CN109721580B - 3-Phenyl-7,8-dehydrograpevine derivative, its preparation method, pharmaceutical composition and use - Google Patents

Abstract

The invention discloses a novel 3-phenyl-7, 8-dehydrograpevine (Amurensin H) derivative with anti-inflammatory activity and anti-inflammatory activity thereof. In particular to a 3-aryl-4 substituted benzofuran derivative with a novel structure shown as a general formula (I) or a medically acceptable salt thereof. The invention discloses application of the derivative monomer or the medicinal composition in clinical treatment of inflammation-related diseases.

Description

3-phenyl-7,8-dehydrogluphine derivative, its preparation method and pharmaceutical composition and use

technical field

The present invention relates to the field of biomedicine, in particular to a class of 3-phenyl-7,8-dehydroglupapentin (Amurensin H) derivatives with a benzofuran structure or medically acceptable salts thereof, containing these derivatives The pharmaceutical composition of the drug and its application in the clinical treatment of inflammatory related diseases.

Background technique

Inflammation is the basis of human diseases, and it is a key link in the pathological process of diseases. However, the current anti-inflammatory drugs, such as corticosteroids and non-steroidal anti-inflammatory drugs, still have many problems in clinical application, such as easy to cause gastrointestinal discomfort, bleeding, increase the occurrence of heart disease or systemic coagulation disorders, etc. Risk of Adverse Reactions. Therefore, finding safer and more effective anti-inflammatory drugs is still an important task in the current research and development of anti-inflammatory drugs.

Oligomeric stilbene compounds are a class of natural products with a new structure developed in the past 30 years. Studies have shown that this type of compound has a variety of pharmacological activities, including antibacterial, anti-inflammatory, anti-oxidation, anti-virus, anti-senile dementia, etc. [J .AsianNat.Prod.Res.,2016,18(4):376-407], which has good research and development prospects. At present, a lot of research has been done on the extraction and separation, structure identification and preliminary activity screening of this kind of compounds. However, due to the complex structure and generally low content in natural products, total synthesis is often difficult, and the lack of sample volume greatly limits the development and research process of this type of compound. Therefore, based on active oligomeric stilbene-based lead compounds, through synthesis, structure optimization and structure-activity relationship research, it is of great significance to discover new drugs with better druggability for the development and utilization of such compounds.

Amurensin H is a resveratrol dimer compound with a benzofuran ring isolated from the root of the folk medicinal plant Vitis amurensis [Chin.Chem.Lett.,1999,10(10):817- 820]. Pharmacological activity studies have found that Amurensin H is a natural active ingredient that can inhibit the production of various inflammatory mediators [Acta.Pharmacol.Sin., 2006,27(6):735-740.], and animal experiments have confirmed that the compound It can significantly resist chronic airway inflammation and alleviate the pathological damage of lung tissue in mice with chronic obstructive pulmonary disease (COPD). Further systematic pharmacological experiments show that the natural product has strong activity and low toxicity, and is an active lead compound with in-depth research value. The research on the activity of the AmurensinH compound itself has been publicly reported by our research group, but the structure-activity relationship research on the structure optimization and anti-inflammatory activity of the compound system has not been reported in the literature so far. This patent involves structural optimization and structure-activity relationship research on this compound to improve its physical and chemical properties and anti-inflammatory activity in vivo.

Contents of the invention

The technical problem to be solved by the present invention is to provide a new class of 3-phenyl-4-substituted benzofuran compounds and derivatives thereof. Its preparation method, pharmaceutical composition and application.

The first aspect of the technical solution of the present invention provides a kind of general formula (I), (IA), (IAa), (IAb), (IAc), (IAd) and (IB), (IBa), (IBb), New structure 3-phenyl-4-substituted benzofuran compounds and derivatives thereof shown in (IBc) and (IBd).

The second aspect of the technical solution of the present invention provides a pharmaceutical composition, which includes at least one of the general formula (I), (IA), (IAa), (IAb), (IAc), (IAd) and (IB), (IBa), (IBb), (IBc), and (IBd) 3-phenyl-4-substituted benzofuran compounds, pharmaceutically acceptable salts thereof, and carriers commonly used in the field of pharmacy.

The third aspect of the technical solution of the present invention provides such as general formula ((I), (IA), (IAa), (IAb), (IAc), (IAd) and (IB), (IBa), (IBb), ( 3-phenyl-4-substituted benzofuran compounds and pharmaceutically acceptable salts thereof shown in IBc), (IBd), in the preparation of medicines for prevention, treatment and auxiliary treatment of various inflammatory diseases application.

The various inflammatory diseases include: rheumatoid arthritis, gouty arthritis, lupus erythematosus syndrome, bronchitis, bursitis, tenosynovitis, psoriasis, eczema, burns, dermatitis, inflammatory bowel disease, Crohn's Encephalitis, gastritis, irritable bowel syndrome, ulcerative colitis, multiple sclerosis, autoimmune encephalomyelitis, colorectal cancer, arteritis nodosa, thyroiditis, wind-heat dampness, gingivitis, periodontal Inflammation, mouth ulcer, nephritis, swelling after injury, myocardial ischemia, various infectious pneumonia, physiochemical pneumonia and allergic pneumonia, spasmodic anal pain and rectal fissure, hepatic cholecystitis, cholangitis, cirrhosis cholangitis, primary biliary cirrhosis, and cholecystitis. The compounds described in the present invention include their derivatives and pharmacodynamically acceptable salts.

Specifically, the present invention relates to 3-phenyl-7,8-dehydroglupapentine derivatives (3-phenyl-4-substituted benzofuran derivatives) represented by the general formula (I), and its pharmaceutically acceptable salts:

Wherein, X is selected from O, NR ₅ , S;

R ₁ is selected from H, substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted indolyl, substituted or unsubstituted furyl, substituted or unsubstituted Naphthyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted pyridyl; the substituents of the cycloalkyl, phenyl, indolyl, furyl, naphthyl, quinolinyl and pyridyl are selected from Hydroxy, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C _1-6 alkylthio, methylenedioxy, carboxyl, F, Cl, Br, I, Glu, SO ₃ H, PO ₃ H ₂ ; substitution types include mono-substitution, di-substitution or tri-substitution;

L is selected from substituted or unsubstituted C _0-16 linear or branched alkyl, substituted or unsubstituted C _{0-16 linear} or branched acyl, substituted or unsubstituted C _2-16 straight chain chain or branched alkenyl, C _2-6 alkynyl; the substituent is selected from the group consisting of hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C _1-6 alkylthio, F, Cl, Br, I;

R _is independently selected from H, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _1-6 acyl; wherein the substituent is selected from hydroxyl, nitro, cyano, amino, methyl Amino, dimethylamino, C _1-6 alkoxy, phenyl, F, Cl, Br, I;

R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen, C _1-6 alkyl, C _1-6 acyl, Glu, SO ₃ H, PO ₃ H ₂ ;

Glu represents β-D glucopyranosyl; SO ₃ H represents sulfonyl; PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred 3-phenyl-7,8-dehydroglupapentine derivatives represented by general formula (I) include, but are not limited to compounds represented by general formula (IA), and their pharmaceutical Acceptable salt above, it is characterized in that, described compound is as shown in general formula (IA):

_Wherein , R is selected from H, substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted indolyl, substituted or unsubstituted furyl, substituted or unsubstituted Substituted naphthyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted pyridyl; wherein the substitution of cycloalkyl, phenyl, indolyl, furyl, naphthyl, quinolinyl and pyridyl The group is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyl Oxygen, C _1-6 alkylthio, methylenedioxy, carboxyl, F, Cl, Br, I, Glu, SO ₃ H, PO ₃ H ₂ ; substitution types include mono-substitution, di-substitution or tri-substitution ;

L is selected from substituted or unsubstituted C _0-16 linear or branched alkyl, substituted or unsubstituted C _{0-16 linear} or branched acyl, substituted or unsubstituted C _2-16 straight chain chain or branched alkenyl, C _2-6 alkynyl; the substituent is selected from the group consisting of hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C _1-6 alkylthio, F, Cl, Br, I;

R ₅ is independently selected from H, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _1-6 acyl; wherein, the substituent is selected from hydroxyl, nitro, cyano, amino, methyl Amino, dimethylamino, C _1-6 alkoxy, phenyl, F, Cl, Br, I;

R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen, C _1-6 alkyl, C _1-6 acyl, Glu, SO ₃ H, PO ₃ H ₂ ;

Glu represents β-D glucopyranosyl; SO ₃ H represents sulfonyl; PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred 3-phenyl-7,8-dehydroglupapentine derivatives represented by general formula (IA) include, but are not limited to general formula (IAa), (IAb), (IAc) Shown compound, and pharmaceutically acceptable salt thereof, it is characterized in that, described compound is shown in general formula (IAa), (IAb), (IAc):

Wherein, L is selected from substituted or unsubstituted C _0-16 straight or branched chain alkyl, substituted or unsubstituted C _{0-16 straight} or branched acyl, substituted or unsubstituted C _2-16 straight-chain or branched alkenyl; the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C _1-6 alkoxy, C _1-6 acyl , C _1-6 acyloxy, F, Cl, Br, I;

R _is independently selected from H, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _1-6 acyl; wherein the substituent is selected from hydroxyl, nitro, cyano, amino, methyl Amino, dimethylamino, C _1-6 alkoxy, phenyl, F, Cl, Br, I;

R ₆ , R ₇ , and R ₈ are each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C _1-6 alkylthio, methylenedioxy, F, Cl, Br, I, Glu, SO ₃ H, PO ₃ H ₂ ;

R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen, C _1-6 alkyl, C _1-6 acyl, Glu, SO ₃ H, PO ₃ H ₂ ;

Glu represents β-D glucopyranosyl; SO ₃ H represents sulfonyl; PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred general formulas (IAa), (IAb), 3-phenyl-7,8-dehydroglupine derivatives shown in (IAc), and pharmaceutically acceptable salts thereof, Features:

The L ₁ is selected from C ₀ , C ₁ , C ₂ , and C ₃ linear alkyl groups;

R ₅ is independently selected from H, C ₁ , C ₂ , C ₃ linear alkyl groups;

R ₆ , R ₇ , and R ₈ are each independently selected from hydrogen, hydroxyl, methoxy, acetyl, and Cl;

R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen and methyl.

According to the present invention, preferred 3-phenyl-7,8-dehydroglupapentine derivatives represented by general formula (IA) include, but are not limited to compounds represented by general formula (IAd), and their pharmaceutical Acceptable salt above, it is characterized in that, described compound is as shown in general formula (IAd):

Wherein, R ₉ is independently selected from hydrogen, substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted C _1-16 branched or straight chain alkyl, substituted or unsubstituted C _{1- 16} straight chain or branched acyl, substituted or unsubstituted C _2-16 straight chain or branched alkenyl, C _2-6 alkynyl; the substituent is selected from hydroxyl, nitro, cyano, amino , methylamino, dimethylamino, phenyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C _1-6 alkylthio, F, Cl, Br , I;

R _is independently selected from H, substituted or unsubstituted C _1-6 alkyl; wherein, the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 alkyl Oxygen, phenyl, F, Cl, Br, I;

R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen, C _1-6 alkyl, C _1-6 acyl, Glu, SO ₃ H, PO ₃ H ₂ ;

Glu represents β-D glucopyranosyl; SO ₃ H represents sulfonyl; PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred general formula (IAd) 3-phenyl-7,8-dehydroglupine derivatives, and pharmaceutically acceptable salts thereof, are characterized in that:

The R ₉ is selected from substituted or unsubstituted C _1-16 straight chain or branched chain alkyl, substituted or unsubstituted C _3-8 cycloalkyl; wherein, the substituent is selected from hydroxyl, nitr group, cyano, amino, methylamino, dimethylamino, phenyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C _1-6 alkylthio , F, Cl, Br, I;

R _is independently selected from hydrogen, C _1-3 linear alkyl;

R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen, methyl, and acetyl;

According to the present invention, preferred general formula (IAd) 3-phenyl-7,8-dehydroglupine derivatives, and pharmaceutically acceptable salts thereof, are characterized in that:

The R ₉ is selected from substituted or unsubstituted C _3-12 linear or branched chain alkyl, substituted or unsubstituted C _5-68 cycloalkyl; wherein, the substituent is selected from hydrogen, hydroxyl , methylamino, dimethylamino, methoxy, acetyl, Cl;

R ₅ is independently selected from hydrogen, C ₁ , C ₂ , C ₃ , straight-chain alkyl;

R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen, methyl, and acetyl;

According to the present invention, preferred 3-phenyl-7,8-dehydroglupapentine derivatives represented by general formula (I) include, but are not limited to compounds represented by general formula (IB), and their pharmaceutical Acceptable salt above, it is characterized in that, described compound is as shown in general formula (IB):

_Wherein , R is selected from H, substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted indolyl, substituted or unsubstituted furyl, substituted or unsubstituted Substituted naphthyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted pyridyl; substituents of said cycloalkyl, phenyl, indolyl, furyl, naphthyl, quinolinyl and pyridyl Selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy group, C _1-6 alkylthio group, methylenedioxy group, carboxyl group, F, Cl, Br, I, Glu, SO ₃ H, PO ₃ H ₂ ; substitution types include mono-substitution, di-substitution or tri-substitution;

L is selected from substituted or unsubstituted C _0-16 straight chain or branched chain alkyl, substituted or unsubstituted C _0-16 straight chain or branched acyl, substituted or unsubstituted C _2-16 straight _chain chain or branched alkenyl, C _2-6 alkynyl; the substituent is selected from the group consisting of hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C _1-6 alkylthio, F, Cl, Br, I;

R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen, C _1-6 alkyl, C _1-6 acyl, Glu, SO ₃ H, PO ₃ H ₂ ;

Glu represents β-D glucopyranosyl; SO ₃ H represents sulfonyl; PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred 3-phenyl-7,8-dehydroglupapentine derivatives represented by general formula (IB) include, but are not limited to general formula (IBa), (IBb), (IBc) Shown compound, and pharmaceutically acceptable salt thereof, it is characterized in that, described compound is shown in general formula (IBa), (IBb), (IBc):

Wherein, L is selected from substituted or unsubstituted C _0-16 straight or branched chain alkyl, substituted or unsubstituted C _{0-16 straight} or branched acyl, substituted or unsubstituted C _2-16 straight-chain or branched alkenyl; said substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 alkoxy, C _1-6 acyl, C _{1 -6} acyloxy, C _1-6 alkylthio, F, Cl, Br, I;

R ₁₀ , R ₁₁ , and R ₁₂ are each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C _1-6 alkylthio, methylenedioxy, F, Cl, Br, I, Glu, SO ₃ H, PO ₃ H ₂ ;

R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen, C _1-6 alkyl, C _1-6 acyl, Glu, SO ₃ H, PO ₃ H ₂ ;

Glu represents β-D glucopyranosyl; SO ₃ H represents sulfonyl; PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred general formula (IBa), (IBb), (IBc) shown in 3-phenyl-7,8-dehydroglupine derivatives, and pharmaceutically acceptable salt thereof, its Features:

The L ₁ is selected from C ₀ , C ₁ , C ₂ , and C ₃ linear alkyl groups;

R ₁₀ , R ₁₁ , and R ₁₂ are each independently selected from hydrogen, hydroxyl, methoxy, acetyl, and Cl;

R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen, methyl, and acetyl.

According to the present invention, preferred 3-phenyl-7,8-dehydroglupapentine derivatives represented by general formula (IB) include, but are not limited to compounds represented by general formula (IBd), and their pharmaceutical Acceptable salt above, it is characterized in that, described compound is as shown in general formula (IBd):

Wherein, R ₁₃ is independently selected from hydrogen, substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted C _1-16 linear or branched chain alkyl, substituted or unsubstituted C _{1- 16} straight chain or branched acyl, substituted or unsubstituted C _2-16 straight chain or branched alkenyl, C _2-6 alkynyl; the substituent is selected from hydroxyl, nitro, cyano, amino , methylamino, dimethylamino, phenyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C _1-6 alkylthio, F, Cl, Br , I;

R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen, C _1-6 alkyl, C _1-6 acyl, Glu, SO ₃ H, PO ₃ H ₂ ;

Glu represents β-D glucopyranosyl; SO ₃ H represents sulfonyl; PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred general formula (IBd) 3-phenyl-7,8-dehydroglupine derivatives, and pharmaceutically acceptable salts thereof, are characterized in that:

The R ₁₃ is selected from substituted or unsubstituted C _1-16 straight chain or straight chain alkyl, substituted or unsubstituted C _3-8 cycloalkyl; wherein, the substituent is selected from hydroxyl, nitr group, cyano, amino, methylamino, dimethylamino, phenyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C _1-6 alkylthio , F, Cl, Br, I;

R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen, methyl, and acetyl;

According to the present invention, preferred general formula (IBd) 3-phenyl-7,8-dehydroglupine derivatives, and pharmaceutically acceptable salts thereof, are characterized in that:

The R ₁₃ is selected from substituted or unsubstituted C _3-12 linear or branched chain alkyl, substituted or unsubstituted C _5-6 cycloalkyl; the substituent is selected from hydroxyl, methylamino, Dimethylamino, Methoxy, Acetyl, Cl;

R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen, methyl, and acetyl;

Specifically, general formula (I), (IA), (IAa), (IAb), (IAc), (IAd) and (IB), (IBa), (IBb), (IBc), (IBd) 3-phenyl-7,8-dehydroglupapentine derivatives and pharmaceutically acceptable salts thereof, characterized in that the compounds are selected from the following groups (compound codes correspond to those in the examples Compound code):

The second aspect of the technical solution of the present invention is to provide a drug containing effective dosage such as general formula (I), (IA), (IAa), (IAb), (IAc), (IAd) and (IB), ( IBa), (IBb), (IBc), (IBd) Pharmaceutical compositions of the compounds described in each case and a pharmaceutically acceptable carrier.

According to the present invention, the compound of the present invention may exist in the form of isomers, and generally speaking "the compound of the present invention" includes the isomers of the compound.

According to the embodiment of the present invention, the compound of the present invention also includes its pharmaceutically acceptable salt, salt hydrate or prodrug.

The present invention also relates to pharmaceutical compositions comprising the compound of the present invention as active ingredient and conventional pharmaceutical excipients or adjuvants. Usually the pharmaceutical composition of the present invention contains 0.1 to 95% by weight of the compound of the present invention. The general content of the compound of the present invention in the unit dosage form is 0.1-100 mg, and the preferred unit dosage form contains 4-50 mg.

Pharmaceutical compositions of compounds of the present invention can be prepared according to methods well known in the art. When used for this purpose, the compound of the present invention can be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants, if necessary, to prepare an appropriate administration form or dosage that can be used as human or veterinary medicine form.

The compound of the present invention or the pharmaceutical composition containing it can be administered in the form of unit dosage, and the route of administration can be enteral or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneal or rectal, etc. The route of administration of the compound of the present invention or the pharmaceutical composition containing it may be injection. Injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection.

The dosage forms for administration may be liquid dosage forms or solid dosage forms. For example, the liquid dosage forms can be true solutions, colloids, particulate dosage forms, emulsion dosage forms, and suspension dosage forms. Other dosage forms such as tablets, capsules, drop pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injections, etc.

The compound of the present invention can be made into common preparations, or sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

For example, in order to form a unit dosage form into a tablet, various carriers known in the art can be widely used. Examples of carriers such as diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate Wetting agents and binders, such as water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, arabic mucilage, gelatin paste, sodium carboxymethylcellulose, Shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrants, such as dry starch, alginate, agar powder, algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbose Alcohol fatty acid esters, sodium lauryl sulfonate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil, etc.; absorption enhancers, For example, quaternary ammonium salt, sodium lauryl sulfate, etc.; lubricants, such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

Carriers known in the art can be widely used, for example, to formulate a dosage unit into a pellet. Examples of carriers are, for example, diluents and absorbents, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, glyceryl monostearate, kaolin, talc, etc.; binders, such as gum arabic , tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium dodecylsulfonate, methylcellulose, ethyl Cellulose etc.

For example, to form a dosage unit into a capsule, the compound of the present invention is mixed with the various carriers mentioned above, and the mixture thus obtained is placed in a hard gelatin capsule or a soft capsule. The active ingredient compound of the present invention can also be made into microcapsules, suspended in an aqueous medium to form a suspension, and can also be packed into hard capsules or made into injections for application.

For example, the compound of the present invention is made into injection preparations, such as solutions, suspension solutions, emulsions, and freeze-dried powder injections. This preparation can be aqueous or non-aqueous, and can contain one and/or more drugs A pharmaceutically acceptable carrier, diluent, binder, lubricant, preservative, surfactant or dispersant. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1,3-propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol esters, fatty acids, and the like. In addition, in order to prepare isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin can be added to the preparation for injection, and in addition, conventional solubilizers, buffers, pH regulators, etc. can also be added. These excipients are commonly used in the art.

In addition, colorants, preservatives, fragrances, correctives, sweeteners or other materials can also be added to the pharmaceutical preparations, if necessary.

In order to achieve the purpose of medication and enhance the therapeutic effect, the medicine or pharmaceutical composition of the present invention can be administered by any known administration method.

The dosage of the compound pharmaceutical composition of the present invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight, personality and individual reaction of the patient or animal, the route of administration, the frequency of administration, Therapeutic purposes, and thus the therapeutic doses of the present invention, can vary widely. In general, the dosages of the key ingredients in the present invention are well known to those skilled in the art. According to the actual amount of drug contained in the final preparation of the compound composition of the present invention, appropriate adjustments can be made to achieve the requirement of its therapeutically effective dose, so as to achieve the preventive or therapeutic purpose of the present invention. Appropriate dosage range of the compound of the present invention per day: the dosage of the compound of the present invention is 0.001-100 mg/kg body weight, preferably 0.1-60 mg/kg body weight, more preferably 1-30 mg/kg body weight, most preferably 2-15 mg/kg body weight kg body weight. The compound of the present invention taken by adult patients is 10-500 mg per day, preferably 10-100 mg, which can be taken once or divided into 2-3 times; the dosage for children is 5-30 mg per kg body weight, preferably 10-20 mg/kg weight. The above dose can be administered in a single dose or divided into several doses, such as two, three or four doses, which are limited by the clinical experience of the administering doctor and the dosage regimen of the treatment means. The compound or composition of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs.

The third aspect of the technical solution of the present invention is to provide a class of 3-phenyl-7,8-dehydrogluphine derivatives (3-phenyl-4-substituted benzofuran compounds) or their medically acceptable The application of salts, salt hydrates or prodrugs in the preparation of anti-inflammatory, immunosuppressive and related disease drugs.

The inflammatory diseases include rheumatoid arthritis, gouty arthritis, lupus erythematosus syndrome, bronchitis, bursitis, tenosynovitis, psoriasis, eczema, burns, dermatitis, inflammatory bowel disease, Crohn's disease, gastritis , irritable bowel syndrome, ulcerative colitis, multiple sclerosis, autoimmune encephalomyelitis, colorectal cancer, arteritis nodosa, thyroiditis, rheumatic fever, gingivitis, periodontitis, mouth ulcers, Nephritis, swelling after damage, myocardial ischemia, various infectious pneumonia, physicochemical pneumonia and allergic pneumonia, spasmodic anal pain and rectal fissure, hepatic cholecystitis, cholangitis, sclerosing cholangitis, original Episodic biliary cirrhosis and cholecystitis. A common feature of these diseases at the cellular level is hyperactivation of macrophages, which produces excess NO.

The present invention has carried out the experiment that the compound inhibits the production of NO by macrophages stimulated by LPS, and shows from the cell level that the inventive benzofuran derivative has the activity of inhibiting the production of excessive NO by macrophages. At the same time, by studying the effects of the invented compound on otitis in mice induced by croton oil, delayed immune response in mice and paw swelling in mice induced by carrageenan, it was found that benzofuran derivatives still have good anti-inflammatory effects in vivo. and immunosuppressive activity.

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

Raw materials for the preparation of compounds of the present invention, such as methyl 3,5-dihydroxybenzoate, 1-(3,5-dimethoxyphenyl)-2-bromoacetophenone, alcohols of different structures, phenols Amines and amines can be purchased commercially or prepared according to existing techniques.

The basic synthetic method of key reaction raw material compound 1 among the present invention comprises the following steps:

Step 1: Preparation of methyl 3-methoxy-5-hydroxybenzoate.

Methyl 3,5-dihydroxybenzoate reacts with methyl iodide in acetone under the catalysis of K ₂ CO ₃ solid. The reaction mixture is filtered and concentrated under reduced pressure. The obtained solid is purified by recrystallization or chromatographic separation to obtain the target product 3- Methyl methoxy-5-hydroxybenzoate.

Step 2: Synthesis of 3-(2-(3,5- Methyl dimethoxyphenyl)-2-oxyethyl)-5-methoxybenzoate (1a).

Methyl 3-methoxy-5-hydroxybenzoate and 1-(3,5-dimethoxyphenyl)-2-bromoacetophenone were carried out in anhydrous acetone under the catalysis of K ₂ CO ₃ solid Heating to reflux for reaction, the reaction solution is concentrated under reduced pressure, and the obtained product is purified by recrystallization or chromatography to obtain the target product 1a.

Step 3: compound 1a is cyclized to generate compound 1b:

The product 1a obtained in step 2 was reacted in dichloromethane with methanesulfonic acid as a catalyst, the reaction liquid was washed to neutrality, concentrated to dryness under reduced pressure, and the obtained solid product was recrystallized or chromatographically separated and purified to obtain the target product 1b. In this reaction, the catalyst is methanesulfonic acid (MSA), bismuth trifluoromethanesulfonate (Bi(OTf) ₃ ), trifluoroacetic acid (TFA), iron trichloride (FeCl ₃ ), preferably methanesulfonic acid and trifluoromethanesulfonic acid Bismuth methanesulfonate; the reaction temperature is 25-60°C, preferably 40°C.

Step 4: Compound 1b is hydrolyzed to synthesize compound 1:

Compound 1b was dissolved in a mixed solution of THF, MeOH and H ₂ O (1:1:1, v/v/v), and heated under reflux with NaOH as a catalyst. 1 mol/L HCl solution was added dropwise to the reaction solution until no white precipitate was precipitated. The reaction mixture was suction-filtered, the obtained solid was washed with distilled water, and dried to obtain compound 1 as a white powdery solid.

The basic synthetic method of compound described in the present invention comprises following two kinds:

The first method includes the following steps:

Step 1: Synthesis of methoxy esters or methoxyamine derivatives by condensation reaction of compound 1 with alcohols, phenols and amines.

Compound 1 is condensed with alcohols, phenols and amines under the catalysis of HOBt and EDCI in dry dichloromethane, the reaction solution is concentrated under reduced pressure, and the obtained product is purified by recrystallization or chromatographic separation to obtain methoxy base esters or methoxyamine target products.

Step 2: Demethylation of methoxy ester or methoxy amine derivative to synthesize phenolic hydroxyl ester or phenolic hydroxyl amine derivative.

The product obtained in step 1 is reacted with _BBr3 in dry dichloromethane to remove the methyl group, the reaction solution is washed with water and saturated brine to remove the acid and concentrated under reduced pressure, and the obtained product is purified by recrystallization or chromatographic separation to obtain phenolic hydroxyl ester or The target product of phenolic hydroxylamines. The specific reaction temperature is -50°C-25°C.

The second method includes the following steps:

Step 1: Condensation reaction of compound 1 with alcohols, phenols and amines to synthesize methoxy esters or methoxyamine derivatives.

Compound 1 is condensed with alcohols, phenols and amines under the catalysis of DMAP and EDCI in dry dichloromethane, the reaction solution is concentrated under reduced pressure, and the obtained product is purified by recrystallization or chromatographic separation to obtain methoxy base esters or methoxyamine target products.

Step 2: Demethylation of methoxy ester or methoxy amine derivative to synthesize phenolic hydroxyl ester or phenolic hydroxyl amine derivative.

The product obtained in step 1 is reacted with _BBr3 in dry dichloromethane to remove the methyl group. After the reaction solution is washed with water and saturated brine to remove the acid, the obtained product is concentrated under reduced pressure to obtain the phenolic hydroxyl ester through recrystallization or chromatographic separation and purification. Or phenolic hydroxylamine target products. The specific reaction temperature is -50°C-25°C.

Beneficial technical effect

At present, although there have been many reports on the anti-inflammatory activity of compounds with benzofuran structure, so far, there is no research on the structure-activity relationship of stilbene dimer compounds with benzofuran structure. See literature report. There is no information about 3-phenyl-7,8-dehydrogluphine (Amurensin H) derivatives or their medically acceptable salts and the use of such compounds in the treatment of inflammatory diseases in the existing literature and technology. Report; there is no report about the new structural compound of 3-phenyl-4 substituted benzofuran or its medically acceptable salt, and the use of this type of compound in the treatment of inflammatory diseases.

Detailed description of the invention:

The cycloalkyl group of C _3-8 refers to a substituted or unsubstituted cycloalkyl group with 3, 4, 5, 6, 7, 8 carbon atoms, and the alkynyl group of C _2-6 refers to a substituted or unsubstituted cycloalkyl group with a carbon number of 2, 3, 4, 5, 6 straight chain or branched chain alkynyl, C _0-3 straight chain alkyl refers to the straight chain alkyl of 0, 1, 2, 3 carbon atoms; C _1-3 straight chain alkyl Alkyl refers to straight chain alkyl with 1, 2, 3 carbon atoms, and C _1-6 alkyl refers to straight or branched chain with 1, 2, 3, 4, 5, 6 carbon atoms. Alkyl group, the alkoxy group of _C1-6 refers to the linear or branched alkoxyl group with carbon number of 1, 2, 3, 4, 5, 6, the acyl group of _C1-6 refers to the number of carbon atoms 1, 2, 3, 4, 5, 6 straight chain or branched chain acyl, C _1-6 acyloxy means a straight chain or branched chain with 1, 2, 3, 4, 5, 6 carbon atoms Acyloxy, C _1-6 alkylthio refers to straight chain or branched chain alkylthio with carbon number of 1, 2, 3, 4, 5, 6, C _0-16 straight chain or branched alkane The group refers to a straight chain or branched chain alkyl group with carbon atoms of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, C _0-16 straight-chain or branched-chain acyl refers to carbon atoms of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 Straight chain or branched chain acyl, C _2-16 straight chain or branched chain alkenyl refers to the number of carbon atoms is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16 straight-chain or branched alkenyl.

Detailed ways

In order to further clarify the present invention, a series of examples are given below, these examples are completely illustrative, they are only used to specifically describe the present invention, and should not be construed as limiting the present invention.

The synthetic route of compound intermediate 1b in the embodiment:

Example 1:

3-(3,5-Dimethoxyphenyl)-6-methoxy-4-benzofurancarboxylic acid (1)

The synthetic route of compound 1:

Compound 1b (10.0 g, 29.2 mmol) was added to 150 mL of a mixed solution of THF, MeOH and H ₂ O (1:1:1, v/v/v), stirred to dissolve, and 1.17 g of NaOH was added. The reaction mixture was heated to reflux for 12 h, and the reaction raw materials were hydrolyzed completely. The reaction solution was evaporated under reduced pressure at 42°C to remove most of the solvent, and 1 mol/L HCl solution was added dropwise until no white precipitate was precipitated. The reaction mixture was suction-filtered, washed with distilled water, and dried to obtain compound 1 (9.48 g, 98.9%) as a white powdery solid.

Compound 1: white powder. ¹ H NMR (500MHz, acetone-d ₆ )δ7.89(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); ¹³ C NMR(125MHz, acetone-d ₆ ): 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 C ₁₈ H ₁₇ O ₆ ,329.1025). Implementation The synthetic route of compound 2-12 in the example:

Synthetic end product (compound code number is corresponding to the compound code number in the embodiment)

The synthetic method of compound 2-12 in the embodiment:

Method A: Dissolve compound 1 (100mg, 0.30mmol) in 50mL of dry dichloromethane, add HOBt (49.8mg, 0.37mmol) and EDCI (70.1mg, 0.37mmol), stir at room temperature for 20min, add alcohols or phenols For compound (1.2equiv), continue to stir at room temperature for 3-6h, TLC monitors the completion of the reaction, and stops the reaction. The reaction solution was concentrated under reduced pressure, and the remaining solid was prepared and separated on a silica gel preparation plate (selecting a suitable developer according to different compounds) to obtain the target product.

Method B: Dissolve compound 1 (100mg, 0.30mmol) in 50mL of dry dichloromethane, add DMAP (44.7mg, 0.37mmol) and EDCI (70.1mg, 0.37mmol), stir at room temperature for 20min, add alcohols or phenols Compound (1.2equiv) continued to stir at room temperature for 3-6h, and the reaction was complete as monitored by TLC. The reaction solution was concentrated under reduced pressure, and the remaining solid was prepared and separated on a silica gel preparation plate (selecting a suitable developer according to different compounds) to obtain the target product.

Example 2:

3-(3,5-Dimethoxyphenyl)-6-methoxy-4-benzofurancarboxylic acid acetic anhydride (2)

Synthesized according to method B, the alcohol compound added was 4-acetamidophenoxyethyl ester (70.6 mg, 0.36 mmol), using petroleum ether: acetone (2:1) as a developing solvent, prepared and separated on a silica gel plate to obtain the target product, Yield 79.9%. The physicochemical parameters of compound 2 are as follows:

Compound 2: off-white solid, yield=39.1%. ¹ H NMR (500MHz, acetone-d ₆ ): 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); ¹³ C NMR(125MHz,acetone-d ₆ ):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] ⁺ .

Example 3:

Octyl 3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxylate (3)

Synthesized according to method B, the added alcohol compound was n-octanol (1.2 equiv), petroleum ether: acetone (2:1) was used as developing solvent, prepared and separated on silica gel preparation plate to obtain the target product with a yield of 79.9%. The physicochemical parameters of compound 3 are as follows:

Compound 3: Pale yellow oily liquid, yield=79.9%. ¹ H NMR(600MHz,acetone-d ₆ ):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). ¹³ C NMR(125MHz,acetone-d ₆ ):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.forC ₂₆ H ₃₃ O _6,441.2272 ).

Example 4:

Cyclohexyl 3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxylate (4)

Synthesized according to method A, the added alcohol compound was cyclohexanol, petroleum ether: acetone (2:1) was used as developing solvent, prepared and separated on silica gel preparation plate to obtain the target product with a yield of 50.6%. The physicochemical parameters of compound 4 are as follows:

Compound 4: yellow oily liquid, yield=50.6%. ¹ H NMR (600MHz, acetone-d ₆ ): 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). ¹³ C NMR(125MHz, acetone-d ₆ ):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),26.371,2 (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 C ₂₄ H ₂₇ O ₆ ,411.1802).

Example 5:

3-(3,5-Dimethoxyphenyl)-6-methoxy-4-benzofurancarboxylic acid-2-furylmethyl ester (5)

Synthesized according to method B, the alcohol compound added is furfuryl alcohol (2-furan methanol), using petroleum ether: ethyl acetate: dichloromethane (5:1:2) as a developing solvent, silica gel preparation plate preparation and separation to obtain the target product, Yield 85.9%. The physicochemical parameters of compound 5 are as follows:

Compound 5: off-white solid, yield=85.9%. ¹ H NMR (500MHz, acetone-d ₆ ): 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); ¹³ C NMR(125MHz, acetone-d ₆ ):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(5+)70(5+), -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 C ₂₃ H ₂₁ O ₇ ,409.1282).

Embodiment 6:

3-(3,5-Dimethoxyphenyl)-6-methoxy-4-benzofurancarboxylic acid-4-chlorophenyl ester (6)

Synthesized according to method B, the added alcohol compound was p-chlorophenol, petroleum ether: acetone (2:1) was used as developing solvent, and silica gel preparation plate was prepared and separated to obtain the target product with a yield of 91.5%. The physicochemical parameters of compound 6 are as follows:

Compound 6: Pale yellow solid, yield=91.5%. ¹ H NMR (500MHz, acetone-d ₆ ): 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); ¹³ CNMR(125MHz,acetone-d ₆ ):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 C ₂₄ H ₂₀ ClO ₆ , 439.0943).

Embodiment 7:

3-(3,5-Dimethoxyphenyl)-6-methoxy-4-benzofurancarboxylic acid-2-methylphenyl ester (7)

Synthesized according to method B, the added alcohol compound was p-o-cresol, petroleum ether: acetone (2:1) was used as developing solvent, the target product was prepared and separated on silica gel preparation plate, and the yield was 96.3%. The physical and chemical parameters of compound 7 are as follows:

Compound 7: white solid, yield=96.3%. ¹ H NMR (500MHz, acetone-d ₆ ): 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); ¹³ C NMR ( 125MHz,acetone-d ₆ ):δ165.02,161.59(2×C),158.53,158.14,150.15,144.69,135.54,131.60,130.84,127.36,126.64,125.85,123.83,122.60,119.18(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 C ₂₅ H ₂₃ O ₆ ,419.1489).

Embodiment 8:

3-(3,5-Dimethoxyphenyl)-6-methoxy-4-benzofurancarboxylic acid-4-fluorophenylmethyl ester (8)

Synthesized according to method B, the added alcohol compound was p-fluorobenzyl alcohol, petroleum ether: acetone (2:1)) was used as developing solvent, the target product was prepared and separated on silica gel preparation plate, and the yield was 89.6%. The physicochemical parameters of compound 8 are as follows:

Compound 8: white solid, yield=89.6%. ¹ H NMR (500MHz, acetone-d ₆ ): 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=2.5 Hz, 2H), 6.47(t, J=2.5Hz, 1H), 4.77(s, 2H), 3.92(s, 3H), 3.80(s, 6H); ¹³ C NMR(125 MHz, acetone-d ₆ ) :δ167.73, 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, 115.93(2×C) ×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 C ₂₅ H ₂₂ FO ₆ ,437.1395).

Embodiment 9:

3-(3,5-Dimethoxyphenyl)-6-methoxy-4-benzofurancarboxylic acid-4-bromophenylmethyl ester (9)

Synthesized according to method B, the added alcohol compound was p-bromobenzyl alcohol, petroleum ether: acetone (2:1)) was used as developing solvent, the target product was prepared and separated on silica gel preparation plate, and the yield was 50.8%. The physicochemical parameters of compound 9 are as follows:

Compound 9: white solid, yield=50.8%. ¹ H NMR (600MHz, acetone-d ₆ ): 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); ¹³ C NMR(125MHz, acetone-d ₆ ):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 C ₂₅ H ₂₂ BrO ₆ ,497.0594).

Example 10:

3-(3,5-Dimethoxyphenyl)-6-methoxy-4-benzofurancarboxylic acid-2-phenylethyl ester (10)

Synthesized according to method B, the added alcohol compound was phenylethyl alcohol, petroleum ether: acetone (5:2) was used as the developing solvent, the target product was prepared and separated on a silica gel preparation plate, and the yield was 62.7%. The physicochemical parameters of compound 10 are as follows:

Compound 10: white solid, yield=62.7%. ¹ H NMR (500MHz, acetone-d ₆ ): 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); ¹³ C NMR(125MHz, acetone-d ₆ ): 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),100.30,100.16,66.31,55.42 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 C ₂₆ H ₂₅ O ₆ ,433.1646).

Example 11:

3-(3,5-Dimethoxyphenyl)-6-methoxy-4-benzofurancarboxylic acid-4-acetylphenyl ester (11)

Synthesized according to method B, the alcohol compound added is p-4-hydroxyacetophenone, using petroleum ether: ethyl acetate: dichloromethane (3:1:2) as a developing agent, prepared and separated on a silica gel preparation plate to obtain the target product, Yield 79.7%. The physicochemical parameters of compound 11 are as follows:

Compound 11: off-white solid, yield=79.7%. ¹ H NMR (500MHz, acetone-d ₆ ): 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=2.5Hz, 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); ¹³ C NMR(125MHz, acetone-d ₆ ):δ196.83,165.36, 161.92(2×C),158.65,158.17,154.93,144.75, (+ )-ESI-MSm/z:447.2[M+H] ⁺ ,469.2[M+Na] ⁺ ,485.1[M+K] ⁺ .HR-ESI-MS m/z:447.1433[M+H] ⁺ (calcd .for C ₂₆ H ₂₃ O ₇ ,447.1438).

Example 12:

3-(3,5-Dimethoxyphenyl)-6-methoxy-4-benzofurancarboxylic acid-2-(1H-indol-3-yl)ethyl ester (12)

Synthesized according to method B, the added alcohol compound was 3-indole alcohol, petroleum ether: acetone (2:1) was used as developing solvent, the target product was prepared and separated on silica gel preparation plate, and the yield was 80.0%. The physicochemical parameters of compound 12 are as follows:

Compound 12: Pale yellow oily liquid, yield=80.0%. ¹ H NMR (500MHz, acetone-d ₆ ): 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); ¹³ C NMR (125MHz, acetone-d ₆ ): 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 C ₂₈ H ₂₅ NO ₆ Na, 494.1574).

The synthetic route of compound 13-16 in the embodiment:

Synthetic final product (compound code number is corresponding to the compound code number in the embodiment):

Example 13:

3-(3,5-Dihydroxyphenyl)-6-hydroxy-4-benzofurancarboxylic acid (13)

The synthetic method of compound 13 in the embodiment:

Compound 1 (500.0mg, 1.52mmol) was dissolved in 60mL of dichloromethane and cooled to -50°C. Under vigorous stirring, slowly drop into BBr ₃ dichloromethane solution [BBr ₃ 15.2mL (10equiv, 1mmol/L) dissolved in 30mL DCM], keep at -50°C for 2h, through -50°C, -25°C, -10 The temperature was slowly raised to room temperature at several temperature ranges of 0 °C and 0 °C, and the reaction was continued overnight at room temperature. The completion of the reaction was monitored by TLC, and the reaction was quenched with methanol. The reaction mixture solution was diluted with 100 mL ethyl acetate, washed with water and saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was dissolved in a small amount of mixed solution of ethyl acetate and methanol, using dichloromethane:methanol (10:1) as the developing solvent, and the crude product was separated on a silica gel preparation plate, and the obtained crude product was further separated by a gel column, and the methanol was eluted to give a pale yellow solid.

Compound 13: Pale yellow solid (118.9 mg, 27.3%). ¹ H NMR (500MHz, cd ₃ od): 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). ¹³ CNMR(125MHz,acetone-d ₆ ):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 C ₁₅ H ₁₁ O ₆ ,287.0550).

Example 14:

Methyl 3-(3,5-dihydroxyphenyl)-6-hydroxy-4-benzofurancarboxylate (14)

Compound 1b was used as raw material, synthesized according to the synthesis method of compound 13, using dichloromethane: methanol (10:1) as developing solvent, and separated on silica gel preparation plate to obtain compound 14.

Compound 14: khaki solid (56.03 mg, 10.6%). ¹ H NMR (500MHz,acetone-d ₆ ): 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). ¹³ C NMR (125MHz, acetone-d ₆ ):δ168.07,159.28(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[MH] ^- .HR-ESI-MS m/z:301.0716[M+H] ⁺ (calcd.for C ₁₆ H ₁₃ O ₆ , 301.0707).

Example 15:

3-(3,5-Dihydroxyphenyl)-6-hydroxy-4-benzofuranoic acid octyl (15)

Compound 3 was used as a raw material, synthesized with reference to the synthetic method of compound 13, using dichloromethane:methanol (10:1) as a developing solvent, and separated on a silica gel preparation plate to obtain compound 15.

Compound 15: Pale brown solid (27.7 mg, 43.8%). ¹ H NMR (500MHz, acetone-d ₆ ): 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); ¹³ C NMR(125MHz, acetone-d ₆ ):δ168.02,159.44(2×C),158.09 ( -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.forC ₂₃ H ₂₇ O ₆ , 399.1802).

Example 16:

2-Phenylethyl 3-(3,5-dihydroxyphenyl)-6-hydroxy-4-benzofurancarboxylate (16)

Compound 10 was used as raw material, synthesized with reference to the synthetic method of compound 13, using dichloromethane:methanol (10:1) as developing solvent, and separated on silica gel preparation plate to obtain compound 16.

Compound 16: Pale yellow solid (9.9 mg, 16.2%). ¹ H NMR (500MHz, acetone-d ₆ ): 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). ¹³ C NMR (125MHz, acetone-d ₆ ): 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.forC ₂₃ H ₁₉ O ₆ ,391.1176).

The synthetic route of compound 17～33 in the embodiment:

Synthetic final product (compound code number is corresponding to the compound code number in the embodiment):

The synthetic method of compound 17～33 in the embodiment:

Synthetic method A: Compound 1 (100mg, 0.30mmol) was dissolved in 50mL of dry dichloromethane, HOBt (49.8mg, 0.37mmol) or EDCI (70.1mg, 0.37mmol) were added successively, stirred at room temperature for 20 min, and the corresponding amine derivatives (about 1.2 equiv). The reaction solution was stirred at room temperature for about 4 h, and the reaction was stopped after monitoring the completion of the reaction by TLC. After the reaction solution was concentrated to dryness under reduced pressure, the remaining solid was separated on a silica gel preparation plate (selecting a suitable developer according to different compounds) to obtain the target product.

Synthesis method B: Compound 1 (100mg, 0.30mmol) was dissolved in 50mL of dry dichloromethane, DMAP (44.7mg, 0.37mmol) and EDCI (70.1mg, 0.37mmol) were added, stirred at room temperature for 20min, and the corresponding amine was added to derivatize matter (about 1.2 equiv). The reaction solution was stirred at room temperature for about 4 h, and the reaction was stopped after monitoring the completion of the reaction by TLC. The reaction solution was concentrated under reduced pressure, and the remaining solid was separated on a silica gel preparation plate (selecting a suitable developer according to different compounds) to obtain the target product.

Example 17:

N-methyl-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxamide (17)

Synthesized with reference to method A, the added amine compound was methylamine, and dichloromethane:methanol (40:1) was used as the developing solvent, and the silica gel preparation plate was prepared and separated, and the yield was 87.3%. The physicochemical parameters of compound 17 are as follows:

Pale yellow solid, yield=87.3%. ¹ H NMR (500MHz, acetone-d ₆ ): 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 ); ¹³ C NMR (125MHz, acetone-d ₆ ): 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-MSm/z:342.2[M+H] ⁺ ,364.1[M+Na] ⁺ ,380.1[M+K] ⁺ .HR-ESI-MS m/z:342.1339[M+H] ⁺ (calcd. for C ₁₉ H ₂₀ NO ₅ ,342.1336).

Example 18:

N-Propyl-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxamide (18)

Synthesized with reference to method B, the added amine compound was n-propylamine, and oil ether: acetone (2:1) was used as the developer, and the silica gel preparation plate was prepared and separated, and the yield was 94.4%. The physicochemical parameters of compound 18 are as follows:

Compound 18: white solid, yield=94.4%. ¹ H NMR (500MHz, acetone-d ₆ ): 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=2.5Hz,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); ¹³ C NMR (125MHz, acetone-d ₆ ): δ167.98, 161.72 (2×C) (+)-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.forC ₂₁ H ₂₄ NO ₅ , 370.1649).

Example 19:

N-dodecyl-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxamide (19)

Synthesized with reference to method A, the added amine compound was dodecylamine, and oil ether: acetone (2:1) was used as a developing solvent to prepare and separate on a silica gel preparation plate, with a yield of 95.4%. The physicochemical parameters of compound 19 are as follows:

Compound 19: white solid, yield=95.4%. ¹ H NMR (500MHz, acetone-d ₆ ): 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=2.0Hz,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); ¹³ C NMR(125MHz,acetone-d ₆ ):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. 27.80,23.34,14.36.(+)-ESI-MS m/z:496.2[M+H] ⁺ ,518.3[M ⁺ Na] ⁺ . calcd.for C ₃₀ H ₄₂ NO ₅ ,496.3057)..

Example 20:

N-(3-Dimethylamino-1-propyl)-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxamide (20)

Synthesized by referring to method B, the added amine compound is N,N'-dimethyl-1,3-propanediamine, using chloroform:methanol (6:1) as the developer, prepared and separated on silica gel preparation plate, the yield 90.7%. The physicochemical parameters of compound 20 are as follows:

Compound 20: light yellow solid, yield=90.7%. ¹ H NMR (500MHz,acetone-d ₆ )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). ¹³ C NMR(125MHz, acetone-d ₆ ):δ168.44,161.53(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),53.67,37.24.(+23.5 )-ESI-MS m/z: 413.3[M+H] ⁺ ,435.3[M+Na] ⁺ .HR-ESI-MS m/z: 413.2074 [M+H] ⁺ (calcd.forC ₂₃ H ₂₉ N ₂ O ₅ ,413.2071).

Example 21:

[N-3-(3,5-Dimethoxyphenyl)-6-methoxy-4-benzofuroyl]methionine methyl ester (21)

Compound 1 (100mg, 0.30mmol) was dissolved in 50mL of dry dichloromethane, DMAP (44.7mg, 0.37mmol), EDCI (70.1mg, 0.37mmol) and DIPEA (151μL, 0.91mmol) were added successively, and stirred at room temperature for 20min , add L-methionine methyl ester (1.2 equiv), continue to stir at room temperature for 4h, TLC monitors the completion of the reaction, stop the reaction. The reaction solution was concentrated under reduced pressure, and the remaining solid was separated on a silica gel preparation plate using petroleum ether: acetone (2:1) as a developing solvent to obtain the target product. Yield 54.2%.

Compound 21: off-white solid, yield=54.2%. ¹ H NMR (500MHz, acetone-d ₆ )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) ^.13 C NMR(125MHz,acetone-d ₆ ):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 C ₂₄ H ₂₈ NO ₇ , 474.1581).

Example 22:

N-cyclopentyl-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxamide (22)

Synthesized with reference to method A, the amine compound added was cyclopentylamine, petroleum ether: ethyl acetate: dichloromethane (3:1:2) was used as the developing solvent, and the silica gel preparation plate was prepared and separated, and the yield was 82.6%. The physicochemical parameters of compound 22 are as follows:

Compound 22: white solid, yield=82.6%. ¹ H NMR (500MHz, acetone-d ₆ ): 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＝2.0Hz,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); ¹³ C NMR(125MHz,acetone-d ₆ ):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 z:396.1821[M+H] ⁺ (calcd.for C ₂₃ H ₂₆ NO ₅ ,396.1805)..

Example 23:

N-(2-furylmethyl)-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxamide (23)

Synthesized with reference to method A, the added amine compound was furanmethylamine, and petroleum ether: acetone (2:1) was used as the developer, and the silica gel preparation plate was prepared and separated, and the yield was 84.9%. The physicochemical parameters of compound 23 are as follows:

Compound 23: Pale yellow solid, yield=84.9%. ¹ H NMR(500MHz,acetone-d ₆ ):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); ¹³ C NMR (125MHz, acetone-d ₆ ):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(562×C),1090.567(1,558.567, 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 C ₂₃ H ₂₂ NO ₆ ,408.1442).

Example 24:

N-(4-methylphenyl)-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxamide (24)

Synthesized with reference to method B, the added amine compound was p-toluidine, and petroleum ether: acetone (2:1) was used as the developer, and the silica gel preparation plate was prepared and separated, and the yield was 54.8%. The physicochemical parameters of compound 24 are as follows:

Compound 24: off-white solid, yield=54.2%. ¹ H NMR (600MHz, acetone-d ₆ ): 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) ; ¹³ C NMR (125MHz, acetone-d ₆ ): 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, 1220.31( ×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 C ₂₅ H ₂₄ NO ₅ ,418.1649).

Example 25:

N-(4-chlorophenyl)-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxamide (25)

Synthesized with reference to method B, the added amine compound was p-chloroaniline, and petroleum ether: acetone (2:1) was used as the developer, and the silica gel preparation plate was prepared and separated, and the yield was 65.1%. The physicochemical parameters of compound 25 are as follows:

Compound 25: pale yellow-brown solid, yield=65.1%. ¹ H 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). ¹³ C NMR(125MHz,acetone-d ₆ ):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] ⁺ .

Example 26:

N-(phenylmethyl)-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxamide (26)

Synthesized with reference to method B, the added amine compound was benzylamine, and petroleum ether: acetone (2:1) was used as the developing solvent, and the silica gel preparation plate was prepared and separated, and the yield was 92.4%. The physicochemical parameters of compound 26 are as follows:

Compound 26: white solid, yield=92.4%. ¹ H NMR (500MHz, acetone-d ₆ ): 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); ¹³ C NMR (125MHz, acetone-d ₆ ): 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 C ₂₅ H ₂₄ NO ₅ , 418.1649).

Example 27:

N-(methyl)-N-(phenylmethyl)-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxamide (27)

Synthesized with reference to method B, the added amine compound was N-benzylmethylamine, petroleum ether: acetone (2:1) was used as the developer, and the silica gel preparation plate was prepared and separated, and the yield was 64.5%. The physicochemical parameters of compound 27 are as follows:

Pale yellow oily liquid (a pair of enantiomers), yield=64.5%. ¹ H NMR (500MHz, CDCl ₃ ): 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). ¹³ C NMR(125MHz, ₍ 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 C ₂₆ H ₂₆ NO ₅ ,432.1805).

Example 28:

N-(4-chlorophenylmethyl)-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxamide (28)

Synthesized with reference to method B, the amine compound added was 4-chlorobenzylamine, and petroleum ether: acetone (2:1) was used as the developer, and the silica gel preparation plate was prepared and separated, and the yield was 96.3%. The physicochemical parameters of compound 28 are as follows:

Compound 28: off-white solid, yield=96.3%. ¹ H NMR (500MHz, acetone-d ₆ ): 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); ¹³ C NMR(125MHz, acetone-d ₆ ): δ 168.22, 161.73(2×C), 158.84, ( ),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 C ₂₅ H ₂₃ ClNO ₅ , 452.1259).

Example 29:

N-(2-chlorophenylmethyl)-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxamide (29)

Synthesized by referring to method B, the amine compound added was 2-chlorobenzylamine, and petroleum ether: acetone (2:1) was used as the developer, and the silica gel preparation plate was prepared and separated, and the yield was 66.3%. The physicochemical parameters of compound 29 are as follows:

Compound 29: off-white solid, yield=66.3%. ¹ H NMR (500MHz, acetone-d ₆ ): 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); ¹³ C NMR (125MHz, acetone-d ₆ ): 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/zESI-MS.(+m) :452.0[M+H] ⁺ ,474.0[M+Na] ⁺ ,490.0[M+K] ⁺ . HR-ESI-MS m/z: 452.1281[M+H] ⁺ (calcd.for C ₂₅ H ₂₃ ClNO _5,452.1259 ).

Example 30:

N-[2-(4-chlorophenyl)ethyl]-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxamide (30)

Synthesized with reference to method B, the amine compound added was 4-chlorophenethylamine, and petroleum ether: acetone (2:1) was used as the developing solvent, and it was prepared and separated on a silica gel preparation plate, and the yield was 70.4%. The physicochemical parameters of compound 30 are as follows:

Compound 30: white solid, yield=70.4%. ¹ H NMR (500MHz, acetone-d ₆ ): 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); ¹³ C NMR(125 MHz,acetone-d ₆ ):δ168. 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),123.68,117.20,111.99,107.51,10 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 C ₂₆ H ₂₅ ClNO ₅ , 466.1416)..

Example 31:

N-[2-(1H-indol-3-yl)ethyl]-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxamide (31)

Synthesized with reference to method B, the added amine compound was tryptamine (β-indoleethylamine), and petroleum ether: acetone (3: 1) was used as the developer, and the silica gel preparation plate was prepared and separated, and the yield was 95.1%. The physicochemical parameters of compound 31 are as follows:

Compound 31: pale brown solid, yield=95.1%. ¹ H NMR(500MHz,acetone-d ₆ ):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＝2.5Hz, 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); ¹³ C NMR (125MHz, acetone-d ₆ ): 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 C ₂₈ H ₂₇ N ₂ O ₅ ,471.1914).

Example 32:

N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzo Furamide (32)

Synthesized by referring to method B, the amine compound added is 2-(5-methoxy-1H-indol-3-yl)ethylamine, petroleum ether: acetone (2:1) is used as the developing agent, and the silica gel preparation plate is prepared It was isolated with a yield of 91.0%. The physicochemical parameters of compound 32 are as follows:

Compound 32: brown solid, yield=91.0%. ¹ H NMR (500MHz,acetone-d ₆ ):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); ¹³ C 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),251.03 -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 C ₂₉ H ₂₉ N ₂ O ₆ , 501.2020).

Example 33:

N-{2-[(5-(3-(3,5-dimethoxyphenyll)-6-methoxy-4-benzofuroyl)oxy)-1H-indole-3 -yl]ethyl}-3-(3,5-dimethoxyphenyl)-6-methoxy-4-benzofurancarboxamide (33)

Synthesized with reference to method B, the added amine compound was 5-hydroxytryptamine, and petroleum ether: acetone (2:1) was used as the developer, and the silica gel preparation plate was prepared and separated, and the yield was 34.2%. The physicochemical parameters of compound 33 are as follows:

Compound 33: off-white solid, yield=34.2%. ¹ H NMR (500MHz, acetone-d ₆ ): 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＝2.5 Hz, 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); ¹³ C NMR(125MHz,acetone-d ₆ ):δ168.08, 166.76,161.85(2×C),161.72(2×C),158.81,158.66,158.19,157.90,144.62,144.49, 143.27,135.664,135.30,134. , 133.21,128.33,127.18,124.56,123.98,123.72,118.64, 117.19,116.27,114.33,113.01.01.98,111.08,107.43 (2 × C), 107.27 (2 × C), 100.66,100.5.51,100.5.51,100.5.5100.5.5. ,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 C ₄₆ H ₄₁ N ₂ O ₁₁ ,797.2705).

The synthetic route of compound 34～43 in the embodiment:

Synthetic final products 34～43 (compound codes correspond to the compound codes in the examples):

The synthetic method of compound 34～43 in the embodiment:

The 3-aryl-substituted amide derivative (about 70 mg) was dissolved in 20 mL of dry dichloromethane and cooled to -50°C. Under vigorous stirring, slowly dropwise into a solution of BBr ₃ in dichloromethane [BBr ₃ (10equiv, 1mmol/L) was dissolved in 15mL of dry dichloromethane]. After the dropwise addition, keep stirring at -50°C for 2h, slowly raise the temperature to -25°C, -10°C and 0°C respectively, and stir at -25°C, -10°C and 0°C for 2h respectively. Then react at room temperature overnight, and TLC monitors the completion of the reaction. The reaction solution was cooled to -50°C, and 6 mL of methanol was added dropwise for analysis. The reaction solution was diluted with 100 mL of ethyl acetate, washed with 50 mL of water, washed with saturated brine, the aqueous phase was back-extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was washed with ethyl acetate and methanol The mixed solvent (or the mixed solvent of acetone and methanol) was dissolved, separated on a silica gel preparation plate, and purified by gel to obtain the target compound. The eluent of gel purification is usually methanol, and occasionally a mixed solvent of chloroform methanol or dichloromethane methanol is used.

Example 34:

N-Methyl-(3,5-dihydroxyphenyl)-6-hydroxy-4-benzofurancarboxamide (34)

The physicochemical parameters of compound 34 are as follows:

Compound 34: off-white solid (30.4 mg, 49.6%). ¹ H NMR (500MHz, acetone-d ₆ ): 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 ); ¹³ C NMR (125MHz, acetone-d ₆ ): 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 C ₁₆ H ₁₄ NO ₅ ,300.0866).

Example 35:

N-dodecyl-(3,5-dihydroxyphenyl)-6-hydroxy-4-benzofurancarboxamide (35)

The physicochemical parameters of compound 35 are as follows:

Compound 35: pale yellow solid (20.0 mg, 31.2%). ¹ H NMR (500MHz, acetone-d ₆ ): 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); ¹³ C NMR (125MHz, acetone-d ₆ ): 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 z:452[MH] ^- ,488[M+Cl] ^- ; HR-ESI-MS m/z:454.2590 [M+H] ⁺ (calcd.for C ₂₇ H ₃₆ NO ₅ ,454.2588).

Example 36:

N-(3-Dimethylamino-1-propyl)-3-(3,5-dihydroxyphenyl)-6-hydroxy-4-benzofurancarboxamide (36)

The physicochemical parameters of compound 36 are as follows:

Compound 36: Pale yellow solid (24.6 mg, 39.2%). ¹ H NMR (500MHz, CD ₃ OD): 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). ¹³ C NMR(150MHz,CD ₃ OD):δ167.72,159.64(2×C),158.60, 156.75,143.43,135.82,131.23,123.78,118.52,112.86,108.33,102.9 , 100.79, 56.80, 45.45, 37.65, 25.28. (+)-ESI-MS m/z: 371.1[M ⁺ H] ⁺ . C ₂₀ H ₂₃ N ₂ O ₅ , 371.1601).

Example 37:

N-(2-furylmethyl)-3-(3,5-dihydroxyphenyl)-6-hydroxy-4-benzofurancarboxamide (37)

The physicochemical parameters of compound 37 are as follows:

Compound 37: Pale yellow solid (23.0 mg, 36.6%). ¹ H NMR (500MHz, acetone-d ₆ )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). ¹³ C NMR (125MHz,acetone-d ₆ ):δ167.84,159.33(2×C),157.88,156.16,152.88,142.69,142.67,134.97,132.37,123.70,116.85,112.58,111.152,108.14,102.7 ,100.07,37.09.(+)-ESI-MS m/z:388[M+Na] ⁺ ,404[M+K] ⁺ ; (-)-ESI-MS m/z:364[MH] ^- ,400 [M+Cl] ^- ; HR-ESI-MS m/z:366.0991[M+H] ⁺ (calcd. for C ₂₀ H ₁₆ NO ₆ ,366.0972).

Example 38:

N-Methyl-N-(phenylmethyl)-3-(3,5-dihydroxyphenyl)-6-hydroxy-4-benzofurancarboxamide (38)

The physicochemical parameters of compound 38 are as follows:

Compound 38, pale yellow solid (52.4 mg, 83.0%), a mixture of isomers). ¹ H NMR (500MHz, acetone-d ₆ ) 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). ¹³ C NMR (125 MHz, acetone-d ₆ ): δ170.51, 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),103.01,102.94,99.53,54.85,50.47,35.03. 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 C ₂₃ H ₂₀ NO ₅ ,390.1336).

Example 39:

N-(4-methylphenyl)-3-(3,5-dihydroxyphenyl)-6-hydroxy-4-benzofurancarboxamide (39)

The physicochemical parameters of compound 39 are as follows:

Compound 39: Pale brown solid (21.2 mg, 34.0%). ¹ H NMR(500MHz,acetone-d ₆ ):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=2.0Hz,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); ¹³ C NMR (125MHz, acetone-d ₆ ): δ165.98, 159.28(2×C), 157.95, 156.20, 142.80, (+)-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 C ₂₂ H ₁₈ NO ₅ , 376.1179).

Example 40:

N-(4-chlorophenyl)-3-(3,5-dihydroxyphenyl)-6-hydroxy-4-benzofurancarboxamide (40)

The physicochemical parameters of compound 40 are as follows:

Compound 40: pale tan solid (39.3 mg, 62.3%). ¹ H NMR (500MHz, cd ₃ od): 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); ¹³ C NMR (125 MHz, cd ₃ od): δ168.89, 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, 1208.26 ×C),102.61, 100.99.(+)-ESI-MS m/z:417.9[M+Na] ⁺ .HR-ESI-MS m/z:396.0644[M+H] ⁺ (calcd. for C ₂₁ H ₂₅ ClNO ₅ ,396.0633).

Example 41:

N-(phenylmethyl)-3-(3,5-dihydroxyphenyl)-6-hydroxy-4-benzofurancarboxamide (41)

The physicochemical parameters of compound 41 are as follows:

Compound 41: off-white solid (34.7 mg, 55.1%). ¹ H NMR (500MHz, acetone-d ₆ ): 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); ¹³ C NMR(125MHz,acetone-d ₆ ): 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 [MH] ^- ,410[ M+Cl] ^- ; HR-ESI-MSm/z: 376.1195[M+H] ⁺ (calcd.for C ₂₂ H ₁₈ NO ₅ , 376.1179).

Example 42:

N-(4-chlorophenylmethyl)-3-(3,5-dihydroxyphenyl)-6-hydroxy-4-benzofurancarboxamide (42)

The physicochemical parameters of compound 42 are as follows:

Compound 42: Pale brown solid (39.0 mg, 61.5%). ¹ H NMR (500MHz, acetone-d ₆ ): 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); ¹³ C NMR (125MHz, acetone-d ₆ ): 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 C ₂₂ H ₁₇ ClNO ₅ ,410.0790).

Example 43:

N-[2-(1H-indol-3-yl)ethyl]-3-(3,5-dihydroxyphenyl)-6-hydroxy-4-benzofurancarboxamide (43)

The physicochemical parameters of compound 43 are as follows:

Compound 43: Pale brown solid (37.3 mg, 58.6%). ¹ H NMR (500MHz, acetone-d ₆ ): δ9.96 (s, 1H), δ9.54 (s, 2H), δ7.72 (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=2.5Hz,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[MH] ^- , 463[M+Cl] ^- ; HR-ESI-MS m /z:429.1450[M+H] ⁺ (calcd. for C ₂₂ H ₂₁ N ₂ O ₅ ,429.1445).

The anti-inflammatory and immunosuppressive activity of the compounds of the present invention are as follows:

Example 1: Inhibitory activity of compounds on LPS-induced NO production in primary mouse peritoneal macrophages.

Macrophages, which perform non-specific immune functions of the body, can produce inflammatory factors such as NO under the induction of bacterial lipopolysaccharide LPS, participate in and mediate inflammatory reactions, and have a high level in the initial stage of various inflammatory immune processes and in the process of pathological development Level. By detecting the amount of NO produced by primary cultured mouse macrophages, it can be used as an index for preliminary observation and screening of components or compounds with certain anti-inflammatory activities in vitro.

experimental method:

同时，用MTT法测定细胞增殖抑制率；并测定对NO生成具有显著抑制活性化合物的IC₅₀值(用Probit加权回归分析法计算)。The primary mouse peritoneal macrophages were inoculated in 96-well plates, and different test compounds (10 ^-5 M) and positive control drug dexamethasone (Dex) were added for pre-protection for 1 h; then, 1 μg/ml LPS was added at 37 After culturing for 24 h in a 5% CO ₂ incubator at ℃, the supernatant was collected,

At the same time, the inhibition rate of cell proliferation was determined by MTT method; and the IC ₅₀ value of the compound with significant inhibitory activity on NO generation was determined (calculated by Probit weighted regression analysis method).

Experimental results:

The results are shown in Table 1. Compared with the lead compound Amurensin H, the structurally modified compound has significantly reduced toxicity while maintaining activity. Among them, compounds 11, 12, 27, 28, 32, 35, and 43 not only have significant NO production inhibitory activity, but also have significantly lower toxicity than Amurensin H and positive control drugs.

Table 1. Effects of Amurensin H derivatives on LPS-induced NO production in primary mouse peritoneal macrophages.

*The compound code corresponds to the compound code in the examples.

Example 2: Effects of Compounds on Croton Oil-Induced Otitis in Mice.

experimental method:

Take 18-20g male Kunming mice and divide them into random groups. The animals in each group are coated with 0.02ml of croton oil on both sides of the left ear respectively; 30 minutes later, the animals in each group are subcutaneously injected with the test compound at 50mg/kg body weight respectively. The same volume of vehicle was given to the group; 4 hours after the administration, the mice were killed by neck dislocation, and both ears were cut off along the baseline of the auricles, and the ear pieces at the same position of the left and right ears were removed with a 6 mm diameter punch, weighed with an analytical balance, and the ear swelling was calculated. degree (ear swelling degree=left ear piece weight-right ear piece weight) and ear swelling inhibition rate [ear swelling inhibition rate (%)=(model group average ear swelling degree-administration group ear swelling degree)/model group average ear swelling degree Swelling group × 100%].

Experimental results:

The experimental results are shown in Table 2. Compared with the model control group, compounds 11, 12, and 35 can significantly reduce the otitis induced by croton oil in mice (P<0.01 or 0.05).

Table 2. Effects of Amurensin H derivatives on otitis induced by croton oil in mice (Mean±SD, n=10) ^a .

^a Compared with the model group, "*" means p<0.05, "**" means p<0.01.

The compound code of ^b corresponds to the compound code in the examples.

Example 3: Effects of compounds on DNFB-induced DTH inflammatory response in mice.

18-20g male ICR mice were taken and randomly divided into groups. Except for the blank group given equal volume of vehicle, animals in other groups were sensitized by spraying 0.05mL of 1% DNFB solution after abdominal hair removal, and strengthened with the same dose of DNFB on the second day. At the same time, starting from the third day of animal sensitization, animals in each group were given subcutaneous injection of 20 mg/kg of the test compound, once a day, for 3 consecutive days; the blank group and model control group were given equal volumes of vehicle. On the 5th day after the animals were sensitized, except the blank group, the animals in each group were challenged by applying 0.01mL of 1% DNFB solution to the left ear. After 24 hours, the animals were sacrificed, and the ears were cut off along the baseline of the auricles, and a 6mm-diameter puncture was made. The holers removed the ear pieces at the same position of the left and right ears respectively, weighed them with an analytical balance, and calculated the degree of ear swelling and the inhibition rate of ear swelling (%).

Experimental results:

The experimental results are shown in Table 3. Compared with the model group, compounds 11 and 12 had a significant inhibitory effect on DTH ear swelling induced by DNFB sensitization and challenge (P<0.05 or 0.01).

Table 3. Effects of Amurensin H derivatives on DNFB-induced DTH inflammatory response in mice (Mean±SD, n=10) ^a .

^a Compared with the model group, "*" means p<0.05, "**" means p<0.01.

The compound code of ^b corresponds to the compound code in the examples.

Example 4: Effect of compounds on carrageenan-induced paw swelling in mice.

experimental method:

Take 18-20g male Kunming mice, divide them into groups randomly, and subcutaneously inject 0.05ml of 0.1% carrageenan into the left sole of each group of animals; 30 minutes later, each group of animals will subcutaneously inject 50mg/kg Compound, the model control group was given equal volume of vehicle; 4h after the administration, the mice were killed by neck dislocation, the feet were cut off along the ankle joints, weighed with an analytical balance, and the swelling degree of the feet was calculated (foot swelling degree=left foot weight-right foot weight) and Inhibition rate of paw swelling [inhibition rate of paw swelling (%)=(average paw swelling degree of model group-paw swelling degree of administration group)/average paw swelling degree of model group×100%].

Experimental results:

The experimental results are shown in Table 4. Compared with the model control group, compounds 11 and 12 can significantly reduce carrageenan-induced mouse paw swelling (P<0.01 or 0.05).

Table 4. Effects of Amurensin H derivatives on carrageenan-induced mouse paw swelling (Mean±SD, n=10) ^a .

^a Compared with the model group, "*" means p<0.05, "**" means p<0.01.

The compound code of ^b corresponds to the compound code in the examples.

Claims (10)

1. a kind of 3-phenyl-7,8-dehydroglupapentine derivatives and pharmaceutically acceptable salts thereof, it is characterized in that, described compound is such as general formula (IAa), (IAb), (IAc ) as shown:

Wherein, L is selected from substituted or unsubstituted C _0-16 straight chain or branched chain alkyl; the substituent is selected from hydroxyl, _nitro , cyano, amino, methylamino, dimethylamino, C _{1- 6} alkoxy, F, Cl, Br, I; R _is independently selected from H, substituted or unsubstituted C _1-6 alkyl; wherein, the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 alkyl Oxygen, F, Cl, Br, I; R ₆ , R ₇ , and R ₈ are each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 alkylthio, F, Cl, Br, I; R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen and C _1-6 alkyl groups. 2. 3-phenyl-7 according to claim 1, 8-dehydrogluphine derivatives and pharmaceutically acceptable salts thereof, characterized in that: The L ₁ is selected from C ₀ , C ₁ , C ₂ , and C ₃ linear alkyl groups; R ₅ is independently selected from H, C ₁ , C ₂ , C ₃ linear alkyl groups; R ₆ , R ₇ , and R ₈ are each independently selected from hydrogen, hydroxyl, methoxy, acetyl, and Cl; R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen and methyl. 3. A 3-phenyl-7,8-dehydroglupapentine derivative and a pharmaceutically acceptable salt thereof, characterized in that said compound is such as general formula (IBa), (IBb), (IBc) Shown:

Wherein, L is selected from substituted or unsubstituted C _0-16 straight chain or branched chain alkyl; the substituent is selected from hydroxyl, _nitro , cyano, amino, methylamino, dimethylamino, C _{1- 6} alkoxy, C _1-6 alkylthio, F, Cl, Br, I; R ₁₀ , R ₁₁ , and R ₁₂ are each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 alkylthio, F, Cl, Br, I; R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen and C _1-6 alkyl groups. 4. 3-phenyl-7,8-dehydroglupapentine derivatives and pharmaceutically acceptable salts thereof according to claim 3, characterized in that, The L ₁ is selected from C ₀ , C ₁ , C ₂ , and C ₃ linear alkyl groups; R ₁₀ , R ₁₁ , and R ₁₂ are each independently selected from hydrogen, hydroxyl, methoxy, acetyl, and Cl; R ₂ , R ₃ , and R ₄ are each independently selected from hydrogen and methyl. 5. 3-phenyl-7,8-dehydroglupapentine derivatives and pharmaceutically acceptable salts thereof according to any one of claims 1-4, characterized in that said compounds are selected from the following group:

6. A pharmaceutical composition comprising the 3-phenyl-7,8-dehydroglupapentin derivatives and pharmaceutically acceptable salts thereof and pharmaceutically acceptable salts thereof described in any one of claims 1-5 in an effective dosage. Composition of acceptable excipients. 7. according to the pharmaceutical composition of claim 6, it is characterized in that, described pharmaceutical composition is selected from tablet, capsule, pill, injection. 8. The pharmaceutical composition according to claim 6, characterized in that, the pharmaceutical composition is selected from sustained-release preparations and various particle delivery systems. 9. The 3-phenyl-7,8-dehydroglupapentine derivatives and pharmaceutically acceptable salts thereof described in any one of claims 1-5 are used in the preparation of treatment and/or prevention of inflammation and/or immunity Inhibition of drug use. 10. The application according to claim 9, wherein inflammation and immunosuppression include: rheumatoid arthritis, gouty arthritis, lupus erythematosus syndrome, bronchitis, bursitis, tenosynovitis, psoriasis, eczema, burns, dermatitis, inflammatory Enteropathy, Crohn's disease, gastritis, irritable bowel syndrome, multiple sclerosis, autoimmune encephalomyelitis, colorectal cancer, arteritis nodosa, thyroiditis, rheumatism, gingivitis, periodontal Inflammation, oral ulcer, nephritis, swelling after injury, myocardial ischemia, various infectious pneumonia, physicochemical pneumonia and allergic pneumonia, spasmodic anal pain and rectal fissure, hepatic cholecystitis, cholangitis, primary Biliary cirrhosis and cholecystitis.