CN109721580B

CN109721580B - 3-phenyl-7, 8-dehydrograpevine derivatives, preparation method, pharmaceutical composition and use thereof

Info

Publication number: CN109721580B
Application number: CN201811265976.6A
Authority: CN
Inventors: 姚春所; 林明宝; 侯琦; 白金叶; 石建功; 张纪法; 范燕楠; 滕彬豪
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2017-10-27
Filing date: 2018-10-29
Publication date: 2022-11-04
Anticipated expiration: 2038-10-29
Also published as: CN109721580A

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-dehydrograpevine derivatives, preparation method, pharmaceutical composition and use thereof

Technical Field

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

Background

Inflammation is the basis of human diseases, and is causality to many pathological changes of diseases, which 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 more problems in clinical application, such as easily causing discomfort and bleeding of digestive tract, and increasing the risk of adverse reactions such as heart disease or systemic coagulation disorder disease. Therefore, the search for safer and more effective anti-inflammatory drugs remains an important task for the research and development of the current anti-inflammatory drugs.

The oligomeric stilbene compounds are natural products with novel structures developed in nearly 30 years, and researches show that the compounds have various pharmacological activities, including antibiosis, anti-inflammation, antioxidation, antivirus, anti-senile dementia and the like [ J.Asian Nat.Prod.Res.,2016,18 (4): 376-407], and have good research and development prospects. At present, a great deal of research is carried out on the extraction and separation, the structure identification and the primary activity screening of the compounds. However, due to the complex structure, the content of the compound in natural products is low, the total synthesis is difficult, and the development and research process of the compound is greatly limited by the lack of sample quantity. Therefore, based on the active oligomeric stilbene lead compound, through synthesis, structure optimization and structure-activity relationship research, a new medicament with better medicament forming property is discovered, and the method has important significance for developing and utilizing the compound.

Amurensin H is a resveratrol dimer compound having a benzofuran ring isolated from the root of Vitis amurensis (Vitis amurensis), a medicinal herb [ Chin. Chem. Lett.,1999,10 (10): 817-820]. Pharmacological activity researches show that Amurensin H is a natural active ingredient with an inhibiting effect on the generation of various inflammatory mediators [ acta Pharmacol.sin.,2006,27 (6): 735-740 ], and animal experiments prove that the compound can obviously resist chronic airway inflammation and relieve the pathological damage of lung tissues of mice suffering from Chronic Obstructive Pulmonary Disease (COPD). Further systemic pharmacological experiments show that the natural product has strong activity and low toxicity, and is an active lead compound with deep research value. The research on the activity of the Amurensin H compound per se has been published by the research group, but the structure-activity relationship research on the structure optimization and the anti-inflammatory activity of the compound system is not reported in the literature. The patent relates to the work of carrying out structural optimization and structure-activity relationship research on the compound so as to improve the physicochemical property and the in vivo anti-inflammatory activity of the compound.

Disclosure of Invention

The invention aims to solve the technical problem of providing a 3-phenyl-4-substituted benzofuran compound with a novel structure and a derivative thereof. A preparation method, a pharmaceutical composition and an application thereof.

The first aspect of the technical scheme of the invention provides a novel structure of 3-phenyl-4-substituted benzofuran compound shown as general formulas (I), (IA), (IAa), (IAb), (IAc), (IAd) and (IB), (IBa), (IBb), (IBc) and (IBd) and derivatives thereof.

In a second aspect of the technical scheme of the present invention, there is provided a pharmaceutical composition, which comprises at least one 3-phenyl-4-substituted benzofuran compound shown in general formulas (I), (IA), (IAa), (IAb), (IAc), (IAd), and (IB), (IBa), (IBc), (IBd), and pharmaceutically acceptable salts thereof, and carriers commonly used in the pharmaceutical field.

The third aspect of the technical scheme of the invention provides an application of 3-phenyl-4-substituted benzofuran compounds shown as general formulas ((I), (IA), (IAa), (IAb), (IAc), (IAd) and (IB), (IBa), (IBb), (IBc) and (IBd) and pharmaceutically acceptable salts thereof in preparation of medicines for preventing, treating and adjunctively treating various inflammatory diseases.

The various inflammatory diseases include: rheumatic arthritis, gouty arthritis, lupus erythematosus, 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, nodular arteritis, thyroiditis, wind-heat-dampness, gingivitis, periodontitis, canker sores, nephritis, swelling following insult, myocardial ischemia, various infectious pneumonia, physicochemical pneumonia and allergic pneumonia, spastic anal pain and rectal fissure, hepatobiliary cystitis, cholangitis, sclerosing cholangitis, primary biliary cirrhosis and cholecystitis. The compounds of the present invention include derivatives and pharmaceutically acceptable salts thereof.

Specifically, the invention relates to a 3-phenyl-7, 8-dehydrograpevine derivative (3-phenyl-4-substituted benzofuran derivative) shown as a general formula (I) and pharmaceutically acceptable salts thereof:

wherein X is selected from O and NR ₅ 、S；

R ₁ Selected from H, substituted or unsubstituted C _3-8 Substituted or unsubstituted phenyl, substituted or unsubstituted indolyl, substituted or unsubstituted furyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyridyl; the substituents of the cycloalkyl, phenyl, indolyl, furyl, naphthyl, quinolyl and pyridyl are selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 Alkyl of (C) _1-6 Alkoxy group of (C) _1-6 Acyl group of (1), C _1-6 Acyloxy group of (2), C _1-6 Alkylthio, methylenedioxy, carboxyl, F, cl, br, I, glu, SO ₃ H、PO ₃ H ₂ (ii) a The substitution types comprise mono-substitution, di-substitution or tri-substitution;

L ₁ selected from substituted or unsubstituted C _0-16 Straight or branched alkyl of, substituted or unsubstituted C _0-16 A straight or branched acyl group of (A), a substituted or unsubstituted C _2-16 Straight-chain or branched alkenyl of, C _2-6 Alkynyl of (1); the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl and C _1-6 Alkoxy group of (1), C _1-6 Acyl group of (1), C _1-6 Acyloxy group of (2) and (C) _1-6 Alkylthio, F, cl, br, I;

R ₅ independently selected from H, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1-6 Acyl group of (4); wherein the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino and C _1-6 Alkoxy, phenyl, F, cl, br, I;

R ₂ 、R ₃ 、R ₄ each independently selected from hydrogen and C _1-6 Alkyl of (C) _1-6 Acyl group, glu, SO ₃ H、PO ₃ H ₂ ；

Glu represents beta-D glucopyranosyl; SO (SO) ₃ H represents a sulfonyl group; PO (PO) ₃ H ₂ Represents a phosphoryl group.

According to the present invention, preferred 3-phenyl-7, 8-dehydrograpevine derivatives represented by the general formula (I) include, but are not limited to, compounds represented by the general formula (IA), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by the general formula (IA):

wherein R is ₁ Selected from H, substituted or unsubstituted C _3-8 Substituted or unsubstituted phenyl, substituted or unsubstituted indolyl, substituted or unsubstituted furyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyridyl; wherein the substituents of said cycloalkyl, phenyl, indolyl, furyl, naphthyl, quinolyl and pyridyl are selected from the group consisting of hydroxy, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 Alkyl of (C) _1-6 Alkoxy group of (1), C _1-6 Acyl group of (1), C _1-6 Acyloxy group of (2) and (C) _1-6 Alkylthio, methylenedioxy, carboxyl, F, cl, br, I, glu, SO ₃ H、PO ₃ H ₂ (ii) a The substitution type comprises mono-substitution, di-substitution or tri-substitution;

L ₁ selected from substituted or unsubstituted C _0-16 Straight or branched alkyl of, substituted or unsubstituted C _0-16 Straight or branched acyl of (2), substituted or unsubstituted C _2-16 Straight-chain or branched alkenyl of, C _2-6 Alkynyl of (a); the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl and C _1-6 Alkoxy group of (C) _1-6 Acyl group of (1), C _1-6 Acyloxy group of (2) and (C) _1-6 Alkylthio, F, cl, br, I;

R ₅ independently selected from H, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1-6 Acyl group of (4); wherein, the substituent is selected from hydroxyl, nitryl, cyano, amino, methylamino, dimethylamino and C _1-6 Alkoxy, phenyl, F, cl, br, I;

R ₂ 、R ₃ 、R ₄ each independently selected from hydrogen, C _1-6 Alkyl of (C) _1-6 Acyl group, glu, SO ₃ H、PO ₃ H ₂ ；

Preferred 3-phenyl-7, 8-dehydrograpevine derivatives of formula (IA) according to the present invention include, but are not limited to, compounds of formula (IAa), (IAb), (IAc), and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IAa), (IAb), (IAc):

wherein L is ₁ Selected from substituted or unsubstituted C _0-16 Straight or branched alkyl, substituted or unsubstituted C _0-16 A straight or branched acyl group of (A), a substituted or unsubstituted C _2-16 Straight-chain or branched alkenyl of (1); the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl and C _1-6 Alkoxy group of (C) _1-6 Acyl group of (1), C _1-6 Acyloxy, F, cl, br, I;

R ₅ independently selected from H, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1-6 Acyl group of (4); wherein is substitutedThe group is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 Alkoxy, phenyl, F, cl, br, I;

R ₆ 、R ₇ 、R ₈ each independently selected from hydrogen, hydroxy, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 Alkyl of (C) _1-6 Alkoxy group of (1), C _1-6 Acyl group of (1), C _1-6 Acyloxy group of (2) and (C) _1-6 Alkylthio, methylenedioxy, F, cl, br, I, glu, SO ₃ H、PO ₃ H ₂ ；

Glu represents beta-D glucopyranosyl; SO (SO) ₃ H represents a sulfonyl group; PO ₃ H ₂ Represents a phosphoryl group.

According to the present invention, preferred 3-phenyl-7, 8-dehydrograpevine derivatives represented by the general formulae (IAa), (IAb), (IAc), and pharmaceutically acceptable salts thereof are characterized in that:

said L ₁ Is selected from C ₀ 、C ₁ 、C ₂ 、C ₃ The linear alkyl group of (1);

R ₅ independently selected from H, C ₁ 、C ₂ 、C ₃ The linear alkyl group of (1);

R ₆ 、R ₇ 、R ₈ each independently selected from hydrogen, hydroxy, methoxy, acetyl, cl;

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

Preferred 3-phenyl-7, 8-dehydrograpevine derivatives of formula (IA) according to the present invention include, but are not limited to, compounds of formula (IAd), and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IAd):

wherein R is ₉ 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 A straight or branched acyl group, a substituted or unsubstituted C _2-16 Linear or branched alkenyl of, C _2-6 Alkynyl of (1); the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl and C _1-6 Alkoxy group of (1), C _1-6 Acyl group of (1), C _1-6 Acyloxy group of (2) and (C) _1-6 Alkylthio, F, cl, br, I;

R ₅ independently selected from H, substituted or unsubstituted C _1-6 Alkyl groups of (a); wherein the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino and C _1-6 Alkoxy, phenyl, F, cl, br, I;

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

r is as described ₉ Selected from substituted or unsubstituted C _1-16 Straight or branched alkyl of, substituted or unsubstituted C _3-8 Cycloalkyl of (a); wherein the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl and C _1-6 Alkoxy group of (1), C _1-6 Acyl group of (1), C _1-6 Acyloxy group of (2) and (C) _1-6 Alkylthio, F, cl, br, I;

R ₅ independently selected from hydrogen, C _1-3 The linear alkyl group of (1);

R ₂ 、R ₃ 、R ₄ are independently selected fromFrom hydrogen, methyl, acetyl;

according to the present invention, a preferred 3-phenyl-7, 8-dehydrograpevine derivative represented by the general formula (IAd), and a pharmaceutically acceptable salt thereof, is characterized in that:

said R ₉ Selected from substituted or unsubstituted C _3-12 Straight or branched alkyl, substituted or unsubstituted C _5-68 Cycloalkyl groups of (a); wherein the substituents are selected from hydrogen, hydroxy, methylamino, dimethylamino, methoxy, acetyl, cl;

R ₅ independently selected from hydrogen, C ₁ 、C ₂ 、C ₃ The linear alkyl group of (1);

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

according to the present invention, preferred 3-phenyl-7, 8-dehydrograpevine derivatives represented by the general formula (I) include, but are not limited to, compounds represented by the general formula (IB), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by the general formula (IB):

wherein R is ₁ Selected from H, substituted or unsubstituted C _3-8 Substituted or unsubstituted phenyl, substituted or unsubstituted indolyl, substituted or unsubstituted furyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyridyl; the substituents of the cycloalkyl, phenyl, indolyl, furyl, naphthyl, quinolyl and pyridyl are selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 Alkyl of (C) _1-6 Alkoxy group of (C) _1-6 Acyl group of (1), C _1-6 Acyloxy group of (2) and (C) _1-6 Alkylthio, methylenedioxy, carboxyl, F, cl, br, I, glu, SO ₃ H、PO ₃ H ₂ (ii) a The substitution types comprise mono-substitution, di-substitution or tri-substitution;

L ₁ selected from substituted orUnsubstituted C _0-16 Straight or branched alkyl, substituted or unsubstituted C _0-16 A straight or branched acyl group, a substituted or unsubstituted C _2-16 Linear or branched alkenyl of, C _2-6 Alkynyl of (1); the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl and C _1-6 Alkoxy group of (1), C _1-6 Acyl group of (1), C _1-6 Acyloxy group of (2), C _1-6 Alkylthio, F, cl, br, I;

Glu represents beta-D glucopyranosyl; SO ₃ H represents a sulfonyl group; PO (PO) ₃ H ₂ Represents a phosphoryl group.

Preferred 3-phenyl-7, 8-dehydrograpevine derivatives of formula (IB) according to the present invention include, but are not limited to, compounds of formula (IBa), (IBb), (IBc), and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IBa), (IBb), (IBc):

wherein L is ₁ Selected from substituted or unsubstituted C _0-16 Straight or branched alkyl, substituted or unsubstituted C _0-16 A straight or branched acyl group, a substituted or unsubstituted C _2-16 Straight-chain or branched alkenyl of (1); the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino and C _1-6 Alkoxy group of (C) _1-6 Acyl group of (1), C _1-6 Acyloxy group of (2), C _1-6 Alkylthio, F, cl, br, I;

R ₁₀ 、R ₁₁ 、R ₁₂ each independently selected from hydrogen, hydroxy, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 Alkyl of (C) _1-6 Alkoxy group of (1), C _1-6 Acyl group of (1), C _1-6 Acyl of (2)Oxy radical, C _1-6 Alkylthio, methylenedioxy, F, cl, br, I, glu, SO ₃ H、PO ₃ H ₂ ；

According to the invention, preferred 3-phenyl-7, 8-dehydrograpevine derivatives of general formula (IBa), (IBb), (IBc), and pharmaceutically acceptable salts thereof, are characterized in that:

R ₁₀ 、R ₁₁ 、R ₁₂ each independently selected from hydrogen, hydroxy, methoxy, acetyl, cl;

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

According to the present invention, preferred 3-phenyl-7, 8-dehydrograpevine derivatives represented by the general formula (IB) include, but are not limited to, compounds represented by the general formula (IBd), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by the general formula (IBd):

wherein R is ₁₃ Independently selected from hydrogen, substituted or unsubstituted C _3-8 Cycloalkyl, substituted or unsubstituted C _1-16 Straight or branched alkyl, substituted or unsubstituted C _1-16 A straight or branched acyl group of (A), a substituted or unsubstituted C _2-16 Linear or branched alkenyl of, C _2-6 Alkynyl of (a); the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino, phenyl and C _1-6 Alkoxy group of (C) _1-6 Acyl group of (1), C _1-6 Acyloxy group of (2) and (C) _1-6 Alkylthio, F, cl, br, I;

Glu represents beta-D glucopyranosyl; SO ₃ H represents a sulfonyl group; PO ₃ H ₂ Represents a phosphoryl group.

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

said R ₁₃ Selected from substituted or unsubstituted C _1-16 Linear or linear alkyl, substituted or unsubstituted C _3-8 Cycloalkyl groups of (a); wherein, the substituent is selected from hydroxyl, nitryl, cyano, amino, methylamino, dimethylamino, phenyl and C _1-6 Alkoxy group of (C) _1-6 Acyl group of (1), C _1-6 Acyloxy group of (2) and (C) _1-6 Alkylthio, F, cl, br, I;

said R ₁₃ Selected from substituted or unsubstituted C _3-12 Straight or branched alkyl, substituted or unsubstituted C _5-6 Cycloalkyl groups of (a); the substituent is selected from hydroxyl, methylamino, dimethylamino, methoxy, acetyl and Cl;

in particular, the 3-phenyl-7, 8-dehydrograpevine derivatives represented by general formulas (I), (IA), (IAa), (IAb), (IAc), (IAd) and (IB), (IBa), (IBb), (IBc), (IBd) and pharmaceutically acceptable salts thereof, wherein the compounds are selected from the following groups (the compound codes correspond to those in the examples):

in a second aspect of the present invention there is provided a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of each of the general formulae (I), (IA), (IAa), (IAb), (IAc), (IAd) and (IB), (IBa), (IBc), (IBd) and a pharmaceutically acceptable carrier.

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

According to an embodiment of the invention, said compound of the invention also comprises a pharmaceutically acceptable salt, hydrate or prodrug thereof.

The invention also relates to pharmaceutical compositions containing a compound of the invention as active ingredient and conventional pharmaceutical excipients or auxiliaries. Typically, the pharmaceutical compositions of the present invention contain from 0.1 to 95% by weight of a compound of the present invention. The compounds of the invention are generally present in an amount of 0.1 to 100mg in a unit dosage form, with a preferred unit dosage form containing 4 to 50mg.

Pharmaceutical compositions of the compounds of the invention may be prepared according to methods well known in the art. For this purpose, the compounds of the invention can, if desired, be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants and brought into a suitable administration form or dosage form for use as human or veterinary medicine.

The compound of the present invention or the pharmaceutical composition containing it can be administered in unit dosage form, and the administration route can be intestinal or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum. The route of administration of the compounds of the invention or the pharmaceutical compositions containing them may be by injection. The injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection, etc.

The administration dosage form can be liquid dosage form or solid dosage form. For example, the liquid dosage form can be true solution, colloid, microparticle, emulsion, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.

The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.

For example, to form a unit dosage form into a tablet, a wide variety of carriers known in the art can be used. As examples of the carrier, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; wetting agents and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrating agents such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.

For example, to form the administration units into pills, carriers well known in the art are widely used. Examples of the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, glycerin monostearate, kaolin, talc or the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.

For example, to encapsulate the administration units, the compounds of the invention are mixed with the various carriers described above, and the mixture thus obtained is placed in hard gelatin or soft gelatin capsules. The effective component of the compound can also be prepared into microcapsules, and the microcapsules can be suspended in an aqueous medium to form a suspension, and can also be filled into hard capsules or prepared into injections for application.

For example, the compounds of the present invention may be formulated as injectable preparations, such as solutions, suspensions, emulsions, lyophilized powders, which may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, fatty acid, etc. In addition, for the preparation of isotonic injection, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, pH adjusters and the like may also be added. These adjuvants are commonly used in the art.

In addition, colorants, preservatives, flavors, flavorings, sweeteners, or other materials may also be added to the pharmaceutical preparation, if desired.

For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

The dose of the pharmaceutical composition of the compound of the present invention to be administered depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight, character and individual response of the patient or animal, the administration route, the number of administration, the therapeutic purpose, and thus the therapeutic dose of the present invention may be widely varied. Generally, the dosages of the ingredients of the invention to be used are well known to those skilled in the art. The prophylactic or therapeutic objectives of the present invention can be accomplished by appropriate adjustment of the actual amount of drug contained in the final formulation of the compound composition of the present invention to achieve the desired therapeutically effective amount. Suitable daily dosage ranges for the compounds of the invention: the compounds of the invention are used in an amount of 0.001 to 100mg/kg body weight, preferably 0.1 to 60mg/kg body weight, more preferably 1 to 30mg/kg body weight, most preferably 2 to 15mg/kg body weight. The compound of the invention is taken by adult patients at a daily dose of 10-500 mg, preferably 10-100 mg, and can be taken once or in 2-3 times; the dose administered to children is 5 to 30mg per kg body weight, preferably 10 to 20mg per kg body weight. The above-mentioned dosage may be administered in a single dosage form or divided into several, e.g., two, three or four dosage forms, which is limited by the clinical experience of the administering physician and the dosage regimen of the therapeutic means. The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents.

The third aspect of the technical scheme of the invention provides application of 3-phenyl-7, 8-dehydrograpevine derivatives (3-phenyl-4-substituted benzofuran compounds) or pharmaceutically acceptable salts, hydrates or prodrugs thereof in preparation of anti-inflammatory and immunosuppressive drugs and drugs for related diseases.

The inflammatory diseases comprise 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, nodular arteritis, thyroiditis, rheumatic fever, gingivitis, periodontitis, canker sore, nephritis, swelling after damage, myocardial ischemia, various infectious pneumonia, physicochemical pneumonia and allergic pneumonia, spastic anal pain and rectal fissure, hepatocystic inflammation, cholangitis, sclerosing cholangitis, primary biliary cirrhosis, cholecystitis and the like. The common features of such diseases at the cellular level are: macrophages are over activated and produce excess NO.

The invention carries out the experiment of the compound on inhibiting the macrophage stimulated by LPS from generating NO, and shows that the benzofuran derivative has the activity of inhibiting the macrophage from generating excessive NO on a cellular level. Meanwhile, by researching the influence of the compound on croton oil induced mouse otitis, mouse delayed immunoreaction and carrageenan induced mouse foot swelling, the benzofuran derivative still has good anti-inflammatory and immunosuppressive activity in vivo.

The fourth aspect of the present invention is to provide a method for preparing the derivatives of the first aspect

The starting materials for preparing the compounds according to the invention, such as methyl 3, 5-dihydroxybenzoate, 1- (3, 5-dimethoxyphenyl) -2-bromoacetophenone, alcohols, phenols and amines of different structures, are commercially available or can be prepared according to the prior art.

The basic synthesis method of the key reaction raw material compound 1 in the invention comprises the following steps:

the method comprises the following steps: preparation of methyl 3-methoxy-5-hydroxybenzoate.

Methyl 3, 5-dihydroxybenzoate and methyl iodide in acetone at K ₂ CO ₃ Reacting under solid catalysis, filtering the reaction mixture, concentrating under reduced pressure, recrystallizing or chromatographing the obtained solidSeparating and purifying to obtain the target product 3-methoxy-5-hydroxybenzoic acid methyl ester.

Step two: methyl 3-methoxy-5-hydroxybenzoate was reacted with 1- (3, 5-dimethoxyphenyl) -2-bromoacetophenone to synthesize methyl 3- (2- (3, 5-dimethoxyphenyl) -2-oxyethyl) -5-methoxybenzoate (1 a).

3-methoxy-5-hydroxybenzoic acid methyl ester and 1- (3, 5-dimethoxyphenyl) -2-bromoacetophenone in anhydrous acetone at K ₂ CO ₃ Heating reflux reaction is carried out under the catalysis of solid, reaction liquid is decompressed and concentrated, and the obtained product is recrystallized or separated and purified by chromatography to obtain the target product 1a.

Step three: cyclization of compound 1a to give compound 1b:

and (3) reacting the product 1a obtained in the step two in dichloromethane by using methane sulfonic acid as a catalyst, washing the reaction solution to be neutral, concentrating under reduced pressure to be dry, and performing recrystallization or chromatographic separation and purification on the obtained solid product to obtain a target product 1b. In the reaction, the catalyst is Methane Sulfonic Acid (MSA) and bismuth trifluoromethanesulfonate (Bi (OTf) ₃ ) Trifluoroacetic acid (TFA), ferric chloride (FeCl) ₃ ) Preferably methanesulfonic acid and bismuth trifluoromethanesulfonate; the reaction temperature is 25-60 deg.C, preferably 40 deg.C.

Step four: compound 1b hydrolysis reaction compound 1:

compound 1b is dissolved in THF, meOH, and H ₂ Heating and refluxing the mixed solution of O (1: 1, v/v/v) by using NaOH as a catalyst for reaction, evaporating most of the solvent from the obtained reaction solution under reduced pressure, and dropwise adding 1mol/L HCl solution into the rest reaction solution until no white precipitate is precipitated. And (3) carrying out suction filtration on the reaction mixture, washing the obtained solid with distilled water, and drying to obtain a white powdery solid compound 1.

The basic synthesis method of the compound comprises the following two methods:

the first method comprises the following steps:

the method comprises the following steps: the compound 1, alcohols, phenols and amine compounds are subjected to condensation reaction to synthesize methoxyl ester or methoxyl amine derivatives.

The compound 1 and alcohols, phenols and amine compounds are subjected to condensation reaction in dry dichloromethane under the catalysis of HOBt and EDCI, the reaction liquid is subjected to reduced pressure concentration, and the obtained product is subjected to recrystallization or chromatographic separation and purification to obtain a methoxy ester or methoxy amine target product.

Step two: and (3) removing methyl from the methoxyl ester or methoxyl amine derivative to synthesize the phenolic hydroxyl ester or phenolic hydroxyl amine derivative.

The product obtained in step one is reacted with BBr in dry dichloromethane ₃ Carrying out reaction to remove methyl, washing the reaction liquid with water and saturated salt water to remove acid, then carrying out reduced pressure concentration, and carrying out recrystallization or chromatographic separation and purification on the obtained product to obtain the phenolic hydroxyl ester or phenolic hydroxyl amine target product. The specific reaction temperature is-50 ℃ to 25 ℃.

The second method comprises the following steps:

the method comprises the following steps: the compound 1 is condensed with alcohols, phenols and amine compounds to synthesize methoxyl ester or methoxyl amine derivatives.

Carrying out condensation reaction on the compound 1, alcohols, phenols and amine compounds in dry dichloromethane under the catalysis of DMAP and EDCI, decompressing and concentrating reaction liquid, and recrystallizing or carrying out chromatographic separation and purification on obtained products to obtain methoxy ester or methoxy amine target products.

The product obtained in step one is reacted with BBr in dry dichloromethane ₃ The methyl is removed by reaction, the reaction liquid is washed by water and saturated salt solution to remove acid, and the product obtained by decompression concentration is purified by recrystallization or chromatographic separation to obtain the target product of phenolic hydroxyl ester or phenolic hydroxyl amine. The specific reaction temperature is-50 ℃ to 25 ℃.

Advantageous technical effects

At present, although there are many reports on the anti-inflammatory activity of compounds having a benzofuran structure, no report on the structure-activity relationship of systems of stilbene dimer compounds having a benzofuran structure has been found so far. No reports about 3-phenyl-7, 8-dehydrograpevine pentatin (Amurensin H) derivatives or medically acceptable salts thereof and the application of the compounds in treating inflammatory diseases are found in the prior literatures and the prior art; no report about the new structural compound of 3-phenyl-4 substituted benzofuran or the pharmaceutically acceptable salt thereof and the application of the compound in treating inflammatory diseases is found.

Detailed description of the invention:

C _3-8 the cycloalkyl group of (2) is a substituted or unsubstituted cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms, C _2-6 The alkynyl group of (A) means a straight-chain or branched alkynyl group having 2, 3, 4, 5 or 6 carbon atoms, C _0-3 The straight-chain alkyl group of (2) is a straight-chain alkyl group having 0, 1, 2 or 3 carbon atoms; c _1-3 The straight-chain alkyl group (2) means a straight-chain alkyl group having 1, 2 or 3 carbon atoms, C _1-6 The alkyl group of (A) means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, C _1-6 The alkoxy group of (A) is a straight-chain or branched alkoxy group having 1, 2, 3, 4, 5 or 6 carbon atoms, C _1-6 The acyl group (C) is a straight or branched acyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, C _1-6 The acyloxy group (b) is a straight or branched acyloxy group having 1, 2, 3, 4, 5 or 6 carbon atoms, C _1-6 Alkylthio in (2) means a straight-chain or branched alkylthio group having 1, 2, 3, 4, 5, 6 carbon atoms, C _0-16 The straight chain or branched alkyl group of (2) means a straight chain or branched alkyl group having 0, 1, 2, 3, 4, 5, 6, 7,8, 9,10, 11, 12, 13, 14, 15, 16 carbon atoms, C _0-16 The straight or branched acyl group of (2) means a straight or branched acyl group having 0, 1, 2, 3, 4, 5, 6, 7,8, 9,10, 11, 12, 13, 14, 15, 16 carbon atoms, C _2-16 The straight-chain or branched alkenyl group of (2) means a straight-chain or branched alkenyl group having 2, 3, 4, 5, 6, 7,8, 9,10, 11, 12, 13, 14, 15, 16 carbon atoms.

Detailed Description

To further illustrate the present invention, a series of examples are given below, which are purely illustrative and are intended to be a detailed description of the invention only and should not be understood as limiting the invention.

Synthetic route for compound intermediate 1b in the examples:

example 1:

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

Synthetic route to compound 1:

compound 1b (10.0 g, 29.2mmol) was added 150mL of THF, meOH, and H ₂ O (1: 1, v/v/v) was dissolved in the mixed solution by stirring, and 1.17g of NaOH was added. The reaction mixture was heated under reflux for 12 h and the reaction feed was completely hydrolyzed. Most of the solvent was distilled off under reduced pressure at 42 ℃ and 1mol/L HCl solution was added dropwise until no white precipitate precipitated. The reaction mixture was filtered with suction, washed with distilled water, and dried to obtain compound 1 (9.48g, 98.9%) as a white powder 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) synthetic routes for compounds 2-12 in the examples:

synthesis of the end product (the compound code number corresponds to the compound code number in the examples)

Synthetic methods for compounds 2-12 in the examples:

method A Compound 1 (100mg, 0.30mmol) was dissolved in 50mL dry dichloromethane, HOBt (49.8mg, 0.37mmol) and EDCI (70.1mg, 0.37mmol) were added, stirring was continued at room temperature for 20min, alcohol or phenol compound (1.2 equiv) was added, stirring was continued at room temperature for 3-6h, TLC was used to monitor completion of the reaction, and the reaction was stopped. And (3) concentrating the reaction solution under reduced pressure, and separating the residual solid by using a silica gel preparation plate (selecting a proper developing agent according to different compounds) to obtain a target product.

Method B Compound 1 (100mg, 0.30mmol) was dissolved in 50mL dry dichloromethane, DMAP (44.7mg, 0.37mmol) and EDCI (70.1mg, 0.37mmol) were added, stirring was carried out at room temperature for 20min, alcohol or phenol compound (1.2 equiv) was added, stirring was continued at room temperature for 3-6h, and completion of the reaction was monitored by TLC. And (3) concentrating the reaction solution under reduced pressure, and separating the residual solid by using a silica gel preparation plate (selecting a proper developing agent 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 added alcohol compound was 4-acetamidophenol ethyl ester (70.6 mg,0.36 mmol), petroleum ether and acetone (2: 1) were used as developing agents, and the target product was obtained by preparative separation on silica gel plates with a yield of 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:

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

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

compound 3: light 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.for C ₂₆ H ₃₃ O ₆ ,441.2272).

Example 4:

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

Synthesized according to the method A, the added alcohol compound is cyclohexanol, petroleum ether and acetone (2: 1) are used as developing agents, and a silica gel preparation plate is prepared and separated to obtain a target product with the 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),26.01,24.37(2×C).(+)-ESI m/z:411[M+H] ⁺ ,433[M+Na] ⁺ ,449[M+K] ⁺ . HR-ESI-MS m/z:411.1804[M+H] ⁺ (calcd.for C ₂₄ H ₂₇ O ₆ ,411.1802).

Example 5:

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

Synthesized according to the method B, the added alcohol compound is furfuryl alcohol (2-furanmethanol), petroleum ether, ethyl acetate and dichloromethane (5: 1: 2) are used as developing agents, and the target product is obtained by silica gel preparation plate preparation and separation, and the yield is 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, 56.47,55.70(2×C).(+)-ESI-MS m/z:409.2[M+H] ⁺ ,431.2[M+Na] ⁺ ,447.1[M+K] ⁺ . HR-ESI-MS m/z:409.1277[M+H] ⁺ (calcd.for C ₂₃ H ₂₁ O ₇ ,409.1282).

Example 6:

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

Synthesized according to the method B, the added alcohol compound is p-chlorophenol, petroleum ether and acetone (2: 1) are used as developing agents, and the target product is obtained by silica gel preparation plate preparation and separation, and the yield is 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 C NMR(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).

Example 7:

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

Synthesized according to the method B, the added alcohol compound is p-o-methyl phenol, and the reaction is carried out by using petroleum ether: acetone (2. The physicochemical 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, 150.15,144.69,135.54,131.60,130.84,127.36,126.64,125.85,123.83,122.63,119.17, 114.70,108.01(2×C),100.83,99.76,56.51,55.60(2×C),16.30.(+)-ESI-MS m/z: 419.2[M+H] ⁺ ,441.2[M+Na] ⁺ ,457.1[M+K] ⁺ .HR-ESI-MS m/z:419.1499[M+H] ⁺ (calcd.for C ₂₅ H ₂₃ O ₆ ,419.1489).

Example 8:

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

Synthesized according to the method B, the added alcohol compound is p-fluorobenzyl alcohol, petroleum ether and acetone (2: 1)) are used as developing agents, and silica gel preparation plates are prepared and separated to obtain the target product with the yield of 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＝2.5Hz, 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, 132.51,132.49,132.51,131.24,131.17,127.02,123.69,118.47,115.81,115.63,113.85 (2×C),106.99(2×C),100.29,100.17,66.59,56.44,55.66(2×C).(+)-ESI-MS m/z: 437.3[M+H] ⁺ ,459.2[M+Na] ⁺ ,475.2[M+K] ⁺ .HR-ESI-MS m/z:437.1412[M+H] ⁺ (calcd.for C ₂₅ H ₂₂ FO ₆ ,437.1395).

Example 9:

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

Synthesized according to the method B, the added alcohol compound is p-bromobenzyl alcohol, petroleum ether and acetone (2: 1)) are used as developing agents, and the target product is obtained by silica gel preparation plate preparation and separation with the yield of 50.8 percent. 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 the method B, the added alcohol compound is phenethyl alcohol, petroleum ether and acetone (5. 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),100.30,100.16,66.31,56.42, 55.74(2×C),34.89.(+)-ESI-MS m/z:433.2[M+H] ⁺ ,455.3[M+Na] ⁺ ,471.1[M+K] ⁺ . HR-ESI-MS m/z:433.1627[M+H] ⁺ (calcd.for 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 added alcohol compound was p-4-hydroxyacetophenone, and the target product was isolated by silica gel plate preparation using petroleum ether, ethyl acetate, dichloromethane (3. 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＝2.5 Hz,1H),6.99(d,J＝9.0Hz,2H),6.59(d,J＝2.5Hz,2H),6.37(t,J＝2.5Hz,1H),3.98 (s,3H),3.75(s,6H),2.57(s,3H)； ¹³ C NMR(125MHz,acetone-d ₆ ):δ196.83,165.36, 161.92(2×C),158.65,158.17,154.93,144.75,135.66,135.59,130.19(2×C),125.70, 123.79,122.24(2×C),119.03,114.82,107.65(2×C),101.13,99.91,56.58,55.67(2× C),26.69.(+)-ESI-MS m/z:447.2[M+H] ⁺ ,469.2[M+Na] ⁺ ,485.1[M+K] ⁺ .HR-ESI-MS m/z:447.1433[M+H] ⁺ (calcd.for 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 the method B, the added alcohol compound is 3-indoleethanol, petroleum ether and acetone (2: 1) are used as developing agents, and the target product is obtained by silica gel preparation plate preparation and separation, and the yield is 80.0%. The physicochemical parameters of compound 12 are as follows:

compound 12: light 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).

Synthetic routes for compounds 13-16 in the examples:

synthesis of the final product (compound code number corresponds to the compound code number in the examples):

example 13:

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

Synthesis of compound 13 in the examples:

compound 1 (500.0 mg, 1.52mmol) was dissolved in 60mL of dichloromethane and cooled to-50 ℃. Under vigorous stirring, BBr is slowly dropped ₃ Dichloromethane solution [ BBr ] ₃ 15.2mL (10equiv, 10mmol/L) of the solution was dissolved in 30mL of DCM]Keeping the temperature at 50 ℃ below zero for reaction for 2h, slowly heating to room temperature through several temperature ranges of 50 ℃ below zero, 25 ℃ below zero, 10 ℃ below zero and 0 ℃, continuing the reaction at room temperature overnight, monitoring the reaction by TLC, and quenching the reaction by methanol. The reaction mixture was diluted with 100mL of ethyl acetate, washed with water, washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Dissolving the residue with a small amount of mixed solution of ethyl acetate and methanol, separating with silica gel plate using dichloromethane and methanol (10: 1) as developing agent to obtain crude product, separating with gel column, and eluting with methanol to obtain light 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 C NMR(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:

3- (3, 5-dihydroxyphenyl) -6-hydroxy-4-benzofurancarboxylic acid methyl ester (14)

Compound 1b was synthesized by the synthesis method of compound 13 using dichloromethane: methanol (10.

Compound 14: an earthy yellow solid (56.03mg, 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[M-H] ^- .HR-ESI-MS m/z:301.0716[M+H] ⁺ (calcd.for C ₁₆ H ₁₃ O ₆ , 301.0707).

Example 15:

octyl 3- (3, 5-dihydroxyphenyl) -6-hydroxy-4-benzofurancarboxylate (15)

Compound 3 was synthesized by the synthesis method of compound 13 using dichloromethane-methanol (10.

Compound 15: a pale brown solid (27.7mg, 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),158.09,155.97,143.46,135.95,127.72,124.11, 117.99,114.13,107.74(2×C),102.36,101.82,65.74,32.55,29.89(2×C),28.70, 26.63,23.27,14.36.(+)-ESI-MS m/z:399.4[M+H] ⁺ ,421.3[M+Na] ⁺ ,437.2[M+K] ⁺ . HR-ESI-MS m/z:399.1804[M+H] ⁺ (calcd.for C ₂₃ H ₂₇ O ₆ ,399.1802).

Example 16:

3- (3, 5-dihydroxyphenyl) -6-hydroxy-4-benzofurancarboxylic acid 2-phenylethyl ester (16)

Compound 10 was synthesized according to the synthesis method of compound 13 using dichloromethane: methanol (10.

Compound 16: pale yellow solid (9.9mg, 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.for C ₂₃ H ₁₉ O ₆ ,391.1176).

Synthetic routes for compounds 17-33 in the examples:

synthesis of compounds 17 to 33 in examples:

synthesis method A Compound 1 (100mg, 0.30mmol) was dissolved in 50mL dry dichloromethane, HOBt (49.8mg, 0.37mmol) or EDCI (70.1mg, 0.37mmol) was added sequentially, stirred at room temperature for 20min, and the corresponding amine derivative (about 1.2 equiv) was added. The reaction solution was stirred at room temperature for about 4h, and the reaction was stopped by TLC monitoring completion of the reaction. After the reaction solution is decompressed and concentrated to be dry, the residual solid is separated by a silica gel preparation plate (selecting proper developing agent according to different compounds) to obtain the target product.

Synthesis method B Compound 1 (100mg, 0.30mmol) was dissolved in 50mL dry dichloromethane, DMAP (44.7 mg, 0.37mmol) and EDCI (70.1mg, 0.37mmol) were added, stirring was carried out at room temperature for 20min, and the corresponding amine derivative (about 1.2 equiv) was added. The reaction solution was stirred at room temperature for about 4h, and the reaction was stopped after completion of the TLC monitoring. The reaction solution is decompressed and concentrated, and the residual solid is separated by a silica gel preparation plate (selecting a proper developing agent according to different compounds) to obtain the target product.

Example 17:

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

Synthesized according to method A, the added amine compound is methylamine, dichloromethane and methanol (40: 1) are used as developing agents, and the yield is 87.3 percent after preparation and separation of silica gel preparation plates. 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-MS m/z:342.2[M+H] ⁺ ,364.1[M+Na] ⁺ ,380.1[M+K] ⁺ .HR-ESI-MS m/z:342.1339[M+H] ⁺ (calcd.for C ₁₉ H ₂₀ NO ₅ ,342.1336).

Example 18:

n-propyl-3- (3, 5-dimethoxyphenyl) -6-methoxy-4-benzofurancarboxamide (18)

According to the synthesis of the method B, the added amine compound is n-propylamine, the mixture is prepared and separated by using oleyl ether, acetone (2). 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＝2.5 Hz,2H),6.47(t,J＝2.5Hz,1H),3.90(s,3H),3.81(s,6H),2.89(dd,J＝14.5,7.5Hz, 2H),1.25(dt,J＝14.5,7.5Hz,2H),0.75(t,J＝7.5Hz,3H)； ¹³ C NMR(125MHz, acetone-d ₆ ):δ167.98,161.72(2×C),158.83,157.89,143.18,134.88,133.39,123.76, 117.21,112.04,107.24(2×C),100.45,97.85,56.29,55.63(2×C),42.14,22.77,11.78. (+)-ESI-MS m/z:370.1[M+H] ⁺ ,392.1[M+Na] ⁺ ,408.0[M+K] ⁺ .HR-ESI-MS m/z: 370.1663[M+H] ⁺ (calcd.for C ₂₁ H ₂₄ NO ₅ ,370.1649).

Example 19:

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

According to the synthesis of the method A, the added amine compound is lauryl amine, oil ether and acetone (2. 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＝2.0 Hz,2H),6.46(t,J＝2.0Hz,1H),3.90(s,3H),3.82(s,6H),2.93(dd,J＝12.0,6.0Hz, 2H),1.37–1.08(m,20H),0.88(t,J＝6.5Hz,3H)； 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), 30.11,30.09,27.80,23.34,14.36.(+)-ESI-MS m/z:496.2[M+H] ⁺ ,518.3[M+Na] ⁺ . HR-ESI-MS m/z:496.3072[M+H] ⁺ (calcd.for C ₃₀ H ₄₂ NO ₅ ,496.3057)..

Example 20:

n- (3-dimethylamino-1-propyl) -3- (3, 5-dimethoxyphenyl) -6-methoxy-4-benzofurancarboxamide (20)

According to the synthesis of the method B, the added amine compound is N, N' -dimethyl-1, 3-propane diamine, chloroform and methanol (6: 1) are used as developing agents, and the amine compound is obtained by silica gel preparation plate preparation and separation, and the yield is 90.7%. The physicochemical parameters of compound 20 are as follows:

compound 20: pale 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),53.67,37.23, 23.54.(+)-ESI-MS m/z:413.3[M+H] ⁺ ,435.3[M+Na] ⁺ .HR-ESI-MS m/z:413.2074 [M+H] ⁺ (calcd.for C 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 dried dichloromethane, DMAP (44.7mg, 0.37mmol), EDCI (70.1mg, 0.37mmol) and DIPEA (151. Mu.L, 0.91 mmol) were sequentially added, and after stirring at room temperature for 20min, L-methionine methyl ester (1.2 equiv) was added, stirring was continued at room temperature for 4h, and the reaction was stopped by TLC monitoring for completion of the reaction. Concentrating the reaction solution under reduced pressure, and separating the residual solid on a silica gel preparation plate by using petroleum ether and acetone (2: 1) as developing agents to obtain a target product. The yield was 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)

According to the synthesis of method a, the added amine compound is cyclopentylamine, and the mixture is prepared and separated by silica gel preparation plates with petroleum ether, ethyl acetate, dichloromethane (3. 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＝2.0 Hz,2H),6.47(t,J＝2.0Hz,1H),3.96–3.90(m,1H),3.89(s,3H),3.81(s,6H), 1.66～1.58(m,2H),1.53～1.50(m,2H),1.40–1.48(m,2H),1.11～1.184(m,2H)； 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:396.1821[M+H] ⁺ (calcd.for C ₂₃ H ₂₆ NO ₅ ,396.1805)..

Example 23:

n- (2-Furanmethyl) -3- (3, 5-dimethoxyphenyl) -6-methoxy-4-benzofurancarboxamide (23)

According to the synthesis of the method A, the added amine compound is furylamine, petroleum ether and acetone (2. 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(2×C),100.57, 98.18,56.31,55.64(2×C),37.08.(+)-ESI-MS m/z:408.1[M+H] ⁺ ,430.2[M+Na] ⁺ , 446.0[M+K] ⁺ .HR-ESI-MS m/z:408.1458[M+H] ⁺ (calcd.for C ₂₃ H ₂₂ NO ₆ ,408.1442).

Example 24:

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

According to the synthesis of the method B, the added amine compound is p-toluidine, petroleum ether and acetone (2. 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),123.82,120.31(2×C),112.29,107.27 (2×C),100.32,98.51,56.39,55.42(2×C),20.89.(+)-ESI-MS m/z:418.3[M+H] ⁺ , 440.3[M+Na] ⁺ ,456.2[M+K] ⁺ .HR-ESI-MS m/z:418.1652[M+H] ⁺ (calcd.for C ₂₅ H ₂₄ NO ₅ ,418.1649).

Example 25:

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

According to the synthesis of the method B, the added amine compound is p-chloroaniline, petroleum ether and acetone (2. The physicochemical parameters of compound 25 are as follows:

compound 25: pale yellowish 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)

According to the synthesis of the method B, the added amine compound is benzylamine, petroleum ether and acetone (2. 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)

According to the synthesis of the method B, the added amine compound is N-benzyl methylamine, petroleum ether and acetone (2. The physicochemical parameters of compound 27 are as follows:

light yellow oily liquid (one 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,CDCl ₃ ):δ169.87,169.80,160.84(2×C),160.82(2×C),158.43, 158.40,156.71,156.62,130.30,130.00,128.73(2×C),128.69(2×C),128.28(2×C), 127.73,127.50,127.32(2×C),122.76,122.67,116.61,116.35,111.23,110.94,106.46 (2×C),106.39(2×C),100.66,100.50,97.57,97.50,56.13,56.07,55.66(4×C), 54.42,49.84,35.52,31.83.(+)-ESI-MS m/z:432.3.[M+H] ⁺ ,454.3[M+Na] ⁺ .,470.2 [M+K] ⁺ .HR-ESI-MS m/z:432.1812[M+H] ⁺ (calcd.for C ₂₆ H ₂₆ NO ₅ ,432.1805).

Example 28:

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

According to the synthesis of the method B, the added amine compound is 4-chlorobenzylamine, petroleum ether and acetone (2. 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),158.84,157.92,143.36,138.52,134.87,132.98,132.74,130.29 (2×C),129.06(2×C),123.70,117.27,112.20,107.27(2×C),100.66,98.11,56.32, 55.67(2×C),43.44.(+)-ESI-MS m/z:452.1[M+H] ⁺ ,474.1[M+Na] ⁺ ,490.1[M+K] ⁺ . HR-ESI-MS m/z:452.1280[M+H] ⁺ (calcd.for C ₂₅ H ₂₃ ClNO ₅ ,452.1259).

Example 29:

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

According to the synthesis of the method B, the added amine compound is 2-chlorobenzylamine, petroleum ether and acetone (2). 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),41.70.(+)-ESI-MS m/z:452.0[M+H] ⁺ ,474.0[M+Na] ⁺ ,490.0[M+K] ⁺ . HR-ESI-MS m/z:452.1281[M+H] ⁺ (calcd.for C ₂₅ H ₂₃ ClNO ₅ ,452.1259).

Example 30:

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

According to the synthesis of the method B, the added amine compound is 4-chlorophenylethylamine, petroleum ether and acetone (2. 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),123.68,117.20,111.99,107.33(2×C), 100.51,97.99,56.30,55.68(2×C),41.63,34.99.(+)-ESI-MS m/z:466.0[M+H] ⁺ , 488.0[M+Na] ⁺ .HR-ESI-MS m/z:466.1429[M+H] ⁺ (calcd.for 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)

According to the synthesis method B, the added amine compound is tryptamine (beta-indoleethylamine), petroleum ether and acetone (3: 1) are used as developing agents, and the tryptamine compound is prepared and separated by using a silica gel preparation plate, and the yield is 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＝2.5 Hz,1H),7.09～6.99(m,5H),6.65(d,J＝2.0Hz,2H),6.47(t,J＝2.0Hz,1H),3.88(s, 3H),3.79(s,6H),3.30(dd,J＝13.5,7.5Hz,2H),2.66(t,J＝7.5Hz,2H)； 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-benzofurancarboxamide (32)

According to the synthesis of the method B, the added amine compound is 2- (5-methoxy-1H-indol-3-yl) ethylamine, petroleum ether and acetone (2. 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),41.04,25.53.(+)-ESI-MS m/z:501.1[M+H] ⁺ ,523.1 [M+Na] ⁺ ,539.0[M+K] ⁺ .HR-ESI-MS m/z:501.2029[M+H] ⁺ (calcd.for C ₂₉ H ₂₉ N ₂ O ₆ , 501.2020).

Example 33:

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

According to the synthesis of the method B, the added amine compound is 5-hydroxytryptamine, petroleum ether and acetone (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＝2.5Hz,2H),6.61(dd,J＝9.0,2.5Hz,1H),6.49(t,J＝2.5Hz,1H),6.43(t, J＝2.5Hz,1H),3.99(s,3H),3.87(s,3H),3.78(s,6H),3.72(s,6H),3.27(td,J＝7.5, 5.5Hz,2H),2.62(dd,J＝15.0,8.0Hz,2H)； 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, 143.27,135.64,135.30,134.96,133.21,128.33,127.18,124.56,123.98,123.72,118.64, 117.19,116.27,114.33,113.73,112.01,111.98,111.08,107.43(2×C),107.27(2×C), 100.66,100.51,100.40,98.01,56.53,56.26,55.68(4×C),41.01,25.32.(+)-ESI-MS m/z:797.0[M+H] ⁺ ,819.1[M+Na] ⁺ ,835.0[M+K] ⁺ .HR-ESI-MS m/z:797.2728[M+H] ⁺ (calcd.for C ₄₆ H ₄₁ N ₂ O ₁₁ ,797.2705).

Synthetic routes for compounds 34 to 43 in the examples:

synthesis of the end products 34 to 43 (the compound numbers correspond to those of the examples):

synthesis of compounds 34 to 43 in examples:

the 3-position aryl-substituted amide derivative (about 70 mg) was dissolved in 20mL of dry methylene chloride and cooled to-50 ℃. Under vigorous stirring, BBr is slowly dropped ₃ Dichloromethane solution [ BBr ] ₃ (10equiv, 1mmol/L) was dissolved in 15mL of dry dichloromethane]. After the dropwise addition, the temperature is kept at minus 50 ℃ and stirring is continued for 2h, the temperature is slowly increased to minus 25 ℃, minus 10 ℃ and 0 ℃ respectively, and stirring is carried out for 2h at minus 25 ℃, minus 10 ℃ and 0 ℃ respectively. The reaction was then allowed to proceed overnight at room temperature and monitored by TLC for completion. The reaction solution is cooled to-50 ℃, and 6mL of analytical methanol is added dropwise. The reaction mixture was diluted with 100mL of ethyl acetate, washed with 50mL 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, the residue was dissolved in a mixed solvent of ethyl acetate and methanol (or a mixed solvent of acetone and methanol), separated on a silica gel preparation plate, and gel-purified to obtain the objective compound. The eluent for gel purification is usually methanol, 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 (30.4mg, 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:452[M-H] ^- ,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 (24.6mg, 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, 156.75,143.43,135.82,131.23,123.78,118.52,112.86,108.33,102.91,100.79,56.80, 45.45,37.65,25.28.(+)-ESI-MS m/z:371.1[M+H] ⁺ .HR-ESI-MS m/z:371.1601 [M+H] ⁺ (calcd.for C ₂₀ H ₂₃ N ₂ O ₅ ,371.1601).

Example 37:

n- (2-Furanmethyl) -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, 156.16,152.88,142.69,142.67,134.97,132.37,123.70,116.85,112.58,111.12,108.14 2×C),107.71,102.65,100.07,37.09.(+)-ESI-MS m/z:388[M+Na] ⁺ ,404[M+K] ⁺ ； (-)-ESI-MS m/z:364[M-H] ^- ,400[M+Cl] ^- ；HR-ESI-MS m/z:366.0991[M+H] ⁺ (calcd. for 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, a pale yellow solid (52.4mg, 83.0%) as a mixture of one pair of isomers. ¹ H NMR(500 MHz,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),103.01,102.94,99.53,54.85,50.47,35.91, 32.03.ESI-MS m/z390.0[M+H] ⁺ ,412.0[M+Na] ⁺ ,428.0[M+K] ⁺ .HR-ESI-MS m/z: 390.1327[M+H] ⁺ (calcd.for 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: light brown solid (21.2mg, 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＝2.0 Hz,1H),7.09(d,J＝2.0Hz,1H),6.98(d,J＝8.0Hz,2H),6.42(d,J＝2.0Hz,2H), 6.10(t,J＝2.0Hz,1H),2.24(s,3H)； ¹³ C NMR(125MHz,acetone-d ₆ ):δ165.98, 159.28(2×C),157.95,156.20,142.80,137.12,134.65,133.39,132.85,129.33(2×C), 123.94,120.92(2×C),116.86,112.88,107.96(2×C),102.52,100.29,20.90. (+)-ESI-MS m/z:398[M+Na] ⁺ ；(-)-ESI-MS m/z:410[M+Cl] ^- ；HR-ESI-MS m/z: 376.1191[M+H] ⁺ (calcd.for 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 (39.3mg, 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),117.69,112.75,108.26(2×C),102.61, 100.99.(+)-ESI-MS m/z:417.9[M+Na] ⁺ .HR-ESI-MS m/z:396.0644[M+H] ⁺ (calcd. for 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: an off-white solid (34.7mg, 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 [M-H] ^- ,410[M+Cl] ^- ；HR-ESI-MS m/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-benzofuran carboxamide (42)

The physicochemical parameters of compound 42 are as follows:

compound 42: light brown solid (39.0mg, 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: light brown solid (37.3mg, 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＝2.5 Hz,2H),6.38(t,J＝2.5Hz,1H),3.34–3.29(m,2H),2.69(t,J＝7.5Hz,2H). (+)-ESI-MS m/z:429[M+H] ⁺ ,451[M+Na] ⁺ ,467[M+K] ⁺ ；(-)-ESI-MS m/z:427[M-H] ^- , 463[M+Cl] ^- ；HR-ESI-MS m/z:429.1450[M+H] ⁺ (calcd.for C ₂₂ H ₂₁ N ₂ O ₅ ,429.1445).

The pharmacological test methods and results of the anti-inflammatory and immunosuppressive activities of the compounds of the present invention are as follows (the compound numbers in the pharmacological test section correspond to the compound numbers in the examples):

example 1: the compound has the inhibitory activity on LPS (lipopolysaccharide) induced primary mouse peritoneal macrophage NO generation.

Macrophages perform the nonspecific immune function of an organism, can generate inflammatory factors such as NO and the like under the induction of bacterial Lipopolysaccharide (LPS), participate and mediate inflammatory reaction, and have higher levels in the initial stage of various inflammatory immune processes and the pathological development process. By detecting the NO production amount of the primary cultured mouse macrophage, the method can be used as an index for preliminarily observing and screening components or compounds with certain anti-inflammatory activity in vitro.

The experimental method comprises the following steps:

inoculating primary mouse abdominal cavity macrophage in 96-well plate, adding different compounds to be tested (10) ^-5 M) and a positive control drug dexamethasone (Dex) for 1h; then, adding 1. Mu.g/ml LPS at 37 ℃ and 5% ₂ After culturing for 24 hours in an incubator, collecting supernatant,

meanwhile, the cell proliferation inhibition rate is measured by an MTT method; and determining the IC of the compound having a significant inhibitory activity on NO production ₅₀ Values (calculated using Probit weighted regression analysis).

The experimental results are as follows:

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

Table 1 effect of amurensin H derivatives on LPS-induced generation of peritoneal macrophage NO in primary mice.

* The compound numbers correspond to those in the examples.

Example 2: effect of compounds on croton oil-induced otitis in mice.

The experimental method comprises the following steps:

taking 18-20g of male Kunming mice, randomly grouping, and respectively coating 0.02ml of croton oil on the two sides of the left ear of each group of animals; after 30 minutes, the animals are injected subcutaneously with 50mg/kg body weight, and the model control group is administered with the same volume of vehicle; after 4h of administration, the mice were sacrificed by removing the neck, both ears were cut off along the auricle base line, ear pieces at the same positions of the left and right ears were removed with a 6mm diameter punch, weighed on an analytical balance, and the ear swelling degree (ear swelling degree = left ear piece weight-right ear piece weight) and the ear swelling inhibition rate [ ear swelling inhibition rate (%) = (model group average ear swelling degree-administration group ear swelling degree)/model group average ear swelling group × 100% ]werecalculated.

The experimental results are as follows:

as shown in table 2, compounds 11, 12, and 35 significantly reduced croton oil-induced otitis media in mice (P <0.01 or 0.05) compared to the model control group.

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

^a Comparing with the model group, "+" indicates p<0.05, "' indicates p<0.01.

^b The compound numbers correspond to the compound numbers in the examples.

Example 3: effect of compounds on DNFB-induced inflammatory responses in mouse DTH.

18-20g of male ICR mice were randomly grouped. Animals in each group were plated with 1% DNFB solution 0.05mL after abdominal depilation except for the blank group given an equal volume of vehicle and boosted the next day with the same dose of DNFB. Meanwhile, the animals in each group are injected subcutaneously with 20mg/kg of the test compound 1 time a day for 3 days beginning on the 3 rd day of animal sensitization; the blank and model control groups were given equal volumes of vehicle. On the 5 th day after animal sensitization, animals of each group were challenged with 0.01mL of 1% dnfb solution in the left ear except for the blank group, and after 24 hours, the animals were sacrificed, both ears were cut along the base line of auricle, the ear pieces at the same positions of the left and right ears were removed with a 6 mm-diameter punch, weighed on an analytical balance, and the degree of ear swelling and the inhibition rate (%) of ear swelling were calculated.

The experimental results are as follows:

as shown in table 3, compounds 11 and 12 showed significant inhibition of the ear swelling degree of DTH induced after DNFB sensitization and challenge (P <0.05 or 0.01) compared to the model group.

TABLE 3 Effect of Amurensin H derivatives on DNFB-induced inflammatory responses in mouse DTH (Mean + -SD, n = 10) ^a .

^a Comparing with the model group, "+" indicates p<0.05, "' indicates p<0.01.

^b The compound numbers correspond to those in the examples.

Example 4: effect of compounds on carrageenan-induced foot swelling in mice.

The experimental method comprises the following steps:

taking 18-20g of male Kunming mice, randomly grouping, and injecting 0.05ml of carrageenan with the concentration of 0.1% under the skin of the left sole of each group of animals; after 30 minutes, the animals are injected subcutaneously with 50mg/kg body weight, and the model control group is administered with the same volume of vehicle; after 4h of administration, the mice were sacrificed by decapitation, both feet were cut along the ankle joints, weighed on an analytical balance, and the degree of foot swelling (degree of foot swelling = left foot weight-right foot weight) and the rate of inhibition of foot swelling [ rate of inhibition of foot swelling (%) = (average degree of foot swelling in model group-degree of foot swelling in administration group)/average degree of foot swelling in model group × 100% ]wascalculated.

The experimental results are as follows:

the results of the experiment are shown in table 4, compounds 11, 12 significantly reduced carrageenan-induced paw swelling in mice compared to the model control group (P <0.01 or 0.05).

TABLE 4 Effect of Amurensin H derivatives on carrageenan-induced foot swelling in mice (Mean + -SD, n = 10) ^a .

^a Comparing with the model group, "+" indicates p<0.05, ". Indicates p<0.01.

^b The compound numbers correspond to the compound numbers in the examples.

Claims

1. A3-phenyl-7, 8-dehydrograpevine derivative and pharmaceutically acceptable salts thereof, wherein said compound is represented by the general formula (IAa), (IAb), (IAc):

wherein L is ₁ Selected from substituted or unsubstituted C _0-16 Straight or branched chain alkyl of (a); the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino and C _1-6 Alkoxy, F, cl, br, I;

R ₅ independently selected from H, substituted or notSubstituted C _1-6 Alkyl groups of (a); wherein the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino and C _1-6 Alkoxy, F, cl, br, I;

R ₆ 、R ₇ 、R ₈ each independently selected from hydrogen, hydroxy, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 Alkyl of (C) _1-6 Alkoxy group of (1), C _1-6 Acyl group of (1), C _1-6 Alkylthio, F, cl, br, I;

R ₂ 、R ₃ 、R ₄ each independently selected from hydrogen and C _1-6 Alkyl group of (1).

2. 3-phenyl-7, 8-dehydrograpevine derivatives and pharmaceutically acceptable salts thereof according to claim 1, characterized in that:

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

3. A3-phenyl-7, 8-dehydrograpevine derivative and pharmaceutically acceptable salts thereof, characterized in that the compound is represented by the general formula (IBa), (IBb), (IBc):

wherein L is ₁ Selected from substituted or unsubstituted C _0-16 Straight or branched chain alkyl of (a); the substituent is selected from hydroxyl, nitro, cyano, amino, methylamino, dimethylamino and C _1-6 Alkoxy group of (C) _1-6 Alkylthio of、F、Cl、Br、I；

R ₁₀ 、R ₁₁ 、R ₁₂ Each independently selected from hydrogen, hydroxy, nitro, cyano, amino, methylamino, dimethylamino, C _1-6 Alkyl of (C) _1-6 Alkoxy group of (C) _1-6 Acyl group of (1), C _1-6 Alkylthio, F, cl, br, I;

4. 3-phenyl-7, 8-dehydrograpevine derivative and pharmaceutically acceptable salts thereof according to claim 3, characterized in that,

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

5. The 3-phenyl-7, 8-dehydrograpevine derivative and pharmaceutically acceptable salts thereof according to any one of claims 1-4, wherein said compound is selected from the group consisting of:

6. a pharmaceutical composition comprising an effective amount of the 3-phenyl-7, 8-dehydrograpevine derivative of any one of claims 1-5 and pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.

7. The pharmaceutical composition of claim 6, wherein said pharmaceutical composition is selected from the group consisting of tablets, capsules, pills, and injections.

8. The pharmaceutical composition of claim 6, wherein said pharmaceutical composition is selected from the group consisting of a sustained release formulation and a microparticle delivery system.

9. Use of a 3-phenyl-7, 8-dehydrograpevine derivative according to any one of claims 1-5 and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment and/or prevention of inflammation and/or immunosuppression.

10. Use according to claim 9, wherein the inflammation and immunosuppression comprise: rheumatoid arthritis, gouty arthritis, lupus erythematosus syndrome, bronchitis, bursitis, tenosynovitis, psoriasis, eczema, burns, dermatitis, inflammatory bowel disease, crohn's disease, gastritis, irritable bowel syndrome, multiple sclerosis, autoimmune encephalomyelitis, colorectal cancer, nodular arteritis, thyroiditis, wind-heat wetness, gingivitis, periodontitis, canker sores, nephritis, swelling occurring after injury, myocardial ischemia, various infectious pneumonia, physicochemical pneumonia and allergic pneumonia, spastic anal pain and rectal fissure, hepatobiliary cystitis, cholangitis, primary biliary cirrhosis, and cholecystitis.