WO2023177191A1 - Composition for preventing or treating fibrotic diseases, comprising dimethylchalcone derivative as active ingredient - Google Patents

Abstract

The present invention relates to a composition for preventing or treating fibrotic diseases, the composition comprising a dimethylchalcone derivative as an active ingredient, and more specifically, to a composition for alleviating, preventing, or treating fibrotic diseases, the composition comprising a derivative of 2',4'-dihydroxy-6'-methoxy-3'5'-dimethylchalcone as an active ingredient. The DMC derivatives according to the present invention exhibit the effect of inhibiting the expression of PAI-1 and α-SMA by TGFβ1. Thus, the DMC derivatives can effectively prevent or treat various fibrotic diseases including renal fibrosis.

Description

Composition for preventing or treating fibrotic disease containing a dimethyl chalcone derivative as an active ingredient

The present invention relates to a composition for preventing or treating fibrotic diseases containing a dimethyl chalcone derivative as an active ingredient, and more specifically, 2',4'-dihydroxy-6'-methoxy-3',5'-dimethyl chalcone. It relates to a composition for preventing, improving, or treating fibrotic disease, which contains a derivative of as an active ingredient.

The present invention claims priority based on Korean Patent Application No. 10-2022-0032392 filed on March 15, 2022 and Korean Patent Application No. 10-2023-0032966 filed on March 14, 2023, and the above All contents disclosed in the specifications and drawings of the applications are incorporated into this application.

Fibrosis of biological tissues is a phenomenon in which excessive accumulation of extracellular matrix, such as collagen, occurs in tissues during the process of injury and repair of damaged tissues. This type of fibrosis can occur in all organs in the body, and is especially likely to occur when damage is severe and extensive and when damage and recovery are repeated, such as in chronic diseases. When fibrosis occurs, damaged tissue is replaced by fibrotic tissue that cannot function normally, reducing organ function. Therefore, when fibrosis occurs extensively, organ function is greatly reduced, causing various diseases. In particular, if fibrosis occurs in internal organs that directly affect life, such as the liver, lungs, kidneys, and heart, it can have a fatal impact on health. In general, the process by which fibrosis occurs can be divided into 1) the process of exposure to a fibrosis-causing disease (usually a chronic disease) or triggering substance, and 2) the resulting fibrosis process (inflammation, fibrosis, and angiogenesis). When inflammation and damage occur due to fibrosis-causing diseases or substances, fibrosis and angiogenesis are promoted by growth factors and cytokines secreted by cells participating in this process. Therefore, fibrotic diseases can be treated by removing the cause (disease or substance) that causes fibrosis or suppressing the fibrosis process. However, it is virtually impossible to completely eliminate the cause of fibrosis. There are cases where the cause is unknown, such as idiopathic pulmonary fibrosis, and most causes include chronic viral hepatitis and steatohepatitis, which are the main causes of liver fibrosis, diabetes, which causes heart and kidney fibrosis, and aging, which often causes various fibrotic diseases. Complete cure is impossible. Therefore, treatment of fibrotic diseases must include not only treatment of the causative disease, but also treatment that suppresses the fibrosis process (inflammation, fibrosis, and angiogenesis). However, a treatment that inhibits the fibrosis process has not yet been developed. Therefore, there is a need to develop new treatments that can efficiently prevent and treat these fibrotic diseases.

The present invention was devised to solve the problems in the prior art as described above, and provides 2',4'-dihydroxy-6'-methoxy-3',5'- that can simultaneously treat complex symptoms of fibrotic disease. The purpose is to provide a composition for preventing, improving, or treating fibrotic diseases containing a derivative of dimethyl chalcone as an active ingredient.

However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art to which the present invention belongs from the description below. will be.

The present invention uses a derivative of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a composition for preventing, improving, or treating fibrotic diseases, comprising: The composition may preferably be a pharmaceutical composition, food composition, functional food composition, etc., but is not limited thereto:

[Formula 1]

In Formula 1,

R ₀ , R ₁ , and R ₂ is each independently a hydroxy group (OH), a methoxymethoxy group (OCH ₂ OCH ₃ ; OMOM), or a C1-C10 alkoxy group,

R ₃ to R ₇ are each independently a halogen atom, hydrogen (H), deuterium (D), hydroxy group (OH), thiol group (SH), amino group (NH ₂ ), nitrile group, nitro group, substituted or unsubstituted. Substituted C1-C10 alkylamino group, substituted or unsubstituted C1-C10 alkoxy group, substituted or unsubstituted C1-C10 alkylsulfoxy group, substituted or unsubstituted C1-C10 alkyl group, substituted or unsubstituted C2-C10 alkyl group. Kenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C6-C20 aryl group, substituted or unsubstituted C1-C10 alkylthio group, and substituted or unsubstituted C1-C10 alkylsulfonyl group. It is one selected from the group,

The 'substituted or unsubstituted' refers to a halogen group, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, imide group, amino group, phosphine oxide group, alkoxy group, aryloxy group, alkylthioxy group, aryl Thioxy group, alkylsulfoxy group, arylsulfoxy group, silyl group, boron group, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, alkylaryl group, alkylamine group. It may be substituted or unsubstituted with one or more substituents selected from the group consisting of aralkylamine group, heteroarylamine group, arylamine group, arylphosphine group, and heterocyclic group, but is not limited thereto.

In one embodiment of the present invention, R ₀ , R ₁ , and At least one of R ₂ may not be OH, but is not limited thereto.

Additionally, in one embodiment of the present invention, when R ₀ and R ₁ are simultaneously a methoxy group (OCH ₃ ; OMe) or OMOM, R ₂ may not be OH or OMOM, but is not limited thereto.

Additionally, in one embodiment of the present invention, R ₆ and R ₇ may each independently be H, OH, a C1-C5 alkoxy group, or OMOM, but are not limited thereto. More preferably, R ₆ and R ₇ may each independently be H, OH, OMe, or OMOM.

Additionally, in one embodiment of the present invention, the alkylthio group may be a C1-C5 alkylthio group, more preferably a methylthio group or an ethylthio group, but is not limited thereto.

The halogen element is a group 17 element of the periodic table and may include fluorine (F), chlorine (Cl), bromine (Br), iodine (I), etc., but is not limited thereto.

Throughout this specification, C1-C10 includes C1-C10, C1-C8, C1-C5, C1-C3, and C1-C2, etc. Likewise, C2-C10 includes C2-C10, C2-C8, C2-C6, C2-C5, C2-C4, and C2-C3, etc. C6-C20 includes C6-C18, C6-C15, C6-C12, C6-C10, and C6-C8, etc.

In one embodiment of the present invention, the derivative of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone represented by Formula 1 is preferably represented by Formula 2 to Formula 2 below: It may be any one or more compounds selected from the group consisting of 40 or a pharmaceutically acceptable salt thereof, but if it is a derivative derived from 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone. This is not limited to:

Throughout this specification, 'compound represented by formula N' may be referred to simply as 'compound N' or 'formula N'.

In another embodiment of the present invention, the derivative of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone represented by Formula 1 is PAI-1 and α-SMA. It may be characterized by inhibiting the expression or activity of one or more selected from the group consisting of, but is not limited to this.

In another embodiment of the present invention, the fibrotic disease may preferably be any one or more selected from the group consisting of renal fibrosis, liver cirrhosis, cardiac fibrosis, scleroderma, skeletal muscle fibrosis, liver fibrosis, pulmonary fibrosis, and diabetic fibrosis. , PAI-1, and α-SMA, as long as it is a fibrotic disease that can be treated by inhibiting the expression or activity of one or more selected from the group consisting of PAI-1 and α-SMA.

In addition, the present invention uses a derivative of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Provided is a method for preventing or treating fibrotic disease, comprising the step of administering a composition comprising the same to an individual in need thereof.

In addition, the present invention provides a derivative of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone represented by Formula 1, or Provided is the use of a composition containing pharmaceutically acceptable salts thereof as active ingredients.

In addition, the present invention provides a 2',4'-dihydroxy-6'-method represented by Formula 1 above for producing a drug used for fibrotic disease (i.e., a drug for preventing, improving, or treating fibrotic disease). Provided is a use of derivatives of toxy-3',5'-dimethylchalcone or pharmaceutically acceptable salts thereof.

DMC derivatives according to the present invention have the effect of suppressing the increase in expression of PAI-1 and α-SMA caused by TGFβ1. Therefore, DMC derivatives can effectively prevent or treat various fibrotic diseases, including renal fibrosis.

Figure 1 shows the results of confirming the effect of DMC derivatives on PAI-1 expression according to an embodiment of the present invention.

Figure 2 shows the results of confirming the effect of DMC derivatives on α-SMA expression according to an embodiment of the present invention.

3 to 5 show the structural formulas of DMC derivatives according to an embodiment of the present invention.

Derivatives of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone of the present invention inhibit the increase in expression of PAI-1 and α-SMA caused by TGFβ1, and the present invention Derivatives of can effectively prevent, improve, and treat fibrotic diseases.

As used herein, “fibrotic diseases” may comprehensively include diseases that exhibit hardening of parts of organs, and may include common diseases such as activation of abnormal fibroblasts and accumulation of extracellular matrix (ECM). It refers to a disease that exhibits characteristics. The fibrotic disease may be, but is not limited to, renal fibrosis, liver cirrhosis, cardiac fibrosis, scleroderma, skeletal muscle fibrosis, liver fibrosis, pulmonary fibrosis, or diabetic fibrosis. Additionally, the fibrotic disease may be diffuse fibrosis or focal fibrosis, but is not limited thereto.

As used herein, “renal fibrosis” includes renal tubular interstitial fibrosis. In various fibrotic diseases, including renal fibrosis, the expression of PAI-1 (plasminogen activator inhibitor 1) is increased by TGFβ1. The renal tubulointerstitial fibrosis is a typical feature of chronic kidney disease and eventually leads to end-stage renal disease (ESRD). The main causes of chronic kidney disease (CKD) are diabetes and high blood pressure, and sepsis, ischemia, and obstructive kidney disease are also major causes.

Through specific examples, the present inventors confirmed that DMC derivatives according to the present invention effectively inhibit the expression of PAI-1 and α-SMA induced by TFG β1. That is, the DMC derivative according to the present invention may be characterized by inhibiting the expression or activity of one or more selected from the group consisting of PAI-1 and α-SMA. Furthermore, the DMC derivatives according to the present invention may exert particularly excellent prevention, improvement, and/or treatment effects on fibrotic diseases accompanied by increased expression or activity of PAI-1 and/or α-SMA, but are limited thereto. That is not the case.

In the present invention, “expression of PAI-1 or α-SMA protein” means the final production of PAI-1 or α-SMA protein, and “inhibition of expression of PAI-1 or α-SMA” means PAI- 1 or suppressing the expression of mRNA at the transcription stage of the α-SMA coding gene, or reducing the translation of the mRNA. In the present invention, inhibition of mRNA expression activates an action mechanism that can reduce transcription of the PAI-1 or α-SMA gene in the upstream action mechanism of the PAI-1 or α-SMA coding gene, or, conversely, activates the action mechanism that can reduce the transcription of the PAI-1 or α-SMA gene. Upstream mechanisms that can promote transcription of the α-SMA gene may be suppressed, and methylation of the PAI-1 or α-SMA gene promoter region, or methylation of the PAI-1 or α-SMA gene expression, may be suppressed. All concepts that can directly or indirectly inhibit PAI-1 or α-SMA expression, such as histone modification, are included in the present invention. In the present invention, the reduction in translation of PAI-1 or α-SMA mRNA may include any mechanism that can reduce the translation of produced PAI-1 or α-SMA mRNA, such as translation of PAI-1 or α-SMA mRNA. It may promote the expression or activity of miRNAs, etc., or inhibit the activity of enzymes related to the translation of PAI-1 or α-SMA mRNA, but is not limited thereto.

In addition, in the present invention, "activity of PAI-1 or α-SMA protein" refers to the activity of PAI-1 or α-SMA protein produced through the translation process or the PAI-1 or α-SMA protein already produced and present in the cell. Referring to activity, “reduction in the activity of PAI-1 or α-SMA protein” refers to PAI-1 through processes such as post-translational modification or through activation/inactivation of proteins that interact together. 1 or a decrease in the activity of α-SMA protein.

In the present specification, “TGFβ1 (transforming growth factor β1)” is mainly secreted by damaged kidney epithelial cells and is also secreted by macrophages in kidney tissue. The TGFβ1 causes fibrosis by activating vascular pericytes and interstitial fibroblasts.

As used herein, “α-SMA (alpha smooth muscle actin)” is a marker protein for myofibroblasts, activated fibrotic cells considered to be the main effector cells of tissue fibrosis. Therefore, α-SMA is used as a representative marker protein for fibrosis, and activation of the TGF-β1/α-SMA/collagen pathway in fibroblasts is known to further progress and worsen fibrosis (Cell Physiol Biochem 2018;47:851- 863).

In the present specification, “PAI-1 (plasminogen activator inhibitor 1)” promotes ECM (extracellular matrix) accumulation and inhibits ECM decomposition, causing fibrosis. In addition, in response to TGFβ1, the expression of ECM-related proteins such as α-SMA (α-smooth muscle actin), collagen I, and fibronectin increases, thereby promoting fibrosis.

As used herein, “liver fibrosis” refers to the complex interaction between various types of cells in liver tissue, namely hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells. It is accomplished through. Specifically, the death of hepatocytes activates HSCs and macrophages in the liver, and the activated HSCs and macrophages secrete pro-inflammatory cytokines to attract other immune cells. HSCs are the main donors of myofibroblasts, and as HSCs are activated, the expression of ECM (extracellular matrix) proteins such as collagen-1 and α-SMA increases. In addition, TGFβ1 secreted from hepatocytes that become necrotic due to liver damage activates surrounding HSCs and directly trans-differentiates them into myofibroblasts. Meanwhile, SMAD2/3 mediates TGFβ1 signaling. When TGFβ1 binds to the receptor, SMAD3 is phosphorylated and activated, moves into the nucleus, and induces the expression of collagen, α-SMA, and E-cadherin. Additionally, ECM degradation is suppressed by expressing TIMP-1.

In the present specification, “dimethyl chalcone derivative (DMC derivative)” is not limited as long as it is a derivative derived from dimethyl chalcone, but is preferably a dimethyl chalcone having a variously substituted chalcone structure using phloroglucinol as a starting material. It may be, but is not limited to, a chalcone derivative.

The present invention may also include a pharmaceutically acceptable salt of the DMC derivative of the present invention as an active ingredient. As used herein, the term “pharmaceutically acceptable salt” includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases.

Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid. , benzoic acid, malonic acid, gluconic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, etc. Acid addition salts can be prepared by conventional methods, for example, by dissolving the compound in an excessive amount of aqueous acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone, or acetonitrile. It can also be prepared by heating equimolar amounts of the compound and an acid or alcohol in water and then evaporating the mixture to dryness, or suction filtering the precipitated salt.

Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium. The alkali metal or alkaline earth metal salt can be obtained, for example, by dissolving the compound in an excessive amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. At this time, it is particularly pharmaceutically suitable to produce sodium, potassium or calcium salts as metal salts, and the corresponding silver salts can be obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (eg, silver nitrate).

The content of the DMC derivative of the present invention or a pharmaceutically acceptable salt thereof in the composition of the present invention can be appropriately adjusted depending on the symptoms of the disease, the degree of progression of the symptoms, the patient's condition, etc., for example, 0.0001 to 99.9 based on the total weight of the composition. It may be % by weight, or 0.001 to 50% by weight, but is not limited thereto. The content ratio is a value based on the dry amount with the solvent removed.

The pharmaceutical composition according to the present invention may further include appropriate carriers, excipients, and diluents commonly used in the preparation of pharmaceutical compositions. The excipient may be, for example, one or more selected from the group consisting of diluents, binders, disintegrants, lubricants, adsorbents, humectants, film-coating materials, and controlled-release additives.

The pharmaceutical composition according to the present invention can be prepared as powder, granules, sustained-release granules, enteric-coated granules, solutions, eye drops, ellipsis, emulsions, suspensions, spirits, troches, perfumes, and limonadese according to conventional methods. , tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric-coated capsules, pills, tinctures, soft extracts, dry extracts, liquid extracts, injections, capsules, perfusate, It can be formulated and used in the form of external preparations such as warning agents, lotions, paste preparations, sprays, inhalants, patches, sterilized injection solutions, or aerosols, and the external preparations include creams, gels, patches, sprays, ointments, and warning agents. , it may have a dosage form such as lotion, liniment, pasta, or cataplasma.

Carriers, excipients, and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, and calcium. These include phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

Additives to tablets, powders, granules, capsules, pills, and troches according to the present invention include corn starch, potato starch, wheat starch, lactose, white sugar, glucose, fructose, di-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, and phosphoric acid. Calcium monohydrogen, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropylmethyl. Excipients such as cellulose (HPMC), HPMC 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, and Primogel; Gelatin, gum arabic, ethanol, agar powder, cellulose acetate phthalate, carboxymethyl cellulose, calcium carboxymethyl cellulose, glucose, purified water, sodium caseinate, glycerin, stearic acid, sodium carboxymethyl cellulose, sodium methyl cellulose, methyl cellulose, microcrystalline cellulose, dextrin. , hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, refined shellac, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, etc. binders can be used, Hydroxypropyl methyl cellulose, corn starch, agar powder, methyl cellulose, bentonite, hydroxypropyl starch, sodium carboxymethyl cellulose, sodium alginate, calcium carboxymethyl cellulose, calcium citrate, sodium lauryl sulfate, silicic acid anhydride, 1-hydroxy Propylcellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amylose, guar gum, sodium bicarbonate, polyvinylpyrrolidone, calcium phosphate, gelled starch, gum arabic, Disintegrants such as amylopectin, pectin, sodium polyphosphate, ethyl cellulose, white sugar, magnesium aluminum silicate, di-sorbitol solution, light anhydrous silicic acid; Calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopodium, kaolin, petrolatum, sodium stearate, cacao fat, sodium salicylate, magnesium salicylate, polyethylene glycol (PEG) 4000, PEG 6000, liquid paraffin, hydrogen. Added soybean oil (Lubri wax), aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, Macrogol, synthetic aluminum silicate, silicic anhydride, higher fatty acids, higher alcohol, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, Lubricants such as starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine, and light anhydrous silicic acid can be used.

Additives for the liquid according to the present invention include water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, sucrose monostearate, polyoxyethylene sorbitol fatty acid esters (twin esters), polyoxyethylene monoalkyl ethers, lanolin ethers, Lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethyl cellulose, etc. can be used.

A solution of white sugar, other sugars, or sweeteners, etc. may be used in the syrup according to the present invention, and if necessary, flavoring agents, colorants, preservatives, stabilizers, suspending agents, emulsifiers, thickening agents, etc. may be used.

Purified water can be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. can be used as needed.

Suspensions according to the present invention include acacia, tragacantha, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC 1828, HPMC 2906, HPMC 2910, etc. Topics may be used, and surfactants, preservatives, stabilizers, colorants, and fragrances may be used as needed.

Injections according to the present invention include distilled water for injection, 0.9% sodium chloride injection, IV solution, dextrose injection, dextrose + sodium chloride injection, PEG, lactated IV solution, ethanol, propylene glycol, non-volatile oil - sesame oil. , solvents such as cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristic acid, and benzene benzoate; Solubilizers such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, Tween, nicotinic acid amide, hexamine, and dimethylacetamide; Weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and buffering agents such as gums; Isotonic agents such as sodium chloride; Stabilizers such as sodium bisulfite (NaHSO ₃ ) carbon dioxide gas, sodium metabisulfite (Na ₂ S ₂ O ₅ ), sodium sulfite (Na ₂ SO ₃ ), nitrogen gas (N ₂ ), and ethylenediaminetetraacetic acid; Sulfurizing agents such as sodium bisulfide 0.1%, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetate, and acetone sodium bisulfite; Analgesics such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; It may contain suspending agents such as CM sodium, sodium alginate, Tween 80, and aluminum monostearate.

Suppositories according to the present invention include cacao oil, lanolin, witepsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, Subanal, cottonseed oil, peanut oil, palm oil, cacao butter + Cholesterol, lecithin, Lanet wax, glycerol monostearate, Tween or Span, Imhausen, monolene (propylene glycol monostearate), glycerin, Adeps solidus, Buytyrum Tego -G), Cebes Pharma 16, Hexalide Base 95, Cotomar, Hydrocote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Hydro Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Massa-MF, Massaupol, Masupol-15, Neosupostal-N, Paramound-B, Suposiro (OSI, OSIX, A, B, C, D, H, L), suppositories type IV (AB, B, A, BC, BBG, E, BGF, C, D, 299), Supostal (N, Es), Wecobi (W, R, S, M, Fs), Tegestor triglyceride base (TG-95, MA, 57) and The same mechanism can be used.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include the extract with at least one excipient, such as starch, calcium carbonate, and sucrose. ) or prepared by mixing lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.

Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.

The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat the disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, drug activity, and It can be determined based on factors including sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the medical field.

The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art to which the present invention pertains.

The pharmaceutical composition of the present invention can be administered to an individual through various routes. All modes of administration are contemplated, including oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal space (intrathecal) injection, sublingual administration, buccal administration, intrarectal injection, vaginal injection. It can be administered by internal insertion, ocular administration, ear administration, nasal administration, inhalation, spraying through the mouth or nose, dermal administration, transdermal administration, etc.

The pharmaceutical composition of the present invention is determined depending on the type of drug as the active ingredient along with various related factors such as the disease to be treated, the route of administration, the patient's age, gender, weight, and severity of the disease.

As used herein, “prevention” refers to all actions that suppress or delay the onset of fibrotic disease by administering the composition according to the present invention.

As used herein, “treatment” refers to any action in which symptoms of fibrotic disease are improved or beneficially changed by administration of the composition according to the present invention.

As used herein, “improvement” means the act of reducing at least the degree of a parameter related to the condition being treated, for example, a symptom. At this time, the composition of the present invention can be used simultaneously or separately with a drug for treatment to prevent or improve fibrotic disease.

As used herein, “individual” refers to a subject to whom the composition of the present invention can be administered, preferably a patient with a fibrotic disease, but there is no limitation to the subject.

Additionally, the present invention provides a kit for preventing, improving, or treating fibrotic diseases, comprising the compound according to the present invention or a pharmaceutically acceptable salt thereof.

In the present invention, “kit” refers to a tool containing the compound of the present invention or a pharmaceutically acceptable salt thereof and used for the purpose of preventing or treating fibrotic diseases. In addition to the compound, the kit may include other components, compositions, solutions, devices, etc. commonly required for the preparation, storage, and administration of the materials. For example, the kit may include instructions instructing the properties of the compound according to the present invention, its derivative, or pharmaceutically acceptable salt thereof, their appropriate use and storage, etc.

In addition, the present invention includes derivatives of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone represented by Formula 1 or food-acceptable salts thereof as active ingredients. Provides a food composition for preventing or improving fibrotic diseases.

In the present invention, the term “foodologically acceptable salt” includes salts derived from foodologically acceptable organic acids, inorganic acids, or bases.

In this specification, “food composition” can be used in various foods, such as beverages, gum, tea, vitamin complexes, health supplements, etc., and can be used in pills, powders, granules, drops, tablets, capsules, or It can be used in the form of a beverage. The food composition includes a health functional food composition. At this time, the amount of the DMC derivative of the present invention in the food or beverage can generally be 0.01 to 30% by weight of the total food weight in the case of the food composition of the present invention, and 0.02 to 10g based on 100 mL in the case of the health drink composition. Preferably, it can be added at a rate of 0.3 to 1 g.

More specifically, when using the compound of the present invention, a derivative thereof, or a foodologically acceptable salt thereof as a food additive, the compound may be added as is or used together with other foods or food ingredients, and may be used as appropriate according to conventional methods. It can be used easily. The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment). In general, when manufacturing food or beverages, the compound of the present invention may be added in an amount of 15% by weight or less, or 10% by weight or less, based on the raw materials. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

The food composition of the present invention is an essential ingredient, and there is no particular limitation on the ingredients added other than the DMC derivative of the present invention, and includes common food additives used in the industry, such as natural carbohydrates, flavoring agents, flavoring agents, colorants, fillers, It may contain stabilizers, various nutrients, vitamins, minerals (electrolytes), etc. Examples of the natural carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, etc.; polysaccharides such as dextrins, cyclodextrins; Conventional sugars such as xylitol, sorbitol, and erythritol can be used. Examples of the flavoring agent include natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.). . Examples of flavoring agents include honey, D-mannitol, maltitol solution, and krill concentrate. In addition, it may contain pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. These ingredients can be used independently or in combination. The proportion of these additives is not critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.

Below, preferred embodiments are presented to aid understanding of the present invention. However, the following examples are provided only to make the present invention easier to understand, and the content of the present invention is not limited by the following examples.

[Example]

Example 1. Preparation of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone derivative

Derivatives of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone shown in Table 1 below were synthesized.

Reaction route 1 for producing compounds represented by Formulas 2 to 7 and Formulas 24 to 40 according to embodiments of the present invention is as follows.

<Reaction path 1>

<Reaction step 1>

59.30 mL (6.34 mol) of dimethylformamide was added to a two-neck round bottom flask, and 49.12 mL (6.34 mol) of phosphorus(V) oxychloride was added dropwise at 0°C using a dropping funnel and stirred vigorously for 30 minutes. Anhydrous phloroglucinol (40 g, 3.17 mol) of formula A was dissolved in 1,4-dioxane (200 mL), then added dropwise to the Vilsmeyer reagent prepared previously at 0°C and strongly stirred. After stirring at room temperature for more than 4 hours, a yellow solid was obtained. This compound was transferred to a 2 L round bottom flask, DI water (1.5 L) was added and stirred vigorously for 3 hours. After stirring, the precipitated yellow solid was filtered and dried in a vacuum oven at 30°C for 12 hours to obtain light orange chemical formula B (56.84 g, 98.4%).

mp = 221-224℃; TLC R _f = 0.208 (n-hexane: acetone = 1:2); IR ν _max (cm ^-1 ) 2887.88, 1598.70, 1503.24, 1438.64, 1393.32, 1253.50, and 1186.97; ^1H NMR (300 MHz, DMSO-d ₆ ) δ12.52 (br s, 2H, -OH), 10.01 (s, 2H, CHO), 5.90 (s, 1H, ArH); and ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ191.37 (2C), 169.42 (2C), 169.02 (1C), 103.77 (2C) and 94.07 (1C).

<Reaction step 2>

Chemical formula B (9 g, 49.42 mmol) was added to a round bottom flask, a nitrogen atmosphere was created, and 500 mL of dry acetone was injected using a syringe. After stirring for 10 minutes, dimethyl sulfate (5.16 mL, 54.36 mmol) and sodium bicarbonate (1.66 g, 19.77 mmol) were added. Sodium bicarbonate (1.66 g, 19.77 mmol) was added twice more at 12-hour intervals to this mixture, and stirred at 42°C for 8 days. After the reaction, it was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed using 1% aqueous HCl solution, water, and saturated aqueous NaCl solution, and dried using MgSO ₄ . The solvent was removed by distillation under reduced pressure and separated using column chromatography ( n -hexane : acetone = 20 : 1) to obtain white chemical formula C (6.51 g, 67.2 %).

mp = 139-140℃; TLC R _f = 0.647 (n-hexane: acetone = 3:2); IR ν _max (cm ^-1 ) 2897.52, 1614.13, 1593.88, 1188.90, and 1080.90; ¹ H NMR (300 MHz, CDCl ₃ ) δ13.64 (s, 1H, -OH), 13.09 (s, 1H, -OH), 10.18 (s, 1H, -CHO), 10.05 (s, 1H, -CHO) ), 5.92 (s, 1H, Ar-H), 3.95 (s, 3H, -OCH ₃ ); and ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ191.85 (1C), 191.48 (1C), 171.21 (1C), 168.89 (1C), 168.87 (1C), 104.60 (1C), 104.53 (1C) 91.96 (1C), and 57.46 (1C).

<Reaction Step 3>

Zinc powder (30 g) was stirred in 1% HCl aqueous solution (300 mL) for 1 hour, then mercury(II) chloride (0.9 g) and 3% HCl aqueous solution (150 mL) were added and vigorously stirred at room temperature for 4 hours. Zinc amalgam was prepared by stirring. The amalgam was filtered, washed with 1,4-dioxane, and then placed in a solution of Chemical Formula C and 1,4-dioxane (200 mL). 36% HCl aqueous solution (12 mL) was slowly added to this mixture at 0 °C and stirred for 30 minutes. The reaction mixture was filtered and diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous NaCl solution, and dried using MgSO ₄ . Afterwards, the solvent was removed by distillation under reduced pressure. The product was separated using column chromatography ( n -hexane : acetone = 30 : 1) to obtain white chemical formula D (2.44 g, 94.9 %).

mp = 95-96℃; TLC R _f = 0.500 (n-hexane: acetone = 3:2); IR ν _max (cm ^-1 ) 3375.78, 2920.66, 2852.20, 1615.09, 1505.17, 1454.06, 1329.68, 1275.68, 1208.18, 1112.73, and 1088.62; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ8.83 (s, 1H, -OH), 7.95 (s, 1H, -OH), 6.01 (s, 1H, Ar-H), 3.63 (s, 3H) , -OCH ₃ ), 1.91(s, 3H, -CH ₃ ) and 1.90 (s, 3H, -CH ₃ ); and ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ155.92 (1C), 154.41 (1C), 153.99 (1C), 103.70 (1C), 103.15 (1C), 91.50 (1C), 55.48 (1C) 9.21 (1C), and 9.01 (1C).

<Reaction Step 4>

Add Chemical Formula D (5.5 g, 32.7 mmol) to a round bottom flask, then add acetic anhydride (30.93 mL, 327.2 mmol) using a syringe, and slowly add boron trifluoride diethyl etherate (4.93 mL, 39.3 mmol) at 0°C. did. The mixture was stirred at room temperature for 1 hour and diluted with ethyl acetate. The organic layer was washed with 1% aqueous HCl solution, water, and saturated aqueous NaCl solution, dried using MgSO ₄ , and then distilled under reduced pressure to remove the solvent to obtain Chemical Formula D-1.

After adding Chemical Formula D-1 (7 g, 27.7 mmol) to a round bottom flask, boron trifluoride-acetic acid complex (15.43 mL, 111.1 mmol) was added using a syringe and refluxed for 4 hours. After cooling to room temperature, it was diluted with ethyl acetate, and the organic layer was washed with 1% HCl aqueous solution, water, and saturated NaCl aqueous solution, dried using MgSO ₄ , and then distilled under reduced pressure to remove the solvent to obtain Chemical Formula D-2.

Chemical formula D-2 (4.54 g, 18.0 mmol), methanol/water (1:1 v/v, 30 mL), and potassium carbonate (9.96 g, 72.0 mmol) were added to the round bottom flask and stirred overnight. The mixture was diluted with ethyl acetate, and the organic layer was washed with 1% HCl aqueous solution, water, and saturated NaCl aqueous solution, dried using MgSO ₄ , and then distilled under reduced pressure to remove the solvent. The product was separated using column chromatography ( n -hexane : acetone = 250 : 1) to obtain chemical formula E as a light yellow solid. The overall yield of the three-step reaction to prepare Formula E from Formula D was 72%.

mp = 156°C; TLC R _f = 0.634 (n-hexane: acetone = 1:1); IR ν _max (cm ^-1 ) 3268.75, 2920.66, 2852.20, 1604.48, 1573.63, 1438.64, 1419.35, 1366.32, 1305.57, 1271.82, 1214.93, 1189.86, and 110 1.15; ^1H NMR (300 MHz, DMSO-d ₆ ) δ13.63 (s, 1H, -OH), 9.56 (s, 1H, -OH), 3.67 (s, 3H, -OCH ₃ ), 2.62 (s, 3H , -COCH ₃ ), 2.04 (s, 3H, -CH ₃ ), and 1.98 (s, 3H, -CH ₃ ); and ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ203.05 (1C), 161.02 (1C), 160.77 (1C), 158.78 (1C) 109.61 (1C), 107.74 (1C), 106.80 (1C), 61.37 (1C), 31.03 (1C), 9.23 (1C), and 8.20 (1C).

<5 steps of reaction>

Add chemical formula E (0.95 g, 4.52 mmol) and potassium carbonate (0.75 g, 5.42 mmol) to a round bottom flask, then add dry acetone (40 mL) and chloromethyl methyl ether (0.42 mL, 5.42 mmol) and It was refluxed for an hour. After cooling to room temperature, it was diluted with ethyl acetate, and the organic layer was washed with 1% aqueous HCl solution, water, and saturated aqueous NaCl solution, dried using MgSO ₄ , and then distilled under reduced pressure to remove the solvent. The product was separated using column chromatography ( n -hexane : acetone = 50 : 1) to obtain light yellow chemical formula F (1.085 g, 94.4 %).

mp = 59-60℃; TLC R _f = 0.676 (n-hexane: acetone = 1:1); IR ν _max (cm ^-1 ) 2953.45, 2921.63, 2852.20, 1601.55, 1454.06, 1409.71, 1355.71, 1317.14, 1267.97, 1218.79, and 1172.51; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ12.80 (br s, 1H, -OH), 5.00 (s, 3H, -CH ₂ -O), 3.71 (s, 3H, -OCH ₃ ), 3.51 (s, 3H, -OCH ₃ ), 2.65 (s, 3H, -COCH ₃ ), 2.10 (s, 3H, -CH ₃ ), and 2.04 (s, 3H, -CH ₃ ); and ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ204.33 (1C), 160.79 (1C), 159.09 (1C), 158.21 (1C), 115.34 (1C), 114.69 (1C), 112.42 (1C), 98.96 (1C), 61.52 (1C), 57.14 (1C), 31.59 (1C), 9.76 (1C), and 9.25 (1C).

<6 steps of reaction>

Add chemical formula F (1.42 g, 5.58 mmol) and potassium hydroxide (0.94 g, 16.7 mmol) to a round bottom flask, then add ethanol (30 mL) to completely dissolve them. Appropriately substituted benzaldehyde (6.70 mmol) was added to this solution and stirred at room temperature for 7 days. After dilution with ethyl acetate, the organic layer was washed with 1% NH ₄ Cl aqueous solution, water, and saturated NaCl aqueous solution, dried using MgSO ₄ , and then distilled under reduced pressure to remove the solvent. It was separated using column chromatography ( n -hexane : acetone = 500 : 1) and recrystallized using methanol to obtain yellow solids of Chemical Formulas 11 to 15, Chemical Formulas 24 to 30, Chemical Formulas 34 to 36, and Chemical Formula 38.

[Formula 11 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethylphenyl)-3-(3,4-difluorophenyl)-2-propen-1-one )] Yield: 84.6%

TLC R _f = 0.65 ( n -hexane/acetone = 3:2); IR ν _max (cm ^-1 ) 2926, 23611, 1603, 1410, 1111; ^1H NMR (CDCl ₃ , 600MHz) δ12.95 (s, 1H, OH), 7.86 (d, J = 15.64 Hz, 1H, -C=CH), 7.74 (d, J = 15.64 Hz, 1H, -C =CH), 7.46 (ddd, J = 11.02 Hz, J = 7.63 Hz, J = 2.00 Hz, 1H, Ar-H), 7.37-7.35 (m, 1H, Ar-H), 7.21 (ddd, J = 9.92 Hz, J = 8.27 Hz, J = 8.21 Hz, 1H, Ar-H), 5.02 (s, 2H, -CH ₂ ), 3.65 (s, 3H, -OCH ₃ ), 3.63 (s, 3H, -OCH ₃₎ ), 2.19 (s, 3H, -CH ₃ ), 2.17 (s, 3H, -CH ₃ )

[Formula 12 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethyphenyl)-3-(4-chlorophenyl)-2-propen-1-one)] Yield: 86.2%

TLC R _f = 0.67 ( n -hexane/acetone = 3:2); ^1H NMR (CDCl ₃ , 600MHz) δ 13.01 (s, 1H, OH), 7.92 (d, J = 15.69 Hz, 1H, -C=CH), 7.80 (d, J = 15.69 Hz, 1H, -C= CH), 7.58 (d, J = 8.50 Hz, 2H, Ar-H), 7.39 (d, J = 8.50 Hz, 2H, Ar-H), 5.02 (s, 2H, -CH ₂ ), 3.65 (s, 3H, -OCH ₃ ), 3.63 (s, 3H, -OCH ₃ ), 2.19 (s, 3H, -OCH ₃ ), 2.17 (s, 3H, -OCH ₃ ); ¹³ C NMR (CDCl ₃ , 150 MHz) δ 193.9 (1C), 161.8 (1C), 161.6 (1C), 158.6 (1C), 142.0 (1C), 136.4 (1C), 133.8 (1C), 129.7 (2C) , 129.4 (2C), 127.2 (1C), 116.1 (1C), 116.0 (1C), 112.1 (1C), 99.5 (1C), 62.5 (1C), 57.9 (1C), 9.7 (1C), 9.6 (1C) .

[Formula 13 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethyphenyl)-3-(4-methylthiophenyl)-2-propen-1-one)] Yield: 85.9%

TLC R _f = 0.59 ( n -hexane/acetone = 3:2); ^1H NMR (CDCl ₃ , 600MHz) δ 13.13 (s, 1H, OH), 7.92 (d, J = 15.93 Hz, 1H, -C=CH), 7.82 (d, J = 15.93 Hz, 2H, -C= CH), 7.56 (d, J = 6.84 Hz, 1H, Ar-H), 7.25 (d, J = 6.84 Hz, 2H, Ar-H), 5.02 (s, 2H, -CH ₂ ), 3.65 (s, 3H, -OCH ₃ ), 3.63 (s, 3H, -OCH ₃ ), 2.52 (s, 3H, -SCH ₃ ), 2.19 (s, 3H, -CH ₃ ), 2.17 (s, 3H, -CH ₃ ) ; ¹³ C NMR (CDCl ₃ , 150 MHz) δ 194.0 (1C), 161.6 (1C), 161.5 (1C), 158.6 (1C), 143.2 (1C), 142.4 (1C), 131.8 (1C), 129.0 (2C) , 126.2 (1C), 125.6 (1C), 116.0 (1C), 115.9 (1C), 112.1 (1C), 99.4 (1C), 62.4 (1C), 57.8 (1C), 15.3 (1C), 9.7 (1C) , 9.6 (1C).

[Formula 14 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-(trifluoromethyl)phenyl)-2-propen-1- one)] Yield: 88.4%

^1H NMR (CDCl ₃ , 600MHz) δ 12.95 (s, 1H, OH), 8.01 (d, J = 15.71 Hz, 1H, -C=CH), 7.83 (d, J = 15.71 Hz, 1H, -C= CH), 7.74 (d, J = 8.06 Hz, 2H, Ar-H), 7.67 (d, J = 8.06 Hz, 2H, Ar-H), 5.03 (s, 2H, -CH ₂ ), 3.66 (s, 3H, -OCH ₃ ), 3.63 (s, 3H, -OCH ₃ ), 2.20 (s, 3H, -CH ₃ ), 2.18 (s, 3H, -CH ₃ ); ¹³ C NMR (CDCl ₃ , 150 MHz) δ 193.8 (1C), 162.0 (1C), 161.7 (1C), 158.7 (1C), 141.1 (1C), 138.7 (1C), 131.7 (d, J = 291.74 Hz, 1C), 129.1 (q, J = 35.05 Hz, 1C), 129.1 (1C), 128.6 (2C), 126.0 (q, J = 3.82 Hz, 2C), 116.2 (1C), 116.1 (1C), 112.0 (1C) ), 99.5 (1C), 66.3 (1C), 62.5 (1C), 9.7 (1C), 9.6 (1C).

[Formula 15 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethylphenyl)-3-(2,5-dimethoxyphenyl)-2-propen-1-one )] Yield: 81.8%

TLC R _f = 0.60 ( n -hexane/acetone = 3:2); IR ν _max (cm ^-1 ) 2935, 2358, 1624, 1457, 1143; ^1H NMR (CDCl ₃ , 300MHz) δ 13.21 (s, 1H, OH), 8.21 (d, J = 15.80 Hz, 1H, -C=CH), 7.98 (d, J = 15.80 Hz, 1H, -C= CH), 7.20 (d, J = 2.96 Hz, 1H, Ar-H), 6.94 (dd, J = 8.82 Hz, J = 2.96 Hz, 1H, Ar-H), 6.88 (d, J = 8.82 Hz, 1H) , Ar-H), 5.02 (s, 2H, -CH ₂ ), 3.88 (s, 3H, -OCH ₃ ), 3.82 (s, 3H, -OCH ₃ ), 3.66 (s, 3H, -OCH ₃ ), 3.63 (s, 3H, -OCH ₃ ), 2.19 (s, 3H, -CH ₃ ), 2.17 (s, 3H, -CH ₃ ); ¹³ C NMR (DMSO-d ₆ , 150 MHz) δ 194.5 (1C), 161.6 (1C), 161.4 (1C), 158.7 (1C), 153.7 (1C), 153.5 (1C), 143.2 (1C), 138.7 ( 1C), 127.1 (1C), 117.2 (1C), 115.9 (1C), 115.8 (1C), 113.5 (1C), 112.6 (1C), 112.2 (1C), 99.4 (1C), 62.4 (1C), 57.8 ( 1C), 56.3 (1C), 56.0 (1C), 9.7 (1C), 9.6 (1C).

[Formula 24 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-fluorophenyl)-2-propen-1-one)] Yield: 91.7%

mp = 68℃; TLC R _f = 0.719 (n-hexane: acetone = 1:1); IR ν _max (cm ^-1 ) 3440.94 2943.39, 1628.88, 1603.67, 1508.86, 1143.68, and 1113.05; ¹ H NMR (600 MHz, CDCl ₃ ) δ 13.03 (s, 1H, OH), 7.907.87 (d, J = 15.65 Hz, 1H, C=CH), 7.847.81 (d, J = 15.62 Hz, 1H , C=CH), 7.657.62 (q, J = 8.28 Hz, J = 5.53 Hz, 2H, ArH), 7.127.09 (t, J = 8.46 Hz, J = 8.46 Hz, 2H, ArH), 5.02 ( 2H, -CH2-O-), 3.66 (s, 3H, OCH ₃ ), 3.62 (s, 3H, OCH ₃ ), 2.19 (s, 3H, CH ₃ ), and 2.17 (s, 3H, CH ₃ ); and ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 194.14(1C), 164.69163.04(1C), 160.54(1C), 158.49(1C), 157.63(1C), 142.76(1C), 131.69131.67( 1C), 131.39131.33 (2C), 127.18127.17 (1C), 116.64116.50(2C), 116.17(1C), 115.43(1C), 114.09(1C), 99.45(1C), 62.42(1C), 57.6 0 (1C), 9.98(1C), and 9.92(1C).

[Formula 25 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethylphenyl)-3-phenyl-2-propen-1-one)] Yield: 93.1%

mp = 66℃; TLC R _f = 0.703 (n-hexane: acetone = 1:1); IR ν _max (cm ^-1 ) 3461.57, 2958.27, 1630.64, 1563.19, 1345.28, 1144.75, 1113.27, 1057.07, 940.13 and 1225.54; ¹ H NMR (600 MHz, CDCl ₃ ) δ 13.08 (s, 1H, OH), 7.987.95 (d, J = 15.65 Hz, 1H, C=CH), 7.887.86 (d, J = 15.68 Hz, 1H , C=CH), 7.667.65 (m, 2H, ArH), 7.447.39 (m, 3H, ArH), 5.02 (s, 2H, -CH2-O-), 3.67 (s, 3H, OCH ₃ ) , 3.63 (s, 3H, OCH ₃ ), 2.20 (s, 3H, , CH ₃ ), and 2.18 (s, 3H, CH ₃ ); and ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 194.23 (1C), 160.54 (1C), 158.58 (1C), 157.65 (1C), 143.96 (1C), 135.01 (1C), 131.13 (1C), 129.55 (2C), 129.00(2C), 127.30 (1C), 116.12 (1C), 115.44 (1C), 114.10 (1C), 99.46 (1C), 62.43 (1C), 57.61 (1C), 10.00 (1C), and 9.93 (1C).

[Formula 26 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-tolyl)-2-propen-1-one)] Yield: 85.2%

mp = 61℃; TLC R _f = 0.721 (n-hexane: acetone = 1:1); IR ν _max (cm ^-1 ) 3391.10, 2932.35, 1625.94, 1601.35, 1586.41, 1547.84, 1341.49, 1163.11, 1137.07, 1096.09, 1060.42 and 980.87; ¹ H NMR (600 MHz, CDCl ₃ ) δ 13.12 (s, 1H, -OH), 7.94-7.92 (d, J = 15.61 Hz, 1H, -C=CH), 7.87-7.85 (d, J = 15.64 Hz) , 1H, -C=CH), 7.56-7.55 (d, J = 7.81 Hz, 2H, Ar-H), 7.23-7.22 (d, J = 7.82 Hz, 2H, Ar-H), 5.02 (s, 2H) , -CH2-O-), 3.66 (s, 3H, -OCH ₃ ), 3.62 (s, 3H, -OCH ₃ ), 2.40 (s, 3H, , -CH ₃ ), 2.20 (s, 3H, , - CH ₃ ), and 2.17 (s, 3H, -CH ₃ ); and ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 194.18 (1C), 160.49 (1C), 158.63 (1C), 157.64 (1C), 144.22 (1C), 141.30 (1C), 132.29 (1C), 130.18 (2C), 129.05(2C), 126.20 (1C), 116.11 (1C), 115.41 (1C), 114.02 (1C), 99.45 (1C), 62.40 (1C), 57.60 (1C), 21.52 (1C), 9.99 (1C), and 9.92 (1C).

[Formula 27 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-isopropylphenyl)-2-propen-1-one)] Yield: 83.9%

mp = 65℃; TLC R _f =0.730 (n-hexane: acetone = 1:1); IR ν _max (cm ^-1 ) 3420.22, 2961.13, 1633.54, 1560.36, 1344.72, 1141.05, 1110.29, and 985.97; ¹ H NMR (600 MHz, CDCl ₃ ) δ 13.12 (s, 1H, -OH), 7.95-7.92 (d, J = 15.65 Hz, 1H, -C=CH), 7.88-7.86 (d, J = 15.57 Hz) , 1H, -C=CH), 7.60-7.58 (d, J = 7.9 Hz, 2H, Ar-H), 7.29-7.27 (d, J = 7.94 Hz, 2H, Ar-H), 5.02 (s, 2H) , -CH2-O-), 3.66 (s, 3H, -OCH ₃ ), 3.63 (s, 3H, -OCH ₃ ), 2.98-2.91 (septet, J = 6.96 Hz, 1H, -CH), 2.20 (s , 3H, -CH ₃ ), 2.17 (s, 3H, , -CH ₃ ), and 1.28-1.27 (d, J = 6.91 Hz, 6H, -CH ₃ ); and ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 194.16 (1C), 160.56 (1C), 158.74 (1C), 157.70 (1C), 152.03 (1C), 144.18 (1C), 132.70 (1C), 129.19 (2C), 127.55(2C), 126.23 (1C), 116.12 (1C), 115.41 (1C), 113.93 (1C), 99.45 (1C), 62.42 (1C), 57.60 (1C), 33.86 (1C), 24.03 (2C), 9.99 (1C), and 9.92 (1C).

[Formula 28 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-methoxymethoxyphenyl)-2-propen-1-one)] Yield: 83.1%

mp = 66℃; TLC R _f = 0.633 (n-hexane: acetone = 1:1); IR ν _max (cm ^-1 ) 3431.67, 2958.57, 1631.02, 1152.50, 1140.45, 1057.15, 1054.54, 1005.70// 1632.64, 1560.69, 1512.01, and 1156.51; ¹ H NMR (600 MHz, CDCl ₃ ) δ 13.14 (s, 1H, -OH), 7.88-7.86 (d, J = 15.61 Hz, 1H, -C=CH), 7.86-7.83 (d, J = 15.64 Hz) , 1H, -C=CH), 7.61-7.59 (d, J = 7.81 Hz, 2H, Ar-H), 7.08-7.06 (d, J = 7.82 Hz, 2H, Ar-H), 5.22 (s, 2H) , -CH2-O-), 5.02 (s, 2H, -CH2-O-), 3.66 (s, 3H, -OCH ₃ ), 3.62 (s, 3H, -OCH ₃ ), 3.49 (s, 3H, - OCH ₃ ), 2.19 (s, 3H, , -CH ₃ ), and 2.17 (s, 3H, -CH ₃ ); and ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 194.04 (1C), 160.41 (1C), 159.32 (1C), 158.69 (1C), 157.62 (1C), 144.07 (1C), 130.84(2C), 128.57 (1C), 125.16 (1C), 116.99(2C), 116.03 (1C), 115.38 (1C), 114.01 (1C), 99.44 (1C), 94.15 (1C), 62.38 (1C), 57.60 (1C), 56.20 (1C), 10.00 (1C), and 9.93 (1C).

[Formula 29 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-methoxyphenyl)-2-propen-1-one)] Yield: 92.7%

mp = 88℃; TLC R _f = 0.650 (n-hexane: acetone = 1:1); IR ν _max (cm ^-1 ) 3530.27 2945.69, 1625.57, 1548.34, 1511.09, 1172.30, 1141.29 1113.79, and 939.40; ¹ H NMR (600 MHz, CDCl ₃ ) δ 13.16 (s, 1H, -OH), 7.89-7.86 (d, J = 15.76 Hz, 1H, -C=CH), 7.86-7.83 (d, J = 15.68 Hz) , 1H, -C=CH), 7.62-7.60 (d, J = 8.77 Hz, 2H, Ar-H), 6.94-6.93 (d, J = 8.76 Hz, 2H, Ar-H), 5.02 (s, 2H) , -CH2-O-), 3.86 (s, 3H, -OCH ₃ ), 3.66 (s, 3H, -OCH ₃ ), 3.62 (s, 3H, -OCH ₃ ), 2.19 (s, 3H, -CH ₃ ), and 2.17 (s, 3H, -CH ₃ ); and ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ194.01 (1C), 161.94 (1C), 160.37 (1C), 158.67 (1C), 157.61 (1C), 144.37 (1C), 130.96(2C), 127.60 (1C), 124.63 (1C), 116.05 (1C), 115.37 (1C), 115.08(2C), 113.99 (1C), 99.44 (1C), 62.37 (1C), 57.60 (1C), 55.86 (1C), 9.99 (1C), and 9.92 (1C).

[Formula 30 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-( N,N -dimethylamino)phenyl)-2- propen-1-one)] Yield: 76.4%

TLC R _f = 0.57 (n-hexane/acetone = 3:2); ^1H NMR (DMSO-d ₆ , 600MHz) δ12.64 (s, 1H, OH), 7.73 (d, J=15.46 Hz, 1H, -C=CH), 7.56 (d, J=8.94 Hz, 2H, Ar-H), 7.54 (d, J=15.46 Hz, 1H, -C=CH), 6.74 (d, J=7.48 Hz, 2H, Ar-H), 5.0(s, 2H, -CH ₂ ), 3.62 (s, 3H, -OCH ₃ ), 3.52 (s, 3H, -OCH ₃ ), 3.01 (s, 6H, -N-(CH ₃ ) ₂ ), 2.11 (s, 3H, -CH ₃ ), 2.06 ( s, 3H, -CH ₃ ); ¹³ C NMR (DMSO-d ₆ , 600MHz) δ 192.9 (1C), 159.7 (1C), 158.7 (1C), 157.1 (1C), 152.1 (1C), 145.6 (1C), 130.6 (2C), 121.7 (1C) ), 120.2 (1C), 115.4 (1C), 114.7 (1C), 113.1 (1C), 111.9 (2C), 98.97 (1C), 61.8 (1C), 57.1 (1C), 39.6 (2C), 9.5 (1C) ), 9.4 (1C)

[Formula 34 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethylphenyl)-3-(2-fluorophenyl)-2-propen-1-one)] Yield: 86.2%

^1H NMR (CDCl ₃ , 600MHz) δ13.08 (s, 1H, OH), 8.04 (d, J=15.83 Hz, 1H, -C=CH), 7.98 (d, J=15.83 Hz, 1H, -C =CH), 7.67 (dt, J=7.51 Hz, J=1.69 Hz, 1H, Ar-H), 7.37 (dq, J=8.04 Hz, J=7.41 Hz, J=1.69 Hz, 1H, Ar-H) , 7.19 (t, J=7.41 Hz, 1H, Ar-H), 7.13 (dd, J=10.40 Hz, J=8.04 Hz, 1H, Ar-H), 5.02 (s, 2H, -CH ₂ ), 3.67 (s, 3H, -OCH ₃ ), 3.62 (s, 3H, -OCH ₃ ), 2.19 (s, 3H, -OCH ₃ ), 2.17 (s, 3H, -OCH ₃ ); ¹³ C NMR (CDCl ₃ , 150 MHz) δ 194.1 (1C), 161.9 (d, J=254.55 Hz, 1C), 161.8 (1C), 161.7 (1C), 158.7 (1C), 135.9 (d, J=2.68 Hz, 1C), 131.8 (d, J=8.81 Hz, 1C), 129.4 (d, J=2.88 Hz, 1C), 129.1 (d, J=6.47 Hz, 1C), 124.6 (d, J=3.62 Hz, 1C), 123.5 (1C), 123.4 (1C), 116.4 (d, J=21.98 Hz, 1C), 116.1 (d, J=23.04 Hz, 1C), 112.1 (1C), 99.4 (1C), 62.5 (1C) ), 57.9 (1C), 9.8 (1C), 9.6 (1C)

[Formula 35 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethylphenyl)-3-(3-fluorophenyl)-2-propen-1-one)] Yield: 88.5%

TLC R _f = 0.59 (n-hexane/acetone = 3:2); ^1H NMR (DMSO-d ₆ , 600MHz) δ11.83z (s, 1H, OH), 7.70 (d, J=15.82 Hz, 1H, -C=CH), 7.65 (d, J=15.82 Hz, 1H, -C=CH), 7.62 (dd, J=10.15 Hz, J=2.33 Hz 1H, Ar-H), 7.59 (d, J=7.78 Hz, 1H, Ar-H), 7.49 (ddd, J=8.15 Hz) , J=7.78 Hz, J=5.98 Hz, 1H, Ar-H), 7.28 (ddd, J=10.89 Hz, J=8.15 Hz, J=2.33 Hz ,1H, Ar-H), 5.02(s, 2H, -CH ₂ ), 3.61 (s, 3H, -OCH ₃ ), 3.52 (s, 3H, -OCH ₃ ), 2.11 (s, 3H, -CH ₃ ), 2.08 (s, 3H, -CH ₃ ); ¹³ C NMR (DMSO-d ₆ , 150 MHz) δ 193.7 (1C), 162.4 (d, J = 244.14 Hz, 1C), 160.1 (1C), 157.8 (1C), 157.1 (1C), 141.7 (1C), 137.5 (d, J = 8 Hz, 1C), 131.0 (d, J = 8.4 Hz, 1C), 128.4 (1C), 124.7 (d, J = 2.54 Hz, 1C), 117.2 (d, J = 21.35 Hz, 1C), 115.7 (1C), 115.0 (1C), 114.8 (d, J = 21.93 Hz, 1C), 113.8 (1C), 99.0 (1C), 61.9 (1C), 57.1 (1C), 9.5 (1C), 9.4 (1C).

[Formula 36 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-ethoxy-3-fluorophenyl)-2-propen-1 -one)] Yield: 75.2%

mp. 80-81°C; TLC R _f = 0.62 ( n -hexane/acetone = 3:2); IR ν _max (cm ^-1 ) 2935, 2359, 1627, 1425, 1146; ^1H NMR (CDCl ₃ , 600MHz) δ 13.08 (s, 1H, OH), 7.82 (d, J = 15.63 Hz, 1H, -C=CH), 7.78 (d, J = 15.63 Hz, 1H, -C= CH), 7.41 (dd, J = 12.00 Hz, J = 2.47 Hz, 1H, Ar-H), 7.33 (d, J = 8.55 Hz, 1H, Ar-H), 6.96 (t, J = 8.55 Hz, 1H) , Ar-H), 5.02 (s, 2H, -CH ₂ ), 4.16 (q, J = 6.99 Hz, 2H, -CH ₂ ), 3.66 (s, 3H, -OCH ₃ ), 3.62 (s, 3H, -OCH ₃ ), 2.19 (s, 3H, -CH ₃ ), 2.17 (s, 3H, -CH ₃ ), 1.48 (t, J = 6.99 Hz, 3H, -CH ₃ ); ¹³ C NMR (DMSO-d ₆ , 150 MHz) δ 193.8 (1C), 161.6 (1C), 161.6 (1C), 158.9 (1C), 158.6 (1C), 152.8 (d, J = 246.81 Hz, 1C), 149.2 (d, J = 10.95 Hz, 1C), 142.5 (d, J = 2.51 Hz, 1C), 128.5 (d, J = 6.46 Hz, 1C), 126.1 (d, J = 3.15 Hz, 1C), 125.4 ( 1C), 116.0 (1C), 115.9 (1C), 115.1 (d, J = 18.75 Hz, 1C), 114.4 (1C), 112.1 (1C), 99.4 (1C), 65.0 (1C), 62.4 (1C), 57.8 (1C), 14.8 (1C), 9.7 (1C), 9.6 (1C).

[Formula 38 (1-(2′-hydroxy-4′-(methoxymethoxy)-6′-methoxy-3′,5′-dimethylphenyl)-3-(2-chlorophenyl)-2-propen-1-one)] Yield: 85.7%

^1H NMR (CDCl ₃ , 600MHz) δ12.98 (s, 1H, OH), 8.24 (d, J=15.66 Hz, 1H, -C=CH), 7.92 (d, J=15.66 Hz, 1H, -C =CH), 7.76 (dd, J=7.31 Hz, J=2.17 Hz, 1H, Ar-H), 7.45 (dd, J=7.56 Hz, J=1.76 Hz, 1H, Ar-H), 7.34-7.29 ( m, 2H, Ar-H), 5.02 (s, 2H, -CH ₂ ), 3.66 (s, 3H, -OCH ₃ ), 3.62 (s, 3H, -OCH ₃ ), 2.19 (s, 3H, -OCH ₃ ), 2.17 (s, 3H, -OCH ₃ ); ¹³ C NMR (CDCl ₃ , 150 MHz) δ 193.8 (1C), 161.7 (1C), 161.5 (1C), 158.5 (1C), 138.7 (1C), 135.6 (1C), 133.4 (1C), 131.1 (1C) , 130.3 (1C), 128.9 (1C), 127.7 (1C), 127.1 (1C), 115.9 (1C), 115.8 (1C), 99.3 (1C), 62.4 (1C), 57.7 (1C), 9.5 (1C) , 9.4 (1C).

<7 steps of reaction>

Add one compound (2.3 mmol) of Formulas 11 to 15, Formulas 24 to 30, Formulas 34 to 36, and Formula 38 and 30 mL of methanol into a round bottom flask, and then add p -toluenesulfonic acid (0.528 g, 2.76 mmol). It was stirred at room temperature for 24 hours. After dilution with ethyl acetate, the organic layer was washed with 1% aqueous HCl solution, water, and saturated aqueous NaCl solution, dried using MgSO ₄ , and then distilled under reduced pressure to remove the solvent. By separation using column chromatography ( n -hexane : acetone = 500 : 1), white formulas 2 to 10, formulas 31 to 33, formulas 37, 39, and 40 were obtained.

[Formula 2 (1-(2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-fluorophenyl)-2-propen-1-one)] Yield: 90.1%

mp = 110℃; TLC R _f = 0.623 (n-hexane: acetone = 1:1); IR ν _max (cm ^-1 ) 3375.95, 2926.49, 1630.57, 1604.34, 1543.85, 1510.49, 1416.08, 1237.34, 1165.80, 1157.02, and 1113.64; ¹ H NMR (600 MHz, CDCl ₃ ) δ13.56 (s, 1H, OH), 7.927.89 (d, J = 15.65 Hz, 1H, C=CH), 7.817.79 (d, J = 15.66 Hz, 1H, C=CH), 7.647.62 (q, J = 8.55 Hz, J = 5.45 Hz, 2H, Ar-H), 7.11-7.09 (t, J = 8.56 Hz, J = 8.56 Hz, 2H, Ar- H), 5.37 (s, 1H, -OH), 3.66 (s, 3H, -OCH ₃ ), 2.15 (s, 3H, -CH ₃ ), and 2.13 (s, 3H, -CH ₃ ); and ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ192.76(1C), 164.53-162.88(1C), 161.70(1C), 161.66(1C), 158.73(1C), 141.65(1C), 132.01-131.99 (1C), 131.14-131.08(2C), 126.92-126.91(1C), 116.63-116.46(2C), 110.59(1C), 108.25(1C), 107.60(1C), 62.34(1C), 9.40(1C), and 8.78(1C).

[Formula 3 (1-(2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-tolyl)-2-propen-1-one)] Yield: 90.5%

mp = 126°C; TLC R _f = 0.656 (n-hexane: acetone = 1:1); IR ν _max (cm ^-1 ) 3373.74, 2917.05, 1625.81, 1609.97 1540.24, 1359.81, 1163.45, and 1111.58; ¹ H NMR (600 MHz, CDCl ₃ ) δ13.65 (s, 1H, -OH), 7.96-7.94 (d, J = 15.62 Hz, 1H, -C=CH), 7.85-7.82 (d, J = 15.67 Hz, 1H, -C=CH), 7.55-7.54 (d, J = 7.72 Hz, 2H, Ar-H), 7.23-7.21 (d, J = 7.76 Hz, 2H, Ar-H), 5.42 (s, 1H, -OH), 3.66 (s, 3H, -OCH ₃ ), 2.39 (s, 3H, -CH ₃ ), 2.15 (s, 3H, -CH ₃ ), and 2.13 (s, 3H, -CH ₃ ) ; and ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ192.78(1C), 161.73(1C), 161.65(1C), 158.70(1C), 143.07(1C), 140.95(1C), 132.63(1C), 130.17 (2C) , 128.84 (2C) , 125.93(1C), 110.57(1C), 108.20(1C), 107.58(1C), 62.30(1C), 21.51(1C), 9.41(1C), and 8.79(1C) .

[Formula 4 (1-(2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-isopropylphenyl)-2-propen-1-one)] Yield: 98.4%

mp = 101℃; TLC R _f = 0.656 (n-hexane: acetone = 1:1); IR ν _max (cm ^-1 ) 3343.73, 2956.05, 1628.47, 1605.90, 1552.23, 1354.84, 1166.48, and 1113.41; ¹ H NMR (600 MHz, CDCl ₃ ) δ13.65 (s, 1H, -OH), 7.97-7.94 (d, J = 15.65 Hz, 1H, -C=CH), 7.86-7.83 (d, J = 15.62 Hz, 1H, -C=CH), 7.59-7.58 (d, J = 7.99 Hz, 2H, Ar-H), 7.28-7.27 (d, J = 7.97 Hz, 2H, Ar-H), 5.36 (s, 1H, -OH), 3.66 (s, 3H, -OCH ₃ ), 2.97-2.92 (septet, J = 6.92 Hz, 1H, -CH), 2.16 (s, 3H, -CH ₃ ), 2.13 (s, 3H) , -CH ₃ ) and 1.28-1.27 (d, J = 6.89 Hz, 6H, -CH ₃ ); and ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ192.77 (1C), 161.74 (1C), 161.66 (1C), 158.71 (1C), 151.71 (1C), 143.05 (1C), 133.02 (1C), 128.98(2C), 127.54(2C), 125.99 (1C), 110.58 (1C), 108.21 (1C), 107.58 (1C), 62.31 (1C), 33.85 (1C), 24.06(2C), 9.41 (1C), and 8.79 (1C).

[Formula 5 (1-(2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-methoxyphenyl)-2-propen-1-one)] Yield: 94.9%

mp = 164°C; TLC R _f = 0.590 (n-hexane: acetone = 1:1); IR ν _max (cm ^-1 ) 3516.40, 2943.09, 1628.13, 1606.73, 1558.04, 1509.35, 1348.72, 1162.34, and 1109.43; ¹ H NMR (600 MHz, CDCl ₃ ) δ13.69 (s, 1H, -OH), 7.89-7.87 (d, J = 15.55 Hz, 1H, -C=CH), 7.85-7.82 (d, J = 15.62 Hz, 1H, -C=CH), 7.61-7.59 (d, J = 8.57 Hz, 2H, Ar-H), 6.94-6.92 (d, J = 8.46 Hz, 2H, Ar-H), 5.44 (s, 1H, -OH), 3.85 (s, 3H, -OCH ₃ ), 3.66 (s, 3H, -OCH ₃ ), 2.15 (s, 3H, -CH ₃ ), and 2.13 (s, 3H, -CH ₃ ) ; and ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ192.71 (1C), 161.73 (1C), 161.70 (1C), 161.38 (1C), 158.64 (1C), 143.24 (1C), 130.70(2C), 127.94 (1C), 124.34 (1C), 115.07(2C), 110.48 (1C), 108.23 (1C), 107.57 (1C), 62.27 (1C), 55.84 (1C), 9.41 (1C), and 8.79 (1C) .

[Formula 6 (1-(2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylphenyl)-3-(3,4-difluorophenyl)-2-propen-1-one)] Yield: 89.7%

TLC R _f = 0.59 ( n -hexane/acetone = 3:2); IR ν _max (cm ^-1 ) 3373, 2922, 2359, 1603, 1457, 1111; ^1H NMR (CDCl ₃ , 600MHz) δ13.47(s, 1H, OH), 7.88 (d, J = 15.69 Hz, 1H, -C=CH), 7.71(d, J = 15.69 Hz, 1H, -C =CH), 7.45 (ddd, J =10.93 Hz, J = 7.57 Hz, J = 1.95 Hz 1H, Ar-H), 7.36-7.34 (m, 1H, Ar-H), 7.20 (ddd, J =10.00 Hz , J = 8.33 Hz, J = 8.20 Hz, Ar-H), 5.38 (s, 1H, OH), 3.64 (s, 3H, -OCH ₃ ), 2.15 (s, 3H, -CH ₃ ), 2.13 (s , 3H, -CH ₃ ); ¹³ C NMR (DMSO-d ₆ , 150 MHz) δ192.9 (1C), 162.2 (1C), 159.6 (1C), 158.9 (1C), 151.4 (dd, J = 244.34 Hz, 13.03 Hz, 1C), 150.6 (dd, J = 249.48 Hz, J = 13.11 Hz, 1C), 140.4 (1C), 127.9 (1C), 125.3 (d, J = 3.45 Hz, 1C), 125.2 (d, J = 3.45 Hz, 1C), 118.0 (d, J = 17.67 Hz, 1C), 116.5 (d, J = 17.34 Hz, 1C), 109.1 (1C), 109.0 (1C) 106.7 (1C), 62.5 (1C), 8.3 (1C), 7.6 ( 1C).

[Formula 7 (1-(2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-( N,N -dimethylamino)phenyl)-2-propen-1- one)] Yield: 88.3%

TLC R _f = 0.57 (n-hexane/acetone = 3:2); ^1H NMR (CDCl ₃ , 600MHz) δ13.90 (s, 1H, OH), 7.86 (d, J=15.47 Hz, 1H, -C=CH), 7.81 (d, J=15.47 Hz, 1H, -C =CH), 7.55 (d, J=8.36 Hz, 2H, Ar-H), 6.69 (d, J=8.36 Hz, 2H, Ar-H), 3.65 (s, 3H, -OCH ₃ ), 3.03 (s , 6H, -N-(CH ₃ ) ₂ ), 2.15 (s, 3H, -CH ₃ ) , 2.12 (s, 3H, -CH ₃ ); ¹³ C NMR (CDCl ₃ , 150 MHz) δ193.2 (1C), 162.1 (1C), 159.0 (1C), 158.7 (1C), 152.1 (1C), 144.6 (1C), 130.5 (2C), 123.3 (1C) ), 121.3 (1C), 112.1 (2C), 109.2 (1C), 108.9 (1C), 106.8 (1C), 62.3 (1C), 40.2 (2C), 8.4 (1C), 7.8 (1C).

[Formula 8 (1-(2′, 4′-dihydroxy-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-chlorophenyl)-2-propen-1-one)] Yield: 91.2%

TLC R _f = 0.57 ( n -hexane/acetone = 3:2); ¹ H NMR (DMSO- d ₆ , 600 MHz) δ13.57 (s, 1H, OH), 7.92 (d, J = 15.50 Hz, 1H, -C=C-Hz), 7.76 (d, J = 8.37 Hz, Ar-H), 7.74 (d, J = 15.50 Hz, 1H, -C=CH), 7.52 (d, J = 8.37 Hz, 1H, Ar-H), 3.59 (s, 3H, -OCH ₃ ), 2.06 (s, 3H, -CH ₃ ), 2.01 (s, 3H, -CH ₃ ); ¹³ C NMR (DMSO- d ₆ , 150 MHz) δ 192.2 (1C), 161.4 (1C), 161.3 (1C), 161.0 (1C), 160.7 (1C), 158.3 (1C), 140.8 (1C), 134.8 ( 1C), 133.8 (1C), 130.0 (1C), 129.1 (1C), 127.3 (1C), 110.2 (1C), 107.7 (1C), 107.1 (1C), 61.9 (1C), 8.9 (1C), 8.3 ( 1C).

[Formula 9 (1-(2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-(trifluoromethyl)phenyl)-2-propen-1-one)] Yield : 92.0%

^1H NMR (CDCl ₃ , 600MHz) δ13.46 (s, 1H, OH), 8.03 (d, J = 15.69 Hz, 1H, -C=CH), 7.81 (d, J = 15.69 Hz, 1H, -C =CH), 7.74 (d, J = 8.09 Hz, 2H, Ar-H), 7.67 (d, J = 8.09 Hz, 2H, Ar-H), 5.37 (s, 1H, OH), 3.65 (s, 3H) , -OCH ₃ ), 2.16 (s, 3H, -CH ₃ ), 2.14 (s, 3H, -CH ₃ ); ¹³ C NMR (CDCl ₃ , 150 MHz) δ193.0 (1C), 162.3 (1C), 159.6 (1C), 159.0 (1C), 140.6 (1C), 138.9 (1C), 134.6 (d, J = 293.62 Hz , 1C), 129.6 (1C), 129.3 (q, J = 35.05 Hz, 1C), 128.5 (2C), 126.0 (q, J = 3.72 Hz, 2C), 109.1 (1C), 109.1 (1C), 106.7 ( 1C), 62.5 (1C), 8.3 (1C), 7.6 (1C)

[Formula 10 (1-(2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylphenyl)-3-(2,5-dimethoxyphenyl)-2-propen-1-one)] Yield: 92.5%

TLC R _f = 0.50 ( n -hexane/acetone = 3:2); IR ν _max (cm ^-1 ) 3440, 2924, 2362, 1616, 1457, 1163; ^1H NMR (CDCl ₃ , 300MHz) δ 13.75 (s, 1H, OH), 8.18 (d, J = 15.82 Hz, 1H, -C=CH), 8.00 (d, J = 15.82 Hz, 1H, -C= CH), 7.20 (d, J = 2.91 Hz, 1H, Ar-H), 6.93 (dd, J = 8.97 Hz, J = 2.91 Hz, 1H, Ar-H), 6.87 (d, J = 8.97 Hz, 1H) , Ar-H), 5.75 (s, 1H, OH), 3.87 (s, 3H, -OCH ₃ ), 3.81 (s, 3H, -OCH ₃ ), 3.65 (s, 3H, -OCH ₃ ), 2.14 ( s, 3H, -CH3) , 2.12 (s, 3H, -CH3); 13C NMR (DMSO-d6, 150 MHz) δ 193.8 (1C), 162.2 (1C), 159.1 (1C), 159.0 (1C), 153.7 (1C), 153.4 (1C), 138.1 (1C), 127.3 (1C) , 125.2 (1C), 116.9 (1C), 113.4 (1C), 112.6 (1C), 109.3 (1C), 108.8 (1C), 106.6 (1C), 62.5 (1C), 56.2 (1C), 56.0 (1C) , 8.4 (1C), 7.7 (1C).

[Formula 31 (1-(2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylphenyl)-3-(2-fluorophenyl)-2-propen-1-one)] Yield: 93.7%

^1H NMR (DMSO-d ₆ , 600MHz) δ13.60 (s, 1H, OH), 8.07 (d, J=15.84 Hz, 1H, -C=CH), 7.96 (d, J=15.84 Hz, 1H, -C=CH), 7.66 (t, J=7.64 Hz, 1H, Ar-H), 7.37 (q, J=6.89 Hz, 1H, Ar-H), 7.18 (t, J=7.55 Hz, ,1H, Ar-H), 7.12 (t, J=9.41 Hz, 1H, Ar-H), 5.41 (s, 1H, OH), 3.67 (s, 3H, -OCH ₃ ), 2.15 (s, 3H, -CH ₃ ), 2.13 (s, 3H, -CH ₃ ); ¹³ C NMR (CDCl ₃ , 150 MHz) δ 193.4 (1C), 162.3 (1C), 161.7 (d, J=255.19 Hz, 1C), 159.4 (1C), 159.1 (1C), 135.3 (d, J=2.93 Hz, 1C), 131.6 (d, J=8.71 Hz, 1C), 129.3 (d, J=3 Hz, 1C), 129.2 (d, J=6.38 Hz, 1C), 124.6 (d, J=3.58 Hz, 1C), 123.6 (1C), 123.6 (1C), 116.4 (d, J=21.91 Hz, 1C), 109.1 (d, J=24.62 Hz, 1C), 106.7 (1C), 62.5 (1C), 8.4 (1C) ), 7.7 (1C).

[Formula 32 (1-(2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylphenyl)-3-(3-fluorophenyl)-2-propen-1-one)] Yield: 95.8%

^1H NMR (CDCl ₃ , 600MHz) δ 13.51 (s, 1H, OH), 7.96 (d, J = 15.66 Hz, 1H, -C=CH), 7.77 (d, J = 15.66 Hz, 1H, -C= CH), 7.41-7.36 (m, 2H, Ar-H), 7.34 (d, J = 9.67 Hz, 1H, Ar-H), 7.11-7.07 (m, 1H, Ar-H), 5.37 (s, 1H) , OH), 3.66 (s, 3H, -OCH ₃ ), 2.16 (s, 3H, -CH ₃ ), 2.13 (s, 3H, -CH ₃ ); ¹³ C NMR (CDCl ₃ , 150 MHz) δ 193.3 (1C), 163.3 (d, J=243.91, 1C), 162.3 (1C), 159.6 (1C), 159.1 (1C), 141.4 (d, J=1.65, 1C), 137.9 (d, J=7.75, 1C), 130.6 (d, J=8.4, 1C), 128.3 (1C), 124.7 (d, J= 2.28, 1C), 117.2 (d, J= 20.68, 1C) ), 114.6 (d, J=21.84, 1C), 109.2 (1C), 109.1 (1C), 106.8 (1C), 62.6 (1C), 8.4 (1C), 7.7 (1C).

[Formula 33 (1-(2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-ethoxy-3-fluorophenyl)-2-propen-1-one)] Yield: 88.6%

TLC R _f = 0.56 ( n -hexane/acetone = 3:2); IR ν _max (cm ^-1 ) 3438, 2924, 2359, 1615, 1436, 1163; ^1H NMR (CDCl ₃ , 600MHz) δ 13.61 (s, 1H, OH), 7.84 (d, J = 15.56 Hz, 1H, -C=CH), 7.75 (d, J = 15.56 Hz, 1H, -C= CH), 7.40 (dd, J = 12.11 Hz, J = 2.12 Hz, 1H, Ar-H), 7.32 (d, J = 8.46 Hz, 1H, Ar-H), 6.96 (t, J = 8.46 Hz, 1H) , Ar-H), 5.51 (s, 1H, OH), 4.16 (q, J = 7.00 Hz, 2H, -CH ₂ ), 3.69 (s, 3H, -OCH ₃ ), 2.15 (s, 3H, -CH ₃ ) , 2.12 (s, 3H, -CH ₃ ), 1.47 (t, J = 7.00 Hz, 3H, -CH ₃ ); ¹³ C NMR (DMSO-d ₆ , 150 MHz) δ 193.1 (1C), 162.1 (1C), 159.3 (1C), 158.9 (1C), 152.8 (d, J = 246.65 Hz, 1C), 149.0 (d, J = 10.96 Hz, 1C), 141.9 (d, J = 2.33 Hz, 1C), 128.7 (d, J = 6.63 Hz, 1C), 126.0 (d, J = 3.21 Hz, 1C), 125.6 (1C), 115.0 ( d, J = 18.76 Hz, 1C), 114.9 (1C), 109.1 (1C), 109.0 (1C), 106.7 (1C), 65.0 (1C), 62.4 (1C), 14.8 (1C), 8.3 (1C), 7.7 (1C)

[Formula 37 (1-(2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylphenyl)-3-(2-chlorophenyl)-2-propen-1-one)] Yield: 96.1%

^1H NMR (DMSO-d ₆ , 600MHz) δ13.50 (s, 1H, OH), 8.22 (d, J=15.67 Hz, 1H, -C=CH), 7.95 (d, J=15.67 Hz, 1H, -C=CH), 7.76 (dd, J=6.89 Hz, J=2.55 Hz, 1H, -C=CH), 7.44 (dd, J=6.81 Hz, J= 2.28 Hz, 1H, -C=CH), 7.33-7.28 (m, 2H), 3.65 (s, 3H, -OCH ₃ ), 2.15 (s, 3H, -CH ₃ ), 2.13 (s, 3H, -CH ₃ ); ¹³ C NMR (CDCl ₃ , 150 MHz) δ 193.2 (1C), 162.2 (1C), 159.5 (1C), 159.1 (1C), 138.3 (1C), 135.6 (1C), 133.7 (1C), 130.9 (1C) , 130.4 (1C), 129.3 (1C), 127.8 (1C), 127.2 (1C), 109.2 (1C), 109.1 (1C), 106.7 (1C), 62.5 (1C), 8.3 (1C), 7.7 (1C) .

[Formula 39 (1-(2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylphenyl)-3-phenyl-2-propen-1-one)] Yield: 98.9%

mp 126℃; TLC R _f = 0.62 ( n -hexane/acetone = 1:1); IR ν _max (cm ^-1 ); 3354, 2936, 1628, 1609, 1538 1360, 1220, 1166, 1111, 987; ¹ H NMR (CDCl ₃ , 600 MHz) δ 13.61 (s, 1H, -OH), 7.99 (d, J = 15.67 Hz, 1H, -C=CH), 7.84 (d, J = 15.67 Hz, 1H, - C=CH), 7.65-7.64 (m, 2H, Ar-H), 7.43-7.38 (m, 3H, Ar-H), 5.44 (s, 1H, -OH), 3.66 (s, 3H, -OCH ₃ ), 2.16 (s, 3H, -CH ₃ ), 2.13 (s, 3H, -CH ₃ ); ¹³ C NMR (DMSO-d ₆ , 150 MHz) δ 192.4 (1C), 161.3 (1C), 161.2 (1C), 158.3 (1C), 142.4 (1C), 134.9 (1C), 130.4 (1C), 129.1 ( 2C), 128.3 (2C), 126.6 (1C), 110.1 (1C), 107.8 (1C), 107.1 (1C), 61.9 (1C), 8.9 (1C), 8.3 (1C).

[Formula 40 (1-(2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylphenyl)-3-(4-hydroxyphenyl)-2-propen-1-one)] Yield: 90.5%

mp 180 °C; TLC R _f = 0.52 ( n -hexane/acetone = 1:1); IR ν _max (cm ^-1 ); 3390, 3329, 2930, 1634, 1606, 1556, 1450, 1431, 1168, 1110; ¹ H NMR (CDCl ₃ , 600 MHz) δ 13.66 (s, 1H, -OH), 7.87 (d, J = 15.64 Hz, 1H, -C=CH), 7.82 (d, J = 15.64 Hz, 1H, - C=CH), 7.56 (d, J = 8.56 Hz, 2H, Ar-H), 6.87 (d, J = 8.56 Hz, 2H, Ar-H), 5.30 (s, 1H, -OH), 5.21 (s , 1H, -OH), 3.66 (s, 3H, -OCH ₃ ), 2.15 (s, 3H, -CH ₃ ), 2.13 (s, 3H, -CH ₃ ); ¹³ C NMR (DMSO-d ₆ , 150 MHz) δ 192.2 (1C), 161.2 (1C), 160.8 (1C), 160.0 (1C), 158.1 (1C), 143.4 (1C), 130.5 (2C), 125.9 ( 1C), 122.7 (1C), 116.0 (2C), 110.0 (1C), 107.7 (1C), 107.1 (1C), 61.8 (1C), 8.9 (1C), 8.3 (1C)

Reaction route 2 for producing compounds represented by formulas 16 to 23 according to an embodiment of the present invention is shown as follows.

<Reaction path 2>

<Reaction step 1>

Same as <Reaction Step 1> above.

<Reaction Step 8>

300 mL of 1% HCl aqueous solution and 30 g of Zn were added to a 1000 mL beaker and stirred. Then, 450 mL of 3% HCl and mercury(II) chloride (HgCl _2, 0.9 g) were added and strongly stirred at room temperature. After washing the prepared zinc amalgam with water and 1,4-dioxane, it was added to a solution of Chemical Formula B (3 g, 19.46 mmol) and solvent 1,4-dioxane (300 mL) and stirred for 20 minutes. The reaction mixture was cooled to 0°C, and 36% HCl aqueous solution (12 mL) was slowly added and stirred. The mixture was filtered using 200 mL of water and diluted with 300 mL of ethyl acetate. The organic solvent layer was washed with water and saturated aqueous NaCl solution, and then dried using MgSO ₄ . The solvent was removed by distillation under reduced pressure, and the product was separated using column chromatography ( n -hexane : acetone = 8 : 1) to obtain red-brown chemical formula G (1.717 g, 67.4 %).

mp 162-163℃; TLC R _f = 0.67 (n-hexane:acetone = 1:2); IR ν _max (cm ^-1 ) 3527, 3465, 3425, 2921, 2852, 1609, 1457, 1433, 1247, 1150; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ8.62 (s, 2H, -OH), 7.76 (s, 1H, -OH), 5.92 (s, 1H, Ar-H), 1.86 (s, 6H) , -CH ₃ ); ¹³ C NMR (DMSO-d ₆ , 150 MHz) δ154.1 (2C), 153.2 (2C), 102.6 (1C), 94.6 (1C), 8.7 (2C).

<Reaction step 9>

Chemical formula G (1.717 g, 11.14 mmol) and potassium carbonate (K ₂ CO ₃ , 6.1573 g, 44.55 mmol) were dissolved in dry acetone, then dimethyl sulfate (DMS 4.2154 ml, 44.55 mmol) was injected and refluxed for one day. The mixture was cooled to room temperature, diluted with 300 mL of ethyl acetate, and washed with 1% HCl aqueous solution. The organic solvent layer was washed with water and saturated aqueous NaCl solution, and dried using MgSO ₄ . The solvent was removed by distillation under reduced pressure and separated using column chromatography ( n -hexane : acetone = 300 : 1) to obtain a white solid with chemical formula H (2.1550 g, 98.6%).

mp 152-155℃; TLC R _f = 0.69 (n-hexane:acetone = 3:2); IR ν _max (cm ^-1 ) 2926, 1608, 1496, 1464, 1435, 1401, 1321, 1219, 1193, 1127; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ6.41 (s, 1H, Ar-H), 3.77 (s, 6H, -OCH ₃ ), 3.57 (s, 3H, -OCH ₃ ), 1.98 (s , 6H, -CH ₃ ); ¹³ C NMR (DMSO-d ₆ , 150 MHz) δ157.2 (1C), 156.3 (2C), 109.9 (2C), 91.8 (1C), 59.7 (1C), 55.5 (2C), 8.5 (2C).

<10 steps of reaction>

Acetic anhydride (2.07 mL, 21.96 mmol) was injected into Formula H (2.1550 g, 10.98 mmol). The solution temperature was lowered to 0°C, and boron-trifluoride diethyl etherate (BF ₃ Et ₂ O, 2.7582 mL, 21.96 mmol) was added. The reaction temperature was maintained at 90°C and stirred for 3 hours. Afterwards, the reaction was cooled to room temperature and diluted with 300 mL of ethyl acetate. Then, the organic solvent layer was washed using 1% HCl aqueous solution, water, and saturated NaCl aqueous solution, and dried using MgSO ₄ . The solvent was removed by distillation under reduced pressure and separated using column chromatography ( n -hexane) to obtain chemical formula I (1.8812 g, 76.4%) as a yellow solid.

mp 48-50℃; TLC R _f = 0.66 (n-hexane:acetone = 3:2); IR ν _max (cm ^-1 ) 3440, 2941, 1621, 1454, 1417, 1364, 1318, 1283, 1198, 1171, 1120; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ12.80 (s, 1H, -OH), 3.71 (s, 3H, -OCH ₃ ), 3.69 (s, 3H, -OCH ₃ ), 2.65 (s, 3H,-COCH ₃ ), 2.09 (s, 3H, -CH ₃ ), 2.03 (s, 3H, -CH ₃ ); ¹³ C NMR (DMSO-d ₆ , 150 MHz) δ203.8(1C), 163.2 (1C), 158.8 (1C), 156.7 (1C), 115.4 (1C), 114.8 (1C), 113.9 (1C), 61.6 (1C), 59.9 (1C), 31.4 (1C), 8.7 (2C).

<Reaction Step 11>

Chemical formula I (1.8812 g, 8.389 mmol) and potassium carbonate (K ₂ CO ₃ , 1.3913 g, 10.06 mmol) were dissolved in dry acetone, then dimethyl sulfate (DMS, 0.9519 mL, 10.06 mmol) was injected and left for one day. It was refluxed. The reaction mixture was cooled at room temperature, diluted with 300 mL of ethyl acetate, and washed with 1% HCl aqueous solution. The organic solvent layer was washed with water and saturated NaCl aqueous solution, and moisture was removed using MgSO ₄ . The solvent was removed by distillation under reduced pressure, and the product was separated using column chromatography ( n -hexane : acetone = 300 : 1) to obtain a white solid of formula J (1.933g, 96.7%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ3.71 (s, 3H, -OCH ₃ ), 3.69 (s, 6H, -OCH ₃ ), 2.66 (s, 3H, -COCH ₃ ), 2.10 (s , 3H, -CH ₃ ), 2.04 (s, 3H, -CH ₃ )

<12 steps of reaction>

After dissolving Chemical Formula J (0.25 g, 1.0492 mmol) in 20 mL of methanol, appropriately substituted benzaldehyde (1.259 mmol) was added. Potassium hydroxide (KOH, 0.1761g, 3.1471 mmol) dissolved in 10 mL methanol was added to this solution and stirred for 48 hours. The reaction was diluted with 150 mL of ethyl acetate and neutralized with 100 mL of NH ₄ Cl aqueous solution. The organic solvent layer was washed with water and a saturated aqueous NaCl solution, and moisture was removed using MgSO ₄ . The solvent was removed by distillation under reduced pressure, and the mixture was separated using column chromatography ( n -hexane or n -hexane : acetone = 300 : 1) to obtain Chemical Formulas 16 to 23.

[Formula 16 (1-(3′,5′-dimethyl-2′,4′,6′-trimethoxyphenyl)-3-(4-fluorophenyl)-2-propen-1-one)] Yield: 93.1%

¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.34-7.26 (d, J = 16.17 Hz, 1H, -C=CH), 7.11-7.05 (d, J = 16.13 Hz, 1H, -C=CH) ), 7.87-7.2 (m, 2H, Ar-H), 7.28-7.18 (m, 2H, Ar-H), 3.69 (s, 3H, -OCH ₃ ), 3.58 (s, 6H, -OCH ₃ ), and 2.13 (s, 6H, -CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ194.36(1C), 164.72(1C), 163.06(1C), 159.07(1C), 154.24(1C), 144.17(1C), 131.56(1C), 131.50(1C) ), 131.20(1C), 131.18(1C), 128.75(1C), 125.03(1C), 120.51(2C), 116.49(1C), 116.35(1C), 62.00(1C), 60.17(1C), 9.59(2C) )).

[Formula 17 (1-(3′,5′-dimethyl-2′,4′,6′-trimethoxyphenyl)-3-phenyl-2-propen-1-one)] Yield: 96.31%

¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.32-7.24 (d, J = 16.17 Hz, 1H, -C=CH), 7.14-7.05 (d, J = 16.11 Hz, 1H, -C=CH) ), 7.74-7.67 (m, 2H, Ar-H), 7.46-7.35 (m, 3H, Ar-H), 3.70 (s, 3H, -OCH ₃ ), 3.58 (s, 6H, -OCH ₃ ), and 2.13 (s, 6H, -CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ194.45(1C), 159.08(1C), 154.25(1C), 145.46(1C), 134.50(1C), 131.20(1C), 129.42(2C), 129.14(2C) ), 128.85(1C), 125.02(1C), 120.52(2C), 70.22(1C), 62.02(2C), 60.20(1C), 9.61(2C).

[Formula 18 (1-(3′,5′-dimethyl-2′,4′,6′-trimethoxyphenyl)-3-(4-tolyl)-2-propen-1-one)] Yield: 92.1%

¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.28-7.21 (d, J = 16.19 Hz, 1H, -C=CH), 7.07-7.00 (d, J = 16.12 Hz, 1H, -C=CH) ), 7.61-7.55 (d, J = 8.23 Hz, 2H, Ar-H), 7.24-7.17 (d, J = 8.00 Hz, 2H, Ar-H), 3.70 (s, 3H, -OCH ₃ ), 3.58 (s, 6H, -OCH ₃ ), 2.32 (s, 3H, -CH ₃ ), and 2.13 (s, 6H, -CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ194.45(1C), 159.00(1C), 154.19(2C), 145.62(1C), 141.31(1C), 131.77(1C) 130.05(2C), 129.15(2C) , 127.95(1C), 125.11(1C), 120.49(2C), 61.99(2C), 60.18(1C), 21.48(1C), 9.6(2C).

[Formula 19 (1-(3′,5′-dimethyl-2′,4′,6′-trimethoxyphenyl)-3-(4-isopropylphenyl)-2-propen-1-one)] Yield: 94.3%

¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.29-7.22 (d, J = 16.17 Hz, 1H, -C=CH), 7.10-6.95 (d, J = 16.12 Hz, 1H, -C=CH) ), 7.65-7.58 (d, J = 8.20 Hz, 2H, Ar-H), 7.29-7.25 (d, J = 8.10 Hz, 2H, Ar-H), 3.70 (s, 3H, -OCH ₃ ), 3.58 (s, 6H, -OCH ₃ ), 3.00-2.80 (septet, J = 6.96 Hz, 1H, -CH), 2.13 (s, 3H, -CH ₃ ), 1.20 (s, 3H, -CH ₃ ), and 1.18 (s, 3H, -CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ194.40(1C), 159.01(1C), 154.22(2C), 152.04(1C), 145.53(1C), 132.19(1C), 129.28(2C), 128.04(1C) ), 127.41(2C), 125.10(1C), 120.48(2C), 61.98(2C), 60.19(1C), 33.82(1C), 24.00(2C), 9.61(2C).

[Formula 20 (1-(3′,5′-dimethyl-2′,4′,6′-trimethoxyphenyl)-3-(4-methoxymethoxyphenyl)-2-propen-1-one)] Yield: 92.9%

¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.27-7.17 (d, J = 16.11 Hz, 1H, -C=CH), 7.02-6.93 (d, J = 16.23 Hz, 1H, -C=CH) ), 7.70-7.62 (d, J = 8.79 Hz, 2H, Ar-H), 7.06-7.0 (d, J = 8.74 Hz, 2H, Ar-H), 5.23 (2H, -CH2-O-), 3.70 (s, 3H, -OCH ₃ ), 3.58 (s, 6H, -OCH ₃ ), 3.37 (s, 3H, -OCH ₃ ), and 2.13 (s, 6H, -CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ194.33(1C), 159.29(1C), 158.92(1C), 154.16(2C), 145.35(1C), 130.92(2C), 128.03(1C), 127.09(1C) ), 125.21(1C), 120.46(2C), 116.83(2C), 94.12(1C), 61.97(2C), 60.18(1C), 56.18(1C), 9.61(2C).

[Formula 21 (1-(3′,5′-dimethyl-2′,4′,6′-trimethoxyphenyl)-3-(4-methoxyphenyl)-2-propen-1-one)] Yield: 91.8%

¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.27-7.13 (d, J = 16.10 Hz, 1H, -C=CH), 7.02-6.88 (d, J = 15.90 Hz, 1H, -C=CH) ), 7.70-7.60 (d, J = 8.70 Hz, 2H, Ar-H), 7.00-6.93 (d, J = 8.79 Hz, 2H, Ar-H), 3.79 (s, 3H, -OCH ₃ ), 3.69 (s, 3H, -OCH ₃ ), 3.58 (s, 6H, -OCH ₃ ), and 2.13 (s, 6H, -CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ194.33(1C), 161.88(1C), 158.88(1C), 154.14(2C), 145.58(1C), 131.03(2C), 127.05(1C), 126.66(1C) ), 125.27(1C), 120.45(2C), 114.92(2C), 61.96(2C), 60.18(1C), 55.81(1C), 9.61(2C).

[Formula 22 (1-(3′,5′-dimethyl-2′,4′,6′-trimethoxyphenyl)-3-(4-hydroxyphenyl)-2-propen-1-one)] Yield: 88.1%

¹ H NMR (300 MHz, DMSO-d ₆ ) δ10.09 (s, 1H, -OH), 7.20-7.10 (d, J = 16.07 Hz, 1H, -C=CH), 6.91-6.83 (d, J = 16.01 Hz, 1H, -C=CH), 7.56-7.48 (d, J = 8.69 Hz, 2H, Ar-H), 6.80-6.74 (d, J = 8.62 Hz, 2H, Ar-H), 3.69 ( s, 3H, -OCH ₃ ), 3.57 (s, 6H, -OCH ₃ ), and 2.12 (s, 6H, -CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ194.26(1C), 160.65(2C), 158.81(1C), 154.12(2C), 146.14(1C), 131.22(2C), 125.71(1C), 125.34(1C) ), 120.41(2C), 116.32(2C), 61.93(2C), 60.17(1C), 9.59(2C).

[Formula 23 (1-(3′,5′-dimethyl-2′,4′,6′-trimethoxyphenyl)-3-(4-( N,N -dimethylamino)phenyl)-2-propen-1-one) ] Yield: 78.3%

¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.16-7.06 (d, J = 15.94 Hz, 1H, -C=CH), 6.83-6.75 (d, J = 15.90 Hz, 1H, -C=CH) ), 7.52-7.43 (d, J = 8.90 Hz, 2H, Ar-H), 6.71-6.63 (d, J = 8.94 Hz, 2H, Ar-H), 3.69 (s, 3H, -OCH ₃ ), 3.57 (s, 6H, -OCH ₃ ), 2.98 (s, 6H, -NCH ₃ ), and 2.12 (s, 6H, -CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ193.91(1C), 158.60(1C), 154.04(2C), 152.44(1C), 146.83(1C), 130.91(2C), 125.69(1C), 123.61(2C) ), 121.58(1C), 120.34(2C), 112.20(2C), 111.31(1C), 61.89(2C), 60.17(1C), 9.61(2C).

Example 2. Confirmation of the effect of DMC derivatives on PAI-1 expression

PAI-1 promotes the accumulation of ECM (extracellular matrix) and inhibits ECM degradation, causing fibrosis. In addition, PAI-1 promotes fibrosis by increasing the expression of ECM-related proteins such as α-SMA (α-smooth muscle actin), collagen I, and fibronectin in response to TGF β1. α-SMA is a representative marker of fibrosis, and its expression is low in normal myofibroblasts, but its expression is greatly increased in myofibroblasts of fibrous tissue, and it is a protein that promotes fiber formation.

Therefore, in order to confirm the effect of the DMC derivative of Example 1 on the expression of PAI-1 and α-SMA, 5 μM of DMC was added to the NRK-49F cell line, a rat renal fibroblast cell line of Example 1. After the derivatives were treated for 3 hours, 2 ng/ml of TGFβ1 was treated for 6 hours. Then, RNA was isolated from the cells, and the amounts of PAI-1 and α-SMA RNA were measured by qPCR. The results are shown in Figures 1 and 2.

As shown in Figure 1, in the group treated only with TGFβ1, the expression of PAI-1 increased by about 8-fold due to TGFβ1, but in the group treated with the DMC derivative according to the present invention, the mRNA level of PAI-1 was significantly decreased. As a result, it was confirmed that the DMC derivative according to the present invention has the effect of suppressing the increase in the expression of PAI-1 caused by TGFβ1. In addition, as shown in Figure 2, the expression of α-SMA significantly increased in the group treated with only TGFβ1, while the expression of α-SMA significantly decreased in the group treated with DMC derivatives. In other words, it was confirmed that the DMC derivative of the present invention also inhibits the increase in expression of α-SMA caused by TGFβ1.

In summary, the above results show that the DMC derivatives of the present invention exhibit anti-fibrotic activity as agents that inhibit the expression of PAI-1 and α-SMA, and therefore can be used as a treatment for various fibrotic diseases, including renal fibrosis.

The description of the present invention described above is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive.

The present invention relates to a composition for preventing or treating fibrotic diseases containing a dimethyl chalcone derivative as an active ingredient, and more specifically, 2',4'-dihydroxy-6'-methoxy-3',5'-dimethyl chalcone. It relates to the use of improving, preventing, and/or treating fibrotic diseases. The DMC derivatives of the present invention effectively inhibit the expression of PAI-1 and α-SMA by TGFβ, and are expected to be used in the prevention, improvement, and treatment of various fibrosis-related diseases, including renal fibrosis.

Claims (11)

1. A fibrotic disease comprising a derivative of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient: Pharmaceutical composition for the prevention or treatment of:

   [Formula 1]

   

   In Formula 1,

   R ₀ , R ₁ , and R ₂ is each independently a hydroxy group (OH), a methoxymethoxy group (OCH ₂ OCH ₃ ; OMOM), or a C1-C10 alkoxy group,

   R ₀ , R ₁ , and At least one of R ₂ is not OH,

   When R ₀ and R ₁ are simultaneously a methoxy group (OCH ₃ ; OMe) or OMOM at the same time, R ₂ is not OH or OMOM;

   R ₃ to R ₇ are each independently a halogen atom, hydrogen (H), deuterium (D), hydroxy group (OH), thiol group (SH), amino group (NH ₂ ), nitrile group, nitro group, substituted or unsubstituted. Substituted C1-C10 alkylamino group, substituted or unsubstituted C1-C10 alkoxy group, substituted or unsubstituted C1-C10 alkylsulfoxy group, substituted or unsubstituted C1-C10 alkyl group, substituted or unsubstituted C2-C10 alkyl group. Kenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C6-C20 aryl group, substituted or unsubstituted C1-C10 alkylthio group, and substituted or unsubstituted C1-C10 alkylsulfonyl group. It is one selected from the group,

   The 'substituted or unsubstituted' refers to a halogen group, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, imide group, amino group, phosphine oxide group, alkoxy group, aryloxy group, alkylthioxy group, aryl Thioxy group, alkylsulfoxy group, arylsulfoxy group, silyl group, boron group, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, alkylaryl group, alkylamine group. It is substituted or unsubstituted with one or more substituents selected from the group consisting of aralkylamine group, heteroarylamine group, arylamine group, arylphosphine group, and heterocyclic group.
2. According to paragraph 1,

   The derivative of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone represented by Formula 1 is one or more compounds selected from the group consisting of Formulas 2 to 40, or pharmaceuticals thereof. Pharmaceutical composition, which is an acceptable salt:

   
3. According to paragraph 1,

   A pharmaceutical composition, wherein the fibrotic disease is at least one selected from the group consisting of renal fibrosis, cirrhosis, cardiac fibrosis, scleroderma, skeletal muscle fibrosis, liver fibrosis, pulmonary fibrosis, and diabetic fibrosis.
4. According to paragraph 1,

   Derivatives of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone represented by Formula 1 have the expression or activity of at least one selected from the group consisting of PAI-1 and α-SMA. A pharmaceutical composition, characterized in that it inhibits.
5. A fibrotic disease comprising a derivative of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone represented by the following formula (1) or a food-acceptable salt thereof as an active ingredient: Food composition for preventing or improving:

   [Formula 1]

   

   In Formula 1,

   R ₀ , R ₁ , and R ₂ is each independently a hydroxy group (OH), a methoxymethoxy group (OCH ₂ OCH ₃ ; OMOM), or a C1-C10 alkoxy group,

   R ₀ , R ₁ , and At least one of R ₂ is not OH,

   When R ₀ and R ₁ are simultaneously a methoxy group (OCH ₃ ; OMe) or OMOM at the same time, R ₂ is not OH or OMOM;

   R ₃ to R ₇ are each independently a halogen atom, hydrogen (H), deuterium (D), hydroxy group (OH), thiol group (SH), amino group (NH ₂ ), nitrile group, nitro group, substituted or unsubstituted. Substituted C1-C10 alkylamino group, substituted or unsubstituted C1-C10 alkoxy group, substituted or unsubstituted C1-C10 alkylsulfoxy group, substituted or unsubstituted C1-C10 alkyl group, substituted or unsubstituted C2-C10 alkyl group. Kenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C6-C20 aryl group, substituted or unsubstituted C1-C10 alkylthio group, and substituted or unsubstituted C1-C10 alkylsulfonyl group. It is one selected from the group,

   The 'substituted or unsubstituted' refers to a halogen group, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, imide group, amino group, phosphine oxide group, alkoxy group, aryloxy group, alkylthioxy group, aryl Thioxy group, alkylsulfoxy group, arylsulfoxy group, silyl group, boron group, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, alkylaryl group, alkylamine group. It is substituted or unsubstituted with one or more substituents selected from the group consisting of aralkylamine group, heteroarylamine group, arylamine group, arylphosphine group, and heterocyclic group.
6. According to clause 5,

   The derivative of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone represented by Formula 1 is one or more compounds selected from the group consisting of Formulas 2 to 40, or a food thereof. Food composition, which is a scientifically acceptable salt:

   
7. According to clause 5,

   A food composition, wherein the fibrotic disease is at least one selected from the group consisting of renal fibrosis, cirrhosis, cardiac fibrosis, scleroderma, skeletal muscle fibrosis, liver fibrosis, pulmonary fibrosis, and diabetic fibrosis.
8. According to clause 5,

   Derivatives of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone represented by Formula 1 have the expression or activity of at least one selected from the group consisting of PAI-1 and α-SMA. A food composition characterized by suppressing .
9. Administering a derivative of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone represented by the following formula (1) or a pharmaceutically acceptable salt thereof to an individual in need thereof. Method for preventing or treating fibrosing disease, comprising the steps:

   [Formula 1]

   

   In Formula 1,

   R ₀ , R ₁ , and R ₂ is each independently a hydroxy group (OH), a methoxymethoxy group (OCH ₂ OCH ₃ ; OMOM), or a C1-C10 alkoxy group,

   R ₀ , R ₁ , and At least one of R ₂ is not OH,

   When R ₀ and R ₁ are simultaneously a methoxy group (OCH ₃ ; OMe) or OMOM at the same time, R ₂ is not OH or OMOM;

   R ₃ to R ₇ are each independently a halogen atom, hydrogen (H), deuterium (D), hydroxy group (OH), thiol group (SH), amino group (NH ₂ ), nitrile group, nitro group, substituted or unsubstituted. Substituted C1-C10 alkylamino group, substituted or unsubstituted C1-C10 alkoxy group, substituted or unsubstituted C1-C10 alkylsulfoxy group, substituted or unsubstituted C1-C10 alkyl group, substituted or unsubstituted C2-C10 alkyl group. Kenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C6-C20 aryl group, substituted or unsubstituted C1-C10 alkylthio group, and substituted or unsubstituted C1-C10 alkylsulfonyl group. It is one selected from the group,

   The 'substituted or unsubstituted' refers to a halogen group, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, imide group, amino group, phosphine oxide group, alkoxy group, aryloxy group, alkylthioxy group, aryl Thioxy group, alkylsulfoxy group, arylsulfoxy group, silyl group, boron group, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, alkylaryl group, alkylamine group. It is substituted or unsubstituted with one or more substituents selected from the group consisting of aralkylamine group, heteroarylamine group, arylamine group, arylphosphine group, and heterocyclic group.
10. Derivatives of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone or pharmaceutically acceptable salts thereof represented by the following formula (1) for the prevention or treatment of fibrotic diseases: Usage:

    [Formula 1]

    

    In Formula 1,

    R ₀ , R ₁ , and R ₂ is each independently a hydroxy group (OH), a methoxymethoxy group (OCH ₂ OCH ₃ ; OMOM), or a C1-C10 alkoxy group,

    R ₀ , R ₁ , and At least one of R ₂ is not OH,

    When R ₀ and R ₁ are simultaneously a methoxy group (OCH ₃ ; OMe) or OMOM at the same time, R ₂ is not OH or OMOM;

    R ₃ to R ₇ are each independently a halogen atom, hydrogen (H), deuterium (D), hydroxy group (OH), thiol group (SH), amino group (NH ₂ ), nitrile group, nitro group, substituted or unsubstituted. Substituted C1-C10 alkylamino group, substituted or unsubstituted C1-C10 alkoxy group, substituted or unsubstituted C1-C10 alkylsulfoxy group, substituted or unsubstituted C1-C10 alkyl group, substituted or unsubstituted C2-C10 alkyl group. Kenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C6-C20 aryl group, substituted or unsubstituted C1-C10 alkylthio group, and substituted or unsubstituted C1-C10 alkylsulfonyl group. It is one selected from the group,

    The 'substituted or unsubstituted' refers to a halogen group, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, imide group, amino group, phosphine oxide group, alkoxy group, aryloxy group, alkylthioxy group, aryl Thioxy group, alkylsulfoxy group, arylsulfoxy group, silyl group, boron group, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, alkylaryl group, alkylamine group. It is substituted or unsubstituted with one or more substituents selected from the group consisting of aralkylamine group, heteroarylamine group, arylamine group, arylphosphine group, and heterocyclic group.
11. Derivatives of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone or pharmaceutically thereof represented by the following formula (1) for the production of drugs for the prevention or treatment of fibrotic diseases: Acceptable uses of salts include:

    [Formula 1]

    

    In Formula 1,

    R ₀ , R ₁ , and R ₂ is each independently a hydroxy group (OH), a methoxymethoxy group (OCH ₂ OCH ₃ ; OMOM), or a C1-C10 alkoxy group,

    R ₀ , R ₁ , and At least one of R ₂ is not OH,

    When R ₀ and R ₁ are simultaneously a methoxy group (OCH ₃ ; OMe) or OMOM at the same time, R ₂ is not OH or OMOM;

    R ₃ to R ₇ are each independently a halogen atom, hydrogen (H), deuterium (D), hydroxy group (OH), thiol group (SH), amino group (NH ₂ ), nitrile group, nitro group, substituted or unsubstituted. Substituted C1-C10 alkylamino group, substituted or unsubstituted C1-C10 alkoxy group, substituted or unsubstituted C1-C10 alkylsulfoxy group, substituted or unsubstituted C1-C10 alkyl group, substituted or unsubstituted C2-C10 alkyl group. Kenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C6-C20 aryl group, substituted or unsubstituted C1-C10 alkylthio group, and substituted or unsubstituted C1-C10 alkylsulfonyl group. It is one selected from the group,

    The 'substituted or unsubstituted' refers to a halogen group, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, imide group, amino group, phosphine oxide group, alkoxy group, aryloxy group, alkylthioxy group, aryl Thioxy group, alkylsulfoxy group, arylsulfoxy group, silyl group, boron group, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, alkylaryl group, alkylamine group. It is substituted or unsubstituted with one or more substituents selected from the group consisting of aralkylamine group, heteroarylamine group, arylamine group, arylphosphine group, and heterocyclic group.

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