d, J=3.0Hz, 1H), 7.20 (dd, J=7.5, 2.5Hz, 1H), 7.15~7.08 (m, 2H), 6.89 (d, J=9.5Hz, 2H), 6.70 (dd, J=7.5,2.5Hz, 1H), 6.54 (d, J=2.5Hz, 2H), 6.34 (t, J=2.5Hz, 1H), 3.99 (s, 3H), 3.80 (s, 3H), 3.69 (s, 6H), 2.08 (s, 3H)；¹³C NMR(125MHz,acetone-d₆):δ164.76,162.13(2×C),160.93, 158.25,156.38, 152.76,150.15,137.12,131.53,130.80,128.97(2×C),127.22,126.52, 125.38,123.65, 122.81,122.71,117.16,114.77(2×C),114.66,109.22(2×C),100.58, 100.06,56.53, 55.64,55.58(2×C),16.36.(+)-ESI-MS m/z:525.2[M+H]⁺,547.2 [M+Na]⁺,563.2[M+K]⁺ .HR-ESI-MS m/z:525.1902[M+H]⁺(calcd.for C₃₂H₂₉O₇, 525.1908).

Embodiment 5:

2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -4- acetyl Base phenylester (5)

It is synthesized according to method B, the alcohol compound of addition is parahydroxyacet-ophenone, with petroleum ether: ethyl acetate: dichloromethane Alkane (5: 1: 2) is solvent, and silica gel prepares plate preparative separation and obtains target product, yield 85.5%.The physical and chemical parameter of compound 5 It is as follows:

Compound 5: faint yellow solid, yield=44.5%.¹H NMR(500MHz,acetone-d₆):δ7.94(d, J =9.0Hz, 2H), 7.51 (d, J=2.5Hz, 1H), 7.50 (d, J=9.0Hz, 2H), 7.42 (d, J=2.5Hz, 1H), 6.99 (d, J=9.0Hz, 2H), 6.90 (d, J=9.0Hz, 2H), 6.54 (d, J=2.5Hz, 2H), 6.29 (t, J=2.5Hz, 1H), 3.99(s,3H),3.81(s,3H),3.68(s,6H),2.58(s,3H)；¹³C NMR(125 MHz,acetone-d₆):δ 196.85,165.15,162.31(2×C),161.00,158.32,156.32,154.89, 152.85,136.99,135.58, 130.05(2×C),129.03(2×C),125.17,123.54,122.60,122.19 (2×C),116.92,114.80(2 ×C),114.49,108.95(2×C),100.77,100.11,56.58,55.63(3 ×C),26.71.(+)-ESI-MS m/ z:553.0[M+H]⁺,575.1[M+Na]⁺,591.2[M+K]⁺. HR-ESI-MS m/z:553.1868[M+H]⁺(calcd.for C₃₃H₂₉O₈,553.1857).

Embodiment 6:

2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -4- fluorobenzene Ylmethyl ester (6)

Synthesize according to method A, the alcohol compound of addition is p-fluorophenol, with petroleum ether: acetone (2: 1) is solvent, Silica gel prepares plate preparative separation and obtains target product, yield 85.5%.The physical and chemical parameter of compound 6 is as follows:

Compound 6: beige solid, yield=49.4%.¹H NMR(500MHz,acetone-d₆):δ7.50(d, J =9.0Hz, 2H), 7.39 (d, J=2.0Hz, 2H), 7.24 (d, J=8.5Hz, 1H), 7.20 (d, J=8.5Hz, 1H), 7.18 (d, J=2.0Hz, 1H), 7.09~7.04 (m, 2H), 6.90 (d, J=9.0Hz, 2H), 6.54 (t, J=2.0Hz, 1H), 6.50 (d, J=2.0Hz, 2H), 4.65 (s, 2H), 3.93 (s, 3H), 3.81 (s, 3H), 3.75 (s, 6H)；¹³C NMR (125MHz,acetone-d₆):δ167.37,164.27,162.23(2×C),160.94, 158.37,156.16,152.38, 137.02,133.03,131.07,131.00,129.07(2×C),126.75,123.61, 121.86,116.84,115.92, 115.74,114.77(2×C),113.47,108.51(2×C),100.68,99.66, 66.22,56.46,55.69(2× C),55.65.(+)-ESI-MS m/z:543.3[M+H]⁺,565.2[M+Na]⁺, 581.2[M+K]⁺.HR-ESI-MS m/z: 543.1813[M+H]⁺(calcd.for C₃₂H₂₈FO₇,543.1814).

Embodiment 7:

2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -4- chlorobenzene Base ester (7)

It is synthesized according to method B, the alcohol compound of addition is parachlorophenol (1.2equiv), with petroleum ether: acetone (2: 1) For solvent, silica gel prepares plate preparative separation and obtains target product, yield 85.5%.The physical and chemical parameter of compound 7 is as follows:

Compound 7: pale yellow oily liquid, yield=85.5%.¹H NMR(500MHz,acetone):δ7.50 (d, J=9.0Hz, 2H), 7.49 (d, J=2.5Hz, 1H), 7.39 (d, J=2.5Hz, 1H), 7.34 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0Hz, 2H), 6.87 (d, J=8.9Hz, 2H), 6.53 (d, J=2.5Hz, 2H), 6.33 (t, J=2.5Hz, 1H),3.98(s,3H),3.80(s,3H),3.70(s,6H)；¹³C NMR(125MHz, acetone-d₆):δ165.36, 162.27(2×C),160.95,158.28,156.27,152.78,150.04,136.99, 131.11,129.60(2×C), 128.99(2×C),125.22,123.77(2×C),123.51,122.49,116.86, 114.77(2×C),114.37, 108.95(2×C),100.65,100.06,56.55,55.63(3×C). (+)-ESI-MS m/z:545.1[M+H]⁺, 567.2[M+Na]⁺,583.1[M+K]⁺.HR-ESI-MS m/z: 545.1356[M+H]⁺(calcd.for C₃₁H₂₆ClO₇, 545.1362)..

Embodiment 8:

2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -4- bromobenzene Ylmethyl ester (8)

Synthesize according to method A, the alcohol compound of addition is p bromophenol, with petroleum ether: acetone (2: 1) is solvent, Silica gel prepares plate preparative separation and obtains target product, yield 47.1%.The physical and chemical parameter of compound 8 is as follows:

Compound 8: white solid, yield=47.1%.¹H NMR(500MHz,acetone-d₆): δ 7.50 (d, J= 8.5Hz, 2H), 7.48 (d, J=8.0Hz, 2H), 7.39 (d, J=2.0Hz, 1H), 7.19 (d, J=2.0Hz, 1H), 7.13 (d, J=8.0Hz, 2H), 6.90 (d, J=8.5Hz, 2H), 6.51 (t, J=2.0Hz, 1H), 6.48 (d, J=2.0Hz, 2H), 4.65(s,2H),3.94(s,2H),3.81(s,2H),3.73(s,6H)；¹³C NMR(125 MHz,acetone-d₆):δ 167.35,162.20(2×C),160.95,158.37,156.17,152.40,136.99, 136.26,132.17(2×C), 130.70(2×C),129.07(2×C),126.60,123.59,122.18,121.90, 116.83,114.77(2×C), 113.53,108.48(2×C),100.65,99.74,66.15,56.47,55.68(2× C),55.65.(+)-ESI-MS m/ z:641.1[M+K]⁺.HR-ESI-MS m/z:603.1017[M+H]⁺(calcd. for C₃₂H₂₈BrO₇,603.1013).

Embodiment 9:

2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -1H- benzo Triazole -1- base ester (9)

It is synthesized according to method B, the alcohol compound of addition is I-hydroxybenzotriazole monohydrate, with petroleum ether: acetic acid Ethyl ester: methylene chloride (3: 1: 2) is solvent, and silica gel prepares plate preparative separation and obtains target product, yield 47.1%.Compound 9 physical and chemical parameter is as follows:

Compound 9: faint yellow solid, yield=20.5%.¹H NMR(500MHz,acetone-d₆):δ8.11(d, J =8.0Hz, 1H), 7.84 (t, J=8.0Hz, 1H), 7.80 (d, J=8.0Hz, 1H), 7.65 (t, J=8.0Hz, 1H), 7.49 (d, J=2.5Hz, 1H), 7.47 (d, J=9.0Hz, 2H), 7.24 (d, J=2.5Hz, 1H), 6.87 (d, J=9.0Hz, 2H), 6.22 (d, J=2.0Hz, 2H), 5.60 (t, J=2.0Hz, 1H), 4.00 (s, 3H), 3.79 (s, 3H), 3.57 (s, 6H)；¹³C NMR(125MHz,acetone):δ164.82,161.59(2×C),161.02, 158.67,155.37,152.16,134.74, 133.80,133.40,132.89,128.73(2×C),127.70,126.70, 123.20,122.59,116.25,116.13, 115.86,114.83(2×C),112.96,107.29(2×C),100.00, 99.74,56.62,55.62,55.32.(+)- ESI-MS m/z:551[M+H]⁺,574[M+Na]⁺,590[M+K]⁺； HR-ESI-MS m/z:574.1561[M+Na]⁺ (calcd.for C₃₁H₂₅N₃NaO₇,574.1585).

The method of methoxyl group is removed in embodiment 10,11:

2,3- diaryl substitute amide derivatives (about 70mg) are dissolved in the dry methylene chloride of 30mL, are cooled to -50 ℃.It is vigorously stirred down, is slowly dropped into BBr₃Dichloromethane solution [BBr₃(12equiv, 1mmol/L in DCM) is dissolved in 15mL In dry methylene chloride].It is added dropwise, keeps -50 DEG C of stirring 2h, be successively to slowly warm up to -25 DEG C, -10 DEG C and 0 DEG C, and - 2h is stirred respectively at 25 DEG C, -10 DEG C and 0 DEG C.Overnight, TLC monitors end of reaction for room temperature reaction.Reaction solution is cooled to -50 DEG C, drop Enter 6mL analysis methanol, reaction solution is with the dilution of 100mL ethyl acetate, and 50mL washing, saturated common salt washing, water phase is with ethyl acetate Back extraction, organic phase merge, and anhydrous sodium sulfate is dry, are concentrated under reduced pressure, and residue is with the mixed solvent of ethyl acetate and methanol (or third The mixed solvent of ketone and methanol) dissolution, plate is prepared with silica gel and separates to obtain crude product, crude product further obtains target chemical combination with gel-purified Object sterling.Gel-purified is needed once in a while usually using methanol as eluant, eluent with chloroform: methanol (3: 7) is eluted.

Embodiment 10:

2- (4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofurancarboxylic acid (10)

Compound 1d is raw material, is reacted according to the method for removing methoxyl group.With methylene chloride: methanol (10: 1) is Solvent, silica gel prepare plate separation and are prepared into compound 10.

Compound 10: light khaki solid (20.6mg, 23.7%).¹H NMR(500MHz,CD₃OD): δ 7.35 (d, J= 9.0Hz, 2H), 6.89 (d, J=2.0Hz, 1H), 6.83 (d, J=2.0Hz, 1H), 6.68 (d, J=9.0 Hz, 2H), 6.34 (d, J=2.0Hz, 2H), 6.24 (s, 1H)¹³C NMR(150MHz,CD₃OD ₆):δ 175.73,159.25(2×C), 158.38,156.55,155.92,151.40,136.94,136.85,129.20(2×C), 123.97,119.88,117.51, 115.99(2×C),111.55,110.10,103.08,98.26.(-)-ESI-MS m/z: 377[M-H]^-；HR-ESI-MS m/z:379.0812[M+H]⁺(calcd.for C₂₁H₁₅O₇,379.0812).

Embodiment 11:

2- (4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofurancarboxylic acid methyl esters (11)

Compound 1c is raw material, is reacted according to the method for removing methoxyl group.With methylene chloride: methanol (20: 1) is Solvent, silica gel prepare plate separation and are prepared into compound 11.

Compound 11: hazel-color solid (44.4mg, 12.7%).¹H NMR(500MHz,acetone-d₆):δ 8.56 (s, 3H), 7.44 (d, J=9.0Hz, 2H), 7.18 (d, J=2.0Hz, 1H), 7.12 (d, J=2.0Hz, 1H), 6.80 (d, J =9.0Hz, 2H), 6.41 (t, J=2.0Hz, 1H), 6.30 (d, J=2.0Hz, 2H), 3.25 (s, 3H)¹³C NMR (125MHz,acetone):δ168.09,159.78(2×C),158.62,156.11,155.68, 151.96,137.39, 129.06(2×C),126.68,122.85,121.49,116.59,116.10(2×C),113.82, 109.07,102.48, 101.33,51.39.(+)-ESI-MS m/z 414.9[M+Na]⁺,431.0[M+K]⁺.HR- ESI-MS m/z:415.0794[M +Na]⁺(calcd.for C₂₂H₁₆NaO₇,415.0788).

The synthetic route of compound 12~26 in embodiment:

The synthetic method of compound 12~26 in embodiment:

Synthetic method A: compound 1d (100mg, 0.23mmol) is dissolved in the dry methylene chloride of 50mL, sequentially adds HOBt (37.6mg, 0.28mmol) and EDCI (53.0mg, 0.28mmol), is sufficiently stirred 20 min.Amine is added in reaction solution 4h is stirred at room temperature in compound (1.2equiv), and TLC monitors reaction raw materials and disappears, and stops reaction.Reaction solution is concentrated under reduced pressure, gained Residue prepares plate separation (solvent is selected according to different situations) with silica gel and obtains corresponding product.

Synthetic method B: compound 1d (100mg, 0.23mmol) is dissolved in the dry methylene chloride of 50mL, sequentially adds After 20min is sufficiently stirred, aminated compounds is added in DMAP (33.7mg, 0.28mmol) and EDCI (53.0mg, 0.28mmol) 4h is stirred at room temperature in (1.2equiv), and TLC monitors raw material and disappears, and stops reaction.Reaction solution is concentrated under reduced pressure, and residue is with silica gel system Slave board separates (solvent is selected according to different situations) and obtains corresponding product.

Embodiment 12:

N- methyl -2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran formyl Amine (12)

The aminated compounds of reference method A synthesis, addition is methylamine, with methylene chloride: methanol (40: 1) is solvent, Silica gel prepares plate preparative separation and obtains, yield 65.7%.The physical and chemical parameter of compound 12 is as follows:

Khaki solid, yield=65.7%.¹H NMR(500MHz,acetone-d₆): δ 7.51 (d, J=8.5 Hz, 2H), 7.22 (d, J=1.5Hz, 1H), 6.90 (d, J=8.5Hz, 2H), 6.88 (d, J=1.5Hz, 1H), 6.67 (d, J =4.0Hz, 1H), 6.52 (s, 3H), 3.90 (s, 3H), 3.81 (s, 3H), 3.79 (s, 6H), 2.33 (d, J=4.5Hz, 3H) ；¹³C NMR(125MHz,acetone-d₆):δ167.79,162.13(2×C),160.76, 158.67,155.84,151.28, 136.12,133.03,128.78(2×C),123.85,120.63,116.70,114.79 (2×C),111.63,108.65(2 ×C),100.94,97.43,56.30,55.70(2×C),55.63,26.05. (+)-ESI-MS m/z:470.2[M+Na]⁺, 486.1[M+K]⁺.HR-ESI-MS m/z:448.1761[M+H]⁺ (calcd.for C₂₆H₂₆NO₆,448.1755).

Embodiment 13:

N- propyl -2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran formyl Amine (13)

Synthesize according to method B, the aminated compounds of addition is n-propylamine, with petroleum ether: acetone (2: 1) is solvent, silicon Glue prepares plate preparative separation and obtains, yield 84.9%.The physical and chemical parameter of compound 13 is as follows:

Compound 13: khaki solid, yield=84.9%.¹H NMR(500MHz,acetone-d₆):δ7.50 (d, J=9.0Hz, 2H), 7.22 (d, J=2.5Hz, 1H), 6.90 (d, J=9.0Hz, 2H), 6.89 (d, J=2.5 Hz, 1H), 6.70 (brs, 1H), 6.54 (d, J=2.0Hz, 2H), 6.52 (t, J=2.0Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.78 (s, 6H), 2.75 (dd, J=13.0,6.5Hz, 2H), 1.23-1.31 (m, 2H), 0.78 (t, J=7.5Hz, 3H)；¹³C NMR(125MHz,acetone-d₆):δ167.37,162.11(2×C),160.72, 158.63,155.85,151.29, 136.13,133.24,128.80(2×C),123.84,120.59,116.83(2×C), 114.77,111.78,108.79(2 ×C),100.85,97.31,56.30,55.67(2×C),55.63,42.08,22.88, 11.83.(+)-ESI-MS m/z: 476.1[M+H]⁺,498.1[M+Na]⁺,514.0[M+K]⁺.HR-ESI-MS m/z:476.2025[M+H]⁺(calcd.for C₂₈H₃₀NO₆,476.2068).

Embodiment 14:

N- dodecyl -2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran Formamide (14)

The aminated compounds of reference method A synthesis, addition is lauryl amine, with petroleum ether: acetone (2: 1) is solvent, silicon Glue prepares plate preparative separation and obtains, yield 96.2%.The physical and chemical parameter of compound 14 is as follows:

Compound 14: reddish tan solid, yield=96.2%.¹H NMR(500MHz,acetone-d₆):δ7.49 (d, J=8.5Hz, 2H), 7.22 (d, J=2.5Hz, 1H), 6.90 (d, J=8.5Hz, 2H), 6.89 (d, J=2.5 Hz, 1H), 6.67 (t, J=5.0Hz, 1H), 6.54 (d, J=2.5Hz, 2H), 6.52 (t, J=2.5Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.79 (s, 6H), 2.77 (t, J=7.0Hz, 2H), 1.28 (m, 20H), 0.87 (t, J=7.0Hz, 3H)；¹³C NMR (125MHz,acetone-d₆):δ167.34,162.11(2×C),160.75,158.64, 155.87,151.33,136.14, 133.24,128.83(2×C),123.87,120.54,116.82,114.77(2×C), 111.82,108.76(2×C), 100.98,97.33,56.31,55.69(2×C),55.63,40.39,32.65,30.40- 30.36(5×C),30.09(2× C),27.85,23.33,14.36.(+)-ESI-MS m/z:602.4[M+H]⁺, 624.4[M+Na]⁺,640.3[M+K]⁺.HR- ESI-MS m/z:602.3481[M+H]⁺(calcd.for C₃₇H₄₈NO₆,602.3476).

Embodiment 15:

N- (3- dimethylamino -1- propyl) -2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxy Base -4- benzofuran carboxamides (15)

The aminated compounds of reference method B synthesis, addition is N'N- dimethyl -1,3- propane diamine, with chloroform: methanol (6: It 1) is solvent, silica gel prepares plate preparative separation and obtains, yield 95.0%.The physical and chemical parameter of compound 15 is as follows:

Compound 15: beige solid, yield=95.0%.¹H NMR(500MHz,acetone-d₆):δ7.50 (d,J =9.0Hz, 1H), 7.22 (s, 1H), 7.14 (s, 1H), 6.91 (s, 1H), 6.90 (d, J=9.0Hz, 2H), 6.55 (s, 2H), 6.52 (s, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.79 (s, 6H), 2.90 (dd, J=12.5,6.5 Hz, 2H), 2.33 (s, 6H), 1.61-1.46 (t, J=6.5Hz, 2H), 0.87 (d, J=6.5Hz, 2H) (+)-ESI-MS m/z:519.3 [M+ H]⁺.

Embodiment 16:

[N-2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran formoxyl] egg Propylhomoserin methyl esters (16)

Reference method B synthesis, compound 1d (100mg, 0.23mmol) are dissolved in the dry methylene chloride of 50mL, successively plus Enter DMAP (33.7mg, 0.28mmol), EDCI (53.0mg, 0.28mmol) and DIPEA (114 μ L, 0.69mmol), stirs After 20min, the L-Methionine methyl esters of 1.2equiv is added.4h is stirred at room temperature in reaction solution, and TLC monitors reaction raw materials and disappears, stops Reaction.Reaction solution is concentrated under reduced pressure, and residue is with petroleum ether: acetone (3: 2) prepares plate preparative separation for solvent silica gel and obtains target Product.

Compound 16: faint yellow solid, yield=38.9%.¹H NMR(500MHz,acetone-d₆):δ7.48(d, J =8.8Hz, 2H), 7.26 (d, J=2.2Hz, 1H), 7.25 (s, 1H), 6.92 (d, J=2.3Hz, 1H), 6.90 (d, J= 8.8Hz, 2H), 6.52 (s, 3H), 4.12 (q, J=6.7Hz, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 3.79 (s, 6H), 3.69 (s, 3H), 2.35 (dt, J=9.1,6.4Hz, 2H), 2.04 (s, 3H), 1.75-1.68 (m, 2H)¹³C NMR (125MHz,CD₃OD):δ172.56,167.79,161.86(2×C),160.73,158.49, 155.84,151.52, 135.76,132.00,128.90(2×C),123.74,120.46,116.77,114.73(2×C), 112.04,108.80, 100.73,97.48,56.30,55.61(2×C),53.10,53.00,52.34,31.94,30.52, 15.08.(+)-ESI- MS m/z:580.0[M+H]⁺,602.1[M+Na]⁺,618.1[M+K]⁺.HR-ESI-MS m/z:580.2009[M+H]⁺ (calcd.for C₃₁H₃₄O₈S,580.2000).

Embodiment 17:

N- cyclopenta -2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran first Amide (17)

The aminated compounds of reference method A synthesis, addition is cyclopentamine, with methylene chloride: methanol (30: 1) is solvent, Silica gel prepares plate preparative separation and obtains, yield 92.1%.

The physical and chemical parameter of compound 17 is as follows:

Compound 17: khaki solid, yield=92.1%.¹H NMR(500MHz,acetone-d₆):δ7.48 (d, J=9.0Hz, 2H), 7.20 (d, J=2.5Hz, 1H), 6.90 (d, J=9.0Hz, 2H), 6.86 (d, J=2.5 Hz, 1H), 6.74 (d, J=6.0Hz, 1H), 6.53 (d, J=2.0Hz, 2H), 6.52 (t, J=2.0Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.78 (s, 6H), 3.72 (q, J=6.5Hz, 1H), 1.71-1.62 (m, 2H), 1.57-1.50 (m, 2H), 1.48- 1.38(m,2H),1.25–1.16(m,2H)；¹³C NMR(125MHz, acetone-d₆):δ167.25,162.05(2×C), 160.71,158.58,155.83,151.25,136.03,133.43, 128.83(2×C),123.88,120.46,116.96, 114.74(2×C),111.89,108.85(2×C),100.91, 97.13,56.29,55.64(3×C),52.23,33.04, 29.84(2×C),24.45(2×C).(+)-ESI-MS m/z: 502.2[M+H]⁺,524.2[M+Na]⁺,540.5[M+K]⁺ .HR-ESI-MS m/z:502.2242[M+H]⁺ (calcd.for C₃₀H₃₂NO₆,502.2224).

Embodiment 18:

N- (2- furyl base) -2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzo Furoylamide (18)

The aminated compounds of reference method B synthesis, addition is furylamine, with petroleum ether: acetone (5: 2) is solvent After silica gel prepares plate preparative separation, then obtained with acetone recrystallization.

The physical and chemical parameter of compound 18 is as follows:

Compound 18: white chunks crystallization, yield=88.1%.¹H NMR(500MHz,acetone-d₆):δ7.52 (d, J=9.0Hz, 2H), 7.39 (d, J=2.0Hz, 1H), 7.24 (d, J=2.0Hz, 1H), 7.11 (t, J=5.0 Hz, 1H), 6.92 (d, J=2.0Hz, 1H), 6.91 (d, J=9.0Hz, 1H), 6.57 (d, J=2.0Hz, 2H), 6.55 (t, J=2.0Hz, 1H), 6.30 (dd, J=3.0,2.0Hz, 1H), 6.13 (d, J=3.0Hz, 1H), 3.91 (d, J=5.8Hz, 2H), 3.90 (s, 3H),3.81(s,3H),3.80(s,6H)；¹³C NMR(125MHz, acetone-d₆):δ167.21,162.16(2×C), 160.76,158.62,155.83,152.76,151.36,142.71, 136.17,132.36,128.75(2×C),123.81, 120.77,116.70,114.78(2×C),111.72,111.12, 108.71(2×C),107.70,101.03,97.66, 56.32,55.70(2×C),55.62,37.00.(+)-ESI-MS m/z:514.2[M+H]⁺,536.2[M+Na]⁺,552.5[M+ K]⁺.HR-ESI-MS m/z:514.1859[M+H]⁺ (calcd.for C₃₀H₂₈NO₇,514.1860).

Embodiment 19:

N- (phenyl methyl) -2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzo furan It mutters formamide (19)

Reference method A synthesis, the aminated compounds of addition are benzylamine.Petroleum ether: ethyl acetate: methylene chloride (3: 1: 2) It prepares plate preparative separation for solvent with silica gel to obtain, yield 93.2%.

The physical and chemical parameter of compound 19 is as follows:

Compound 19: beige solid, yield=93.2%.¹H NMR(500MHz,acetone-d₆):δ7.51 (d,J =9.0Hz, 2H), 7.26 (t, J=7.0Hz, 2H), 7.24 (d, J=2.5Hz, 1H), 7.20 (d, J=7.0 Hz, 1H), 7.16 (d, J=7.0Hz, 2H), 6.95 (d, J=2.5Hz, 1H), 6.90 (d, J=9.0Hz, 2H), 6.59 (d, J=2.5Hz, 2H), 6.57 (t, J=2.5Hz, 1H), 3.96 (d, J=5.8Hz, 2H), 3.90 (s, 3H), 3.81 (s, 3H), 3.80 (s, 6H)；¹³C NMR(125MHz,acetone-d₆):δ167.43,162.17(2×C), 160.76,158.63,155.89,151.41, 139.80,136.21,132.71,129.09(2×C),128.81(2×C), 128.48(2×C),127.67,123.85, 120.72,116.79,114.78(2×C),111.92,108.83(2×C), 101.10,97.55,56.33,55.72(2× C),55.63,43.94.(+)-ESI-MS m/z:522.5[M-H]^-,546.2 [M+Na]⁺.HR-ESI-MS m/z:524.2077 [M+H]⁺(calcd.for C₃₂H₃₀NO₆,524.2068).

Embodiment 20:

N- methyl-N- (phenyl methyl) -2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- Benzofuran carboxamides (20)

Reference method B synthesis, the aminated compounds of addition are N- benzylmethylamine.With petroleum ether: ethyl acetate: methylene chloride =3:1:2 is that solvent carries out preparing plate and purifies to obtain, yield 71.8%.

Compound 20: beige solid (a pair of of enantiomter), yield=71.8%.¹H NMR(500MHz, acetone-d₆): δ 7.55 (d, J=8.9Hz, 2H), 7.54 (d, J=8.9Hz, 2H), 7.16-7.34 (m, 8H), 7.03- 7.08 (m, 2H), 6.92 (d, J=8.8Hz, 2H), 6.84 (d, J=2.3Hz, 1H), 6.80 (d, J=2.2 Hz, 1H), 6.65 (d, J=2.3Hz, 2H), 6.62 (d, J=2.3Hz, 2H), 6.60 (t, J=2.3Hz, 1H), 6.56 (t, J=2.3Hz, 1H), 4.97 (d, J=14.3Hz, 1H), 4.41 (d, J=15.9Hz, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.84 (s, 6H), 3.83 (s, 6H), 3.82 (s, 6H), 3.59 (d, J 22=15.9Hz, 1H), 3.13 (d, J=14.6Hz, 1H), 2.42 (s, 3H),2.39(s,3H).¹³C NMR(125MHz,acetone-d₆): δ168.07,167.98,161.13(2×C),161.04 (2×C),159.91(2×C),158.23,158.11, 154.77,154.58,150.57,137.38,137.05,134.16, 134.09,130.88,130.65,128.53(2×C), 128.45(2×C),127.95(2×C),127.90(2×C), 127.88(2×C),127.29,127.08,126.95 (2×C),122.80,119.30,118.98,115.77,113.91(4 ×C),110.38,110.12,107.78(4×C), 100.57,100.52,95.93,95.86,55.43,55.36,54.88 (2×C),54.86(2×C),54.74,54.22, 54.07,49.24,35.13,30.96.(+)-ESI-MS m/z:538.2 [M+H]⁺,560.2[M+Na]⁺,576.2 [M+K]⁺.HR-ESI-MS m/z:538.2222[M+H]⁺(calcd.for C₃₃H₃₂NO₆,538.2224).

Embodiment 21:

N- (4- aminomethyl phenyl) -2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzo Furoylamide (21)

Reference method B synthesis, the aminated compounds of addition are para-totuidine.With petroleum ether: acetone (2: 1) is solvent Silica gel prepares plate preparative separation and obtains, yield 63.4%.

The physical and chemical parameter of compound 21 is as follows:

Compound 21: white solid, yield=63.4%.¹H NMR(500MHz,acetone-d₆):δ8.64(s, 1H), 7.53 (d, J=9.0Hz, 2H), 7.33 (d, J=8.5Hz, 2H), 7.28 (d, J=2.5Hz, 1H), 7.01 (d, J= 2.5Hz, 1H), 6.99 (d, J=8.5Hz, 2H), 6.90 (d, J=9.0Hz, 2H), 6.50 (d, J=2.5Hz, 2H), 6.05 (t, J=2.5Hz, 1H), 3.93 (s, 3H), 3.80 (s, 3H), 3.61 (s, 6H), 2.28 (s, 3H)¹³C NMR(125MHz, acetone-d₆):δ168.82,161.59(2×C),161.02,158.67,155.37,152.16, 134.74,133.80, 133.40(2×C),132.89,128.73(2×C),127.70(2×C),126.70,123.20, 122.59,116.25, 116.13,115.87,114.83(2×C),112.96,107.29(2×C),99.99,99.74, 56.22,55.62,55.32 (2×C),29.50.(+)-ESI-MS m/z:524.2[M+H]⁺,546.2[M+Na]⁺, 562.2[M+K]⁺.HR-ESI-MS m/ z:524.2061[M+H]⁺(calcd.for C₃₂H₃₀NO₆,524.2068).

Embodiment 22:

N- (4- chlorphenyl) -2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzo furan It mutters formamide (22)

Reference method B synthesis, the aminated compounds of addition are parachloroanilinum.With petroleum ether: acetone (2: 1) is solvent Silica gel prepares plate preparative separation and obtains, yield 53.5%.

The physical and chemical parameter of compound 22 is as follows:

Compound 22: white solid, yield=53.5%.¹H NMR(500MHz,acetone-d₆)δ8.85(s, 1H), 7.52 (d, J=9.0Hz, 2H), 7.47 (d, J=9.0Hz, 2H), 7.29 (s, 1H), 7.18 (d, J=9.0Hz, 2H), 7.01 (s, 1H), 6.89 (d, J=9.0Hz, 2H), 6.47 (s, 2H), 6.03 (d, J=2.0Hz, 1H), 3.92 (s, 3H), 3.79 (s, 3H),3.62(s,6H)；¹³C NMR(125MHz,acetone-d₆):δ166.04,162.11 (2×C),160.81,158.72, 155.80,151.45,138.53,135.71,132.19,128.72(2×C),128.70 (2×C),128.32,123.68, 121.21(2×C),121.11,116.61,114.81(2×C),111.77,108.51 (2×C),100.00,98.20, 56.43,55.63,55.39.(+)-ESI-MS m/z:544.1[M+H]⁺,566.2 [M+Na]⁺,582.2[M+K]⁺.HR-ESI- MS m/z:544.1529[M+H]⁺(calcd.for C₃₁H₂₇ClNO₆, 544.1521).

Embodiment 23:

N- (4- Chlorophenylmethyl) -2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzene And furoylamide (23)

Reference method A synthesis, the aminated compounds of addition are 4- chlorobenzylamine.Petroleum ether: ethyl acetate: methylene chloride (3: 1 : 2) plate preparative separation is prepared with silica gel for solvent and obtained.

The physical and chemical parameter of compound 23 is as follows:

Compound 23: white solid, yield=69.3%.¹H NMR(500MHz,acetone-d₆): δ 7.51 (d, J= 8.5Hz, 2H), 7.28 (d, J=8.0Hz, 2H), 7.25 (d, J=1.5Hz, 1H), 7.17 (d, J=8.0Hz, 2H), 6.95 (d, J=1.5Hz, 1H), 6.91 (d, J=8.5Hz, 2H), 6.57 (d, J=1.5Hz, 1H), 6.55 (t, J=1.5Hz, 1H), 3.96 (d, J=6.0Hz, 2H), 3.91 (s, 3H), 3.81 (s, 3H), 3.79 (s, 6H)；¹³C NMR(125MHz,acetone- d₆):δ167.53,162.13(2×C),160.77,158.63,155.89,151.45, 138.83,136.17,132.94, 132.49,130.22(2×C),129.09(2×C),128.80(2×C),123.80, 120.71,116.74,114.78(2 ×C),111.97,108.82(2×C),101.05,97.60,56.33,55.70(2× C),55.63,43.25.(+)-ESI- MS m/z:558.2[M+H]⁺,580.2[M+Na]⁺,596.2[M+K]⁺. HR-ESI-MS m/z:558.1695[M+H]⁺ (calcd.for C₃₂H₂₉ClNO₆,558.1678).

Embodiment 24:

N- [2- (1H- indol-3-yl) ethyl] -2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxy Base -4- benzofuran carboxamides (24)

It is synthesized according to method A, the aminated compounds of addition is tryptamines (β-indolecthanamine), with petroleum ether: acetone (6: 1) The isolated target product of silica gel column chromatography is carried out for eluant, eluent.

The physical and chemical parameter of compound 24 is as follows:

Compound 24: faint yellow solid, yield=86.6%.¹H NMR(500MHz,acetone-d₆):δ9.95 (s, 1H), 7.56 (d, J=8.0Hz, 1H), 7.51 (d, J=8.5Hz, 2H), 7.35 (d, J=8.0Hz, 1H), 7.22 (d, J= 2.0Hz, 1H), 7.10 (d, J=2.0Hz, 1H), 7.07 (t, J=8.0Hz, 1H), 7.02 (t, J=8.0Hz, 1H), 6.91 (s, 1H), 6.90 (d, J=8.5Hz, 2H), 6.85 (t, J=5.0Hz, 1H), 6.58 (d, J=2.0Hz, 2H), 6.51 (t, J =2.0Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.76 (s, 6H), 3.18-3.11 (m, 2H), 2.73-2.68 (m, 2H)；¹³C NMR(125MHz,acetone-d₆):δ167.43,162.13(2×C), 160.75,158.62,155.88, 151.36,137.69,136.22,133.14,128.83(2×C),128.57,123.88, 123.09,122.08,120.62, 119.40,119.36,116.85,114.77(2×C),113.51,112.10,111.76, 108.88(2×C),101.03, 97.46,56.31,55.71(2×C),55.63,41.12,25.68.(+)-ESI-MS m/z:577.2[M+H]⁺,599.1[M+ Na]⁺.HR-ESI-MS m/z:577.2326[M+H]⁺(calcd.for C₃₅H₃₃N₂O₆,577.2333).

Embodiment 25:

N- [2- (5- methoxyl group -1H- indol-3-yl) ethyl] -2- (4- methoxyphenyl) -3- (3,5- dimethoxy benzene Base) -6- methoxyl group -4- benzofuran carboxamides (25)

It is synthesized according to method B.The aminated compounds of addition is 2- (5- methoxyl group -1H- indol-3-yl) ethamine.With petroleum Ether: acetone (2: 1) prepares plate preparative separation for solvent silica gel and obtains.

The physical and chemical parameter of compound 25 is as follows:

Compound 25: faint yellow solid, yield=66.0%.¹H NMR(500MHz,acetone-d₆):δ9.79 (s, 1H), 7.51 (d, J=9.0Hz, 2H), 7.24 (d, J=8.5Hz, 1H), 7.22 (d, J=2.5Hz, 1H), 7.08 (d, J= 2.5Hz, 1H), 7.05 (d, J=2.5Hz, 1H), 6.91 (d, J=2.5Hz, 1H), 6.90 (d, J=9.0,2H), 6.83 (t, J =5.5Hz, 1H), 6.74 (dd, J=8.5,2.5Hz, 1H), 6.58 (d, J=2.5Hz, 2H), 6.51 (t, J=2.5Hz, 1H), 3.90 (s, 3H), 3.81 (s, 6H), 3.75 (s, 6H), 3.18-3.09 (m, 2H), 2.66 (t, J=7.5Hz, 2H)；¹³C NMR(125MHz,acetone-d₆):δ167.48,162.12(2×C), 160.74,158.61,155.87,154.68, 151.34,136.22,133.08,132.79,128.82(2×C),123.86, 123.76,120.61,116.82(2×C), 113.29,112.71,112.38,111.77,108.80(2×C),101.19, 101.08,97.47,56.30,55.93, 55.70(2×C),55.63,41.05,25.70.(+)-ESI-MS m/z:607.1 [M+H]⁺,629.1[M+Na]⁺,645.0[M +K]⁺.HR-ESI-MS m/z:607.2430[M+H]⁺(calcd.for C₃₆H₃₅N₂O₇,607.2439).

Embodiment 26:

N- [2- (4- methoxyphenyl)] -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran formoxyl] D-trp methyl esters (26)

Synthesize according to method B, the aminated compounds of addition is D-trp, with petroleum ether: acetone (2: 1) is solvent Silica gel prepares plate preparative separation and obtains.

Compound 26: pale yellow oily liquid, yield=48.4%.¹H NMR(500MHz,acetone-d₆):δ 7.53 (d, J=7.2Hz, 1H), 7.51 (d, J=9.0Hz, 2H), 7.34 (d, J=8.0Hz, 1H), 7.23 (d, J=2.2Hz, 1H), 7.09 (s, 1H), 7.07 (td, J=8.0,1.0Hz, 1H), 7.07 (td, J=7.5,1.1Hz, 1H), 6.90 (d, J= 7.7Hz, 2H), 6.89 (d, J=2.2Hz, 1H), 6.55 (d, J=2.3Hz, 2H), 6.51 (t, J=2.3Hz, 1H), 4.31 (td, J=7.0,4.9Hz, 1H), 3.89 (s, 3H), 3.80 (s, 3H), 3.75 (s, 6H), 3.54 (s, 3H), 3.12 (dd, J= 14.5,7.4Hz, 1H), 3.03 (dd, J=14.5,4.9Hz, 1H)¹³C NMR(125 MHz,acetone-d₆):δ172.49, 167.32,161.90(2×C),160.74,158.51,155.81,151.45, 137.40,135.90,132.06,128.86 (2×C),128.71,124.32,123.75,122.11,120.60,119.50, 119.31,116.74,114.73(2×C), 112.12,111.69,110.35,108.75(2×C),100.95,97.70, 56.33,55.60(3×C),54.69, 52.13,28.07.(+)-ESI-MS m/z:635.1[M+H]⁺,657.1 [M+Na]⁺,673.1[M+K]⁺.HR-ESI-MS m/ z:635.2395[M+H]⁺(calcd.for C₃₇H₃₅N₂O₈, 635.2388).

The synthetic route of compound 27~36 in embodiment:

Compound 27~36 in embodiment are synthesized referring to the method for embodiment 10,11:

Embodiment 27:

N- methyl -2- (4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran carboxamides (27)

Compound 27: hazel-color solid (28.0mg, 45.8%).¹H NMR(500MHz,CD₃OD): δ 7.40 (d, J= 8.5Hz, 2H), 7.00 (d, J=2.5Hz, 1H), 6.78 (d, J=2.5Hz, 1H), 6.70 (d, J=8.5 Hz, 2H), 6.30 (t, J=2.0Hz, 1H), 6.28 (d, J=2.0Hz, 1H), 2.40 (s, 3H)；¹³C NMR(125 MHz,CD₃OD):δ171.07, 160.13(2×C),158.85,156.41,156.36,151.94,136.82, 131.32,129.07(2×C),123.29, 120.62,116.23,116.16(2×C),112.05,109.58(2×C), 102.98,99.89,26.29.(+)-ESI-MS m/z:392[M+H]⁺,414[M+Na]⁺；(-)-ESI-MS m/z: 390[M-H]^-；HR-ESI-MS m/z:392.1126[M+ H]⁺(calcd.for C₂₂H₁₈NO₆,392.1129).

Embodiment 28:

N- dodecyl -2- (4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran carboxamides (28)

Compound 28: khaki solid (38.2mg, 52.77%).¹H NMR(500MHz,acetone-d₆):δ8.81(s, 1H), 8.64 (s, 1H), 8.46 (s, 2H), 7.39 (d, J=9.0Hz, 2H), 6.96 (d, J=2.0Hz, 1H), 6.92 (d, J= 2.0Hz, 1H), 6.79 (d, J=9.0Hz, 2H), 6.61 (t, J=5.5Hz, 1H), 6.37 (t, J=2.0Hz, 1H), 6.33 (d, J=2.0Hz, 2H), 2.84 (dd, J=13.0,7.0Hz, 2H), 1.58-1.09 (m, 20H), 0.87 (t, J=7.0Hz, 3H)；¹³C NMR(125MHz,acetone-d₆):δ168.01,159.99 (2×C),158.41,155.88,155.84, 151.21,136.32,132.16,128.91(2×C),123.06,119.97, 116.22,116.09(2×C),112.53, 109.32(2×C),103.02,99.48,40.60,32.64,30.41, 30.38(2×C),30.34,29.58,27.88, 23.33,14.36.(+)-ESI-MS m/z:546[M+H]⁺,568 [M+Na]⁺；(-)-ESI-MS m/z:544[M-H]^-,580 [M+Cl]^-；HR-ESI-MS m/z:546.2855 [M+H]⁺(calcd.for C₃₃H₄₀NO₆,546.2850).

Embodiment 29:

N- (dimethylamino -1- propyl) -2- (4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzo furan It mutters formamide (29)

Compound 29: faint yellow solid (33.6mg, 53.9%).¹H NMR(500MHz,CD₃OD): δ 7.37 (d, J= 8.5Hz, 2H), 7.02 (d, J=2.0Hz, 1H), 6.80 (d, J=2.0Hz, 1H), 6.70 (d, J=8.5 Hz, 2H), 6.30 (s, 3H), 2.92 (t, J=7.5Hz, 2H), 2.61 (t, J=7.5Hz, 2H), 2.53 (s, 6H), 2.18 (dd, J=15.0, 7.5Hz,2H)；¹³C NMR(150MHz,CD₃OD):δ171.14,160.05(2× C),158.90,156.49,156.31, 152.28,130.98,130.84,129.87,129.16(2×C),123.17, 120.47,116.19(2×C),112.38, 109.83(2×C),103.04,100.09,53.72,43.81,37.91, 33.06,28.11.(+)-ESI-MS m/z:463 [M+H]⁺,485[M+Na]⁺；(-)-ESI-MS m/z:461[M-H]^-； HR-ESI-MS m/z:463.1872[M+H]⁺ (calcd.for C₂₆H₂₇N₂O₆,463.1864).

Embodiment 30:

N- cyclopenta -2- (4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran carboxamides (30)

Compound 30: hazel-color solid (50.9mg, 81.8%).¹H NMR(500MHz,CD₃OD): δ 7.35 (d, J= 8.5Hz, 2H), 7.03 (s, 1H), 6.98 (d, J=1.5Hz, 1H), 6.75 (d, J=1.5Hz, 1H), 6.69 (d, J= 8.5Hz, 2H), 6.29 (s, 3H), 3.72 (quint, J=7.0Hz, 1H), 1.76 (dt, J=13.0,7.0Hz, 1H), 1.65- 1.53 (m, 1H), 1.52-1.41 (m, 1H), 1.22 (td, J=13.0,7.0Hz, 1H)；¹H NMR (500MHz,acetone- d₆): δ 7.38 (d, J=9.0Hz, 2H), 7.01 (d, J=2.0Hz, 1H), 6.86 (d, J=2.0Hz, 1H), 6.78 (d, J= 9.0Hz, 2H), 6.60 (d, J=6.0Hz, 1H), 6.38 (t, J=2.0Hz, 1H), 6.34 (d, J=2.0Hz, 2H), 3.81~ 3.75 (m, 1H), 1.76~1.70 (m, 2H), 1.60~1.52 (m, 2H), 1.46~1.39 (m, 2H), 1.32~1.22 (m, 2H).¹³C NMR(150MHz,CD₃OD):δ170.55,160.01 (2×C),158.72,156.40,156.18,151.96, 136.72,131.88,129.11(2×C),123.39,120.44, 116.51,116.23(2×C),112.24,110.02, 109.88(2×C),107.19,106.88,103.18,99.64. 53.05,33.20(2×C),24.91(2×C).(+)- ESI-MS m/z:468[M+Na]⁺,484[M+K]⁺； (-)-ESI-MS m/z:444[M-H]^-,480[M+Cl]^-；HR-ESI-MS m/z:446.1598[M+H]⁺(calcd. for C₂₆H₂₄NO₆,446.1598).

Embodiment 31:

N- furfuryl -2- (4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran carboxamides (31)

Compound 31: faint yellow solid (18.2mg, 29.2%).¹H NMR(500MHz,acetone-d₆):δ7.43 (d, J=9.0Hz, 2H), 7.38 (d, J=1.5Hz, 1H), 7.04 (d, J=2.0Hz, 1H), 6.98 (t, J=5.5 Hz, 1H), 6.89 (d, J=2.0Hz, 1H), 6.80 (d, J=9.0Hz, 2H), 6.43 (t, J=2.0Hz, 1H), 6.39 (d, J=2.0Hz, 2H), 6.29 (dd, J=3.0,1.5Hz, 1H), 6.17 (d, J=3.0Hz, 1H), 3.98 (s, 2H)¹³C NMR(150MHz, CD₃OD):δ170.31,160.13(2×C),158.82,156.39,156.29, 152.48,151.98,143.24, 136.91,131.13,129.06(2×C),123.33,120.69,116.30,116.16 (2×C),112.06,112.29, 109.74(2×C),108.39,103.10,99.95,37.46.(+)-ESI-MS m/z: 457[M]⁺,480[M+Na]⁺；(-)- ESI-MS m/z:456[M-H]^-,492[M+Cl]^-；HR-ESI-MS m/z: 458.1239[M+H]⁺(calcd.for C₂₆H₂₀NO₇,458.1234).

Embodiment 32:

N- (phenyl methyl) -2- (4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran formyl Amine (32)

Compound 32: hazel-color solid (13.7mg, 22.0%).¹H NMR(500MHz,acetone):δ7.43 (d,J =8.5Hz, 1H), 7.26 (t, J=7.5Hz, 2H), 7.20 (d, J=7.5Hz, 2H), 7.19 (t, J=7.5Hz, 1H), 7.05 (d, J=2.0Hz, 1H), 7.02 (t, J=5.5Hz, 1H), 6.92 (d, J=2.0Hz, 1H), 6.80 (d, J=8.5Hz, 2H), 6.45 (d, J=2.0Hz, 1H), 6.41 (d, J=2.0Hz, 1H), 4.03 (d, J=6.0Hz, 2H)¹³C NMR(125MHz, CD₃OD):δ170.57,169.01,158.70(2×C),157.35,154.96, 154.83,150.55,137.90, 135.47,129.93,127.99(2×C),127.62(2×C),127.37(2×C), 126.65,121.88,119.19, 114.89,114.69(2×C),110.68,108.53(2×C),101.71,98.44, 43.10.(+)-ESI-MS m/z: 468.0[M+H]⁺,490.0[M+Na]⁺,505.9[M+K]⁺.HR-ESI-MS m/z:468.1449[M+H]⁺(calcd.for C₂₈H₂₂NO₆,468.1442).

Embodiment 33:

N- methyl-N- (phenyl methyl) -2- (4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzo furan It mutters formamide (33)

Compound 33: faint yellow solid (51.0mg, 81.3%, for a pair of of enantiomter)¹H NMR(500 MHz, Acetone): δ 7.46 (d, J=8.5Hz, 2H), 7.45 (d, J=9.0Hz, 2H), 7.19-7.32 (m, 8H), 7.07-7.10 (m, 2H), 7.02 (d, J=2.1Hz, 1H), 6.99 (d, J=2.1Hz, 1H), 6.81 (d, J=8.9Hz, 4H), 6.79 (d, J =2.1Hz, 1H), 6.72 (d, J=2.1Hz, 1H), 6.45 (t, J=2.2Hz, 1H), 6.43 (d, J=2.2Hz, 1H), 6.40-6.42 (m, 3H), 5.10 (d, J=14.7Hz, 1H), 4.47 (d, J=15.8Hz, 1H), 3.70 (d, J=15.9Hz, 1H), 3.22 (d, J=14.8Hz, 1H), 2.48 (s, 3H), 2.45 (s, 3H)¹³C NMR(125MHz,acetone):δ 170.57,170.47,158.87,158.80,157.76(2×C),157.73(2 ×C),155.70,155.62,155.03, 154.85,150.97,150.90,136.66,136.32,134.52,134.49, 129.10,128.74,128.59(2×C), 128.52(2×C),127.90(2×C),127.86(2×C),127.81 (2×C),127.58,127.30,127.07(2× C),121.88,121.85,118.85,118.51,115.03(2×C), 115.01(2×C),114.93,114.87, 110.43,109.87,108.49(4×C),102.18,102.12,98.31, 98.17,54.94,49.90,35.49, 31.34.(+)-ESI-MS m/z:504[M+Na]⁺；(-)-ESI-MS m/z:480 [M-H]^-,515.9[M+Cl]^-；HR-ESI- MS m/z:482.1590[M+H]⁺(calcd.for C₂₉H₂₄NO₆, 482.1598).

Embodiment 34:

N- (4- aminomethyl phenyl) -2- (4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran first Amide (34)

Compound 34: hazel-color solid (21.2mg, 34.0%).¹H NMR(500MHz,CD₃OD): δ 7.40 (d, J= 9.0Hz, 2H), 7.16 (d, J=8.5Hz, 2H), 7.04 (d, J=2.0Hz, 1H), 6.99 (d, J=8.5 Hz, 2H), 6.89 (d, J=2.0Hz, 1H), 6.69 (d, J=9.0Hz, 2H), 6.29 (d, J=2.0Hz, 1H), 5.93 (s, 1H), 2.27 (s, 3H)；¹³C NMR(125MHz,CD₃OD):δ168.64,159.95,158.78, 156.47,156.34,152.02,136.53, 136.50,134.77,131.91,129.57,129.05,123.37,121.61, 120.90,116.53,116.13, 112.25,109.48,102.92,100.08,21.00.(+)-ESI-MS m/z:468 [M+H]⁺,490[M+Na]⁺；(-)- ESI-MS m/z:466[M-H]^-,502[M+Cl]^-；HR-ESI-MS m/z: 468.1448[M+H]⁺(calcd.for C₂₈H₂₂NO₆,468.1442).

Embodiment 35:

N- (4- chlorphenyl) -2- (4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran formyl Amine (35)

Compound 35: hazel-color solid (46.6mg, 74.2%).¹H NMR(500MHz,CD₃OD) 7.41 (d, J=of δ 7.5Hz, 1H), 7.32 (d, J=8.0Hz, 1H), 7.16 (d, J=7.5Hz, 1H), 7.06 (s, 1H), 6.90 (s, 1H), 6.70 (d, J=8.0Hz, 1H), 6.28 (s, 1H), 5.88 (d, J=2.0Hz, 1H)；¹³C NMR(126 MHz,CD₃OD):δ168.77, 160.01(2×C),158.85,156.46,156.43,152.07,138.00, 136.62,131.58,129.83,129.05 (2×C),128.99(2×C),123.28,122.48(2×C),120.97, 116.40,116.16(2×C),112.23, 109.36(2×C),102.76,100.29.(+)-ESI-MS m/z:488.0 [M+H]⁺,510[M+Na]⁺；525.9[M+K]⁺； (-)-ESI-MS m/z:485.9[M-H]^-,521.9[M+Cl]^-； HR-ESI-MS m/z:488.0907[M+H]⁺ (calcd.for C₂₇H₁₉ClNO₆,488.0895).

Embodiment 36:

Compound 36

N- [2- (1H- indol-3-yl) ethyl)] -2- (4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- Benzofuran carboxamides (36)

Compound 36: hazel-color solid (33.9mg, 53.6%).¹H NMR(500MHz,acetone-d₆):δ7.60 (d, J=7.5Hz, 1H), 7.41 (d, J=9.0Hz, 2H), 7.34 (d, J=7.5Hz, 1H), 7.11 (s, 1H), 7.06 (dt, J= 1.0,7.5Hz, 1H), 7.02 (d, J=2.0Hz, 1H), 7.01 (dt, J=1.0,7.5Hz, 1H), 6.93 (d, J=2.0Hz, 1H), 6.80 (d, J=9.0Hz, 2H), 6.43-6.38 (m, 3H), 3.20 (t, J=8.0Hz, 2H), 2.75 (t, J=8.0Hz, 2H).¹³C NMR(125MHz,CD₃OD):δ170.55,160.14(2×C), 158.81,156.45,156.28,152.02, 138.08,136.92,131.59,129.13(2×C),128.73,123.36, 123.18,122.23,120.54,119.52 (2×C),116.38,116.15(2×C),113.42,112.28,112.07, 109.79,103.20,99.86,41.99, 25.76.(+)-ESI-MS m/z:521[M+H]⁺,543[M+Na]⁺； (-)-ESI-MS m/z:519[M-H]^-,554.9[M+ Cl]^-；HR-ESI-MS m/z:521.1721[M+H]⁺(calcd. for C₃₁H₂₅N₂O₆,521.1707).

Following (the pharmacological evaluation part of anti-inflammatory and immunosuppressive activity the pharmacological test procedures and result of the compounds of this invention Compound numbers correspond to embodiment in compound numbers):

Embodiment 1: the inhibitory activity that compound generates LPS induction Primary mouse peritoneal macrophage NO.

Macrophage executes body non-specific immune function, can produce the inflammation such as NO under bacteria lipopolysaccharide LPS induction Sex factor participates in simultaneously inducing inflammatory reaction, has higher water during inflammation immunologic process initial stage and pathological development It is flat.By detecting the mouse macrophage NO production quantity of originally culture, can be used as external preliminary observation and screening have it is certain anti-inflammatory The index of active component or compound.

Experimental method:

It takes Primary mouse peritoneal macrophage to be inoculated in 96 orifice plates, different untested compounds (10 is added^-5M) and positive Comparison medicine dexamethasone (Dex) protects 1h in advance；Then, 1 μ g/ml LPS is added in 37 DEG C, 5%CO₂It is cultivated for 24 hours in incubator Afterwards, supernatant is collected, using the content of Griess method measurement NO Meanwhile cell proliferation inhibition rate is measured with mtt assay, and measure The IC with remarkable inhibiting activity compound is generated to NO₅₀(being calculated with Probit weighted regression analysis method).

Experimental result:

The results are shown in Table 1, and compared with lead compound Amurensin H, the compound through structure of modification is being kept While active, toxicity is significantly reduced.Wherein, compound 11,18,30,33,35,36, not only there is significant NO to generate and inhibit Activity, and toxicity is substantially less than Amurensin H and positive control drug.

The influence that table 1.Amurensin H derivative generates LPS induction Primary mouse peritoneal macrophage NO

^*Compound numbers correspond to the compound numbers in embodiment

Embodiment 2: influence of the compound to croton oil inducing mouse otitis

Experimental method:

The male mice in kunming of 18-20g is taken, random to be grouped, groups of animals applies croton oil respectively at left ear two sides 0.02ml；After 30 minutes, groups of animals gives test-compound respectively with the subcutaneous injection of 50mg/kg weight, and model control group is given Give isometric solvent；After 4h is administered, takes off neck and put to death mouse, cut ears along auricle base line, diameter 6mm punch removes a left side respectively The auricle of auris dextra same position, assay balance weighing, calculates ear swelling (ear swelling=left auricle weight-auris dextra sheet weight) With ear swelling inhibiting rate

Experimental result:

Experimental result is as shown in table 2, and compared with model control group, compound 18 can significantly mitigate the mouse of croton oil induction Otitis (P < 0.01 or 0.05).

Influence (Mean ± SD, n=10) of the table 2.Amurensin H derivative to croton oil inducing mouse otitis^a.

^aCompared with model group, " * " indicates p < 0.05, and " * * " indicates p < 0.01.

^bCompound numbers correspond to the compound numbers in embodiment

Embodiment 3: the influence of compound Carrageenan inducing mouse foot swelling

Experimental method:

The male mice in kunming of 18-20g is taken, random to be grouped, groups of animals is subcutaneously injected 0.1% jiao respectively at left foot bottom Pitch dish glue 0.05ml；After 30 minutes, groups of animals gives test-compound, model pair respectively with the subcutaneous injection of 50mg/kg weight Isometric solvent is given according to group；It after 4h is administered, takes off neck and puts to death mouse, cut biped along ankle-joint, assay balance weighing calculates foot Swelling (degree of paw swelling=left foot weight-right lumping weight amount) and foot swelling inhibiting rate

Experimental result:

Experimental result is as shown in table 3, and compared with model control group, compound 18 can significantly mitigate the small of carrageenan induction Mouse foot swelling (P < 0.01).

Table 3.Amurensin H derivative Carrageenan inducing mouse foot swelling influence (Mean ± SD, n= 10)^a.

^bCompound numbers correspond to the compound numbers in embodiment.

Claims

1. as (2,3- diphenyl -4- replaces plain (Amurensin H) derivative of 7,8- dehydrogenation grapevine penta shown in logical formula (I) Benzofuran derivatives) and its pharmaceutically acceptable salt:

Wherein, X is selected from O, NR₆,S；

R₁Selected from H, substituted or unsubstituted C_3-8Naphthenic base, substituted or unsubstituted phenyl, substituted or unsubstituted indyl, Substituted or unsubstituted furyl, substituted or unsubstituted naphthalene, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrrole Piperidinyl；Wherein the substituent group of the naphthenic base, phenyl, indyl, furyl, naphthalene, quinolyl and pyridyl group is selected from hydroxyl, nitre Base, cyano, amino, methylamino, dimethylamino, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, C_1-6 Alkylthio group, methylene-dioxy, carboxyl, F, Cl, Br, I, Glu, SO₃H、PO₃H₂；Replace type include it is monosubstituted, two replace or Three replace；

L₁Selected from substituted or unsubstituted C_0-16Linear or branched alkyl group, substituted or unsubstituted C_0-16Linear chain or branched chain acyl Base, substituted or unsubstituted C_2-16Linear chain or branched chain alkenyl, C_2-6Alkynyl；The substituent group be selected from hydroxyl, nitro, cyano, Amino, methylamino, dimethylamino, phenyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, C_1-6Alkylthio group, F, Cl, Br,I；

R₆Independently selected from H, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Acyl group；Wherein, substituent group Selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C_1-6Alkoxy, phenyl, F, Cl, Br, I；

R₂、R₃、R₄、R₅It is each independently selected from hydrogen, C_1-6Alkyl, C_1-6Acyl group, Glu, SO₃H、PO₃H₂；

2. the plain derivative of 7,8- dehydrogenation grapevine penta according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that Shown in the compound such as general formula (IA):

Wherein, R₁Selected from H, substituted or unsubstituted C_3-8Naphthenic base, substituted or unsubstituted phenyl, substituted or unsubstituted Yin Diindyl base, substituted or unsubstituted furyl, substituted or unsubstituted naphthalene, substituted or unsubstituted quinolyl, substitution do not take The pyridyl group in generation；The naphthenic base, phenyl, indyl, furyl, naphthalene, quinolyl and pyridyl group substituent group be selected from hydroxyl, Nitro, cyano, amino, methylamino, dimethylamino, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, C_1-6Alkylthio group, methylene-dioxy, carboxyl, F, Cl, Br, I, Glu, SO₃H、PO₃H₂；Replacing type includes monosubstituted, two substitutions Or three replace；

3. the plain derivative of 7,8- dehydrogenation grapevine penta according to claim 2 and its pharmaceutically acceptable salt, which is characterized in that The compound such as general formula (IAa), (IAb), shown in (IAc):

Wherein, L₁Selected from substituted or unsubstituted C_0-16Linear or branched alkyl group, substituted or unsubstituted C_0-16Straight chain or branch Chain acyl, substituted or unsubstituted C_2-16Linear chain or branched chain alkenyl；The substituent group be selected from hydroxyl, nitro, cyano, amino, Methylamino, dimethylamino, phenyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, F, Cl, Br, I；

R₇、R₈、R₉It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C_1-6Alkyl, C_1-6 Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, C_1-6Alkylthio group, methylene-dioxy, F, Cl, Br, I, Glu, SO₃H、 PO₃H₂；

4. the plain derivative of 7,8- dehydrogenation grapevine penta according to claim 3 and its pharmaceutically acceptable salt, it is characterised in that:

The L₁Selected from C₀、C₁、C₂、C₃Straight chained alkyl；

R₆Independently selected from H, C₁、C₂、C₃Straight chained alkyl；

5. the plain derivative of 7,8- dehydrogenation grapevine penta according to claim 2 and its pharmaceutically acceptable salt, which is characterized in that Shown in the compound such as general formula (IAd):

Wherein, R₁₀Independently selected from hydrogen, substituted or unsubstituted C_3-8Naphthenic base, substituted or unsubstituted C_1-16Straight chain or Branched alkyl, substituted or unsubstituted C_1-16Linear chain or branched chain acyl group, substituted or unsubstituted C_2-16Linear chain or branched chain alkene Base, C_2-6Alkynyl；Wherein, the substituent group is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C_1-6 Alkoxy, C_1-6Acyloxy, C_1-6Alkylthio group, F, Cl, Br, I；

6. the plain derivative of 7,8- dehydrogenation grapevine penta according to claim 5 and its pharmaceutically acceptable salt, it is characterised in that:

The R₁₀Selected from substituted or unsubstituted C_1-16Linear or branched alkyl group, substituted or unsubstituted C_3-8Naphthenic base； Wherein, the substituent group is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C_1-6Alkoxy, C_1-6's Acyl group, C_1-6Acyloxy, C_1-6Alkylthio group, F, Cl, Br, I；

R₆Independently selected from H, C₁、C₂、C₃Straight chained alkyl；

7. the plain derivative of 7,8- dehydrogenation grapevine penta according to claim 6 and its pharmaceutically acceptable salt, it is characterised in that:

The R₁₀Selected from substituted or unsubstituted C_3-12Linear or branched alkyl group, substituted or unsubstituted C_5-6Naphthenic base； Wherein, the substituent group is selected from hydrogen, hydroxyl, methylamino, dimethylamino, methoxyl group, acetyl group, Cl；

R₆Independently selected from H, C₁、C₂、C₃Straight chained alkyl；

8. the plain derivative of 7,8- dehydrogenation grapevine penta according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that Shown in the compound such as general formula (IB):

9. the plain derivative of 7,8- dehydrogenation grapevine penta according to claim 8 and its pharmaceutically acceptable salt, it is characterised in that The compound such as general formula (IBa), (IBb), shown in (IBc):

L₁Selected from substituted or unsubstituted C_0-16Linear or branched alkyl group, substituted or unsubstituted C_0-16Linear chain or branched chain acyl Base, substituted or unsubstituted C_2-16Linear chain or branched chain alkenyl；The substituent group is selected from hydroxyl, nitro, cyano, amino, first ammonia Base, dimethylamino, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, F, Cl, Br, I；

R₁₁、R₁₂、R₁₃It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyloxy, C_1-6Alkylthio group, methylene-dioxy, F, Cl, Br, I, Glu, SO₃H、 PO₃H₂；

10. the plain derivative of 7,8- dehydrogenation grapevine penta according to claim 9 and its pharmaceutically acceptable salt, feature exist In,

The L₁Selected from C₀、C₁、C₂、C₃Straight chained alkyl；

11. the plain derivative of 7,8- dehydrogenation grapevine penta according to claim 8 and its pharmaceutically acceptable salt, feature exist In shown in the compound such as general formula (IBd):

Wherein, R₁₄Independently selected from hydrogen, substituted or unsubstituted C_3-8Naphthenic base, substituted or unsubstituted C_1-16Straight chain or Branched alkyl, substituted or unsubstituted C_1-16Linear chain or branched chain acyl group, substituted or unsubstituted C_2-16Linear chain or branched chain alkene Base, C_2-6Alkynyl；The substituent group is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C_1-6Alcoxyl Base, C_1-6Acyl group, C_1-6Acyloxy, F, Cl, Br, I；

12. the plain derivative of 7,8- dehydrogenation grapevine penta according to claim 11 and its pharmaceutically acceptable salt, feature exist In:

The R₁₄Selected from substituted or unsubstituted C_1-16Linear or branched alkyl group, substituted or unsubstituted C_3-8Naphthenic base； Wherein, the substituent group is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C_1-6Alkoxy, replace Base is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C_1-6Alkoxy, C_1-6Acyl group, C_1-6Acyl Oxygroup, F, Cl, Br, I；

13. the plain derivative of 7,8- dehydrogenation grapevine penta according to claim 12 and its pharmaceutically acceptable salt, feature exist In:

The R₁₄Selected from substituted or unsubstituted C_3-12Linear or branched alkyl group, substituted or unsubstituted C_5-6Naphthenic base； The substituent group is selected from hydrogen, methylamino, dimethylamino, methoxyl group, acetyl group, Cl；

14. the plain derivative of any one of -13 7,8- dehydrogenation grapevine penta and its pharmaceutically acceptable according to claim 1 Salt, which is characterized in that the compound is selected from following group:

Compound R Compound R 10 H 11 Me

15. a kind of pharmaceutical composition, by described in any item 7,8- dehydrogenation grapevine, penta elements of the claim 1-14 of effective dose Derivative and its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or auxiliary material composition.

16. pharmaceutical composition according to claim 15, which is characterized in that the pharmaceutical composition is selected from tablet, capsule, ball Agent, injection.

17. pharmaceutical composition according to claim 15, which is characterized in that described pharmaceutical composition is selected from sustained release preparation, controlled release Preparation and various particulate delivery systems.

18. the claim 1-14 plain derivative of described in any item 7,8- dehydrogenation grapevines penta and its pharmaceutically acceptable salt exist Application in preparation treatment and/or prevention of inflammation and/or immunosuppressive drug.

19. the claim 1-14 plain derivative of described in any item 7,8- dehydrogenation grapevines penta and its pharmaceutically acceptable salt exist Application in preparation treatment and/or prevention of inflammation and/or immunosupress related disease product.

20. application according to claim 19, wherein inflammation and immunosupress related disease include: rheumatoid arthritis, bone Arthritis, rheumatic arthritis, urarthritis, lupus erythematosus syndrome, bronchitis, bursal synovitis, tenosynovitis, ox-hide It is tinea, eczema, burn, dermatitis, inflammatory bowel disease, Ke Laoen disease, gastritis, irritable bowel syndrome, ulcerative colitis, multiple hard Change that disease, Autoimmune Encephalomyelitis, colorectal cancer, arteritis nodosa, thyroiditis, wind-heat be wet, gingivitis, periodontal Swelling, myocardial ischemia, various infectious pneumonias, physics and chemistry pneumonia and the metamorphosis occurred after inflammation, canker sore, ephritis, damage Reactive pneumonia, Chronic Obstructive Pulmonary Disease, asthma, proctalgia fugax and rectum split, liver and gallbladder capsulitis, cholangitis, hardenability Cholangitis, primary biliary cirrhosis and cholecystitis.

21. application according to claim 19, which is characterized in that the product is selected from drug, health care product.