CN109721580A - The plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta, its preparation method and pharmaceutical composition and purposes - Google Patents

The plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta, its preparation method and pharmaceutical composition and purposes Download PDF

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CN109721580A
CN109721580A CN201811265976.6A CN201811265976A CN109721580A CN 109721580 A CN109721580 A CN 109721580A CN 201811265976 A CN201811265976 A CN 201811265976A CN 109721580 A CN109721580 A CN 109721580A
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CN109721580B (en
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姚春所
林明宝
侯琦
白金叶
石建功
张纪法
范燕楠
滕彬豪
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Abstract

The invention discloses plain (Amurensin H) derivative of a kind of novel 3- phenyl -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 3- aryl -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 3- phenyl -7,8- dehydrogenation grapevine penta, its preparation method and pharmaceutical composition with Purposes
Technical field
The present invention relates to biomedicine fields, and in particular to one kind has 3- phenyl -7,8- dehydrogenation of benzofuran structure Plain (Amurensin H) derivative of grapevine penta or its medically acceptable salt, the Pharmaceutical composition containing these derivatives And its application in the clinical treatment of inflammatory 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 ring.Medicine Activity research discovery is managed, Amurensin H is the active skull cap components for having inhibiting effect to the generation of a variety of inflammatory mediators [Acta.Pharmacol.Sin., 2006,27 (6): 735-740.], it is chronic that zoopery confirms that the compound can be resisted significantly Chronic obstructive pulmonary disease (COPD) mouse lung tissue pathology damage is suffered from airway inflammation, alleviation.The pharmacological evaluation of further system is aobvious Show, natural products activity is strong, and toxicity is smaller, is an active lead compound with further investigation value.Amurensin This study group of research of H compound activity aspect itself has disclosed report, but the structure optimization in relation to the system of compounds Document report mistake is had no so far with the structure activity study in terms of anti-inflammatory activity.This patent is related to excellent to this compound progress structure Change and structure activity study is 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 provide a kind of new construction 3- phenyl -4- and replace benzofuran compounds And its derivative.Its 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 3- phenyl -4- shown in (IBd) replace benzofuran compounds 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), 3- phenyl-shown in (IBd) 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), 3- phenyl -4- shown in (IBd) replace benzofuran compounds and its pharmaceutically may be used The salt of receiving is preparing the application in the drug for preventing, treating and assisting in the treatment of various inflammatory diseases.
The various inflammatory diseases include:, rheumatic arthritis, urarthritis, lupus erythematosus syndrome, branch gas Guan Yan, bursal synovitis, tenosynovitis, psoriasis, eczema, burn, dermatitis, inflammatory bowel disease, Ke Laoen disease, gastritis, irritable bowel are comprehensive Disease, ulcerative colitis, multiple sclerosis, Autoimmune Encephalomyelitis, colorectal cancer, arteritis nodosa, first shape Adenositis, wind-heat be wet, gingivitis, periodontitis, canker sore, ephritis, the swelling occurred after damage, myocardial ischemia, various infectivities Pneumonia, physics and chemistry pneumonia and allergy pneumonia, proctalgia fugax and rectum split, liver and gallbladder capsulitis, cholangitis, hardening Property cholangitis, primary biliary cirrhosis and cholecystitis.Compound of the present invention includes in its derivative and pharmacodynamics Acceptable salt.
Specifically, the present invention relates to such as the plain derivative (3- of 3- phenyl -7,8- dehydrogenation grapevine penta shown in logical formula (I) Phenyl -4- replaces benzofuran derivative) and its pharmaceutically acceptable salt:
Wherein, X is selected from O, NR5,S；
R1Selected from H, substituted or unsubstituted C3-8Naphthenic 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, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, methylene-dioxy, carboxyl, F, Cl, Br, I, Glu, SO3H、PO3H2；Replacing type includes monosubstituted, two substitutions Or three replace；
L1Selected from substituted or unsubstituted C0-16Linear or branched alkyl group, substituted or unsubstituted C0-16Straight chain or branch Chain acyl, substituted or unsubstituted C2-16Linear chain or branched chain alkenyl, C2-6Alkynyl；The substituent group be selected from hydroxyl, nitro, Cyano, amino, methylamino, dimethylamino, phenyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, F,Cl,Br,I；
R5Independently selected from H, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Acyl group；Wherein, it takes Dai Ji is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C1-6Alkoxy, phenyl, F, Cl, Br, I；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to logical formula (I) shown in the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta include, but It is not limited to general formula (IA) compound represented and its pharmaceutically acceptable salt, which is characterized in that the compound such as general formula (IA) shown in:
Wherein, R1Selected from H, substituted or unsubstituted C3-8Naphthenic 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, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6 Acyloxy, C1-6Alkylthio group, methylene-dioxy, carboxyl, F, Cl, Br, I, Glu, SO3H、PO3H2；Replacing type includes singly taking Generation, two substitutions or three replace；
L1Selected from substituted or unsubstituted C0-16Linear or branched alkyl group, substituted or unsubstituted C0-16Straight chain or branch Chain acyl, substituted or unsubstituted C2-16Linear chain or branched chain alkenyl, C2-6Alkynyl；The substituent group be selected from hydroxyl, nitro, Cyano, amino, methylamino, dimethylamino, phenyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, F,Cl,Br,I；
R5Independently selected from H, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Acyl group；Wherein, it takes Dai Ji is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C1-6Alkoxy, phenyl, F, Cl, Br, I；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to general formula (IA) shown in the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta include, but It is not limited to general formula (IAa), (IAb), (IAc) compound represented and its pharmaceutically acceptable salt, which is characterized in that institute Compound such as general formula (IAa) is stated, (IAb), (IAc) is shown:
Wherein, L1Selected from substituted or unsubstituted C0-16Linear or branched alkyl group, substituted or unsubstituted C0-16Straight chain Or branched chain acyl, substituted or unsubstituted C2-16Linear chain or branched chain alkenyl；The substituent group is selected from hydroxyl, nitro, cyano, ammonia Base, methylamino, dimethylamino, phenyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, F, Cl, Br, I；
R5Independently selected from H, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Acyl group；Wherein, it takes Dai Ji is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C1-6Alkoxy, phenyl, F, Cl, Br, I；
R6、R7、R8It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C1-6Alkane Base, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, methylene-dioxy, F, Cl, Br, I, Glu, SO3H、PO3H2；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to general formula (IAa), (IAb), the element of 3- phenyl -7,8- dehydrogenation grapevine penta shown in (IAc) Derivative and its pharmaceutically acceptable salt, it is characterised in that:
The L1Selected from C0、C1、C2、C3Straight chained alkyl；
R5Independently selected from H, C1、C2、C3Straight chained alkyl；
R6、R7、R8It is each independently selected from hydrogen, hydroxyl, methoxyl group, acetyl group, Cl；
R2、R3、R4It is each independently selected from hydrogen, methyl.
, according to the invention it is preferred to general formula (IA) shown in the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta include, but It is not limited to general formula (IAd) compound represented and its pharmaceutically acceptable salt, which is characterized in that the compound is such as logical Shown in formula (IAd):
Wherein, R9Independently selected from hydrogen, substituted or unsubstituted C3-8Naphthenic base, substituted or unsubstituted C1-16Branch Or straight chained alkyl, substituted or unsubstituted C1-16Linear chain or branched chain acyl group, substituted or unsubstituted C2-16Linear chain or branched chain alkene Base, C2-6Alkynyl；The substituent group is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C1-6Alcoxyl Base, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, F, Cl, Br, I；
R5Independently selected from H, substituted or unsubstituted C1-6Alkyl；Wherein, substituent group be selected from hydroxyl, nitro, cyano, Amino, methylamino, dimethylamino, C1-6Alkoxy, phenyl, F, Cl, Br, I；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to general formula (IAd) shown in the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta, and its Pharmaceutically acceptable salt, it is characterised in that:
The R9Selected from substituted or unsubstituted C1-16Linear or branched alkyl group, substituted or unsubstituted C3-8Cycloalkanes Base；Wherein, the substituent group is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, F, Cl, Br, I；
R5Independently selected from hydrogen, C1-3Straight chained alkyl；
R2、R3、R4It is each independently selected from hydrogen, methyl, acetyl group；
, according to the invention it is preferred to general formula (IAd) shown in the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta, and its Pharmaceutically acceptable salt, it is characterised in that:
The R9Selected from substituted or unsubstituted C3-12Linear or branched alkyl group, substituted or unsubstituted C5-68Ring Alkyl；Wherein, the substituent group is selected from hydrogen, hydroxyl, methylamino, dimethylamino, methoxyl group, acetyl group, Cl；
R5Independently selected from hydrogen, C1、C2、C3, straight chained alkyl；
R2、R3、R4It is each independently selected from hydrogen, methyl, acetyl group；
, according to the invention it is preferred to logical formula (I) shown in the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta include, but It is 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) shown in:
Wherein, R1Selected from H, substituted or unsubstituted C3-8Naphthenic 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, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyl Oxygroup, C1-6Alkylthio 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 C0-16Linear or branched alkyl group, substituted or unsubstituted C0-16Straight chain or branch Chain acyl, substituted or unsubstituted C2-16Linear chain or branched chain alkenyl, C2-6Alkynyl；The substituent group be selected from hydroxyl, nitro, Cyano, amino, methylamino, dimethylamino, phenyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, F,Cl,Br,I；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to general formula (IB) shown in the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta include, but It is not limited to general formula (IBa), (IBb), (IBc) compound represented and its pharmaceutically acceptable salt, which is characterized in that institute State compound such as general formula (IBa), (IBb), shown in (IBc):
Wherein, L1Selected from substituted or unsubstituted C0-16Linear or branched alkyl group, substituted or unsubstituted C0-16Straight chain Or branched chain acyl, substituted or unsubstituted C2-16Linear chain or branched chain alkenyl；The substituent group is selected from hydroxyl, nitro, cyano, ammonia Base, methylamino, dimethylamino, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, F, Cl, Br, I；
R10、R11、R12It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C1-6Alkane Base, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, methylene-dioxy, F, Cl, Br, I, Glu, SO3H、PO3H2；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to general formula (IBa), (IBb), penta element of 3- phenyl -7,8- dehydrogenation grapevine shown in (IBc) Derivative and its pharmaceutically acceptable salt, it is characterised in that:
The L1Selected from C0、C1、C2、C3Straight chained alkyl；
R10、R11、R12It is each independently selected from hydrogen, hydroxyl, methoxyl group, acetyl group, Cl；
R2、R3、R4It 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 3- phenyl -7,8- dehydrogenation grapevine penta include, but It is not limited to general formula (IBd) compound represented and its pharmaceutically acceptable salt, which is characterized in that the compound is such as logical Shown in formula (IBd):
Wherein, R13Independently selected from hydrogen, substituted or unsubstituted C3-8Naphthenic base, substituted or unsubstituted C1-16It is straight Chain or branched alkyl, substituted or unsubstituted C1-16Linear chain or branched chain acyl group, substituted or unsubstituted C2-16Linear chain or branched chain Alkenyl, C2-6Alkynyl；The substituent group is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C1-6Alkane Oxygroup, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, F, Cl, Br, I；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to general formula (IBd) shown in the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta, and its Pharmaceutically acceptable salt, it is characterised in that:
The R13Selected from substituted or unsubstituted C1-16Straight chain or straight chained alkyl, substituted or unsubstituted C3-8Ring Alkyl；Wherein, the substituent group is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, F, Cl, Br, I；
R2、R3、R4It is each independently selected from hydrogen, methyl, acetyl group；
, according to the invention it is preferred to general formula (IBd) shown in the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta, and its Pharmaceutically acceptable salt, it is characterised in that:
The R13Selected from substituted or unsubstituted C3-12Linear or branched alkyl group, substituted or unsubstituted C5-6Ring Alkyl；The substituent group is selected from hydroxyl, methylamino, dimethylamino, methoxyl group, acetyl group, Cl；
R2、R3、R4It is each independently selected from hydrogen, methyl, acetyl group；
Specifically, lead to formula (I), (IA), (IAa), (IAb), (IAc), (IAd) and (IB), (IBa), (IBb), (IBc), the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta shown in (IBd) and its pharmaceutically acceptable salt, feature exist In the compound is selected from following group (compound numbers correspond to the compound numbers in embodiment):
The second aspect of technical solution of the present invention there is provided a kind of containing medicine effective dose as logical formula (I), (IA), (IAa), (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.
The third aspect of technical solution of the present invention is to provide the plain derivative (3- of a kind of 3- phenyl -7,8- dehydrogenation grapevine penta Phenyl -4- replaces benzofuran compounds) or its medically acceptable salt, the hydrate of salt or pro-drug it is anti-in preparation Application in scorching and immunosupress and its related disease drug.
The diseases associated with inflammation includes, rheumatic arthritis, urarthritis lupus erythematosus syndrome, bronchus Inflammation, bursal synovitis, tenosynovitis, psoriasis, eczema, burn, dermatitis, inflammatory bowel disease, Ke Laoen disease, gastritis, irritable bowel syndrome, Ulcerative colitis, multiple sclerosis, Autoimmune Encephalomyelitis, colorectal cancer, arteritis nodosa, thyroid gland The swelling that occurs after inflammation, rheumatic fever, gingivitis, periodontitis, canker sore, ephritis, damage, myocardial ischemia, various infectious lungs Scorching, physics and chemistry pneumonia and allergy pneumonia, proctalgia fugax and rectum split, liver and gallbladder capsulitis, cholangitis, hardenability Cholangitis, primary biliary cirrhosis and cholecystitis etc..The universals of this kind of disease on a cellular level show themselves in that macrophage Cell hyperactivity generates 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 1 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 hydrolysis synthesizes compound 1:
Compound 1b is dissolved in THF, MeOH and H2In the mixed solution of O (1: 1: 1, v/v/v), using NaOH as catalyst Heating reflux reaction, gained reaction solution remove most of solvent under reduced pressure, and the HCl solution of 1mol/L is added dropwise into remaining reaction solution Until no white precipitate is precipitated.Reaction mixture filters, obtained solid to distill water washing, dry white powder is solid Body compound 1.
The basic synthetic method of compound of the present invention includes following two:
First method includes the following steps:
Step 1: compound 1 and alcohols, phenols and aminated compounds pass through condensation reaction synthesizing methoxy ester or methoxyl group Amine derivative.
Compound 1 and alcohols, phenols and aminated compounds are under the catalysis of HOBt and EDCI, in dry methylene chloride Condensation reaction is carried out, for reaction solution through being concentrated under reduced pressure, products therefrom obtains methoxy base ester or methoxy through recrystallization or chromatographic separation and purification Base 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 1 and alcohols, phenols and aminated compounds carry out condensation reaction synthesizing methoxy ester or methoxyl group Amine derivative.
Compound 1 and alcohols, phenols and aminated compounds are under the catalysis of DMAP and EDCI, in dry methylene chloride Condensation reaction is carried out, for reaction solution through being concentrated under reduced pressure, products therefrom obtains methoxy base ester or methoxy through recrystallization or chromatographic separation and purification Base amine target product.
Step 2: methoxy base ester or Methoxyamine derivative removing methyl synthesis phenolic hydroxyl group ester or phenolic hydroxyl group amine derivative.
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.It has no in existing literature and technology and spreads out about 3- phenyl -7,8- dehydrogenation grapevine penta plain (Amurensin H) Biology or its medically acceptable salt and such compound are used to treat the report of diseases associated with inflammation；It has no about 3- phenyl- 4 substitution benzofurans novel compounds or its medically acceptable salt and such compound are for treating inflammatory disease The report of disease.
Detailed description of the invention:
C3-8Naphthenic base refer to carbon atom number be 3,4,5,6,7,8 substituted or unsubstituted naphthenic base, C2-6Alkynyl Refer to that carbon atom number is 2,3,4,5,6 linear chain or branched chain alkynyl, C0-3Straight chained alkyl refer to that carbon atom number is 0,1,2,3 Straight chained alkyl；C1-3Straight chained alkyl refer to carbon atom number be 1,2,3 straight chained alkyl, C1-6Alkyl refer to that carbon atom number is 1,2,3,4,5,6 linear or branched alkyl group, C1-6Alkoxy refer to carbon atom number be 1,2,3,4,5,6 linear chain or branched chain Alkoxy, C1-6Acyl group refer to carbon atom number be 1,2,3,4,5,6 linear chain or branched chain acyl group, C1-6Acyloxy refer to carbon original The linear chain or branched chain acyloxy that subnumber is 1,2,3,4,5,6, C1-6Alkylthio group refer to carbon atom number be 1,2,3,4,5,6 it is straight Chain or branched alkylthio, C0-16Linear 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, C0-16Linear 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, C2-16Linear 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 synthetic route of compound intermediate 1b in embodiment:
Embodiment 1:
3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid (1)
The synthetic route of compound 1:
150mL THF, MeOH and H is added in compound 1b (10.0g, 29.2mmol)2The mixing of O (1: 1: 1, v/v/v) is molten In liquid, stirring is allowed to dissolve, and NaOH 1.17g is added.Reaction mixture is heated to reflux 12 h, and reaction raw materials hydrolysis is complete.Reaction Liquid removes most of solvent under reduced pressure at 42 DEG C, is added dropwise to the HCl solution of 1mol/L, until no white precipitate is precipitated.Instead It answers mixture to filter, distills water washing, dry to obtain white powdery solids compound 1 (9.48g, 98.9%).
Compound 1: white powder.1H NMR(500MHz,acetone-d6) δ 7.89 (s, 1H), 7.37 (d, J= 2.0Hz, 1H), 7.31 (d, J=2.0Hz, 1H), 6.54 (d, J=2.0Hz, 2H), 6.43 (t, J=2.0Hz, 1H), 3.94 (s,3H),3.78(s,6H)；13C NMR(125MHz,acetone-d6):δ168.07,161.41,158.52, 158.15, 144.22,135.64,127.81,124.09,118.49,113.85,107.31(2×C),100.30,99.88, 56.40, 55.54(2×C).(+)-ESI-MS m/z:329.2[M+H]+,351.1[M+Na]+,367.0[M+K]+. HR-ESI-MS m/ z:329.1025[M+H]+(calcd.for C18H17O6, 329.1025) and the synthetic route of compound 2-12 in embodiment:
Synthesize final product (compound numbers correspond to the compound numbers in embodiment)
The synthetic method of chemical combination 2-12 in embodiment:
Method A: compound 1 (100mg, 0.30mmol) is dissolved in the dry methylene chloride of 50mL, and HOBt is added 20min is stirred at room temperature in (49.8mg, 0.37mmol) and EDCI (70.1mg, 0.37mmol), and alcohols or phenolic compound is added (1.2equiv) continues that 3-6h is stirred at room temperature, and TLC monitors end of reaction, stops reaction.Reaction solution is concentrated under reduced pressure, remaining solid Plate preparative separation (selecting suitable solvent according to different compounds), which is prepared, with silica gel obtains target product.
Method B: compound 1 (100mg, 0.30mmol) is dissolved in the dry methylene chloride of 50mL, and DMAP is added 20min is stirred at room temperature in (44.7mg, 0.37mmol) and EDCI (70.1mg, 0.37mmol), and alcohols or phenolic compound is added (1.2equiv) continues that 3-6h is stirred at room temperature, and TLC monitors fully reacting.Reaction solution is concentrated under reduced pressure, and remaining solid is prepared with silica gel Plate preparative separation (selecting suitable solvent according to different compounds) obtains target product.
Embodiment 2:
3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid acetic anhydride (2)
It being synthesized according to method B, the alcohol compound of addition is 4- acetaminophenol ethyl ester (70.6mg, 0.36 mmol), With petroleum ether: acetone (2: 1) is solvent, and silica gel prepares plate preparative separation and obtains target product, yield 79.9%.Chemical combination The physical and chemical parameter of object 2 is as follows:
Compound 2: beige solid, yield=39.1%.1H NMR(500MHz,acetone-d6):δ7.89(s, 1H), 7.38 (d, J=2.0Hz, 1H), 7.24 (d, J=2.0Hz, 1H), 6.50 (s, 3H), 3.93 (s, 3H), 3.81 (s, 6H),3.30(s,3H)；13C NMR(125MHz,acetone-d6):δ168.04,161.79(3×C), 158.61,157.97, 144.10,135.80,127.09,123.82,118.81,113.72,107.15(2×C),100.17, 100.09,56.44, 55.68(2×C),51.61..(+)-ESI m/z:393[M+Na]+,409[M+K]+.
Embodiment 3:
3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid monooctyl ester (3)
It is synthesized according to method B, 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 79.9%.The physical and chemical parameter of compound 3 is as follows:
Compound 3: pale yellow oily liquid, yield=79.9%.1H NMR(600MHz,acetone-d6):δ 7.90 (s, 1H), 7.37 (d, J=1.8Hz, 1H), 7.22 (d, J=1.8Hz, 1H), 6.52 (s, 2H), 6.50 (s, 1H), 3.93 (s, 3H), 3.81 (s, 6H), 3.75 (t, J=6.6Hz, 2H), 1.34-1.14 (m, 10H), 1.11 (dd, J=14.4,7.8Hz, 2H), 0.87 (t, J=6.6Hz, 3H)13C NMR(125MHz,acetone-d6):δ 168.07,161.85(2×C), 158.59,158.02,144.10,135.79,127.65,123.81,118.38,113.69, 106.99(2×C),100.15, 99.93,65.87,56.42,55.68(2×C),32.52,29.94,29.84,28.66, 26.55,23.24,14.33.(+)- ESI m/z:441[M+H]+,463[M+Na]+,479[M+K]+.HR-ESI-MS m/z:441.2288[M+H]+(calcd.for C26H33O6,441.2272).
Embodiment 4:
3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid cyclohexyl (4)
Synthesize according to method A, the alcohol compound of addition is cyclohexanol, with petroleum ether: acetone (2: 1) is solvent, silicon Glue prepares plate preparative separation and obtains target product, yield 50.6%.The physical and chemical parameter of compound 4 is as follows:
Compound 4: yellow oily liquid, yield=50.6%.1H NMR(600MHz,acetone-d6):δ7.89 (s, 1H), 7.35 (d, J=2.4Hz, 1H), 7.20 (d, J=2.4Hz, 1H), 6.53 (d, J=2.4Hz, 2H), 6.50 (s, 1H), 4.62-4.47 (m, 1H), 3.93 (s, 3H), 3.81 (s, 6H), 1.58 (d, J=8.4Hz, 4H), 1.47 (dd, J=8.4, 4.1Hz,1H),1.36–1.21(m,3H),1.22–1.07(m,3H).13C NMR(125MHz, acetone-d6):δ167.36, 161.85(2×C),158.57,158.08,144.09,135.58,128.29,123.81, 117.98,113.67,107.26 (2×C),100.10,99.52,74.78,56.40,55.68(2×C),31.63(2× C),26.01,24.37(2×C). (+)-ESI m/z:411[M+H]+,433[M+Na]+,449[M+K]+. HR-ESI-MS m/z:411.1804[M+H]+ (calcd.for C24H27O6,411.1802).
Embodiment 5:
3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -2- furfuryl ester (5)
It is synthesized according to method B, the alcohol compound of addition is furfuryl alcohol (2- furancarbinol), with petroleum ether: ethyl acetate: two Chloromethanes (5: 1: 2) is solvent, and silica gel prepares plate preparative separation and obtains target product, yield 85.9%.The physics and chemistry of compound 5 Parameter is as follows:
Compound 5: beige solid, yield=85.9%.1H NMR(500MHz,acetone-d6):δ7.89(s, 1H), 7.45 (dd, J=2.0,1.0Hz, 1H), 7.38 (d, J=2.5Hz, 1H), 7.24 (d, J=2.5Hz, 1H), 6.54 (t, J=2.5Hz, 1H), 6.51 (d, J=2.5Hz, 2H), 6.34 (dd, J=3.0,2.0Hz, 1H), 6.24 (brd, J=3.0Hz, 1H),4.71(s,2H),3.93(s,3H),3.83(s,6H)；13C NMR(125MHz, acetone-d6):δ167.30, 161.88(2×C),158.63,157.98,150.01,144.22,144.16,135.70, 126.83,123.79,118.76, 113.73,111.46,111.33,107.10(2×C),100.38,100.29,58.83, 56.47,55.70(2×C).(+)- ESI-MS m/z:409.2[M+H]+,431.2[M+Na]+,447.1[M+K]+. HR-ESI-MS m/z:409.1277[M+H]+ (calcd.for C23H21O7,409.1282).
Embodiment 6:
3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -4- chlorobenzene base ester (6)
Synthesize according to method B, the alcohol compound of addition is parachlorophenol, with petroleum ether: acetone (2: 1) is solvent, Silica gel prepares plate preparative separation and obtains target product, yield 91.5%.The physical and chemical parameter of compound 6 is as follows:
Compound 6: faint yellow solid, yield=91.5%.1H NMR(500MHz,acetone-d6):δ7.95(s, 1H), 7.49 (d, J=2.5Hz, 1H), 7.46 (d, J=2.5Hz, 1H), 7.34 (d, J=9.0Hz, 2H), 6.88 (d, J= 9.0Hz, 2H), 6.58 (d, J=253Hz, 2H), 6.40 (t, J=2.5Hz, 1H), 3.98 (s, 3H), 3.75 (s, 6H)；13C NMR(125MHz,acetone-d6):δ165.58,161.92(2×C),158.64,158.15,150.16, 144.70, 135.59,131.25,129.76(2×C),125.83,123.87(2×C),123.76,118.95,114.72, 107.67(2 ×C),101.00,99.87,56.57,55.67.(+)-ESI-MS m/z439.2[M+H]+,461.1 [M+Na]+,477.1[M+ K]+.HR-ESI-MS m/z:439.0946[M+H]+(calcd.for C24H20ClO6, 439.0943).
Embodiment 7:
3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -2- methylbenzene base ester (7)
Synthesize according to method B, the alcohol compound of addition is to ortho-methyl phenol, with petroleum ether: acetone (2:1) is exhibition Agent is opened, silica gel prepares plate preparative separation and obtains target product, yield 96.3%.The physical and chemical parameter of compound 7 is as follows:
Compound 7: white solid, yield=96.3%.1H NMR(500MHz,acetone-d6):δ7.93(s, 1H), 7.52 (d, J=2.5Hz, 1H), 7.49 (d, J=2.5Hz, 1H), 7.20 (dd, J=7.5,2.0Hz, 1H), 7.14 (dt, J= 7.5,2.0Hz, 1H), 7.10 (dt, J=7.5,1.5Hz, 1H), 6.71 (dd, J=7.5,1.5Hz, 1H), 6.56 (d, J= 2.5Hz, 2H), 6.39 (t, J=2.5Hz, 1H), 3.97 (s, 3H), 3.74 (s, 6H), 2.10 (s, 3H)；13C NMR (125MHz,acetone-d6):δ165.02,161.59(2×C),158.53,158.14, 150.15,144.69,135.54, 131.60,130.84,127.36,126.64,125.85,123.83,122.63,119.17, 114.70,108.01(2×C), 100.83,99.76,56.51,55.60(2×C),16.30.(+)-ESI-MS m/z: 419.2[M+H]+,441.2[M+Na]+, 457.1[M+K]+.HR-ESI-MS m/z:419.1499[M+H]+ (calcd.for C25H23O6,419.1489).
Embodiment 8:
3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -4- fluorophenyl methyl ester (8)
Synthesized according to method B, the alcohol compound of addition is to fluorophenyl methanol, with petroleum ether: acetone (2: 1)) it is exhibition Agent is opened, silica gel prepares plate preparative separation and obtains target product, yield 89.6%.The physical and chemical parameter of compound 8 is as follows:
Compound 8: white solid, yield=89.6%.1H NMR(500MHz,acetone-d6):δ7.90(s, 1H), 7.38 (d, J=2.5Hz, 1H), 7.25 (d, J=2.5Hz, 1H), 7.11 (d, J=8.5Hz, 1H), 7.08 (d, J=8.5Hz, 1H), 7.03 (d, J=9.0Hz, 1H), 6.99 (d, J=9.0Hz, 1H), 6.51 (d, J=2.5Hz, 2H), 6.47 (t, J= 2.5Hz,1H),4.77(s,2H),3.92(s,3H),3.80(s,6H)；13C NMR(125 MHz,acetone-d6):δ 167.73,164.26,161.83(2×C),158.58,158.00,144.21,135.67, 132.51,132.49,132.51, 131.24,131.17,127.02,123.69,118.47,115.81,115.63,113.85 (2×C),106.99(2×C), 100.29,100.17,66.59,56.44,55.66(2×C).(+)-ESI-MS m/z: 437.3[M+H]+,459.2[M+Na]+, 475.2[M+K]+.HR-ESI-MS m/z:437.1412[M+H]+ (calcd.for C25H22FO6,437.1395).
Embodiment 9:
3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -4- Bromophenylmethyl ester (9)
Synthesized according to method B, the alcohol compound of addition is to bromobenzene methanol, with petroleum ether: acetone (2: 1)) it is expansion Agent, silica gel prepare plate preparative separation and obtain target product, yield 50.8%.The physical and chemical parameter of compound 9 is as follows:
Compound 9: white solid, yield=50.8%.1H NMR(600MHz,acetone-d6):δ7.90(s, 1H), 7.44 (d, J=8.4Hz, 2H), 7.39 (d, J=2.4Hz, 1H), 7.27 (d, J=2.4Hz, 1H), 7.02 (d, J=8.4Hz, 2H), 6.50 (d, J=2.4Hz, 2H), 6.45 (s, 1H), 4.77 (s, 2H), 3.93 (s, 3H), 3.79 (s, 6H)；13C NMR (125MHz,acetone-d6):δ167.68,161.82(2×C),158.61,158.02, 144.26,135.73,135.64, 132.06(2×C),130.88(2×C),126.91,123.71,122.28,118.53, 113.92,107.00(2×C), 100.26(2×C),66.51,56.47,55.66(2×C).(+)-ESI-MS m/z: 497.1[M+H]+,519.0[M+Na]+, 535.0[M+K]+.HR-ESI-MS m/z:497.0604[M+H]+ (calcd.for C25H22BrO6,497.0594).
Embodiment 10:
3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -2- phenylethylester (10)
Synthesize according to method B, the alcohol compound of addition is benzyl carbinol, with petroleum ether: acetone (5:2) is solvent, silicon Glue prepares plate preparative separation and obtains target product, yield 62.7%.The physical and chemical parameter of compound 10 is as follows:
Compound 10: white solid, yield=62.7%.1H NMR(500MHz,acetone-d6):δ7.93(s, 1H), 7.38 (d, J=2.5Hz, 1H), 7.25 (t, J=7.5Hz, 2H), 7.21 (d, J=2.5Hz, 1H), 7.17 (t, J= 7.5Hz, 1H), 7.11 (d, J=7.5Hz, 2H), 6.57 (s, 3H), 3.94 (t, J=7.5Hz, 2H), 3.92 (s, 3H), 3.81 (s, 6H), 2.44 (t, J=7.5Hz, 2H)；13C NMR(125MHz,acetone-d6):δ167.81, 161.91(2×C), 158.59,158.03,144.20,138.67,136.01,129.62(2×C),129.23(2×C), 127.32,127.24, 123.80,118.52,113.74,107.14(2×C),100.30,100.16,66.31,56.42, 55.74(2×C), 34.89.(+)-ESI-MS m/z:433.2[M+H]+,455.3[M+Na]+,471.1[M+K]+. HR-ESI-MS m/z: 433.1627[M+H]+(calcd.for C26H25O6,433.1646).
Embodiment 11:
3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -4- acetylbenzene base ester (11)
It is synthesized according to method B, the alcohol compound of addition is to 4-hydroxyacetophenone, with petroleum ether: ethyl acetate: dichloro Methane (3:1:2) is solvent, and silica gel prepares plate preparative separation and obtains target product, yield 79.7%.The physics and chemistry of compound 11 Parameter is as follows:
Compound 11: beige solid, yield=79.7%.1H NMR(500MHz,acetone-d6):δ7.96 (d,J =3.5Hz, 1H), 7.94 (d, J=9.0Hz, 2H), 7.50 (d, J=2.5Hz, 1H), 7.48 (d, J=2.5 Hz, 1H), 6.99 (d, J=9.0Hz, 2H), 6.59 (d, J=2.5Hz, 2H), 6.37 (t, J=2.5Hz, 1H), 3.98 (s, 3H), 3.75 (s, 6H),2.57(s,3H)；13C NMR(125MHz,acetone-d6):δ196.83,165.36, 161.92(2×C),158.65, 158.17,154.93,144.75,135.66,135.59,130.19(2×C),125.70, 123.79,122.24(2×C), 119.03,114.82,107.65(2×C),101.13,99.91,56.58,55.67(2× C),26.69.(+)-ESI-MS m/z:447.2[M+H]+,469.2[M+Na]+,485.1[M+K]+.HR-ESI-MS m/z:447.1433[M+H]+ (calcd.for C26H23O7,447.1438).
Embodiment 12:
3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofurancarboxylic acid -2- (1H- indol-3-yl) ethyl ester (12)
Synthesize according to method B, the alcohol compound of addition is 3- indoles ethyl alcohol, with petroleum ether: acetone (2: 1) is expansion Agent, silica gel prepare plate preparative separation and obtain target product, yield 80.0%.The physical and chemical parameter of compound 12 is as follows:
Compound 12: pale yellow oily liquid, yield=80.0%.1H NMR(500MHz,acetone-d6):δ9.98 (s, 1H), 7.93 (s, 1H), 7.50 (d, J=8.0Hz, 1H), 7.38 (d, J=2.0Hz, 1H), 7.35 (d, J=8.0Hz, 1H), 7.24 (d, J=2.0Hz, 1H), 7.08 (dt, J=1.0,8.0Hz, 1H), 7.07 (d, J=1.0Hz, 1H), 7.00 (dt, J=1.0,8.0Hz, 1H), 6.59 (d, J=2.0Hz, 2H), 6.54 (t, J=2.0Hz, 1H), 4.02 (t, J= 8.0Hz, 2H), 3.92 (s, 3H), 3.80 (s, 6H), 2.64 (t, J=8.0Hz, 2H)；13C NMR (125MHz,acetone- d6):δ167.90,161.91(2×C),158.62,158.07,144.20,137.58, 136.02,128.42,127.56, 123.92,123.55,122.16,119.47,119.24,118.57,113.75,112.15, 111.50,107.16(2×C), 100.36,100.14,65.93,56.44,55.72(2×C),24.81.(+)-ESI-MS m/z 472.1[M+H]+,494.2 [M+Na]+,510.1[M+K]+.HR-ESI-MS m/z:494.1590 [M+Na]+(calcd.for C28H25NO6Na, 494.1574).
The synthetic route of compound 13-16 in embodiment:
Synthesize final product (compound numbers correspond to the compound numbers in embodiment):
Embodiment 13:
3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofurancarboxylic acid (13)
The synthetic method of compound 13 in embodiment:
Compound 1 (500.0mg, 1.52mmol) is dissolved in 60mL methylene chloride, is cooled to -50 DEG C.It is vigorously stirred down, slowly Instill BBr3Dichloromethane solution [BBr315.2mL (10equiv, 1mmol/L) is dissolved in 30mL DCM], keep -50 DEG C of reactions 2h is to slowly warm up to room temperature via -50 DEG C, -25 DEG C, -10 DEG C, 0 DEG C of several temperature section, continues room temperature reaction overnight, and TLC monitoring is anti- It should finish, with methanol quenching reaction.Reaction mixture is with the dilution of 100mL ethyl acetate, and washing, saturated common salt is washed, organic Mutually merge, anhydrous sodium sulfate is dry, evaporated under reduced pressure.The a small amount of ethyl acetate of residue and methanol mixed solution dissolution, with dichloromethane Alkane: methanol (10: 1) is solvent, and silica gel prepares plate and separates to obtain crude product, and gained crude product is further separated with gel column, first Alcohol elutes to obtain faint yellow solid.
Compound 13: faint yellow solid (118.9mg, 27.3%).1H NMR(500MHz,cd3od):δ7.56 (s,1H), 7.09 (d, J=2.0Hz, 1H), 7.02 (d, J=2.0Hz, 1H), 6.25 (d, J=2.0Hz, 2H), 6.17 (s, 1H)13C NMR(125MHz,acetone-d6):δ167.79,159.02(2×C),158.70,156.30, 143.68,136.20, 124.59,118.47,114.27(2×C),(2×C),111.42,108.42,102.47(2×C), 101.87.(+)-ESI- MS m/z287.0[M+H]+,309.0[M+Na]+,324.9[M+K]+.HR-ESI-MS m/z:287.0566[M+H]+ (calcd.for C15H11O6,287.0550).
Embodiment 14:
3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofurancarboxylic acid methyl esters (14)
Compound 1b is raw material, and the synthetic method of reference compound 13 synthesizes, with methylene chloride: methanol (10:1) is exhibition Agent is opened, silica gel prepares plate separation and is prepared into compound 14.
Compound 14: khaki solid (56.03mg, 10.6%).1H NMR(500MHz,acetone-d6): δ8.88 (s, 1H), 8.32 (s, 2H), 7.76 (s, 1H), 7.20 (d, J=2.5Hz, 1H), 7.18 (d, J=2.5Hz, 1H), 6.37 (t, J=2.5Hz, 1H), 6.31 (d, J=2.5Hz, 2H), 3.34 (s, 3H)13C NMR(125MHz, acetone-d6):δ 168.07,159.28(2×C),157.97,155.95,143.40,135.93,127.05,124.00, 118.33,114.11, 107.84(2×C),102.21,101.97,51.44.(+)-ESI-MS m/z:323[M+Na]+, 339[M+K]+；299[M- H]-.HR-ESI-MS m/z:301.0716[M+H]+(calcd.for C16H13O6, 301.0707).
Embodiment 15:
3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofurancarboxylic acid monooctyl ester (15)
Compound 3 is raw material, and the synthetic method of reference compound 13 synthesizes, with methylene chloride: methanol (10:1) is expansion Agent, silica gel prepare plate separation and are prepared into compound 15.
Compound 15: hazel-color solid (27.7mg, 43.8%).1H NMR(500MHz,acetone-d6):δ8.84 (s, 1H), 8.30 (s, 2H), 7.76 (s, 1H), 7.19 (d, J=2.0Hz, 1H), 7.17 (d, J=2.0Hz, 1H), 6.36 (d, J= 2.0Hz, 1H), 6.34 (d, J=2.0Hz, 2H), 3.80 (t, J=7.0Hz, 2H), 1.35-1.16 (m, 10H), 1.15 (d, J =7.0Hz, 2H), 0.86 (t, J=7.0Hz, 3H)；13C NMR(125MHz, acetone-d6):δ168.02,159.44(2× C),158.09,155.97,143.46,135.95,127.72,124.11, 117.99,114.13,107.74(2×C), 102.36,101.82,65.74,32.55,29.89(2×C),28.70, 26.63,23.27,14.36.(+)-ESI-MS m/ z:399.4[M+H]+,421.3[M+Na]+,437.2[M+K]+. HR-ESI-MS m/z:399.1804[M+H]+(calcd.for C23H27O6,399.1802).
Embodiment 16:
3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofurancarboxylic acid 2- phenylethylester (16)
Compound 10 is raw material, and the synthetic method of reference compound 13 synthesizes, with methylene chloride: methanol (10:1) is exhibition Agent is opened, silica gel prepares plate separation and is prepared into compound 16.
Compound 16: faint yellow solid (9.9mg, 16.2%).1H NMR(500MHz,acetone-d6):δ8.62 (s, 3H), 7.80 (s, 1H), 7.24 (t, J=7.5Hz, 2H), 7.26-7.22 (m, 3H), 7.17 (t, J=7.5Hz, 2H), 6.45 (t, J=2.0Hz, 1H), 6.40 (d, J=2.0Hz, 2H), 3.97 (t, J=8.0Hz, 2H), 2.47 (t, J=8.0Hz, 2H) .13C NMR(125MHz,acetone-d6):δ167.91,159.50(2×C),158.10, 155.97,143.59,138.79, 136.23,129.76(2×C),129.20(2×C),127.35,127.19,124.06, 118.07,114.25,107.86(2 ×C),102.49,102.00,66.35,34.87.HR-ESI-MS m/z: 391.1170[M+H]+(calcd.for C23H19O6,391.1176).
The synthetic route of compound 17~33 in embodiment:
Synthesize final product (compound numbers correspond to the compound numbers in embodiment):
The synthetic method of compound 17~33 in embodiment:
Synthetic method A: compound 1 (100mg, 0.30mmol) is dissolved in the dry methylene chloride of 50mL, is sequentially added HOBt (49.8mg, 0.37mmol) or and EDCI (70.1mg, 0.37mmol), 20 min are stirred at room temperature, corresponding amine is added and spreads out Biological (about 1.2equiv).About 4h is stirred at room temperature in reaction solution, and TLC monitors end of reaction, stops reaction.Reaction solution is concentrated under reduced pressure into After dry, remaining solid prepares plate separation (selecting suitable solvent according to different compounds) with silica gel and obtains target product.
Synthetic method B: compound 1 (100mg, 0.30mmol) is dissolved in the dry methylene chloride of 50mL, and DMAP is added (44.7mg, 0.37mmol) and EDCI (70.1mg, 0.37mmol), is stirred at room temperature 20min, corresponding amine derivative is added (about 1.2equiv).About 4h is stirred at room temperature in reaction solution, and TLC monitors end of reaction, stops reaction.Reaction solution is concentrated under reduced pressure, remaining solid Plate separation (selecting suitable solvent according to different compounds), which is prepared, with silica gel obtains target product.
Embodiment 17:
N- methyl -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran carboxamides (17)
The aminated compounds of reference method A synthesis, addition is methylamine, with methylene chloride: methanol (40: 1) is solvent, silicon Glue prepares plate preparative separation and obtains, yield 87.3%.The physical and chemical parameter of compound 17 is as follows:
Faint yellow solid, yield=87.3%.1H NMR(500MHz,acetone-d6):δ7.86(s,1H),7.23 (d, J=2.0Hz, 1H), 6.99 (d, J=2.0Hz, 1H), 6.88 (brs, 1H), 6.57 (d, J=2.0Hz, 2H), 6.46 (t, J=2.0Hz, 1H), 3.90 (s, 3H), 3.81 (s, 6H), 2.45 (d, J=4.5Hz, 3H)；13C NMR (125MHz, acetone-d6):δ168.40,161.66(2×C),158.84,157.86,143.17,134.80, 133.21,123.65, 117.27,111.89,107.08(2×C),100.43,97.96,56.28,55.61(2×C), 26.07.(+)-ESI-MS m/z:342.2[M+H]+,364.1[M+Na]+,380.1[M+K]+.HR-ESI-MS m/z:342.1339[M+H]+ (calcd.for C19H20NO5,342.1336).
Embodiment 18:
N- propyl -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran carboxamides (18)
The aminated compounds of reference method B synthesis, addition is n-propylamine, with oily ether: acetone (2:1) is solvent, silica gel It prepares plate preparative separation to obtain, yield 94.4%.The physical and chemical parameter of compound 18 is as follows:
Compound 18: white solid, yield=94.4%.1H NMR(500MHz,acetone-d6):δ7.84(s, 1H), 7.22 (d, J=2.5Hz, 1H), 6.98 (d, J=2.5Hz, 1H), 6.88 (brs, 1H), 6.59 (d, J=2.5 Hz, 2H), 6.47 (t, J=2.5Hz, 1H), 3.90 (s, 3H), 3.81 (s, 6H), 2.89 (dd, J=14.5,7.5Hz, 2H), 1.25 (dt, J=14.5,7.5Hz, 2H), 0.75 (t, J=7.5Hz, 3H)；13C NMR(125MHz, acetone-d6):δ167.98, 161.72(2×C),158.83,157.89,143.18,134.88,133.39,123.76, 117.21,112.04,107.24 (2×C),100.45,97.85,56.29,55.63(2×C),42.14,22.77,11.78. (+)-ESI-MS m/z:370.1 [M+H]+,392.1[M+Na]+,408.0[M+K]+.HR-ESI-MS m/z: 370.1663[M+H]+(calcd.for C21H24NO5,370.1649).
Embodiment 19:
N- dodecyl -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran carboxamides (19)
The aminated compounds of reference method A synthesis, addition is lauryl amine, with oily ether: acetone (2:1) is solvent, silica gel It prepares plate preparative separation to obtain, yield 95.4%.The physical and chemical parameter of compound 19 is as follows:
Compound 19: white solid, yield=95.4%.1H NMR(500MHz,acetone-d6):δ7.85(s, 1H), 7.22 (d, J=2.0Hz, 1H), 6.98 (d, J=2.0Hz, 1H), 6.84 (brs, 1H), 6.60 (d, J=2.0 Hz, 2H), 6.46 (t, J=2.0Hz, 1H), 3.90 (s, 3H), 3.82 (s, 6H), 2.93 (dd, J=12.0,6.0Hz, 2H), 1.37-1.08 (m, 20H), 0.88 (t, J=6.5Hz, 3H)；13C NMR(125MHz,acetone-d6):δ 167.85, 161.70(2×C),158.82,157.89,143.21,134.88,133.37,123.75,117.14,112.04, 107.15 (2×C),100.54,97.84,56.28,55.63(2×C),40.30,32.65,30.40-30.30(5×C), 30.11, 30.09,27.80,23.34,14.36.(+)-ESI-MS m/z:496.2[M+H]+,518.3[M+Na]+. HR-ESI-MS m/ z:496.3072[M+H]+(calcd.for C30H42NO5,496.3057)..
Embodiment 20:
N- (3- dimethylamino -1- propyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran formyl Amine (20)
Reference method B synthesis, the aminated compounds of addition are N, N'- dimethyl -1,3- propane diamine, with chloroform: methanol (6 : 1) it is solvent, silica gel prepares plate preparative separation and obtains, yield 90.7%.The physical and chemical parameter of compound 20 is as follows:
Compound 20: faint yellow solid, yield=90.7%.1H NMR(500MHz,acetone-d6)δ7.86(s, 1H), 7.41 (s, 1H), 7.25 (d, J=2.0Hz, 1H), 7.04 (d, J=2.0Hz, 1H), 6.61 (d, J=2.0Hz, 2H), 6.50 (t, J=2.0Hz, 1H), 3.92 (s, 3H), 3.83 (s, 6H), 3.58 (td, J=7.5,3.0Hz, 2H), 3.35 (s, 6H), 3.10 (dd, J=12.0,6.0Hz, 2H), 1.99-1.83 (m, 3H)13C NMR(125MHz, acetone-d6):δ 168.44,161.53(2×C),158.75,157.87,143.44,135.14,132.49,123.57, 117.20,112.32, 107.22(2×C),100.54,98.08,65.34,56.38,55.80(2×C),53.67,37.23, 23.54.(+)-ESI- MS m/z:413.3[M+H]+,435.3[M+Na]+.HR-ESI-MS m/z:413.2074 [M+H]+(calcd.for C23H29N2O5,413.2071).
Embodiment 21:
[N-3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran formoxyl] methyl methionine (21)
Compound 1 (100mg, 0.30mmol) is dissolved in the dry methylene chloride of 50mL, sequentially add DMAP (44.7mg, 0.37mmol), after 20min is stirred at room temperature, L- is added in EDCI (70.1mg, 0.37mmol) and DIPEA (151 μ L, 0.91mmol) Methyl methionine (1.2equiv) continues that 4h is stirred at room temperature, and TLC monitors end of reaction, stops reaction.Reaction solution is concentrated under reduced pressure, Remaining solid is with petroleum ether: acetone (2: 1) prepares separation on plate in silica gel for solvent and is prepared into target product.Yield 54.2%.
Compound 21: beige solid, yield=54.2%.1H NMR(500MHz,acetone-d6)δ7.92(s, 1H), 7.44 (d, J=6.5Hz, 1H), 7.31 (d, J=2.0Hz, 1H), 7.05 (d, J=2.0Hz, 1H), 6.64 (d, J= 2.0Hz, 2H), 6.52 (t, J=2.0Hz, 1H), 4.29-4.34 (m, 1H), 3.96 (s, 3H), 3.87 (s, 6H), 3.71 (s, 3H),2.25-2.29(m,2H),2.05(s,3H),1.84-1.90(m,1H),1.74-1.78(m,1H). 13C NMR (125MHz,acetone-d6):δ172.53,168.57,161.69(2×C),158.75,157.92, 143.49,134.70, 132.23,123.66,116.94,112.33,107.09(2×C),100.42,98.09,56.31, 55.62(2×C), 53.28,52.34,31.88,30.43.(+)-ESI-MS m/z:474.0[M+H]+,496.0 [M+Na]+,512.0[M+K]+ .HR-ESI-MS m/z:474.1597[M+H]+(calcd.for C24H28NO7, 474.1581).
Embodiment 22:
N- cyclopenta -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran carboxamides (22)
The aminated compounds of reference method A synthesis, addition is cyclopentamine, with petroleum ether: ethyl acetate: methylene chloride (3: It 1:2) is solvent, silica gel prepares plate preparative separation and obtains, yield 82.6%.The physical and chemical parameter of compound 22 is as follows:
Compound 22: white solid, yield=82.6%.1H NMR(500MHz,acetone-d6):δ7.84(s, 1H), 7.21 (d, J=2.0Hz, 1H), 6.96 (d, J=2.0Hz, 1H), 6.87 (brs, 1H), 6.60 (d, J=2.0 Hz, 2H), 6.47 (t, J=2.0Hz, 1H), 3.96-3.90 (m, 1H), 3.89 (s, 3H), 3.81 (s, 6H), 1.66~1.58 (m, 2H), 1.53~1.50 (m, 2H), 1.40-1.48 (m, 2H), 1.11~1.184 (m, 2H)；13C NMR(125MHz,acetone- d6):δ167.66,161.71(2×C),158.75,157.83,143.11,134.87, 133.36,123.78,117.06, 112.11,107.17(2×C),100.57,97.78,56.26,55.63(2×C), 51.96,32.87(2×C),24.37(2 ×C).(+)-ESI-MS m/z:396.2[M+H]+,418.2[M+Na]+, 434.1[M+K]+.HR-ESI-MS m/z: 396.1821[M+H]+(calcd.for C23H26NO5,396.1805)..
Embodiment 23:
N- (2- furfuryl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran carboxamides (23)
The aminated compounds of reference method A synthesis, addition is furylamine, with petroleum ether: acetone (2:1) is solvent, Silica gel prepares plate preparative separation and obtains, yield 84.9%.The physical and chemical parameter of compound 23 is as follows:
Compound 23: faint yellow solid, yield=84.9%.1H NMR(500MHz,acetone-d6):δ7.86 (s, 1H), 7.38 (d, J=2.0Hz, 1H), 7.34 (brs, 1H), 7.24 (d, J=2.0Hz, 1H), 7.02 (d, J=2.0Hz, 1H), 6.60 (d, J=2.0Hz, 2H), 6.48 (t, J=2.0Hz, 1H), 6.29 (dd, J=3.0,2.0Hz, 1H), 6.09 (d, J=3.0Hz, 1H), 4.08 (d, J=5.5Hz, 2H), 3.90 (s, 3H), 3.82 (s, 6H)；13C NMR(125MHz,acetone- d6):δ167.83,161.70(2×C),158.81,157.86,152.62,143.27, 142.73,134.85,132.57, 123.69,117.43,112.05,111.11,107.70,107.24(2×C),100.57, 98.18,56.31,55.64(2× C),37.08.(+)-ESI-MS m/z:408.1[M+H]+,430.2[M+Na]+, 446.0[M+K]+.HR-ESI-MS m/z: 408.1458[M+H]+(calcd.for C23H22NO6,408.1442).
Embodiment 24:
N- (4- aminomethyl phenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran carboxamides (24)
The aminated compounds of reference method B synthesis, addition is para-totuidine, with petroleum ether: acetone (2:1) is solvent, Silica gel prepares plate preparative separation and obtains, yield 54.8%.The physical and chemical parameter of compound 24 is as follows:
Compound 24: beige solid, yield=54.2%.1H NMR(600MHz,acetone-d6):δ8.84 (s, 1H), 7.87 (s, 1H), 7.33 (d, J=7.8Hz, 2H), 7.29 (s, 1H), 7.14 (s, 1H), 7.00 (d, J=7.8 Hz, 2H),6.56(s,2H),6.16(s,1H),3.93(s,3H),3.64(s,6H),2.26(s,2H)；13C NMR (125MHz, acetone-d6):δ166.10,161.65(2×C),158.89,157.88,143.30,137.25, 134.51,133.53, 132.90,130.11,129.41(2×C),123.82,120.31(2×C),112.29,107.27 (2×C),100.32, 98.51,56.39,55.42(2×C),20.89.(+)-ESI-MS m/z:418.3[M+H]+, 440.3[M+Na]+,456.2[M +K]+.HR-ESI-MS m/z:418.1652[M+H]+(calcd.for C25H24NO5,418.1649).
Embodiment 25:
N- (4- chlorphenyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran carboxamides (25)
The aminated compounds of reference method B synthesis, addition is parachloroanilinum, with petroleum ether: acetone (2:1) is solvent, Silica gel prepares plate preparative separation and obtains, yield 65.1%.The physical and chemical parameter of compound 25 is as follows:
Compound 25: khaki solid, yield=65.1%.1H NMR(500MHz,acetone)δ9.03(s, 1H), 7.88 (s, 1H), 7.47 (d, J=9.0Hz, 2H), 7.31 (d, J=2.5Hz, 2H), 7.20 (d, J=9.0Hz, 2H), 7.14 (d, J=2.5Hz, 1H), 6.53 (d, J=2.5Hz, 2H), 6.14 (t, J=2.3Hz, 1H), 3.93 (s, 3H), 3.66 (s,6H).13C NMR(125MHz,acetone-d6):δ166.44,161.66(2×C),158.91, 157.79,143.34, 138.50,134.47,132.28,128.85(2×C),128.58,123.62,121.55(2×C), 117.76,112.29, 107.30(2×C),100.02,98.79,56.41,55.42.(+)-ESI-MS m/z:438.1 [M+H]+,460.1[M+Na]+, 476.1[M+K]+.
Embodiment 26:
N- (phenyl methyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran carboxamides (26)
The aminated compounds of reference method B synthesis, addition is benzylamine, with petroleum ether: acetone (2:1) is solvent, silica gel It prepares plate preparative separation to obtain, yield 92.4%.The physical and chemical parameter of compound 26 is as follows:
Compound 26: white solid, yield=92.4%.1H NMR(500MHz,acetone-d6):δ7.87(s, 1H), 7.34 (brs, 1H), 7.24 (d, J=2.5Hz, 1H), 7.32 (t, J=7.5Hz, 2H), 7.19 (t, J=7.5Hz, 1H), 7.10 (d, J=7.5Hz, 2H), 7.04 (d, J=2.5Hz, 1H), 6.64 (d, J=2.0Hz, 2H), 6.50 (t, J= 2.0Hz, 1H), 4.11 (d, J=5.5Hz, 2H), 3.90 (s, 3H), 3.84 (s, 6H)；13C NMR(125MHz, acetone- d6):δ168.12,161.77(2×C),158.84,157.92,143.30,139.49,134.91,132.93, 129.08(2 ×C),128.57(2×C),127.72,123.74,117.31,112.16,107.28(2×C),100.71, 98.05, 56.31,55.68(2×C),44.17.(+)-ESI-MS m/z:418.3[M+H]+,440.2[M+Na]+, 456.2[M+K]+ .HR-ESI-MS m/z:418.1656[M+H]+(calcd.for C25H24NO5,418.1649).
Embodiment 27:
N- (methyl)-N- (phenyl methyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran carboxamides (27)
The aminated compounds of reference method B synthesis, addition is N- benzylmethylamine, with petroleum ether: acetone (2:1) is expansion Agent, silica gel prepare plate preparative separation and obtain, yield 64.5%.The physical and chemical parameter of compound 27 is as follows:
Pale yellow oily liquid (a pair of of enantiomer), yield=64.5%.1H NMR(500MHz,CDCl3):δ7.83(s, 1H), 7.83 (s, 1H), 7.17-7.31 (m, 6H), 7.11-7.14 (m, 2H), 7.01 (d, J=2.3Hz, 1H), 7.07 (d, J =2.2Hz, 1H), 7.02 (d, J=2.2Hz, 1H), 6.98 (d, J=2.3Hz, 1H), 6.89-6.93 (m, 2H), 6.68 (d, J =2.3Hz, 4H), 6.52 (t, J=2.3Hz, 1H), 6.50 (t, J=2.3Hz, 1H), 5.16 (d, J=14.7Hz, 1H), 4.35 (d, J=15.4Hz, 1H), 3.89 (s, 3H), 3.88 (s, 6H), 3.87 (s, 6H), 3.85 (s, 3H), 3.37 (d, J= 15.4Hz, 1H), 3.13 (d, J=14.67Hz, 1H), 2.51 (s, 3H), 2.29 (s, 3H)13C NMR(125MHz,CDCl3): δ169.87,169.80,160.84(2×C),160.82(2×C),158.43, 158.40,156.71,156.62,130.30, 130.00,128.73(2×C),128.69(2×C),128.28(2×C), 127.73,127.50,127.32(2×C), 122.76,122.67,116.61,116.35,111.23,110.94,106.46 (2×C),106.39(2×C),100.66, 100.50,97.57,97.50,56.13,56.07,55.66(4×C), 54.42,49.84,35.52,31.83.(+)-ESI- MS m/z:432.3.[M+H]+,454.3[M+Na]+.,470.2 [M+K]+.HR-ESI-MS m/z:432.1812[M+H]+ (calcd.for C26H26NO5,432.1805).
Embodiment 28:
N- (4- Chlorophenylmethyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran carboxamides (28)
The aminated compounds of reference method B synthesis, addition is 4- chlorobenzylamine, with petroleum ether: acetone (2:1) is solvent, Silica gel prepares plate preparative separation and obtains, yield 96.3%.The physical and chemical parameter of compound 28 is as follows:
Compound 28: beige solid, yield=96.3%.1H NMR(500MHz,acetone-d6):δ7.86 (s, 1H), 7.42 (brs, 1H), 7.25 (d, J=8.5Hz, 2H), 7.24 (d, J=2.5Hz, 1H), 7.11 (d, J=8.5Hz, 2H), 7.03 (d, J=2.5Hz, 1H), 6.62 (d, J=2.5Hz, 2H), 6.48 (t, J=2.5Hz, 1H), 4.11 (d, J= 6.0Hz,2H),3.90(s,3H),3.83(s,6H)；13C NMR(125MHz,acetone-d6):δ 168.22,161.73(2× C),158.84,157.92,143.36,138.52,134.87,132.98,132.74,130.29 (2×C),129.06(2× C),123.70,117.27,112.20,107.27(2×C),100.66,98.11,56.32, 55.67(2×C),43.44. (+)-ESI-MS m/z:452.1[M+H]+,474.1[M+Na]+,490.1[M+K]+. HR-ESI-MS m/z:452.1280[M+ H]+(calcd.for C25H23ClNO5,452.1259).
Embodiment 29:
N- (2- Chlorophenylmethyl) -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran carboxamides (29)
The aminated compounds of reference method B synthesis, addition is 2- chlorobenzylamine, with petroleum ether: acetone (2:1) is solvent, Silica gel prepares plate preparative separation and obtains, yield 66.3%.The physical and chemical parameter of compound 29 is as follows:
Compound 29: beige solid, yield=66.3%.1H NMR(500MHz,acetone-d6):δ7.87 (s, 1H), 7.39 (m, 1H), 7.36-7.31 (m, 1H), 7.26 (d, J=2.5Hz, 1H), 7.25-7.18 (m, 3H), 7.07 (d, J =2.5Hz, 1H), 6.63 (d, J=2.0Hz, 2H), 6.50 (t, J=2.0Hz, 1H), 4.20 (d, J=6.0Hz, 2H), 3.91 (s,3H),3.83(s,6H)；13C NMR(125MHz,acetone-d6):δ168.33, 161.78(2×C),158.86, 157.90,143.33,143.29,136.82,134.84,132.66,130.07,129.91, 129.34,127.88, 123.68,117.40,112.25,107.42,107.39,100.59,98.15,56.35, 55.69(2×C),41.70.(+)- ESI-MS m/z:452.0[M+H]+,474.0[M+Na]+,490.0[M+K]+. HR-ESI-MS m/z:452.1281[M+H]+ (calcd.for C25H23ClNO5,452.1259).
Embodiment 30:
N- [2- (4- chlorphenyl) ethyl] -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran carboxamides (30)
The aminated compounds of reference method B synthesis, addition is 4- chlorophenethylamine, with petroleum ether: acetone (2:1) is expansion Agent, silica gel prepare plate preparative separation and obtain, yield 70.4%.The physical and chemical parameter of compound 30 is as follows:
Compound 30: white solid, yield=70.4%.1H NMR(500MHz,acetone-d6):δ7.86(s, 1H), 7.28 (d, J=8.5Hz, 2H), 7.22 (d, J=2.0Hz, 1H), 7.14 (d, J=8.5Hz, 2H), 7.04 (brs, 1H), 6.95 (d, J=2.0Hz, 1H), 6.62 (d, J=2.5Hz, 2H), 6.49 (t, J=2.5Hz, 1H), 3.90 (s, 3H), 3.81 (s, 6H), 3.23-3.13 (m, 2H), 2.51 (t, J=8.0Hz, 2H)；13C NMR(125 MHz,acetone-d6):δ 168.06,161.73(2×C),158.82,157.89,143.30,139.41,134.98, 133.06,132.28,131.21 (2×C),129.18(2×C),123.68,117.20,111.99,107.33(2×C), 100.51,97.99,56.30, 55.68(2×C),41.63,34.99.(+)-ESI-MS m/z:466.0[M+H]+, 488.0[M+Na]+.HR-ESI-MS m/ z:466.1429[M+H]+(calcd.for C26H25ClNO5, 466.1416)..
Embodiment 31:
N- [2- (1H- indol-3-yl) ethyl] -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran formyl Amine (31)
The aminated compounds of reference method B synthesis, addition is tryptamines (β-indolecthanamine), with petroleum ether: acetone (3:1) For solvent, silica gel prepares plate preparative separation and obtains, yield 95.1%.The physical and chemical parameter of compound 31 is as follows:
Compound 31: hazel-color solid, yield=95.1%.1H NMR(500MHz,acetone-d6):δ9.98 (s, 1H), 7.86 (s, 1H), 7.54 (d, J=7.5Hz, 1H), 7.34 (d, J=7.5Hz, 1H), 7.22 (d, J=2.5 Hz, 1H), 7.09~6.99 (m, 5H), 6.65 (d, J=2.0Hz, 2H), 6.47 (t, J=2.0Hz, 1H), 3.88 (s, 3H), 3.79 (s, 6H), 3.30 (dd, J=13.5,7.5Hz, 2H), 2.66 (t, J=7.5Hz, 2H)；13C NMR (125MHz,acetone-d6): δ168.06,161.72(2×C),158.80,157.89,143.27,137.67, 134.96,133.17,128.49, 123.71,123.09,122.07,119.35,119.32,117.21,113.36,112.11, 112.03,107.30(2×C), 100.59,98.04,56.28,55.66(2×C),41.13,25.47.(+)-ESI-MS m/z:471.2[M+H]+,509.2[M +K]+.HR-ESI-MS m/z:471.1930[M+H]+(calcd.for C28H27N2O5,471.1914).
Embodiment 32:
N- [2- (5- methoxyl group -1H- indol-3-yl) ethyl] -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzene And furoylamide (32)
The aminated compounds of reference method B synthesis, addition is 2- (5- methoxyl group -1H- indol-3-yl) ethamine, with petroleum Ether: acetone (2:1) is solvent, and silica gel prepares plate preparative separation and obtains, yield 91.0%.The physical and chemical parameter of compound 32 is such as Under:
Compound 32: brown solid, yield=91.0%.1H NMR(500MHz,acetone-d6):δ9.79(s, 1H), 7.86 (s, 1H), 7.23 (d, J=8.5Hz, 1H), 7.22 (d, J=2.5Hz, 1H), 7.05 (d, J=2.5Hz, 1H), 7.02 (d, J=2.5Hz, 1H), 7.00 (d, J=2.5Hz, 1H), 6.97 (t, J=5Hz, 1H), 6.74 (dd, J=8.5, 2.5Hz, 1H), 6.64 (d, J=2.5Hz, 2H), 6.47 (t, J=2.5Hz, 1H), 3.89 (s, 3H), 3.79 (s, 9H), 3.33-3.22 (m, 2H), 2.62 (t, J=8.0Hz, 2H)；13C NMR(125MHz,acetone):δ 168.00,161.72(2 ×C),158.82,157.91,154.68,143.27,134.98,133.22,132.79,128.86, 123.77,117.21, 113.19,112.72,112.37,112.03,107.25(2×C),101.16,100.66,98.04, 56.29,55.93, 55.66(2×C),41.04,25.53.(+)-ESI-MS m/z:501.1[M+H]+,523.1 [M+Na]+,539.0[M+K]+ .HR-ESI-MS m/z:501.2029[M+H]+(calcd.for C29H29N2O6, 501.2020).
Embodiment 33:
N- { 2- [(5- (3- (3,5- Dimethoxyphenyl l) -6- methoxyl group -4- benzofuran formoxyl) oxygroup) -1H- Yin Diindyl -3- base] ethyl } -3- (3,5- Dimethoxyphenyl) -6- methoxyl group -4- benzofuran carboxamides (33)
The aminated compounds of reference method B synthesis, addition is serotonine, with petroleum ether: acetone (2:1) is expansion Agent, silica gel prepare plate preparative separation and obtain, yield 34.2%.The physical and chemical parameter of compound 33 is as follows:
Compound 33: beige solid, yield=34.2%.1H NMR(500MHz,acetone-d6):δ10.00 (s, 1H), 7.95 (s, 1H), 7.86 (s, 1H), 7.50 (d, J=2.5Hz, 1H), 7.46 (d, J=2.5Hz, 1H), 7.25 (d, J= 9.0Hz, 1H), 7.21 (d, J=2.5Hz, 1H), 7.10 (d, J=2.5Hz, 1H), 7.01 (d, J=2.5Hz, 1H), 6.98 (t, J=5.0Hz, 1H), 6.88 (d, J=2.5Hz, 1H), 6.64 (d, J=2.5Hz, 2H), 6.62 (d, J=2.5Hz, 2H), 6.61 (dd, J=9.0,2.5Hz, 1H), 6.49 (t, J=2.5Hz, 1H), 6.43 (t, J=2.5Hz, 1H), 3.99 (s, 3H), 3.87 (s, 3H), 3.78 (s, 6H), 3.72 (s, 6H), 3.27 (td, J=7.5,5.5Hz, 2H), 2.62 (dd, J=15.0, 8.0Hz,2H)；13C NMR(125MHz,acetone-d6):δ168.08, 166.76,161.85(2×C),161.72(2× C),158.81,158.66,158.19,157.90,144.62,144.49, 143.27,135.64,135.30,134.96, 133.21,128.33,127.18,124.56,123.98,123.72,118.64, 117.19,116.27,114.33, 113.73,112.01,111.98,111.08,107.43(2×C),107.27(2×C), 100.66,100.51,100.40, 98.01,56.53,56.26,55.68(4×C),41.01,25.32.(+)-ESI-MS m/z:797.0[M+H]+,819.1[M+ Na]+,835.0[M+K]+.HR-ESI-MS m/z:797.2728[M+H]+ (calcd.for C46H41N2O11,797.2705).
The synthetic route of compound 34~43 in embodiment:
Synthesize final product 34~43 (compound numbers correspond to the compound numbers in embodiment):
The synthetic method of compound 34~43 in embodiment:
The amide derivatives (about 70mg) that 3 aryl replace are dissolved in the dry methylene chloride of 20mL, are cooled to -50 DEG C. It is vigorously stirred down, is slowly dropped into BBr3Dichloromethane solution [BBr3(10equiv, 1mmol/L) is dissolved in the dry dichloromethane of 15mL In alkane].After being added dropwise, is kept for -50 DEG C continue to stir 2h, be to slowly warm up to -25 DEG C, -10 DEG C and 0 DEG C respectively, and -25 DEG C, 2h is stirred respectively at -10 DEG C and 0 DEG C.Then overnight, TLC monitors end of reaction for room temperature reaction.Reaction solution is cooled to -50 DEG C, 6mL is added dropwise and analyzes methanol.Reaction solution is with the dilution of 100mL ethyl acetate, and 50mL washing, saturated common salt washing, water phase is with acetic acid second Ester back extraction, organic phase merge, and anhydrous sodium sulfate is dry, are concentrated to dryness, residue is molten with the mixing of ethyl acetate and methanol Agent (or mixed solvent of acetone and methanol) dissolution prepares plate separation with silica gel, and gel-purified obtains target compound.Gel-purified Eluant, eluent be usually methanol, use the mixed solvent of chloroform methanol or dichloromethane methanol once in a while.
Embodiment 34:
N- methyl-(3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran carboxamides (34)
The physical and chemical parameter of compound 34 is as follows:
Compound 34: beige solid (30.4mg, 49.6%).1H NMR(500MHz,acetone-d6):δ8.84 (s, 1H), 8.40 (s, 2H), 7.69 (s, 2H), 7.04 (d, J=2.0Hz, 1H), 6.99 (d, J=2.0Hz, 1H), 6.79 (s, 1H), 6.38 (d, J=2.0Hz, 2H), 6.34 (t, J=2.0Hz, 1H), 2.49 (d, J=5.0Hz, 3H)；13C NMR (125MHz,acetone-d6):δ168.71,159.34(2×C),157.88,156.25,142.58, 134.82,132.69, 123.64,116.68,112.54,107.99(2×C),102.56,99.97,26.17. (+)-ESI-MS m/z:300.0[M+ H]+,322.0[M+Na]+,338.0[M+K]+.HR-ESI-MS m/z: 300.0870[M+H]+(calcd.for C16H14NO5, 300.0866).
Embodiment 35:
N- dodecyl-(3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran carboxamides (35)
The physical and chemical parameter of compound 35 is as follows:
Compound 35: faint yellow solid (20.0mg, 31.2%).1H NMR(500MHz,acetone-d6):δ8.77 (s, 1H), 8.36 (s, 2H), 7.70 (s, 1H), 7.04 (d, J=2.0Hz, 1H), 6.98 (d, J=2.0Hz, 1H), 6.69 (t, J= 5.0Hz, 1H), 6.39 (d, J=2.0Hz, 2H), 6.35 (t, J=2.0Hz, 1H), 2.99~2.94 (m, 2H), 1.32-1.18 (m, 20H), 0.87 (t, J=6.5Hz, 3H)；13C NMR(125MHz,acetone-d6):δ 167.88,159.39(2×C), 157.92,156.18,142.66,134.94,133.10,123.78,116.59,112.73, 108.08(2×C),102.62, 99.84,40.54,40.40,33.64,32.65,30.42,30.40,30.34(2×C), 30.10(2×C),27.89, 23.34,14.36.(+)-ESI-MS m/z:454[M+H]+,476[M+Na]+,492 [M+K]+；(-)-ESI-MS m/z:452 [M-H]-,488[M+Cl]-；HR-ESI-MS m/z:454.2590 [M+H]+(calcd.for C27H36NO5,454.2588).
Embodiment 36:
N- (3- dimethylamino -1- propyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran carboxamides (36)
The physical and chemical parameter of compound 36 is as follows:
Compound 36: faint yellow solid (24.6mg, 39.2%).1H NMR(500MHz,CD3OD):δ7.65 (s,1H), 7.03 (d, J=2.0Hz, 1H), 6.91 (d, J=2.0Hz, 1H), 6.35 (d, J=2.0Hz, 2H), 6.27 (t, J=2.0Hz, 1H), 3.20 (q, J=7.5Hz, 2H), 3.06 (t, J=7.5Hz, 2H), 2.84 (t, J=7.5Hz, 2H), 2.74 (s, 6H) .13C NMR(150MHz,CD3OD):δ167.72,159.64(2×C),158.60, 156.75,143.43,135.82, 131.23,123.78,118.52,112.86,108.33,102.91,100.79,56.80, 45.45,37.65,25.28. (+)-ESI-MS m/z:371.1[M+H]+.HR-ESI-MS m/z:371.1601 [M+H]+(calcd.for C20H23N2O5, 371.1601).
Embodiment 37:
N- (2- furfuryl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran carboxamides (37)
The physical and chemical parameter of compound 37 is as follows:
Compound 37: faint yellow solid (23.0mg, 36.6%).1H NMR(500MHz,acetone-d6)δ8.81 (s, 1H), 8.41 (s, 2H), 7.72 (s, 1H), 7.38 (dd, J=1.0,2.0Hz, 1H), 7.22 (t, J=5.5Hz, 1H), 7.06 (d, J=2.0Hz, 1H), 6.98 (d, J=2.0Hz, 1H), 6.42 (d, J=2.0Hz, 2H), 6.38 (t, J=2.0Hz, 1H), 6.28 (dd, J=3.0,2.0Hz, 1H), 6.13 (d, J=3.0,1.0Hz, 1H), 4.12 (d, J=5.5Hz, 2H)13C NMR (125MHz,acetone-d6):δ167.84,159.33(2×C),157.88, 156.16,152.88,142.69,142.67, 134.97,132.37,123.70,116.85,112.58,111.12,108.14 2×C),107.71,102.65,100.07, 37.09.(+)-ESI-MS m/z:388[M+Na]+,404[M+K]+； (-)-ESI-MS m/z:364[M-H]-,400[M+ Cl]-；HR-ESI-MS m/z:366.0991[M+H]+(calcd. for C20H16NO6,366.0972).
Embodiment 38:
N- methyl-N- (phenyl methyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran carboxamides (38)
The physical and chemical parameter of compound 38 is as follows:
Compound 38, faint yellow solid (52.4mg, 83.0%), for a pair of of isomer mixture)1H NMR(500 MHz,acetone-d6)δ8.60(brs,4H),7.75(s,1H),7.74(s,1H),7.17-7.31(m,8H),7.04 (brs, 1H),6.99-7.02(m,3H),6.91(brs,1H),6.86(brs,1H),6.49(brs,4H),6.443(brs, 1H), 6.40 (brs, 1H), 5.22 (d, J=15.0Hz, 1H), 4.31 (d, J=15.5Hz, 1H), 3.58 (d, J=15.5Hz, 1H), 3.37 (d, J=15.0Hz, 1H), 2.57 (brs, 3H), 2.38 (brs, 3H)13C NMR(125 MHz,acetone-d6):δ 170.51,170.46,159.52(4×C),157.51,157.41,156.69,142.66, 142.60,137.95,137.42, 133.89(2×C),131.30,131.09,129.40(2×C),129.33(2×C), 128.81(2×C),128.26, 128.01,127.98(2×C),123.66,123.60,116.27,115.93,112.29, 112.01,107.96(2×C), 107.86(2×C),103.01,102.94,99.53,54.85,50.47,35.91, 32.03.ESI-MS m/z390.0[M+ H]+,412.0[M+Na]+,428.0[M+K]+.HR-ESI-MS m/z: 390.1327[M+H]+(calcd.for C23H20NO5, 390.1336).
Embodiment 39:
N- (4- aminomethyl phenyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran carboxamides (39)
The physical and chemical parameter of compound 39 is as follows:
Compound 39: hazel-color solid (21.2mg, 34.0%).1H NMR(500MHz,acetone-d6):δ8.83 (s, 1H), 8.71 (s, 1H), 8.14 (s, 2H), 7.74 (s, 1H), 7.34 (d, J=8.0Hz, 2H), 7.14 (d, J=2.0 Hz, 1H), 7.09 (d, J=2.0Hz, 1H), 6.98 (d, J=8.0Hz, 2H), 6.42 (d, J=2.0Hz, 2H), 6.10 (t, J= 2.0Hz,1H),2.24(s,3H)；13C NMR(125MHz,acetone-d6):δ165.98, 159.28(2×C),157.95, 156.20,142.80,137.12,134.65,133.39,132.85,129.33(2×C), 123.94,120.92(2×C), 116.86,112.88,107.96(2×C),102.52,100.29,20.90. (+)-ESI-MS m/z:398[M+Na]+； (-)-ESI-MS m/z:410[M+Cl]-；HR-ESI-MS m/z: 376.1191[M+H]+(calcd.for C22H18NO5, 376.1179).
Embodiment 40:
N- (4- chlorphenyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran carboxamides (40)
The physical and chemical parameter of compound 40 is as follows:
Compound 40: khaki solid (39.3mg, 62.3%).1H NMR(500MHz,cd3od):δ7.65 (s, 1H), 7.28 (d, J=9.0Hz, 2H), 7.15 (d, J=9.0Hz, 2H), 7.07 (d, J=2.0Hz, 1H), 7.01 (d, J= 2.0Hz, 1H), 6.32 (d, J=2.0Hz, 2H), 5.94 (t, J=2.0Hz, 1H)；13C NMR(125 MHz,cd3od):δ 168.89,159.50(2×C),158.47,156.81,143.08,137.90,135.16,131.84, 130.03,129.07 (2×C),124.07,122.81(2×C),117.69,112.75,108.26(2×C),102.61, 100.99.(+)-ESI- MS m/z:417.9[M+Na]+.HR-ESI-MS m/z:396.0644[M+H]+(calcd. for C21H25ClNO5, 396.0633).
Embodiment 41:
N- (phenyl methyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran carboxamides (41)
The physical and chemical parameter of compound 41 is as follows:
Compound 41: beige solid (34.7mg, 55.1%).1H NMR(500MHz,acetone-d6):δ8.80 (s, 1H), 8.44 (s, 2H), 7.72 (s, 1H), 7.26~7.22 (m, 3H), 7.19 (t, J=7.0Hz, 1H), 7.15 (t, J= 7.0Hz, 2H), 7.05 (d, J=2.0Hz, 1H), 7.01 (d, J=2.0Hz, 1H), 6.46 (d, J=2.0Hz, 2H), 6.40 (t, J=2.0Hz, 1H), 4.15 (d, J=5.5Hz, 2H)；13C NMR(125MHz,acetone-d6): δ168.29,159.41 (2×C),157.90,156.19,142.70,139.57,134.98,132.48,129.08(2× C),128.62(2×C), 127.67,123.72,116.75,112.70,108.18(2×C),102.76,100.07, 44.23.(+)-ESI-MS m/z: 376[M+H]+,398[M+Na]+,414[M+K]+；(-)-ESI-MS m/z:374 [M-H]-,410[M+Cl]-；HR-ESI-MS m/z:376.1195[M+H]+(calcd.for C22H18NO5, 376.1179).
Embodiment 42:
N- (4- Chlorophenylmethyl) -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran carboxamides (42)
The physical and chemical parameter of compound 42 is as follows:
Compound 42: hazel-color solid (39.0mg, 61.5%).1H NMR(500MHz,acetone-d6):δ8.81 (s, 1H), 8.44 (s, 2H), 7.71 (d, J=2.5Hz, 1H), 7.32 (s, 1H), 7.26 (d, J=8.5Hz, 2H), 7.14 (d, J= 8.5Hz, 2H), 7.05 (d, J=2.5Hz, 1H), 7.01 (d, J=2.5Hz, 1H), 6.45 (d, J=2.5Hz, 2H), 6.39 (d, J=2.5Hz, 1H), 4.14 (d, J=3.5Hz, 2H)；13C NMR(125MHz, acetone-d6):δ168.88,159.53 (2×C),157.91,156.28,142.69,138.32,132.99,132.19, 130.41(2×C),129.06(2×C), 123.65,116.57,112.67,107.99(2×C),102.88,100.14, 43.62.(+)-ESI-MS m/z:432.0[M +Na]+,447.9[M+K]+.HR-ESI-MS m/z:410.0796 [M+H]+(calcd.for C22H17ClNO5,410.0790).
Embodiment 43:
N- [2- (1H- indol-3-yl) ethyl] -3- (3,5- dihydroxy phenyl) -6- hydroxyl -4- benzofuran carboxamides (43)
The physical and chemical parameter of compound 43 is as follows:
Compound 43: hazel-color solid (37.3mg, 58.6%).1H NMR(500MHz,acetone-d6):δ9.96 (s, 1H), δ 9.54 (s, 2H), δ 7.72 (s, 1H), 7.58 (d, J=7.5Hz, 1H), 7.34 (d, J=7.5Hz, 1H), 7.08 (d, J =1.5Hz, 1H), 7.06 (td, J=7.5,1.0Hz, 1H), 7.05 (d, J=2.5Hz, 1H), 7.01 (d, J=2.5Hz, 1H), 6.99 (td, J=7.5,1.0Hz, 1H), 6.82 (t, J=5.0Hz, 1H), 6.46 (d, J=2.5 Hz, 2H), 6.38 (t, J=2.5Hz, 1H), 3.34-3.29 (m, 2H), 2.69 (t, J=7.5Hz, 2H) (+)-ESI-MS m/z:429 [M+H]+, 451[M+Na]+,467[M+K]+；(-)-ESI-MS m/z:427[M-H]-, 463[M+Cl]-；HR-ESI-MS m/z: 429.1450[M+H]+(calcd.for C22H21N2O5,429.1445).
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, Meanwhile cell proliferation inhibition rate is measured with mtt assay；And Measure the IC for generating to NO and there is remarkable inhibiting activity compound50Value (is 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 11,12,27,28,32,35,43 not only there is significant NO to generate Inhibitory 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) [ear swelling inhibiting rate (%)=(model group be averaged ear swelling-administration group ear swelling)/model group is flat with ear swelling inhibiting rate Equal ear swelling group × 100%].
Experimental result:
Experimental result is as shown in table 2, and compared with model control group, compound 11,12,35 can significantly mitigate croton oil induction Mouse otitis (P < 0.01 or 0.05).
Influence (Mean ± SD, n=10) of the table 2.Amurensin H derivative to croton oil inducing mouse otitisa.
aCompared with model group, " * " indicates p < 0.05, and " * * " indicates p < 0.01.
bCompound numbers correspond to the compound numbers in embodiment
Embodiment 3: influence of the compound to DNFB inducing mouse DTH inflammatory reaction.
18-20g male ICR mouse is taken, it is random to be grouped.In addition to blank group gives isometric solvent, remaining groups of animals in 1%DNFB solution 0.05mL sensitization is smeared after abdomen depilation, and in second day with same dosage DNFB reinforcement.Meanwhile it being caused in animal Starting within quick 3rd day, groups of animals, which is subcutaneously injected, gives test-compound 20mg/kg, and daily 1 time, for three days on end；Blank group and mould Type control group gives isometric solvent.The 5th day after animal sensitization, in addition to blank group, it is molten that groups of animals Yu Zuoer applies 1%DNFB Liquid 0.01mL is attacked, and after 24 hours, is put to death animal, is cut ears along auricle base line, removed respectively with diameter 6mm punch The auricle of left and right ear same position, assay balance weighing, calculates ear swelling and ear swelling inhibiting rate (%).
Experimental result:
Experimental result is as shown in table 3, compared with model group, causes after 11,12 pairs of DNFB sensitization of compound and attack DTH ear swelling, which has, significantly inhibits effect (P < 0.05 or 0.01).
Influence (Mean ± SD, n=10) of the table 3.Amurensin H derivative to DNFB inducing mouse DTH inflammatory reactiona.
aCompared with model group, " * " indicates p < 0.05, and " * * " indicates p < 0.01.
bCompound numbers correspond to the compound numbers in embodiment
Embodiment 4: 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 [foot swelling inhibiting rate (%)=(model group is flat Equal degree of paw swelling-administration group degree of paw swelling)/model group is averaged degree of paw swelling × 100%].
Experimental result:
Experimental result is as shown in table 4, and compared with model control group, compound 11,12 can significantly mitigate carrageenan induction Mouse foot swelling (P < 0.01 or 0.05).
The influence (Mean ± SD, n=10) of table 4.Amurensin H derivative Carrageenan inducing mouse foot swellinga.
aCompared with model group, " * " indicates p < 0.05, and " * * " indicates p < 0.01.
bCompound numbers correspond to the compound numbers in embodiment.

Claims (21)

1. such as the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta shown in logical formula (I) and its pharmaceutically acceptable salt:
Wherein, X is selected from O, NR5,S；
R1Selected from H, substituted or unsubstituted C3-8Naphthenic 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, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6 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 C0-16Linear or branched alkyl group, substituted or unsubstituted C0-16Linear chain or branched chain acyl Base, substituted or unsubstituted C2-16Linear chain or branched chain alkenyl, C2-6Alkynyl；The substituent group be selected from hydroxyl, nitro, cyano, Amino, methylamino, dimethylamino, phenyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, F, Cl, Br,I；
R5Independently selected from H, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Acyl group；Wherein, substituent group Selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C1-6Alkoxy, phenyl, F, Cl, Br, I；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
2. the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta according to claim 1 and its pharmaceutically acceptable salt, special Sign is, shown in the compound such as general formula (IA):
Wherein, R1Selected from H, substituted or unsubstituted C3-8Naphthenic 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, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, methylene-dioxy, carboxyl, F, Cl, Br, I, Glu, SO3H、PO3H2；Replacing type includes monosubstituted, two substitutions Or three replace；
L1Selected from substituted or unsubstituted C0-16Linear or branched alkyl group, substituted or unsubstituted C0-16Linear chain or branched chain acyl Base, substituted or unsubstituted C2-16Linear chain or branched chain alkenyl, C2-6Alkynyl；The substituent group be selected from hydroxyl, nitro, cyano, Amino, methylamino, dimethylamino, phenyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, F, Cl, Br,I；
R5Independently selected from H, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Acyl group；Wherein, substituent group Selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C1-6Alkoxy, phenyl, F, Cl, Br, I；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
3. the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta according to claim 2 and its pharmaceutically acceptable salt, special Sign is that the compound such as general formula (IAa), (IAb), (IAc) are shown:
Wherein, L1Selected from substituted or unsubstituted C0-16Linear or branched alkyl group, substituted or unsubstituted C0-16Straight chain or branch Chain acyl, substituted or unsubstituted C2-16Linear chain or branched chain alkenyl；The substituent group be selected from hydroxyl, nitro, cyano, amino, Methylamino, dimethylamino, phenyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, F, Cl, Br, I；
R5Independently selected from H, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Acyl group；Wherein, substituent group Selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C1-6Alkoxy, phenyl, F, Cl, Br, I；
R6、R7、R8It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C1-6Alkyl, C1-6 Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, methylene-dioxy, F, Cl, Br, I, Glu, SO3H、 PO3H2；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
4. the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta according to claim 3 and its pharmaceutically acceptable salt, special Sign is:
The L1Selected from C0、C1、C2、C3Straight chained alkyl；
R5Independently selected from H, C1、C2、C3Straight chained alkyl；
R6、R7、R8It is each independently selected from hydrogen, hydroxyl, methoxyl group, acetyl group, Cl；
R2、R3、R4It is each independently selected from hydrogen, methyl.
5. the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta according to claim 2 and its pharmaceutically acceptable salt, special Sign is, shown in the compound such as general formula (IAd):
Wherein, R9Independently selected from hydrogen, substituted or unsubstituted C3-8Naphthenic base, substituted or unsubstituted C1-16Straight chain or branch Alkyl group, substituted or unsubstituted C1-16Linear chain or branched chain acyl group, substituted or unsubstituted C2-16Linear chain or branched chain alkenyl, C2-6Alkynyl；The substituent group is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, F, Cl, Br, I；
R5Independently selected from H, substituted or unsubstituted C1-6Alkyl；Wherein, substituent group be selected from hydroxyl, nitro, cyano, amino, Methylamino, dimethylamino, C1-6Alkoxy, phenyl, F, Cl, Br, I；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
6. the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta according to claim 5 and its pharmaceutically acceptable salt, special Sign is:
The R9Selected from substituted or unsubstituted C1-16Linear or branched alkyl group, substituted or unsubstituted C3-8Naphthenic base； Wherein, the substituent group is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C1-6Alkoxy, C1-6's Acyl group, C1-6Acyloxy, F, Cl, Br, I；
R5Independently selected from hydrogen, C1-3Straight chained alkyl；
R2、R3、R4It is each independently selected from hydrogen, methyl, acetyl group.
7. the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta according to claim 6 and its pharmaceutically acceptable salt, special Sign is:
The R9Selected from substituted or unsubstituted C3-12Linear or branched alkyl group, substituted or unsubstituted C5-6Naphthenic base； Wherein, the substituent group is selected from hydrogen, hydroxyl, methylamino, dimethylamino, methoxyl group, acetyl group, Cl；
R5Independently selected from hydrogen, C1、C2、C3Straight chained alkyl；
R2、R3、R4It is each independently selected from hydrogen, methyl, acetyl group.
8. the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta according to claim 1 and its pharmaceutically acceptable salt, special Sign is, shown in the compound such as general formula (IB):
Wherein, R1Selected from H, substituted or unsubstituted C3-8Naphthenic 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, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, methylene-dioxy, carboxyl, F, Cl, Br, I, Glu, SO3H、PO3H2；Replacing type includes monosubstituted, two substitutions Or three replace；
L1Selected from substituted or unsubstituted C0-16Linear or branched alkyl group, substituted or unsubstituted C0-16Linear chain or branched chain acyl Base, substituted or unsubstituted C2-16Linear chain or branched chain alkenyl, C2-6Alkynyl；The substituent group be selected from hydroxyl, nitro, cyano, Amino, methylamino, dimethylamino, phenyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, F, Cl, Br,I；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
9. the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta according to claim 8 and its pharmaceutically acceptable salt, special Sign is that the compound such as general formula (IBa), (IBb), (IBc) are shown:
Wherein, L1Selected from substituted or unsubstituted C0-16Linear or branched alkyl group, substituted or unsubstituted C0-16Straight chain or branch Chain acyl, substituted or unsubstituted C2-16Linear chain or branched chain alkenyl；The substituent group be selected from hydroxyl, nitro, cyano, amino, Methylamino, dimethylamino, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, F, Cl, Br, I；
R10、R11、R12It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkylthio group, methylene-dioxy, F, Cl, Br, I, Glu, SO3H、 PO3H2；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
10. the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta according to claim 9 and its pharmaceutically acceptable salt, It is characterized in that,
The L1Selected from C0、C1、C2、C3Straight chained alkyl；
R10、R11、R12It is each independently selected from hydrogen, hydroxyl, methoxyl group, acetyl group, Cl；
R2、R3、R4It is each independently selected from hydrogen, methyl, acetyl group.
11. the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta according to claim 8 and its pharmaceutically acceptable salt, It is characterized in that, shown in the compound such as general formula (IBd):
Wherein, R13Independently selected from hydrogen, substituted or unsubstituted C3-8Naphthenic base, substituted or unsubstituted C1-16Straight chain or Branched alkyl, substituted or unsubstituted C1-16Linear chain or branched chain acyl group, substituted or unsubstituted C2-16Linear chain or branched chain alkene Base, C2-6Alkynyl；The substituent group is selected from hydrogen, hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C1-6's Alkoxy, C1-6Acyloxy, C1-6Alkylthio group, F, Cl, Br, I；
R2、R3、R4It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
12. the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta according to claim 11 and its pharmaceutically acceptable salt, It is characterized in that:
The R13Selected from substituted or unsubstituted C1-16Linear or branched alkyl group, substituted or unsubstituted C3-8Naphthenic base； Wherein, the substituent group is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C1-6Alkoxy, C1-6's Acyloxy, C1-6Alkylthio group, F, Cl, Br, I；
R2、R3、R4It is each independently selected from hydrogen, methyl, acetyl group.
13. the plain derivative of 3- phenyl -7,8- dehydrogenation grapevine penta according to claim 12 and its pharmaceutically acceptable salt, It is characterized in that:
The R13Selected from substituted or unsubstituted C3-12Linear or branched alkyl group, substituted or unsubstituted C5-6Naphthenic base； The substituent group is selected from hydrogen, hydroxyl, methylamino, dimethylamino, methoxyl group, acetyl group, Cl；
R2、R3、R4It is each independently selected from hydrogen, methyl, acetyl group.
14. the plain derivative of any one of -13 3- phenyl -7,8- dehydrogenation grapevine penta and its pharmaceutically may be used according to claim 1 The salt of receiving, which is characterized in that the compound is selected from following group:
15. a kind of pharmaceutical composition, by described in any item 3- phenyl -7, the 8- dehydrogenation grapes of the claim 1-14 of effective dose The plain derivative of rattan penta 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 plain derivative of the described in any item 3- phenyl -7,8- dehydrogenation grapevines of claim 1-14 penta and its can pharmaceutically connect Application of the salt received in preparation treatment and/or prevention of inflammation and/or immunosuppressive drug.
19. the plain derivative of the described in any item 3- phenyl -7,8- dehydrogenation grapevines of claim 1-14 penta and its can pharmaceutically connect Application of the salt received 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:, rheumatic arthritis, gout Property arthritis, 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, Colorectal cancer, arteritis nodosa, thyroiditis, wind-heat be wet, gingivitis, periodontitis, canker sore, ephritis, sends out after damage Raw swelling, myocardial ischemia, various infectious pneumonias, physics and chemistry pneumonia and allergy pneumonia, proctalgia fugax and Rectum splits, liver and gallbladder capsulitis, cholangitis, sclerosing 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.
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