CN116986977A

CN116986977A - Halogenated chalcone derivative, preparation method, pharmaceutical composition and application thereof

Info

Publication number: CN116986977A
Application number: CN202210443944.0A
Authority: CN
Inventors: 姚春所; 林明宝; 苏福宝; 侯琦; 杨庆云; 张梓倩; 陈英; 文鑫祝; 李艳秋
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2022-04-26
Filing date: 2022-04-26
Publication date: 2023-11-03

Abstract

The invention belongs to the field of medicines, and discloses halogenated chalcone derivatives, a preparation method, a pharmaceutical composition and application thereof. In particular to a halogenated chalcone derivative shown in a general formula (I) and a pharmaceutically acceptable salt thereof, and application of a compound monomer or a medicinal composition in preparing medicines for treating inflammation and/or inflammation immunity related diseases.

Description

Halogenated chalcone derivative, preparation method, pharmaceutical composition and application thereof

Technical Field

The invention belongs to the field of medicines, and in particular relates to halogenated chalcone derivatives or pharmaceutically acceptable salts thereof, medicinal compositions containing the derivatives and application of the derivatives in clinical treatment of inflammation and/or inflammation immunity-related diseases.

Background

Inflammation is the disease foundation of human diseases, is causal with numerous diseases, and is a key link of pathological processes of the diseases. However, there are still many problems in clinical application of current anti-inflammatory drugs, such as corticosteroids and non-steroidal anti-inflammatory drugs, such as easily causing digestive tract discomfort and bleeding, and increasing the risk of adverse reactions such as occurrence of heart disease or systemic coagulation disorder disease. Therefore, the search for safer and more effective anti-inflammatory drugs remains an important task in the research and development of current anti-inflammatory drugs.

Chalcones are an important class of natural products with a variety of biological activities. From the source, the compounds are produced by cross aldol condensation of aromatic aldehyde ketone. Chalcones exhibit a wide variety of pharmacological activities. The literature reports that it has various biological activities such as anti-tumor, antiparasitic, anti-HIV, antibacterial, anti-inflammatory, antioxidant, free radical scavenging, anti-gastric ulcer, phosphodiesterase inhibiting, alopecia preventing, hair regrowth promoting, etc. The literature reports that chalcone-rich plants have long been used in the treatment of a variety of diseases. Chalcones of different structures isolated from different plants have been found to be useful in the treatment of cancer, viruses and cardiovascular-related diseases. For example, licorice is used in china for the treatment of gastric and duodenal ulcers, bronchial asthma, food and drug poisoning, and skin diseases such as eczema and urticaria. The plant kava pepper (Piper thystinum) growing in the southern Pacific region and rich in chalcone has remarkable anti-inflammatory, antioxidant and liver protecting effects, and can be used for treating various diseases. The common food flavor round nutmeg (Boesenbergia Rotunda) in southeast asia is a versatile folk medicine. Lophira aleta is a medicinal plant rich in chalcone dimers grown in tropical rainforests in Africa for the treatment of dental pain, liver infection, female infertility, fever and other diseases. From the perspective of organic synthesis, the alpha, beta ketene structure of chalcone is a soft electrophile, and is more prone to interact with soft nucleophiles such as sulfhydryl compounds, rather than react with hard nucleophiles such as amino groups and hydroxyl groups in nucleic acid to cause mutation or cancer, thus having higher safety. Therefore, the active chalcone compounds are subjected to intensive activity and structure-activity relation research, and have important significance for developing and utilizing the compounds.

The halogenated chalcone derivative is an active compound of a new structural type which is found in long-term synthesis and structure-activity relation research of polyphenol compounds, and is an analogue of natural chalcone. The patent carries out systematic structural transformation and inflammatory factor NO inhibition activity screening experiments on the compounds, and results show that halogen substitution greatly improves the activity of the compounds, and the obtained compounds have obvious anti-inflammatory activity and obvious research and development values. The invention has important significance for deep development and utilization of the compounds.

Disclosure of Invention

The invention aims to solve the technical problem of providing halogenated chalcone derivatives with new structures, and a preparation method, a pharmaceutical composition and application thereof.

The first aspect of the present invention provides a new structure halogenated chalcone derivative shown in general formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIDa), (IIDb), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIDa) and (IIIDb).

In a second aspect, the present invention provides a pharmaceutical composition comprising at least one halochalcone derivative represented by general formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIDa), (IIDb), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIDa) and (IIIDb), or a pharmaceutically acceptable salt thereof and a carrier commonly used in the pharmaceutical field.

The third aspect of the technical scheme of the invention provides application of halogenated chalcone derivatives shown in general formulas (I), (II), (IIA), (IIB), (IIC), (IID), (IIDa), (IIDb), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIDa) and (IIIDb) or pharmaceutically acceptable salts thereof in preparing medicaments for preventing, treating and assisting in treating various inflammatory immune related diseases.

According to a fourth aspect of the present invention there is provided a process for the preparation of the derivative of the first aspect.

The various inflammatory immune diseases include: rheumatoid arthritis, osteoarthritis, 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, wind-heat dampness, gingivitis, periodontitis, canker sore, nephritis, swelling occurring after damage, myocardial ischemia, various infectious pneumonia, physicochemical pneumonia and allergic pneumonia, spastic anal pain and rectal fissure, hepatobiliary inflammation, cholangitis, sclerosing cholangitis or primary biliary cirrhosis and cholecystitis. The compounds of the present invention include derivatives and pharmaceutically acceptable salts thereof.

Specifically, the invention relates to a halogenated chalcone derivative shown in a general formula (I), or pharmaceutically acceptable salt thereof:

wherein X is selected from F, cl, br, I;

R ₁ 、R ₂ each independently selected from hydrogen, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1-6 Acyl, substituted or unsubstituted benzyl, substituted or unsubstituted C _3-6 Cycloalkyl, cyclopropylmethyl, MOM, glu, SO ₃ H、PO ₃ H ₂ The method comprises the steps of carrying out a first treatment on the surface of the The substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituent is selected from hydroxy, nitro, cyano, amino, carboxyl and C _1-6 Alkoxy, C _3-6 Cycloalkyl, F, cl, br, I;

R ₃ 、R ₄ 、R ₅ each independently selected from hydrogen, hydroxy, nitro, cyano, amino, carboxy, phenyl, methylamino, dimethylamino, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1-6 Alkoxy, substituted or unsubstituted C _1-6 Acyl, substituted or unsubstituted C _1-6 Acyl oxygen, substituted or unsubstituted C _1-6 Alkoxyacyl, substituted or unsubstituted C _1-6 Unsaturated alkoxy, substituted or unsubstituted benzyloxy, substituted or unsubstituted C _3-6 Is C, substituted or unsubstituted _1-6 Alkylthio, cyclopropylmethoxy, F, cl, br, I, glu, MOMO, SO of (a) ₃ H、PO ₃ H ₂ The method comprises the steps of carrying out a first treatment on the surface of the The substitution is selected from monosubstituted, disubstituted, trisubstituted and tetrasubstituted, and the substituent is selected from hydroxy, nitro, cyano, amino, carboxyl and C _1-6 Alkoxy, C _3-6 Cycloalkyl, F, cl, br, I;

MOM represents methoxymethyl; glu represents a beta-D glucopyranosyl group; SO (SO) ₃ H represents a sulfonyl group; PO (Positive oxide) ₃ H ₂ Represents a phosphoryl group.

According to the present invention, a preferred halogenated chalcone derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof is characterized in that the compound is represented by the general formula (II):

wherein R is ₁ 、R ₂ Each independently selected from hydrogen, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1-6 Acyl, substituted or unsubstituted benzyl, substituted or unsubstituted C _3-6 Cycloalkyl, cyclopropylmethyl, MOM, glu, SO ₃ H、PO ₃ H ₂ The method comprises the steps of carrying out a first treatment on the surface of the The substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituent is selected from hydroxy, nitro, cyano, amino, carboxyl and C _1-6 Alkoxy, C _3-6 Cycloalkyl, F, cl, br, I;

According to the present invention, preferred halogenated chalcone derivatives represented by the general formula (II) or pharmaceutically acceptable salts thereof are characterized in that the compounds are represented by the general formulae (IIA), (IIB) and (IIC):

R ₃ 、R ₅ each independently selected from hydrogen, hydroxy, nitro, cyano, amino, carboxy, phenyl, methylamino, dimethylamino, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1-6 Alkoxy, substituted or unsubstituted C _1-6 Acyl, substituted or unsubstituted C _1-6 Acyl oxygen, substituted or unsubstituted C _1-6 Alkoxyacyl, substituted or unsubstituted C _1-6 Unsaturated alkoxy, substituted or unsubstituted benzyloxy, substituted or unsubstituted C _3-6 Is C, substituted or unsubstituted _1-6 Alkylthio, cyclopropylmethoxy, F, cl, br, I, glu, MOMO, SO of (a) ₃ H、PO ₃ H ₂ The method comprises the steps of carrying out a first treatment on the surface of the The substitution is selected from monosubstituted, disubstituted, trisubstituted and tetrasubstituted, and the substituent is selected from hydroxy, nitro, cyano, amino, carboxyl and C _1-6 Alkoxy, C _3-6 Cycloalkyl, F, cl, br, I;

According to the present invention, a preferred halogenated chalcone derivative represented by the general formula (II) or a pharmaceutically acceptable salt thereof is characterized in that the compound is represented by the general formula (IID):

R ₄ 、R ₅ each independently selected from hydrogen, hydroxy, nitro, cyano, amino, carboxy, phenyl, methylamino, dimethylamino, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1-6 Alkoxy, substituted or unsubstituted C _1-6 Acyl, substituted or unsubstituted C _1-6 Acyl oxygen, substituted or unsubstituted C _1-6 Alkoxyacyl, substituted or unsubstituted C _1-6 Unsaturated alkoxy, substituted or unsubstituted benzyloxy, substituted or unsubstituted C _3-6 Is C, substituted or unsubstituted _1-6 Alkylthio, cyclopropylmethoxy, F, cl, br, I, glu, MOMO, SO of (a) ₃ H、PO ₃ H ₂ The method comprises the steps of carrying out a first treatment on the surface of the The substitution is selected from monosubstituted, disubstituted, trisubstituted and tetrasubstituted, and the substituent is selected from hydroxy, nitro, cyano, amino, carboxyl and C _1-6 Alkoxy, C _3-6 Cycloalkyl, F, cl, br, I;

According to the present invention, preferred halogenated chalcone derivatives represented by general formula (IID) or pharmaceutically acceptable salts thereof are characterized in that the compounds are represented by general formulae (IIDa) and (IIDb):

According to the present invention, a preferred halogenated chalcone derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof is characterized in that the compound is represented by the general formula (III):

According to the present invention, preferred halogenated chalcone derivatives represented by general formula (III) or pharmaceutically acceptable salts thereof are characterized in that the compounds are represented by general formulae (IIIA), (IIIB) and (IIIC):

According to the present invention, a preferred halogenated chalcone derivative represented by the general formula (III) or a pharmaceutically acceptable salt thereof is characterized in that the compound is represented by the general formula (IIID):

According to the present invention, preferred halogenated chalcone derivatives represented by general formula (IIID) or pharmaceutically acceptable salts thereof are characterized in that the compounds are represented by general formulae (IIIDa) and (IIIDb):

Specifically, the halogenated chalcone derivatives represented by general formulae (I), (II), (IIA), (IIB), (IIC), (IID), (IIDa), (IIDb), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIDa) and (IIIDb) or pharmaceutically acceptable salts thereof, wherein the compound is selected from the group consisting of the following (the compound code corresponds to the compound code in the examples):

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the second aspect of the technical scheme of the invention provides a pharmaceutical composition containing a pharmaceutically effective dose of the halogenated chalcone derivative as shown in the general formulas (I), (II), (IIA), (IIB), (IIC), (IID), (IIDa), (IIDb), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIDa) and (IIIDb), or pharmaceutically acceptable salts thereof and carriers commonly used in the pharmaceutical field.

According to the present invention, the compound of the present invention may exist in the form of an isomer, and the general term "compound of the present invention" includes the isomer of the compound.

According to an embodiment of the invention, the compounds of the invention also include pharmaceutically acceptable salts, hydrates of salts or prodrugs thereof.

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

Pharmaceutical compositions of the compounds of the present invention may be prepared according to methods well known in the art. For this purpose, the compounds of the invention may, if desired, be combined with one or more solid or liquid pharmaceutical excipients and/or auxiliaries, in suitable administration forms or dosage forms which can be used as human or veterinary medicine.

The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by the enteral or parenteral route, such as oral, intramuscular, subcutaneous, nasal, oral, dermal, peritoneal or rectal, etc. The route of administration of the compounds of the invention or 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 may be liquid dosage form or solid dosage form. For example, the liquid dosage form may 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 of the invention can be prepared into common preparations, and can also be sustained release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.

For example, in order to prepare a unit dosage form into a tablet, various carriers known in the art can be widely used. Examples of carriers include 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; humectants and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, dextrose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, and the like; disintegrants such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, methylcellulose, ethylcellulose, and the like; disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oils and the like; absorption promoters such as quaternary ammonium salts, sodium lauryl sulfate, and the like; lubricants such as 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 bilayer and multilayer tablets.

For example, carriers well known in the art may be widely used for the purpose of making the dosage unit into a pill. Examples of carriers are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, polyvinylpyrrolidone, glycerol monostearate, kaolin, talc and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, and the like; disintegrants such as agar powder, dry starch, alginate, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc.

For example, in order to capsule the administration unit, the compounds of the invention are mixed with the various carriers described above, and the mixture thus obtained is placed in a hard gelatin capsule or a soft capsule. The active ingredient of the compound can be prepared into microcapsules, and the microcapsules can be suspended in an aqueous medium to form a suspension, or can be filled into hard capsules or prepared into injection for application.

For example, the compounds of the present invention may be formulated as injectable formulations, such as solutions, suspension solutions, emulsions, lyophilized powder for injection, 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, polyoxyl isostearyl alcohol, polyoxyethylene sorbitol ester, fatty acids, and the like. In addition, in order to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and further, a conventional cosolvent, a buffer, a pH adjuster, and the like may be added. These adjuvants are commonly used in the art.

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

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

The dosage of the pharmaceutical composition of the present invention depends on many factors such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, character and individual response of the patient or animal, the route of administration, the number of times of administration, the purpose of treatment, and thus the therapeutic dosage of the present invention may vary widely. Generally, the dosages of pharmaceutical ingredients used in the present invention are well known to those skilled in the art. The amount of the actual drug contained in the final formulation of the compound composition of the present invention may be appropriately adjusted to achieve the therapeutically effective amount thereof, thereby achieving the preventive or therapeutic object of the present invention. Daily suitable dosage range of the compounds of the invention: the amount of the compound of the present invention is 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 2-3 times; the dose taken by children is 5-30 mg, preferably 10-20 mg/kg body weight per kg body weight. The above-mentioned dosages may be administered in a single dosage form or in divided dosage forms, for example, two, three or four dosage forms, which are limited by the clinical experience of the administering physician and the administration 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 is to provide an application of halogenated chalcone derivatives and pharmaceutically acceptable salts, hydrates of the salts or prodrugs thereof in preparing medicaments for inflammatory immune related diseases.

The inflammatory immune diseases include rheumatoid arthritis, gouty arthritis lupus erythematosus syndrome, bronchitis, bursitis, tenosynovitis, psoriasis, eczema, burns, dermatitis, inflammatory bowel disease, crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, multiple sclerosis, autoimmune encephalomyelitis, colorectal cancer, nodular arteritis, thyroiditis, rheumatic fever, gingivitis, periodontitis, oral ulcers, nephritis, swelling after damage, myocardial ischemia, various infectious pneumonia, physicochemical pneumonia, allergic pneumonia, spasmodic anal pain and rectal fissure, hepatobiliary bursitis, cholangitis, sclerosing cholangitis, primary biliary cirrhosis, cholecystitis and the like.

The general features of inflammatory immune diseases at the cellular level are represented by: macrophages are overactivated and produce excess NO. Therefore, the invention carries out an experiment of inhibiting the generation of macrophage NO in the abdominal cavity of a primary mouse induced by LPS by the compound, and shows that the 2' -halogenated chalcone derivative has the activity of inhibiting the generation of macrophage NO at the cellular level.

The starting materials, such as 3, 5-dihydroxyacetophenone, used to prepare the compounds of the present invention are commercially available, and key intermediates 1a and 1c are prepared by the method of reference [ adv. Synth. Catalyst. 2019,361,3768-3776], and key intermediate 1b is prepared by the method of reference [ chem. Eur. J.2015,21,11976-11979 ]. The basic synthesis method of the key intermediate compounds 1 a-1 c comprises the following steps:

step one, 3, 5-dihydroxyacetophenone reacts with chloromethyl methyl ether to prepare a MOM-protected dihydroxyacetophenone 3, 5-dihydroxyacetophenone intermediate (1 a).

3, 5-dihydroxyacetophenone reacts with chloromethyl methyl ether in dichloromethane solution by using DIPEA as a catalyst at room temperature, and the reaction product is separated to prepare the MOM-protected dihydroxyacetophenone compound 1a.

And step two, performing chlorination reaction on the compound 1a and NCS to prepare a chlorinated product (1 b) thereof.

The product 1a obtained in the step one is subjected to chlorination reaction with NCS in DMF at room temperature, and a reaction mixture is separated to obtain a chlorinated product 1b.

And thirdly, performing bromination reaction on the compound 1a and NBS to prepare a brominated product (1 c) thereof.

The product 1a obtained in the step one is subjected to bromination reaction with NBS in DMF at room temperature, and a reaction mixture is separated to obtain a brominated product 1c thereof.

The basic synthesis method of the compound comprises the following steps:

step one, the chloro product 1b or bromo product 1c and the substituted or unsubstituted benzaldehyde derivative are subjected to aldol condensation reaction to prepare the halogenated chalcone derivative with the corresponding structure.

In the mixed solution of the chloro product 1b or bromo product 1c and the substituted or unsubstituted benzaldehyde derivative, naOH is used as a catalyst to perform aldol condensation reaction at room temperature to synthesize the corresponding MOM hydroxyl-protected halogenated chalcone derivative.

And step two, removing MOM protecting groups of the MOM protected hydroxyl halogenated chalcone derivative under an acidic condition to prepare the corresponding hydroxyl derivative.

The MOM protected hydroxy halogenated chalcone derivative is reacted with hydrobromic acid in methanol solution at 50 deg.c, and the product is separated to obtain the MOM protected hydroxy halogenated chalcone derivative.

Beneficial technical effects

The inventor of the invention finds that the natural product derivative 2' -bromochalcone has stronger anti-inflammatory activity in the process of total synthesis and activity research of the natural product. On the basis, 2' -bromochalcone is further subjected to synthesis and structure derivatization modification, a series of structure related derivatives are synthesized, and the obtained derivatives are subjected to inflammation inhibition activity evaluation, so that the anti-inflammatory activity of the compounds is confirmed. The compound has remarkable inhibitory activity on generation of LPS-induced primary mouse peritoneal macrophage NO, and has potential application value of further development and research.

2' -bromochalcone is a natural product derivative with a novel structure. Structural studies of the compounds have not been reported in literature so far, and structural-activity relationship studies of the compounds on anti-inflammatory activity and systems have not been reported in literature. There are no reports in the prior literature and technology about 2' -bromochalcone derivatives or pharmaceutically acceptable salts thereof, and the use of such compounds for the treatment of inflammatory diseases. The content of the application is therefore significantly innovative.

Detailed description of the application:

various terms and phrases used herein have the ordinary and customary meaning as understood by those skilled in the art, and even though they are still intended to be more fully described and explained herein, the terms and phrases used herein are to be understood and to have a meaning inconsistent with the ordinary and customary meaning as set forth herein. The following are definitions of various terms used in the present application, which are applicable to terms used throughout the specification of the present application unless otherwise specified in the specific context.

The definitions of the various groups of the compounds of the application are provided below and are used throughout the specification and claims unless otherwise indicated.

The term "alkyl" as referred to herein means an alkyl group having the indicated number of carbon atoms, which may be a straight or branched chain alkyl group, for example, to mention"C of (C) _3-6 Cycloalkyl "of (C) refers to a substituted or unsubstituted cycloalkyl group having 3, 4, 5, 6 carbon atoms, and may include C _3-5 Cycloalkyl, C _3-4 Cycloalkyl, C _4-6 Cycloalkyl, C _4-5 Cycloalkyl, C _5-6 Cycloalkyl, etc., and preferred specific groups such as cyclopropane, cyclopentane, and cyclohexane.

The term "C" as referred to in the present invention _1-6 The "alkyl" of (C) refers to a straight or branched alkyl group having 1, 2, 3, 4, 5, 6 carbon atoms, and may include C _1-5 Alkyl, C _1-4 Alkyl, C _2-5 Alkyl, C _2-4 Alkyl, C _2-3 Alkyl, C _3-5 Alkyl groups, etc., and preferred specific groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.

The term "C" as referred to in the present invention _1-6 Alkoxy "refers to an alkoxy group having 1, 2, 3, 4, 5, 6 carbon atoms, including C _1-5 Alkoxy, C _1-2 Alkoxy, C _2-4 Alkoxy, C _2-3 Alkoxy, C _3-4 Alkoxy, and the like, and preferred specific groups are methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy, and the like.

The term "C" as referred to in the present invention _1-6 Unsaturated alkyl "refers to an unsaturated alkyl group having 1, 2, 3, 4, 5, 6 carbon atoms, and may include C _1-5 Unsaturated alkyl of (C) _1-4 Unsaturated alkyl of (C) _2-5 Unsaturated alkyl of (C) _2-4 And the like, and preferred specific groups such as vinyl, ethynyl, isopropenyl, isobutenyl, isopentenyl, 1, 4-dibutenyl.

The term "C" as referred to in the present invention _1-6 The "acyl" refers to an acyl group having 1, 2, 3, 4, 5, and 6 carbon atoms, and may include C _1-5 Acyl, C _1-3 Acyl, C _2-5 Acyl, C _2-3 Acyl, C _3-4 Acyl, etc., and preferred specific groups, such as formyl, acetyl, propionyl, etc.

Reference to "C" in the present invention _1-6 The "acyloxy group" of (C) refers to a straight-chain or branched acyloxy group having 1, 2, 3, 4, 5, 6 carbon atoms and may include C _1-5 Acyloxy radicals, C _1-3 Acyloxy radicals, C _2-5 Acyloxy radicals, C _2-3 Acyloxy radicals, C _3-4 Acyl groups, etc., and preferred specific groups, such as formyl, acetyl, propionyloxy, etc.

Reference to "C" in the present invention _1-6 Alkoxyacyl "of (C) is an alkanoyl group having 1, 2, 3, 4, 5, 6 carbon atoms and may include C _1-5 Alkoxyacyl, C _1-3 Alkoxyacyl, C _2-5 Alkoxyacyl, C _2-3 Alkoxyacyl, C _3-4 Sub-range groups represented by an alkanoyl group or the like, and preferably specific groups such as methoxyacyl, ethoxyacyl and the like;

the term "C" as referred to in the present invention _1-6 Alkylthio "of (C) refers to straight-chain or branched alkylthio of 1, 2, 3, 4, 5, 6 carbon atoms, and may include C _1-5 Alkylthio, C _1-3 Alkylthio, C _2-5 Alkylthio, C _2-3 Alkylthio, C _3-4 Alkylthio groups and the like, and preferred specific groups, such as methylthio, ethylthio and the like.

Detailed Description

In order to further illustrate the invention, the following examples are given purely by way of illustration and are not to be construed as limiting the invention.

The preparation method of the compounds 1a,1b and 1 c:

step one, 10g (65.79 mmol) of 3, 5-dihydroxyacetophenone was dissolved in 300ml of methylene chloride, DIPEA (43.42 ml,263 mmol) was added under stirring at room temperature, chloromethyl methyl ether liquid (21.2 g,263 mmol) was slowly added dropwise, and stirring was maintained at room temperature for 10 hours, and the reaction was stopped. To the reaction solution was added 300ml of water, extracted with methylene chloride, the organic phase was washed with 5% sodium hydroxide solution, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The colorless oily liquid was subjected to column chromatography separation on 200-300 mesh silica gel, and petroleum ether/acetone (10:1) was eluted to give compound 1a (15.78 g, yield 80%) as a colorless oily liquid. The physicochemical constants of compound 1a are as follows:

Compound 1a: a colorless oily liquid, which is prepared from, ¹ H NMR(500MHz,acetone-d ₆ ):δ:7.26(d,J＝2.29Hz,2H),6.93(t,J＝2.27Hz,1H),5.19(s,4H),3.48(s,3H),2.56(s,3H)；(+)-ESI-MS:m/z 263.0[M+Na] ⁺ .

step two, compound 1a (0.7 g,2.917 mmol) was dissolved in 20ml dry CH ₂ Cl ₂ 2,4, 6-trimethylaniline (40 mg,0.29 mmol), NCS (0.467 g,3.5 mmol) was added thereto with stirring, and the reaction was stopped at room temperature for 12 hours under dark conditions. 15ml of water was added to the reaction solution, extraction was performed with methylene chloride, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the obtained solid was separated by 200-300 mesh silica gel column chromatography, and petroleum ether: ethyl acetate: methylene chloride (40:1:3) was eluted to obtain oily liquid 1b (0.712 g, yield 89%). The physicochemical constants of compound 1b are as follows:

compound 1b: an oily liquid is present in the form of an oil, ¹ H NMR(400MHz,Acetone-d ₆ )δ _H :7.02(d,J＝2.7Hz,1H),6.85(d,J＝2.7Hz,1H),5.32(s,2H),5.23(s,2H),3.49(s,3H),3.44(s,3H),2.55(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :199.68,156.84,154.03,142.11,112.05,108.33,106.64,95.30,94.62,55.80,55.51,29.98.(+)-ESI-MS:m/z 297.0[M+Na] ⁺ .

step three, compound 1a (0.7 g,2.917 mmol) was dissolved in 40ml of dry DMF, NBS (0.399 g,2.916 mmol) was added under stirring, and the reaction was stopped at room temperature for 8h in the absence of light. 50ml of water was added to the reaction solution, extraction was performed with ethyl acetate, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the obtained solid was separated by 200-300 mesh silica gel column chromatography, and petroleum ether: ethyl acetate: dichloromethane (40:1:3) was eluted to obtain oily liquid 1c (0.6 g, yield 64.5%). The physicochemical constants of compound 1c are as follows:

compound 1c: a colorless oily liquid, which is prepared from, ¹ H NMR(500MHz,DMSO-d ₆ )δ _H :7.46(s,1H),7.28(s,1H),5.80(s,2H),5.71(s,2H),3.98(s,3H),3.93(s,3H),3.02(s,3H). ¹³ C NMR(500MHz,DMSO-d ₆ )δ _C :201.17,158.18,155.31,145.25,108.59,106.36,100.36,95.69,95.03,56.28,55.97,30.23.(+)-ESI-MS:m/z 341.0[M+Na] ⁺ .

Example 1:

1- (2-chloro-3, 5-dimethoxymethylphenyl) -3-phenyl- (2E) -2-propen-1-one (1)

Synthetic route for compound 1:

860mg (3.13 mmol) of compound 1b was dissolved in 30ml of a mixed solvent of methanol and water (methanol: water=2:1, v/v), and 125mg (1.2 eq) of NaOH solid was added. After stirring at room temperature for 10 minutes, 332mg (3.13 mmol) of benzaldehyde was added and the reaction was continued for 10 hours. The reaction solution was diluted with 30ml of water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the resultant mixture was separated by 200-300 mesh silica gel column chromatography, and petroleum ether: ethyl acetate: dichloromethane (8:1:3) was eluted to give yellow oily liquid 1 (0.227 g, 80%). The physicochemical parameters of compound 1 are as follows:

compound 1: yellow oily liquid (yield=80%); ¹ H NMR(500MHz,Acetone-d ₆ )δ _H :7.78–7.73(m,2H),7.54–7.46(m,4H),7.17(d,J＝16.2Hz,1H),7.08(d,J＝2.7Hz,1H),6.84(d,J＝2.7Hz,1H),5.37(s,2H),5.27(s,2H),3.54(s,3H),3.48(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :192.76,156.80,153.95,146.05,141.23,134.59,130.86,129.03z,128.66(C×2),126.33,112.56,108.73,106.33,95.25,94.61,55.79,55.48.(+)-HR ESIMS:m/z＝363.0990,calcd for C ₁₉ H ₂₀ O ₅ Cl[M+H] ⁺ :363.0993.

synthetic route for compounds 2-4:

739mg (1.815 mmol) of Compound 1 was dissolved in 40ml of dry methanol, 49% aqueous HBr was slowly added at 50℃and after stirring at 50℃for 6 hours, the reaction mixture was cooled to-10℃and pH was adjusted to neutral with saturated sodium hydrogencarbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the product mixture was separated by column chromatography on silica gel using methylene chloride: methanol=10:1 as eluent to give Compound 2 (158 mg, 24%) as a yellow oily liquid, compound 3 (164 mg, 25%) as a yellow oily liquid, compound 4 (214 mg, 37%). The physicochemical parameters of compounds 2 to 4 are as follows:

Synthesis of end products 2 to 4 (Compound code corresponds to the Compound code in the examples)

Example 2:

1- (2-chloro-3-hydroxy-5-methoxymethylphenyl) -3-phenyl- (2E) -2-propen-1-one (2)

Compound 2: yellow oily liquid (yield=24%); ¹ H NMR(400MHz,Acetone-d ₆ )δ _H :9.06(s,1H),7.74(dd,J＝6.8,2.8Hz,2H),7.52–7.45(m,4H),7.14(d,J＝16.1Hz,1H),6.85(d,J＝2.8Hz,1H),6.68(d,J＝2.8Hz,1H),5.21(s,2H),3.44(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :192.86,156.82,154.20,145.92,141.09,134.64,130.80,129.02(C×2),128.64(C×2),126.36,109.93,107.66,105.92,94.47,55.35.(+)-HR ESIMS:m/z＝319.0729,calcd for C ₁₇ H ₁₆ O ₄ Cl[M+H] ⁺ :319.0731.

example 3:

1- (2-chloro-3-methoxymethyl-5-hydroxyphenyl) -3-phenyl- (2E) -2-propen-1-one (3)

Compound 3: yellow oily liquid (yield=25%); ¹ H NMR(400MHz,Acetone-d ₆ )δ _H :8.84(s,1H),7.73–7.68(m,2H),7.48–7.41(m,4H),7.09(d,J＝16.2Hz,1H),6.85(d,J＝2.7Hz,1H),6.56(d,J＝2.7Hz,1H),5.27(s,2H),3.47(s,3H)； ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :193.00,156.95,154.05,145.86,141.29,134.62,130.80,129.72,129.02(C×2),128.62(C×2),126.45,108.29,105.16,95.11,55.65；(+)-HR ESIMS:m/z＝319.0730,calcd for C ₁₇ H ₁₆ O ₄ Cl[M+H] ⁺ :319.0731.

example 4:

1- (2-chloro-3, 5-dihydroxyphenyl) -3-phenyl- (2E) -2-propen-1-one (4)

Compound 4: yellow oily liquid (yield=37%); ¹ H NMR(500MHz,Acetone-d ₆ )δ _H :8.87(s,1H),8.73(s,1H),7.74(s,2H),7.50-7.45(m,4H),7.12(d,J＝16.2Hz,1H),6.67(s,1H),6.49(s,1H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :193.15,156.97,154.24,145.77,141.13,134.67,130.75,129.02(C×2),128.61(C×2),126.49,107.63,107.06,104.98.(+)-HR ESIMS:m/z＝275.0468,calcd for C ₁₅ H ₁₂ O ₃ Cl[M+H] ⁺ :275.0469.

example 5:

1- (2-bromo-3, 5-dimethoxymethylphenyl) -3-phenyl- (2E) -2-propen-1-one (5) (ZXM-Ph)

Synthetic route to Compound 5 (ZXM-Ph):

compound 1c 1g (3.13 mmol) was dissolved in 30ml of a mixed solvent of methanol and water (methanol: water=2:1, v/v), and 125mg (1.2 eq) of NaOH solid was added. After stirring at room temperature for 10 minutes, 332mg (3.13 mmol) of benzaldehyde was added and the reaction was continued for 10 hours. The reaction solution was diluted with 30ml of water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the resultant mixture was separated by 200-300 mesh silica gel column chromatography, and petroleum ether: ethyl acetate: dichloromethane (8:1:3) was eluted to give yellow oily liquid 1 (1.02 g, 80%). The physicochemical parameters of compound 5 are as follows:

Compound 5: yellow oily liquid (yield=80%); ¹ H NMR(500MHz,Acetone-d ₆ )δ _H :7.72(dd,J＝7.5Hz,3.5Hz,2H),7.46(m,3H),7.44(d,J＝16.2Hz,1H),7.11(d,J＝16.2Hz,1H),7.02(d,J＝2.5Hz,1H),6.79(d,J＝2.5Hz,1H),5.34(s,2H),5.25(s,2H),3.51(s,3H),3.45(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :194.63,158.59,155.79,147.15,144.45,135.57,131.83,130.01(C×2),129.62(C×2),127.16,109.86,106.79,102.08,96.17,95.55,56.80,56.48.(+)-HR ESIMS:m/z＝407.0485,calcd for C ₁₉ H ₂₀ O ₅ Br[M+H] ⁺ :407.0488.

example 6:

1- (2-chloro-3, 5-dimethoxymethylphenyl) -3- (2-methoxyphenyl) - (2E) -2-propen-1-one (6)

Compound 1b 549mg (2 mmol) was dissolved in 30ml of a mixed solvent of methanol and water (methanol: water=2:1, v/v), and 96mg (1.2 eq) of NaOH solid was added. After stirring at room temperature for 10 minutes, 272mg (2 mmol) of o-methoxybenzaldehyde was added thereto, and the reaction was continued for 10 hours. The reaction solution was diluted with 30ml of water, and the precipitated precipitate was filtered, washed with methanol and dried to give Compound 6 (683 mg, 87%) as a pale yellow solid.

Compound 6: pale yellow solid (yield=87%); ¹ H NMR(500MHz,Acetone-d ₆ )δ _H :7.81(d,J＝16.3Hz,1H),7.74(d,J＝7.5Hz,1H),7.45(t,J＝7.4Hz,1H),7.20(d,J＝16.3Hz,1H),7.10(d,J＝8.3Hz,1H),7.07(d,J＝2.4Hz,1H),7.03(t,J＝7.5Hz,1H),6.83(d,J＝2.5Hz,1H),5.36(s,2H),5.26(s,2H),3.91(s,3H),3.53(s,3H),3.47(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :192.96,158.74,156.75,153.91,141.51,141.05,132.48,128.87,126.51,123.03,120.82,112.63,111.59,108.77,106.29,95.23,94.61,55.78,55.48,55.23.(+)-HR ESIMS:m/z＝393.1096,calcd for C ₂₀ H ₂₂ O ₆ Cl[M+H] ⁺ :393.1099.

example 7:

1- (2-chloro-3, 5-dihydroxyphenyl) -3- (2-methoxyphenyl) - (2E) -2-propen-1-one (7)

392mg (1 mmol) of Compound 6 was dissolved in 20ml of dry methanol, 49% aqueous HBr was slowly added at 50℃and the reaction was stirred for 10 hours at 50℃and then cooled to-10℃and then pH was adjusted to neutral with saturated sodium hydrogen carbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the product mixture was separated by column chromatography on silica gel using methylene chloride: methanol=10:1 as eluent to give Compound 7 (274 mg, 90%) as a colourless oil.

Compound 7: colourless oily liquid (yield=90%); ¹ H NMR(400MHz,Acetone-d ₆ )δ _H :8.85(s,1H),8.72(s,1H),7.79(d,J＝16.3Hz,1H),7.74(dd,J＝7.7,1.7Hz,1H),7.44(ddd,J＝8.4,7.3,1.7Hz,1H),7.16(d,J＝16.3Hz,1H),7.10(d,J＝7.8Hz,1H),7.02(t,J＝7.8Hz,1H),6.66(d,J＝2.7Hz,1H),6.48(d,J＝2.7Hz,1H),3.90(s,3H). ¹³ C NMR(101MHz,Acetone-d ₆ )δ _C :193.31,158.68,156.93,154.22,141.43,140.65,132.33,128.79,126.70,123.11,120.80,111.56,107.66,107.05,104.89,55.20.(+)-HR ESIMS:m/z＝305.0572,calcd for C ₁₆ H ₁₄ O ₄ Cl[M+H] ⁺ :305.0575.

example 8:

1- (2-bromo-3, 5-dimethoxymethylphenyl) -3- (2-methoxyphenyl) - (2E) -2-propen-1-one (8)

638mg (2 mmol) of Compound 1c was dissolved in 30ml of a mixed solvent of methanol and water (methanol: water=2:1, v/v), and 96mg (1.2 eq) of NaOH solid was added. After stirring at room temperature for 10 minutes, 272mg (2 mmol) of o-methoxybenzaldehyde was added thereto, and the reaction was continued for 10 hours. The reaction solution was diluted with 30ml of water, and the precipitated precipitate was filtered, washed with methanol and dried to give compound 8 (770 mg, 88%) as a white solid.

Compound 8: white solid (yield=88%); ¹ H NMR(500MHz,Acetone-d ₆ )δ _H :7.77(d,J＝16.3Hz,1H),7.72(d,J＝7.5Hz,1H),7.44(t,J＝7.8Hz,1H),7.15(d,J＝16.3Hz,1H),7.09(d,J＝8.4Hz,1H),7.03–6.98(m,2H),6.79(d,J＝2.5Hz,1H),5.34(s,2H),5.25(s,2H),3.89(s,3H),3.51(s,3H),3.45(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :193.86,158.72,157.58,154.78,143.78,141.16,132.47,128.86,126.37,123.05,120.83,111.60,108.92,105.78,101.19,95.18,94.58,55.81,55.49,55.23.(+)-HR ESIMS:m/z＝437.0592,calcd for C ₂₀ H ₂₂ O ₆ Br[M+H] ⁺ :437.0594.

example 9:

1- (2-bromo-3-hydroxy-5-methoxyphenyl) -3- (3-methoxy-4-hydroxyphenyl) - (2E) -2-propen-1-one (9)

Compound 8, 433 mg (1 mmol) was dissolved in 20ml dry methanol, 49% aqueous HBr was slowly added at 50℃and after stirring for 10 hours, the reaction was cooled to-10℃and pH was adjusted to neutral with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the product mixture was isolated as colorless oily liquid compound 9 (321 mg, 92%) by column chromatography on silica gel with dichloromethane: methanol=10:1 as eluent.

Compound 9: colourless oily liquid (yield=92%); ¹ H NMR(400MHz,Acetone-d ₆ )δ _H :8.91(s,1H),8.75(s,1H),δ7.77(d,J＝16.3Hz,1H),7.73(dd,J＝7.5Hz,1.6Hz,1H),7.47–7.41(m,1H),7.14(d,J＝16.3Hz,1H),7.08(dd,J＝8.4Hz,0.8Hz,1H),7.06–6.99(m,1H),6.65(d,J＝2.7Hz,1H),6.45(d,J＝2.7Hz,1H),3.90(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :194.22,158.66,157.69,155.17,143.71,140.77,132.32,128.78,126.57,123.12,120.80,111.57,107.23,104.38,96.16,55.20.(+)-HR ESIMS:m/z＝349.0068,calcd for C ₁₆ H ₁₄ O ₄ Br[M+H] ⁺ :349.0070.

example 10:

1- (2-chloro-3, 5-dimethoxymethylphenyl) -3- (4-N, N-dimethylphenyl) - (2E) -2-propen-1-one (10)

Compound 1b 549mg (2 mmol) was dissolved in 30ml of a mixed solvent of methanol and water (methanol: water=2:1, v/v), and 96mg (1.2 eq) of NaOH solid was added. After stirring at room temperature for 10 minutes, 298mg (2 mmol) of p-dimethylaminobenzaldehyde was added thereto, and the reaction was continued for 10 hours. The reaction solution was diluted with 30ml of water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the resultant mixture was separated by 200-300 mesh silica gel column chromatography, and petroleum ether: ethyl acetate: dichloromethane (10:1:3) was eluted to give yellow oily liquid 10 (730 g, 90%).

Compound 10: yellow oily liquid (yield=90%); ¹ H NMR(400MHz,Acetone-d ₆ )δ _H :7.54(d,J＝9.0Hz,2H),7.35(d,J＝15.9Hz,1H),7.01(d,J＝2.7Hz,1H),6.84(d,J＝15.9Hz,1H),6.77(d,J＝9.0Hz,2H),6.75(d,J＝2.7Hz,1H),5.33(s,2H),5.24(s,2H),3.51(s,3H),3.45(s,3H),3.05(s,6H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :192.39,156.69,153.83,152.57,147.36,142.13,130.51(C×2),121.86,120.93,111.83(C×2),108.63,105.82,95.22,94.60,55.74,55.43,39.22(C×2).(+)-HR ESIMS:m/z＝406.1412,calcd for C ₂₁ H ₂₅ O ₅ NCl[M+H] ⁺ :406.1415.

example 11:

1- (2-bromo-3, 5-dimethoxymethylphenyl) -3- (4-N, N-dimethylaminophenyl) - (2E) -2-propen-1-one (11)

Compound 1c 638mg (2 mmol) was dissolved in 30ml of a mixed solvent of methanol and water (methanol: water=2:1, v/v), and 96mg (1.2 eq) of NaOH solid was added. After stirring at room temperature for 10 minutes, 298mg (2 mmol) of p-dimethylaminobenzaldehyde was added thereto, and the reaction was continued for 10 hours. The reaction solution was diluted with 30ml of water, filtered, and the precipitate was washed with methanol and dried to give compound 11 (783 mg, 87%) as a yellow solid.

Compound 11: yellow solid (yield=87%); ¹ H NMR(400MHz,Acetone-d ₆ )δ _H :7.50(d,J＝9.0Hz,2H),7.29(d,J＝16.0Hz,1H),6.94(d,J＝2.7Hz,1H),6.77(d,J＝16.0Hz,1H),6.72(d,J＝9.0Hz,2H),6.70(d,J＝2.7Hz,1H),5.30(s,2H),5.21(s,2H),3.48(s,3H),3.42(s,3H),3.01(s,6H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :193.30,157.51,154.72,152.56,147.50,144.37,130.50(C×2),121.88,120.76,111.83(C×2),108.80,105.35,101.20,95.18,94.57,55.78,55.46,39.23(C×2).(+)-HR ESIMS:m/z＝450.0909,calcd for C ₂₁ H ₂₅ O ₅ NBr[M+H] ⁺ :450.0910.

example 12:

1- (2-chloro-3, 5-dimethoxymethylphenyl) -3- (4-methoxyphenyl) - (2E) -2-propen-1-one (12)

Compound 1b 549mg (2 mmol) was dissolved in 30ml of a mixed solvent of methanol and water (methanol: water=2:1, v/v), and 96mg (1.2 eq) of NaOH solid was added. After stirring at room temperature for 10 minutes, 272mg (2 mmol) of p-methoxybenzaldehyde was added thereto, and the reaction was continued for 10 hours. The reaction solution was diluted with 30ml of water, filtered, and the cake was washed with methanol and dried to give compound 12 (730 mg, 93%) as a white solid.

Compound 12: white solid (yield=93%); ¹ H NMR(500MHz,Acetone-d ₆ )δ _H :7.71(d,J＝8.7Hz,2H),7.45(d,J＝16.1Hz,1H),7.07–6.99(m,4H),6.80(d,J＝2.7Hz,1H),5.36(s,2H),5.26(s,2H),3.89(s,3H),3.53(s,3H),3.47(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :192.67,162.20,156.75,153.90,146.13,141.56,130.54(C×2),127.13,124.03,114.49(C×2),112.50,108.67,106.12,95.23,94.60,55.76,55.46,54.95.(+)-HR ESIMS:m/z＝393.1096,calcd for C ₂₀ H ₂₂ O ₆ Cl[M+H] ⁺ :393.1099.

synthesis method of compounds 13-15

Compound 12 (1 mmol) was dissolved in 20ml dry methanol, 49% aqueous HBr was slowly added at 50℃and after stirring for 6 hours, the reaction solution was cooled to-10℃and pH was adjusted to neutral with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the product mixture was separated by column chromatography on silica gel with dichloromethane: methanol=10:1 as eluent to give colorless oily liquid compounds 13 (94 mg, 27%), 14 (87 mg, 25%) and 15 (107 mg, 35%).

Synthesis of end products 13 to 15 (Compound code corresponds to the Compound code in the examples)

Example 13:

1- (2-chloro-3-hydroxy-5-methoxymethylphenyl) -3- (4-methoxyphenyl) - (2E) -2-propen-1-one (13)

Compound 13, colorless oily liquid (yield=27%); ¹ H NMR(500MHz,Acetone-d ₆ )δ _H :9.00(s,1H),7.69(d,J＝8.6Hz,2H),7.43(d,J＝16.1Hz,1H),7.03–6.96(m,3H),6.83(d,J＝2.5Hz,1H),6.65(d,J＝2.5Hz,1H),5.20(s,2H),3.87(s,3H),3.44(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :192.77,162.15,156.78,154.13,145.99,141.42,130.51(C×2),127.18,124.07,114.47(C×2),109.89,107.59,105.70,94.47,55.34,54.94.(+)-HR ESIMS:m/z＝349.0834,calcd for C ₁₈ H ₁₈ O ₅ Cl[M+H] ⁺ :349.0837.

example 14:

1- (2-chloro-3-methoxymethyl-5-hydroxyphenyl) -3- (4-methoxyphenyl) - (2E) -2-propen-1-one (14)

Compound 14, colorless oily liquid (yield=25%); ¹ H NMR(500MHz,Acetone-d ₆ )δ _H :8.83(s,1H),7.69(d,J＝8.6Hz,2H),7.41(d,J＝16.1Hz,1H),7.01(d,J＝8.7Hz,2H),6.97(d,J＝16.1Hz,1H),6.86(d,J＝2.4Hz,1H),6.56(d,J＝2.4Hz,1H),5.30(s,2H),3.86(s,3H),3.50(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :192.90,162.15,156.87,154.01,145.93,141.63,130.48(C×2),127.15,124.17,114.47(C×2),110.03,108.22,104.94,95.10,55.63,54.94.(+)-HR ESIMS:m/z＝349.0835,calcd for C ₁₈ H ₁₈ O ₅ Cl[M+H] ⁺ :349.0837.

example 15:

1- (2-chloro-3, 5-dihydroxyphenyl) -3- (4-methoxyphenyl) - (2E) -2-propen-1-one (15)

Compound 15, colorless oily liquid (yield=35%); ¹ H NMR(400MHz,Acetone-d ₆ )δ _H :8.84(s,1H),8.71(s,1H),7.69(d,J＝8.6Hz,2H),7.42(d,J＝16.1Hz,1H),7.01(d,J＝8.9Hz,2H),6.97(d,J＝16.1Hz,1H),6.64(d,J＝2.7Hz,1H),6.45(d,J＝2.7Hz,1H),3.86(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :193.03,162.10,156.91,154.17,145.82,141.47,130.45(C×2),127.21,124.22,114.46(C×2),113.36,106.97,104.73,54.93.(+)-HR ESIMS:m/z＝305.0574,calcd for C ₁₆ H ₁₄ O ₄ Cl[M+H] ⁺ :305.0575.

example 16:

1- (2-chloro-3, 5-dimethoxymethylphenyl) -3- (3-bromo-4-methoxyphenyl) - (2E) -2-propen-1-one (16)

Compound 1b 549mg (2 mmol) was dissolved in 30ml of a mixed solvent of methanol and water (methanol: water=2:1, v/v), and 96mg (1.2 eq) of NaOH solid was added. After stirring at room temperature for 10 minutes, 430mg (2 mmol) of 3-bromo-4-methoxybenzaldehyde was added thereto, and the reaction was continued for 10 hours. The reaction solution was diluted with 30ml of water, filtered, and the cake was washed with methanol and dried to give compound 16 (849 mg, 90%) as a white solid.

Compound 16, white solid (yield=90%); ¹ H NMR(500MHz,Acetone-d ₆ )δ _H :7.92(d,J＝2.2Hz,1H),7.67(d,J＝7.2Hz,1H),7.35(d,J＝16.1Hz,1H),7.10(d,J＝8.6Hz,1H),7.00(d,J＝16.1Hz,1H),6.97(d,J＝2.5Hz,1H),6.75–6.70(d,J＝2.5Hz,1H),5.27(s,2H),5.17(s,2H),3.90(s,3H),3.44(s,3H),3.38(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :192.57,158.00,156.77,153.92,144.43,141.32,133.13,129.94,128.63,125.25,112.54,112.51,111.77,108.72,106.27,95.24,94.61,56.04,55.78,55.48.(+)-HR ESIMS:m/z＝471.0205,calcd for C ₂₀ H ₂₁ O ₆ BrCl[M+H] ⁺ :471.0204.

synthesis method of compounds 17 to 19

Compound 16 471mg (1 mmol) was dissolved in 20ml dry methanol, 49% aqueous HBr was slowly added at 50℃and after stirring for 6 hours, the reaction solution was cooled to-10℃and pH was adjusted to neutral with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the product mixture was separated by column chromatography on silica gel with dichloromethane: methanol=10:1 as eluent to give colorless oily liquid compounds 17 (128 mg, 30%), 18 (107 mg, 25%) and 19 (115 mg, 30%).

Synthesis of end products 17 to 19 (Compound code corresponds to the Compound code in the examples)

Example 17:

1- (2-chloro-3-hydroxy-5-methoxymethylphenyl) -3- (3-bromo-4-methoxyphenyl) - (2E) -2-propen-1-one (17)

Compound 17, colorless oily liquid (yield=30%); ¹ H NMR(500MHz,Acetone-d ₆ )δ _H :9.04(s,1H),8.01(s,1H),7.75(d,J＝8.5Hz,1H),7.42(d,J＝16.1Hz,1H),7.17(d,J＝8.6Hz,1H),7.07(d,J＝16.1Hz,1H),6.83(d,J＝2.3Hz,1H),6.66(d,J＝2.3Hz,1H),5.20(s,2H),3.97(s,3H),3.44(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :192.58,157.95,156.80,154.14,144.24,141.19,133.10,129.90,128.70,125.30,112.49,111.77,109.92,107.68,105.85,94.48,56.02,55.35.(+)-HR ESIMS:m/z＝426.9939,calcd for C ₁₈ H ₁₇ O ₅ BrCl[M+H] ⁺ :426.9942.

example 18:

1- (2-chloro-3-methoxymethyl-5-hydroxyphenyl) -3- (3-bromo-4-methoxyphenyl) - (2E) -2-propen-1-one (18)

Compound 18, colorless oily liquid (yield=25%); ¹ H NMR(500MHz,Acetone-d ₆ )δ _H :8.85(s,1H),8.00(s,1H),7.74(d,J＝8.5Hz,1H),7.40(d,J＝16.1Hz,1H),7.17(d,J＝8.6Hz,1H),7.05(d,J＝16.1Hz,1H),6.87(d,J＝2.5Hz,1H),6.57(d,J＝2.5Hz,1H),5.29(s,2H),3.97(s,3H),3.50(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :192.72,157.95,156.88,154.04,144.17,141.41,133.08,129.89,128.68,125.40,112.49,111.78,110.07,108.28,105.09,95.11,56.02,55.64.(+)-HR ESIMS:m/z＝426.9940,calcd for C ₁₈ H ₁₇ O ₅ BrCl[M+H] ⁺ :426.9942.

example 19:

1- (2-chloro-3, 5-dihydroxyphenyl) -3- (3-bromo-4-methoxyphenyl) - (2E) -2-propen-1-one (19)

Compound 19, colorless oily liquid (yield=30%); ¹ H NMR(500MHz,Acetone-d ₆ )δ _H :8.86(s,1H),8.73(s,1H),8.01(s,1H),7.75(d,J＝8.5Hz,1H),7.41(d,J＝16.1Hz,1H),7.17(d,J＝8.6Hz,1H),7.05(d,J＝16.1Hz,1H),6.65(d,J＝2.5Hz,1H),6.46(d,J＝2.5Hz,1H),3.97(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :192.83,157.90,156.92,154.20,144.05,141.24,133.05,129.86,128.74,125.44,112.48,111.77,107.62,107.05,104.89,56.01.(+)-HR ESIMS:m/z＝382.9675,calcd for C ₁₆ H ₁₃ O ₄ BrCl[M+H] ⁺ :382.9680.

example 20:

1- (2-bromo-3, 5-dimethoxymethylphenyl) -3- (4-methoxyphenyl) - (2E) -2-propen-1-one (20)

Compound 1c 638mg (2 mmol) was dissolved in 30ml of a mixed solvent of methanol and water (methanol: water=2:1, v/v), and 96mg (1.2 eq) of NaOH solid was added. After stirring at room temperature for 10 minutes, 272mg (2 mmol) of p-methoxybenzaldehyde was added thereto, and the reaction was continued for 10 hours. The reaction solution was diluted with 30ml of water, filtered, and the cake was washed with methanol and dried to give compound 20 (770 mg, 93%) as a white solid.

Compound 20, white solid (yield=93%); ¹ H NMR(400MHz,Chloroform-d)δ _H :7.52(s,1H),7.50(s,1H),7.38(d,J＝16.1Hz,1H),6.95(d,J＝2.8Hz,1H),6.92(s,1H),6.91(d,J＝16.1Hz,1H),6.90(s,1H),6.75(d,J＝2.8Hz,1H),5.27(s,2H),5.16(s,2H),3.85(s,3H),3.54(s,3H),3.47(s,3H). ¹³ C NMR(400MHz,Chloroform-d)δ _C :194.90,162.14,157.53,154.92,147.05,143.60,130.60(C×2),127.27,124.10,114.62(C×2),109.45,106.04,102.13,95.43,94.85,56.72,56.41,55.59.(+)-HR ESIMS:m/z＝437.0589,calcd for C ₂₀ H ₂₂ O ₆ Br[M+H] ⁺ :437.0594.

synthesis method of compounds 21 to 23

Compound 20 4397 mg (1 mmol) was dissolved in 20ml dry methanol, 49% aqueous HBr was slowly added at 50℃and after stirring for 6 hours, the reaction solution was cooled to-10℃and pH was adjusted to neutral with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the product mixture was separated by column chromatography on silica gel with dichloromethane: methanol=10:1 as eluent to give colorless oily liquid compounds 21 (78 mg, 20%), 22 (118 mg, 30%) and 23 (139 mg, 40%).

Synthesis of end products 21 to 23 (Compound code corresponds to the Compound code in the examples)

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Example 21:

1- (2-bromo-3-hydroxy-5-methoxymethylphenyl) -3- (4-methoxyphenyl) - (2E) -2-propen-1-one (21)

Compound 21, colorless oily liquid (yield=20%); ¹ H NMR(400MHz,Acetone-d ₆ )δ _H :9.08(s,1H),7.69(d,J＝8.6Hz,2H),7.40(d,J＝16.1Hz,1H),7.01(d,J＝8.9Hz,2H),6.95(d,J＝16.1Hz,1H),6.81(d,J＝2.7Hz,1H),6.62(d,J＝2.7Hz,1H),5.20(s,2H),3.86(s,3H),3.44(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :193.71,162.14,157.55,155.10,146.13,143.69,130.49(C×2),127.19,123.94,114.47(C×2),107.67,105.14,98.61,94.44,55.35,54.94.(+)-HR ESIMS:m/z＝393.0327,calcd for C ₁₈ H ₁₈ O ₅ Br[M+H] ⁺ :393.0332.

example 22:

1- (2-bromo-3-methoxymethyl-5-hydroxyphenyl) -3- (4-methoxyphenyl) - (2E) -2-propen-1-one (22)

Compound 22, colorless oily liquid (yield=30%); ¹ H NMR(400MHz,Acetone-d ₆ )δ _H :8.88(s,1H),7.68(d,J＝8.7Hz,2H),7.38(d,J＝16.1Hz,1H),7.01(d,J＝8.9Hz,2H),6.94(d,J＝16.1Hz,1H),6.83(d,J＝2.7Hz,1H),6.54(d,J＝2.7Hz,1H),5.30(s,2H),3.86(s,3H),3.50(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :193.79,162.14,157.70,154.88,146.08,143.84,130.47(C×2),127.17,124.02,114.48(C×2),108.48,104.52,98.42,95.06,55.66,54.94.(+)-HR ESIMS:m/z＝393.0327,calcd for C ₁₈ H ₁₈ O ₅ Br[M+H] ⁺ :393.0332.

example 23:

1- (2-bromo-3, 5-dihydroxyphenyl) -3- (4-methoxyphenyl) - (2E) -2-propen-1-one (23)

Compound 23, colorless oily liquid (yield=40%); ¹ H NMR(400MHz,Acetone-d ₆ )δ _H :8.91(s,1H),8.75(s,1H),7.69(d,J＝8.6Hz,2H),7.39(d,J＝16.1Hz,1H),7.01(d,J＝8.7Hz,2H),6.93(d,J＝16.1Hz,1H),6.64(d,J＝2.7Hz,1H),6.42(d,J＝2.7Hz,1H),3.86(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :193.98,162.10,157.69,155.14,145.97,143.71,130.44(C×2),127.22,124.09,114.47(C×2),107.14,104.25,96.12,54.94.(+)-HR ESIMS:m/z＝349.0067,calcd for C ₁₆ H ₁₄ O ₄ Br[M+H] ⁺ :349.0070.

example 24:

1- (2-bromo-3, 5-dimethoxymethylphenyl) -3- (3-bromo-4-methoxyphenyl) - (2E) -2-propen-1-one (24)

Compound 1c 638mg (2 mmol) was dissolved in 30ml of a mixed solvent of methanol and water (methanol: water=2:1, v/v), and 96mg (1.2 eq) of NaOH solid was added. After stirring at room temperature for 10 minutes, 430mg (2 mmol) of 3-bromo-4-methoxybenzaldehyde was added thereto, and the reaction was continued for 10 hours. The reaction solution was diluted with 30ml of water, filtered, washed with methanol, and the resulting solid was dried to give compound 24 (328 mg, 88%) as a white solid.

Compound 24, white solid (yield=88%); ¹ H NMR(400MHz,chloroform-d)δ _H :7.75(d,J＝2.0Hz,1H),7.47(dd,J＝8.6,2.0Hz,1H),7.31(d,J＝16.1Hz,1H),6.94(d,J＝2.7Hz,1H),6.90(d,J＝16.1Hz,1H),6.89(d,J＝8.6Hz,1H),6.72(d,J＝2.7Hz,1H),5.26(s,2H),5.15(s,2H),3.92(s,3H),3.53(s,3H),3.46(s,3H). ¹³ C NMR(400MHz,chloroform-d)δ _C :194.39,157.94,157.48,154.84,144.96,143.23,133.33,129.51,128.50,125.08,112.44,111.91,109.28,106.06,101.94,95.32,94.73,56.62,56.46,56.31.(+)-HR ESIMS:m/z＝514.9698,calcd for C ₂₀ H ₂₁ O ₆ Br ₂ [M+H] ⁺ :514.9699.

synthesis method of compounds 25 to 27

Compound 24 mg (1 mmol) was dissolved in 20ml dry methanol, 49% aqueous HBr was slowly added at 50 ℃ and after stirring reaction was maintained at 50 ℃ for 6 hours, the reaction solution was cooled to-10 ℃, pH was adjusted to neutral with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the product mixture was separated by column chromatography on silica gel with dichloromethane: methanol=10:1 as eluent to give colorless oily liquid compounds 25 (142 mg, 30%), 26 (118 mg, 25%) and 27 (128 mg, 30%).

Synthesis of end products 25 to 27 (Compound code corresponds to the Compound code in the examples)

Example 25:

1- (2-bromo-3-hydroxy-5-methoxymethylphenyl) -3- (3-bromo-4-methoxyphenyl) - (2E) -2-propen-1-one (25)

Compound 25, colorless oily liquid (yield=30%); ¹ H NMR(400MHz,Acetone-d ₆ )δ _H :9.12(s,1H),8.00(d,J＝2.1Hz,1H),7.74(dd,J＝8.6,2.2Hz,1H),7.39(d,J＝16.1Hz,1H),7.17(d,J＝8.6Hz,1H),7.04(d,J＝16.1Hz,1H),6.83(d,J＝2.7Hz,1H),6.62(d,J＝2.7Hz,1H),5.20(s,2H),3.97(s,3H),3.44(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :193.53,157.94,157.57,155.16,144.36,143.46,133.09,129.86,128.72,125.19,112.49,111.77,107.72,105.29,98.61,94.45,56.02,55.36.(+)-HR ESIMS:m/z＝470.9433,calcd for C ₁₈ H ₁₇ O ₅ Br ₂ [M+H] ⁺ :470.9437.

example 26:

1- (2-bromo-3-methoxymethyl-5-hydroxyphenyl) -3- (3-bromo-4-methoxyphenyl) - (2E) -2-propen-1-one (26)

Compound 26, colorless oily liquid (yield=25%); ¹ H NMR(500MHz,Acetone-d ₆ )δ _H :8.88(s,1H),8.00(s,1H),7.74(d,J＝8.6Hz,1H),7.39(d,J＝16.1Hz,1H),7.17(d,J＝8.6Hz,1H),7.02(d,J＝16.1Hz,1H),6.84(d,J＝2.5Hz,1H),6.55(d,J＝2.5Hz,1H),5.29(s,2H),3.97(s,3H),3.50(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :193.61,157.94,157.72,154.90,144.31,143.62,133.07,129.86,128.70,125.25,112.49,111.78,108.54,104.66,98.42,95.07,56.02,55.67.(+)-HR ESIMS:m/z＝470.9435,calcd for C ₁₈ H ₁₇ O ₅ Br ₂ [M+H] ⁺ :470.9437.

example 27:

1- (2-bromo-3, 5-dihydroxyphenyl) -3- (3-bromo-4-methoxyphenyl) - (2E) -2-propen-1-one (27)

Compound 27 as a colorless oily liquid (yield=30%); ¹ H NMR(400MHz,Acetone-d ₆ )δ _H :8.91(s,1H),8.74(s,1H),8.01(d,J＝2.2Hz,1H),7.74(dd,J＝8.6,2.2Hz,1H),7.38(d,J＝16.1Hz,1H),7.17(d,J＝8.6Hz,1H),7.01(d,J＝16.2Hz,1H),6.65(d,J＝2.7Hz,1H),6.43(d,J＝2.7Hz,1H),3.97(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :193.76,157.90,157.70,155.16,144.20,143.49,133.04,129.83,128.75,125.32,112.49,111.77,107.22,104.40,96.12,56.01.(+)-HR ESIMS:m/z＝426.9172,calcd for C ₁₆ H ₁₃ O ₄ Br ₂ [M+H] ⁺ :426.9175.

example 28:

1- (2-chloro-3, 5-dimethoxymethylphenyl) -3- (3-methoxy-4-methoxymethylphenyl) - (2E) -2-propen-1-one (28)

Compound 1b 549mg (2 mmol) was dissolved in 30ml of a mixed solvent of methanol and water (methanol: water=2:1, v/v), and 96mg (1.2 eq) of NaOH solid was added. Stirring at room temperature for 10 min, adding 392mg (2 mmol) of 3-methoxy-4-methoxymethylbenzaldehyde and continuing the reaction for 10h. The reaction solution was diluted with 30ml of water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the resultant mixture was separated by 200-300 mesh silica gel column chromatography, and petroleum ether: ethyl acetate: dichloromethane (8:1:3) was eluted to give 28 (841 mg, 93%) as a colorless oily liquid.

Compound 28, colorless oily liquid (yield=93%); ¹ H NMR(500MHz,Acetone-d ₆ )δ _H :7.44(d,J＝16.0Hz,1H),7.41(s,1H),7.26(d,J＝8.2Hz,1H),7.17(d,J＝8.3Hz,1H),7.07(d,J＝16.0Hz,1H),7.06(d,J＝2.5Hz,1H),6.80(d,J＝2.4Hz,1H),5.36(s,2H),5.26(s,4H),3.92(s,3H),3.54(s,3H),3.48(s,6H). ¹³ C NMR(101MHz,Acetone-d ₆ )δ _C :192.81,156.76,153.91,150.60,149.31,146.41,141.53,128.92,124.77,122.95,116.40,112.49,111.38,108.65,106.10,95.24,94.98,94.61,55.79,55.48(C×2),55.36.(+)-HR ESIMS:m/z＝453.1308,calcd for C ₂₂ H ₂₆ O ₈ Cl[M+H] ⁺ :453.1310.

example 29:

1- (2-bromo-3-hydroxy-5-methoxyphenyl) -3- (3, 4-dimethoxyphenyl) - (2E) -2-propen-1-one (29)

Compound 1c 638mg (2 mmol) was dissolved in 30ml of a mixed solvent of methanol and water (methanol: water=2:1, v/v), and 96mg (1.2 eq) of NaOH solid was added. After stirring at room temperature for 10 minutes, 332mg (2 mmol) of 3, 4-dimethoxybenzaldehyde was added thereto, and the reaction was continued under stirring for 10 hours. The reaction solution was diluted with 30ml of water, filtered, and concentratedWashed with alcohol and dried to give compound 1d (82 mg, 88%) as a white solid. Dissolving compound 1d 467mg (1 mmol) in 20ml dry methanol, slowly adding 49% HBr water solution at 50deg.C, stirring at 50deg.C for 10 hr, cooling to-10deg.C, adjusting pH to neutral with saturated sodium bicarbonate solution, extracting with ethyl acetate, mixing organic phases, washing with saturated saline solution, drying with anhydrous magnesium sulfate, concentrating under reduced pressure, dissolving the obtained oil in 10ml dry acetone, adding K ₂ CO ₃ (138 mg,1 mmol) of solid was stirred at room temperature for 30min and CH was slowly added ₃ I (78 mg,0.55 mmol) and stirring at room temperature was continued for 10h. The reaction was stopped, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure, and the resulting mixture was separated by silica gel column chromatography using methylene chloride: methanol=10:1 as eluent to give compound 29 (161 mg, 41%) as a colorless oily liquid.

Compound 29, colorless oily liquid (yield=41%); ¹ H NMR(400MHz,Acetone-d ₆ )δ _H :9.00(s,1H),7.38(d,J＝3.6Hz,1H),7.36(d,J＝16.0Hz,1H),7.25(dd,J＝8.3,2.0Hz,1H),7.01(d,J＝8.4Hz,1H),6.97(d,J＝16.1Hz,1H),6.69(d,J＝2.7Hz,1H),6.51(d,J＝2.8Hz,1H),3.88(s,3H),3.87(s,3H),3.81(s,3H). ¹³ C NMR(400MHz,Acetone-d ₆ )δ _C :193.97,159.97,155.08,152.18,149.80,146.71,143.75,127.44,124.11,123.47,111.50,110.54,105.32,102.99,97.48,55.26,55.23,55.12.(+)-HR ESIMS:m/z＝393.0328,calcd for C ₁₈ H ₁₈ O ₅ Br[M+H] ⁺ :393.0332.

pharmacological experiments

The pharmacological test method and results of the anti-inflammatory activity of the compounds of the present invention are as follows (the compound codes of the pharmacological test section correspond to those of the examples):

example 1: inhibition activity of novel chalcone derivatives on LPS-induced generation of NO by peritoneal macrophages of primary mice.

Macrophages, which perform the nonspecific immune function of the organism, can produce inflammatory factors such as NO and the like under the induction of bacterial lipopolysaccharide LPS, participate in and mediate inflammatory reactions, and have higher levels in the early stages of various inflammatory immune processes and in the pathological development process. The NO production of the primary cultured mouse macrophage can be detected to be used as an index for initially observing and screening components or compounds with certain anti-inflammatory activity in vitro.

The experimental method comprises the following steps:

taking primary mouse abdominal cavity macrophages to inoculate in a 96-well plate, adding different compounds to be detected (10) ^-5 M) and a positive control drug dexamethasone (Dex) were pre-protected for 1h; then, 1. Mu.g/ml LPS was added at 37℃with 5% CO ₂ Culturing in incubator for 24 hr, collecting supernatant, and determining NO content by Griess method Meanwhile, the MTT method is used for measuring the inhibition rate of cell proliferation; and determining IC having a compound with significant inhibitory activity on NO production ₅₀ Values (calculated using the Probit weighted regression analysis).

Experimental results:

the results are shown in Table 1, and the thus-synthesized halochalcone derivative NO production-inhibiting activity was remarkable. Wherein, the compounds 6, 8 and 24 not only have remarkable NO generation inhibition activity, but also have cytotoxicity remarkably lower than that of positive control drug dexamethasone.

TABLE 1 Effect of halogenated chalcone derivatives on LPS-induced primary mouse peritoneal macrophage NO production ^* .

* Concentration: 10 ^-5 M; the treatment direction is as follows: anti-inflammatory; positive control dexamethasone (DEX, 10) ^-6 M)。

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

Experimental example 2: effect of novel chalcone derivatives on croton oil-induced otitis in mice

The experimental method comprises the following steps:

taking 18-20g male Kunming mice, randomly grouping, and coating 0.02ml of Baba soybean oil on two sides of the left ear of each group of animals; after 30 minutes, animals in the dosing group were given 100mg/kg body weight of the test compound subcutaneously, and the model control group was given an equal volume of vehicle; after 4 hours of administration, mice were sacrificed by cervical removal, ears were cut off along the auricle baseline, ears at the same positions of the left and right ears were removed by a 6mm diameter punch, and the ears were weighed by an analytical balance, and ear swelling degree (ear swelling degree=left ear weight-right ear weight) and ear swelling inhibition rate [ ear swelling inhibition rate (%) = (model group average ear swelling degree-administration group ear swelling degree)/model group average ear swelling group×100% ].

Experimental results:

the experimental results are shown in table 2, and compound 8 has a remarkable inhibiting effect on ear swelling of mice otitis induced by croton oil at doses of 100 and 200mg/kg, and shows good in vivo anti-inflammatory activity.

TABLE 2 Effect of halogenated chalcone derivatives on croton oil induced otitis in mice

* Route of administration: subcutaneous injection; the treatment direction is as follows: anti-inflammatory.

Claims

1. A halochalcone derivative represented by the general formula (I):

wherein X is selected from F, cl, br, I;

R ₁ 、R ₂ each independently selected from hydrogen, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1-6 Acyl, substituted or unsubstituted benzyl, substituted or unsubstitutedSubstituted C _3-6 Cycloalkyl, cyclopropylmethyl, MOM, glu, SO ₃ H、PO ₃ H ₂ The method comprises the steps of carrying out a first treatment on the surface of the The substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituent is selected from hydroxy, nitro, cyano, amino, carboxyl and C _1-6 Alkoxy, C _3-6 Cycloalkyl, F, cl, br, I;

2. The halochalcone derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by general formula (II):

wherein R is ₁ 、R ₂ Each independently selected from hydrogen, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1-6 Acyl, takeSubstituted or unsubstituted benzyl, substituted or unsubstituted C _3-6 Cycloalkyl, cyclopropylmethyl, MOM, glu, SO ₃ H、PO ₃ H ₂ The method comprises the steps of carrying out a first treatment on the surface of the The substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituent is selected from hydroxy, nitro, cyano, amino, carboxyl and C _1-6 Alkoxy, C _3-6 Cycloalkyl, F, cl, br, I;

3. The halochalcone derivative or pharmaceutically acceptable salt thereof according to claim 2, wherein the compound is represented by the general formula (IIA), (IIB) and (IIC):

wherein R is ₁ 、R ₂ Each independently selected from hydrogen, substituted or unsubstituted C _1-6 Is an alkane of (2)Radicals, substituted or unsubstituted C _1-6 Acyl, substituted or unsubstituted benzyl, substituted or unsubstituted C _3-6 Cycloalkyl, cyclopropylmethyl, MOM, glu, SO ₃ H、PO ₃ H ₂ The method comprises the steps of carrying out a first treatment on the surface of the The substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituent is selected from hydroxy, nitro, cyano, amino, carboxyl and C _1-6 Alkoxy, C _3-6 Cycloalkyl, F, cl, br, I;

4. The halochalcone derivative or pharmaceutically acceptable salt thereof according to claim 2, wherein the compound is represented by the general formula (IID):

wherein R is ₁ 、R ₂ Each independently selected from hydrogen, substituted or unsubstitutedC of (2) _1-6 Alkyl, substituted or unsubstituted C _1-6 Acyl, substituted or unsubstituted benzyl, substituted or unsubstituted C _3-6 Cycloalkyl, cyclopropylmethyl, MOM, glu, SO ₃ H、PO ₃ H ₂ The method comprises the steps of carrying out a first treatment on the surface of the The substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituent is selected from hydroxy, nitro, cyano, amino, carboxyl and C _1-6 Alkoxy, C _3-6 Cycloalkyl, F, cl, br, I;

5. The halochalcone derivative or pharmaceutically acceptable salt thereof according to claim 4, wherein the compound is represented by the general formulae (IIDa) and (IIDb):

wherein R is ₁ 、R ₂ Each independently ofIn situ selected from hydrogen, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1-6 Acyl, substituted or unsubstituted benzyl, substituted or unsubstituted C _3-6 Cycloalkyl, cyclopropylmethyl, MOM, glu, SO ₃ H、PO ₃ H ₂ The method comprises the steps of carrying out a first treatment on the surface of the The substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituent is selected from hydroxy, nitro, cyano, amino, carboxyl and C _1-6 Alkoxy, C _3-6 Cycloalkyl, F, cl, br, I;

6. The halochalcone derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by general formula (III):

7. The halochalcone derivative or pharmaceutically acceptable salt thereof according to claim 6, wherein the compound is represented by general formulae (IIIA), (IIIB) and (IIIC):

8. The halochalcone derivative or pharmaceutically acceptable salt thereof according to claim 6, wherein the compound is represented by general formula (IIID):

9. The halochalcone derivative or pharmaceutically acceptable salt thereof according to claim 8, wherein the compound is represented by general formulae (IIIDa) and (IIIDb):

10. The halochalcone derivative or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein the compound is selected from the group consisting of:

11. a pharmaceutical composition comprising an effective amount of a halochalcone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-10 and a pharmaceutically acceptable carrier or adjuvant.

12. The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is selected from the group consisting of tablets, capsules, pills and injections.

13. Pharmaceutical composition according to claim 11, characterized in that the pharmaceutical composition is selected from a slow release formulation, a controlled release formulation or various particulate delivery systems.

14. Use of a halochalcone derivative according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prophylaxis of inflammation and/or inflammation immune-related disorders.

15. The use according to claim 14, wherein the inflammation and inflammation-immune related disorder comprises: rheumatoid arthritis, osteoarthritis, 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, wind-heat dampness, gingivitis, periodontitis, canker sore, nephritis, swelling occurring after damage, myocardial ischemia, various infectious pneumonia, physicochemical pneumonia and allergic pneumonia, spastic anal pain and rectal fissure, hepatobiliary inflammation, cholangitis, sclerosing cholangitis or primary biliary cirrhosis and cholecystitis.