KR20190040895A - Method For Preparing Penchinone A And Its Derivatives And Anti-inflammatory Use Thereof - Google Patents

Abstract

The present invention relates to a method of producing penchinone A having anti-inflammatory activity and a derivative thereof. Also, the present invention provides an anti-inflammatory composition using the penchinone A and the derivative thereof, which are obtained by the method. The anti-inflammatory composition has anti-inflammatory activities, causes little adverse effects, and has long-lasting effects.

Description

TECHNICAL FIELD [0001] The present invention relates to a method for preparing picchinone and derivatives thereof and an antiinflammatory composition comprising the same as an active ingredient.

The present invention relates to a method for the full-synthesis of Penchinone A and its derivatives and to the use of phentichnone and its derivatives for anti-inflammation.

Due to recent developments in the economy, lifestyle diseases such as cancer, diabetes, hypertension, obesity, and vascular diseases are continuously increasing in the world due to changes in living environment and diet. In addition, due to various factors such as environmental changes due to rapid industrial development of modern society, and increased stress, inflammation induced by immunomodulation abnormality is persisted, and the incidence of related diseases is increasing.

The inflammatory response is a mechanism to repair and regenerate damaged tissue as a defense against external physical and chemical stimuli and various infectious agents including tissue damage (Zamora R et al., Mol. Med. 6: 347-373 (2000) ; Mariathasan S and Monack DM. Nat. Rev. Immunol. 7: 31-40 (2007); Lee HN et al., J. Food Sci. Technol. 43: 65-71 (2011)). During the inflammation reaction, plasma accumulates on the inflamed area, diluting the toxicities secreted by the bacteria, increasing the blood flow, and accompanied by symptoms such as erythema, pain, edema, and fever. In normal cases, the organism neutralizes or eliminates the onset factor through inflammatory reaction, regenerates the upper tissue and regenerates the normal structure and function, but chronic inflammatory reaction, which is continuously or excessively caused, causes tissue damage. This inflammatory response induces progression to stomach, colon, bladder, and prostate cancer, and causes various diseases such as rheumatoid arthritis and chronic infection (Hofseth LJ and Ying L. Biochim. Biophys. Acta 1765: 74-84 (2006 ; Yun HY et al., Rev. Neurobiol. 10: 291-316 (1996); Stuehr DJ et al., P. Natl. Acad Sci. USA 88: 7773-7777 (1991)).

(IL-1β), IL-6, IL-6, IL-6, IL-6, IL-6, IL-6, and IL-6 in the presence of inflammatory mediators such as macrophages and monocytes. 8, and IL-12 (Guha M and Mackman N. Cell Signal. 13: 85-94 (2001)). A typical example of an inflammatory response is activation of the toll like receptor (TLR) signaling pathway of macrophages by pathogen associated molecular patterns (PAMPs). Lipopolysaccharide (LPS), a type of endotoxin present in the outer membrane of gram-negative bacteria, belongs to the inflammatory mediator PAMPs present in external microorganisms. TLR4 recognizes LPS with the help of MD-2 or CD14 (Miyake K. Trends Microbiol. 12: 186-192 (2004)), and the lower signaling pathway (NF-κB), which is a transcription factor, which activates NF-κB (NF-κB). Food Sci. Technol. 41: 477-482 (2009)). NF-κB translocated to the nucleus was found to be an inflammatory cytokine (TNF-α, IL-1β, IL-6, IL-8 and IL-12), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 Nitric oxide (NO) induced by iNOS induces gene expression and exacerbates inflammation (Noh KH et al., J. Korean Soc. Food Sci. Nutr. 40: 625-634 (2011) ; Weisze et al., Biochem. J. 316: 209-215 (1996)). Nitric oxide, which is produced by iNOS in macrophages, reacts with superoxide to form peroxynitrite, which acts as a strong oxidizing agent and damages the cells, resulting in a variety of pathologies including inflammation and cancer (Gupta SC et al., Exp Biol Med., 236: 658-671, (2011); Riehemann et al., FEBS Lett., 442: 89-94 (1999)).

Although synthetic medicines such as ibuprofen, antihistamines, steroids, cortisone, immunosuppressants, and immunosuppressants are used, the therapeutic effect is temporary, there are many side effects such as simple symptom relief, hypersensitivity reaction and aggravation of the immune system Fundamental treatment of inflammation is difficult. Non-steroidal anti-inflammatory drugs (NSAIDS), which are now widely used as anti-inflammatory drugs, are known to cause serious side effects such as gastrointestinal disturbances, liver disorders, and renal insufficiency (Rainsford KD, Subcell biochem. , 42: 3-27, 2007, Guruprasad P. Aithal., Rheumatology., 7: 139-150, 2011, Praveen PN Rao et al., Pharmaceuticals., 3: 1530-1549, 2010).

Therefore, there is a continuing need to develop new drugs that have anti-inflammatory activity, have fewer side effects, and continue to be effective.

The present invention discloses phentolinic acid having antiinflammatory activity and a method for producing the same.

It is an object of the present invention to provide a method for producing Penchinone A and derivatives thereof.

Another object of the present invention is to provide an anti-inflammatory composition using Penchinone A and derivatives thereof obtained by the above method.

Other objects and specific objects of the present invention will be described below.

In one aspect, the present invention relates to a method for preparing Penchinone A and derivatives thereof.

The process of the present invention for the production of phentolinic acid comprises the following steps of reaction (1) including oxime-indicating palladium (II) -catalyzed oxidation, acylation, Claisen rearrangement and base- Can be produced according to the methods of [Figure 1] to [Figure 4]. This conversion efficiently provides a variety of allyl-substituted biaryl ketones with site-selectivity and functional group compatibilty. In addition, the synthesized compounds (7a-7g and 8a-8g) were treated with lipid polysaccharide (LPS) -induced RAW264.7 cells for nitric oxide (NO), tumor necrosis factor alpha IL-6), the picchinone derivatives significantly inhibited NO, TNF-a and IL-6 production compared to the positive control dexamethasone. Particularly, phentic acid (Compound 8g) and its derivatives (Compound 8e and Compound 8f) showed a very excellent anti-inflammatory effect.

<Reaction Scheme 1>

Penchinones AD is first isolated in 2015 by Xiong and colleagues as a substance that protects liver function during water leaching from octopus legs ( Penthorum chinense Pursh) (He YC et al. RSC Adv. 5: 76788 2015). Penchinones AD exhibits unique structural features including two pairs of cis-trans isomers with rearranged carbon skeletons.

<Structure of plichinon>

Biaryl ketones have been recognized as important structural motifs in biologically active compounds and functional materials (Surburg, H. and Panten, J. Common Fragrance and Flavor Materials, 5th ed. (2006); Deng, Y et al. , J. Nat. Prod. 70: 2049 (2007), Romins KR et al., J. Med. Chem. 49: 727 (2006)). Recently a transition metal catalyst under oxidative acylation of sp ² CH bond of the structure formation of the biaryl ketone been intensively studied (Sharma, S et al, Curr Org Chem 20:.... 471 (2016); Hummel JR. Et al., JA Chem. Rev. 117: 9163 (2017)). For example, the present inventors first reported Rh (III) -catalytic oxidative acylation of benzamide using aryl aldehyde as an acyl source to obtain a biarylketone compound (Park J. et al., Org. Lett 13: 4390 (2011); Sharma S. et al., Org. Lett. 14: 906 (2012)). Subsequently, Pd (II) -catalyzed acylation reactions of aromatics using various acyl substituents such as aldehydes, alcohols, ethers and toluene derivatives have also been studied under oxidative conditions (Jia X. Sharma S. et al., Adv. Synth. C et al., 355: 1966 (2009); Chan CW et al., Org. Lett. Sharma S. et &lt; RTI ID = 0.0 &gt; al., &Lt; / RTI &gt; Guin S. et al., Org. Lett. 14: 5294 (1984), J. Org. (2012). In general, TBHP is widely used as an oxidizing agent to generate an acyl radical intermediate while transferring the acyl moiety to the sp2CH bond. Accordingly, the present inventors have found that, as an extension of a recent study on the discovery of biologically active compounds based on catalytic CH functionalization, the present inventors have found that Pd (II) -catalyzed oxidative acylation of ketoximes and aldehydes, All synthetic methods of analogues have been proposed.

With respect to the production method of the present invention, the following examples can be referred to for the preferable reaction conditions, specifically, the concentration of the catalyst and additives used, the reaction time, and the reaction temperature.

In another aspect, the present invention relates to an anti-inflammatory composition comprising, as an active ingredient, any one of the following compounds 7a to 8g.

The Examples and Experimental Examples below show that the compounds inhibit the expression of NO, TNF-a and / or IL-6 when treated with LPS (lipopolysaccharide) -mediated mouse macrophage cell line (RAW 264.7 cells). Among these compounds, compounds such as 8g, 8e and 8f showed superior activity to dexamethasone, which is used for inhibiting the expression of NO, TNF-α and IL-6.

In the present specification, the term " active ingredient " alone means an ingredient which exhibits the desired activity or which can exhibit activity together with a carrier which is not itself active.

As used herein, " anti-inflammatory " is meant to include improvement of an inflammatory disease (alleviation of symptoms), treatment, inhibition or delay of onset of such a disease as defined below.

In the present specification, the term " inflammatory disease " means an inflammatory reaction that is determined by an external physical or chemical stimulus or an infection of an external infectious source such as bacteria, fungi, viruses, various allergenic substances, or a local or systemic defense against autoimmunity Which may be defined as a pathological symptom. These inflammatory responses are caused by activation of various inflammatory mediators and enzymes associated with immune cells (e.g., iNOS, COX-2, etc.), secretion of inflammatory mediators (e.g., secretion of NO, TNF-a, IL-6, Cell migration, and tissue destruction, and manifest externally by symptoms such as erythema, pain, edema, fever, loss or loss of specific function of the body. The inflammatory disease may be acute, chronic, ulcerative, allergic or necrotic, so long as it is included in the definition of inflammatory diseases as above, it may be acute, chronic, ulcerative, allergic, Whether it is necrotic or not. Specifically, the inflammatory diseases include asthma, allergic and non-allergic rhinitis, chronic and acute rhinitis, chronic and acute gastritis or enteritis, ulcerative gastritis, acute and chronic nephritis, acute and chronic hepatitis, chronic obstructive pulmonary disease, Inflammatory bowel syndrome, inflammatory pain, migraine headache, headache, back pain, fibromyalgia, fascia disease, viral infection (e.g., C type infection), bacterial infection, fungal infection, burn, wound due to surgical or dental surgery, Rheumatoid arthritis, ankylosing spondylitis, Hodgkin's disease, pancreatitis, conjunctivitis, iritis, scleritis, uveitis, dermatitis (including atopic dermatitis), eczema, multiple sclerosis, etc. Will be included.

The anti-inflammatory composition or the like of the present invention may be contained in any amount (effective amount) as long as it can exhibit the activity of improving the inflammatory diseases intended to be treated according to the purpose of use, formulation, blending purpose, etc., An effective amount will be determined within the range of from 0.001% to 15% by weight based on the total weight of the composition. The term " effective amount " as used herein refers to an amount of an effective amount of a compound of the present invention to be administered to a mammal, preferably a human, to which the composition of the present invention is administered during a period of administration, / Delay, etc., of the active ingredient, which may be indicative of a medical or pharmacological effect. Such effective amounts can be determined experimentally within the ordinary skill of those skilled in the art.

The antiinflammatory composition of the present invention may further contain, in addition to the active ingredient, any compound or natural extract known to have safety and antiinflammatory activity for the purpose of raising or reinforcing antiinflammatory effects or the like. Specific examples of such compounds or extracts include MSM (dimethylsulfonylmethane), N-acetylglucosamine, glucosamine, and individual approval under the Health Functional Foods Act Complex extracts of CMO-containing complex extracts such as FAT (Fatty acid Complex) and Gassiogarifolia, complex extracts such as turmeric extract, chicken breast cartilage powder, rosehip powder, boswellia extract, beeswax alcohol, , Green lipped mussel extract oil, hop extract, and gold extract. Such compounds or natural extracts may be included in the anti-inflammatory compositions of the present invention in combination with one or more of their effectiveness.

The anti-inflammatory composition and the like of the present invention can be grasped as a food composition in a specific aspect.

The food composition of the present invention can be produced in any form and can be used in various forms such as beverages such as tea, juice, carbonated drink, ionic drink, processed oil such as milk and yogurt, gum, rice cake, Korean confectionery, A food, a health food, a food, a tablet, a capsule, a ring, a granule, a liquid, a powder, a slice, a paste, a syrup, a gel, a jelly and a bar. In addition, the food composition of the present invention may be classified into any product category as long as it meets the laws and regulations on the time of manufacture and distribution in the legal and functional category. For example, it may be a health functional food according to the Act on Health Functional Foods, or a confectionery, bean curd, fermented beverages, special-purpose foods, etc. according to each type of food in the food revolution (food standard, .

The food composition of the present invention may contain food additives in addition to the active ingredients thereof. Food additives are generally understood to be substances that are added to foods and mixed or infiltrated into food in the manufacture, processing or preservation of food, and their safety must be ensured since they are taken daily with food and for long periods. Food additives according to the Food Hygiene Act (food additives notification, food additive standards and standards) are limited by the classification of safe synthetic food additives as chemical synthetic products, natural additives and mixed preparations.

These functional food additives can be classified into sweeteners, flavors, preservatives, emulsifiers, acidifiers, and thickeners.

A sweetener is used to impart a sweet taste suitable for foods, and natural or synthetic sweeteners can be used. Preferably, natural sweeteners are used. Examples of natural sweeteners include sugar sweeteners such as corn syrup solids, honey, sucrose, fructose, lactose and maltose.

Flavors may be used to enhance taste or flavor, both natural and synthetic. Preferably, a natural one is used. When using natural ones, the purpose of nutritional fortification can be performed in addition to the flavor. Examples of natural flavoring agents include those obtained from apples, lemons, citrus fruits, grapes, strawberries, peaches, and the like, or those obtained from green tea leaves, Asiatica, Daegu, Cinnamon, Chrysanthemum leaves and Jasmine. Also, those obtained from ginseng (red ginseng), bamboo shoots, aloe vera, banks and the like can be used. The natural flavoring agent may be a liquid concentrate or a solid form of extract. Synthetic flavors may be used depending on the case, and synthetic flavors such as esters, alcohols, aldehydes, terpenes and the like may be used.

As the preservative, calcium sorbate, sodium sorbate, potassium sorbate, calcium benzoate, sodium benzoate, potassium benzoate and EDTA (ethylenediaminetetraacetic acid) can be used. As the emulsifier, acacia gum, carboxymethyl cellulose, Pectin and the like. As the acidulant, math, malic acid, fumaric acid, adipic acid, phosphoric acid, gluconic acid, tartaric acid, ascorbic acid, acetic acid, phosphoric acid and the like can be used. The acidulant may be added so that the food composition has a proper acidity for the purpose of inhibiting the growth of microorganisms other than the purpose of enhancing the taste.

Examples of the thickening agent include suspending agents, sedimentation agents, gel-forming agents, bulking agents and the like.

The food composition of the present invention may contain physiologically active substances or minerals which are known in the art and which are stable as a food additive in addition to the above-mentioned food additives in order to supplement and supplement functional and nutritional properties.

Examples of such physiologically active substances include catechins contained in green tea and the like, vitamins such as vitamin B1, vitamin C, vitamin E and vitamin B12, tocopherol, dibenzoyl thiamine, etc. Examples of minerals include calcium preparations such as calcium citrate, magnesium stearate , Iron preparations such as iron citrate, chromium chloride, potassium iodide, selenium, germanium, vanadium, zinc and the like.

The food composition of the present invention may contain an appropriate amount of the above-mentioned food additives according to the product type so as to achieve the purpose of addition thereof.

With regard to other food additives that can be included in the food composition of the present invention, reference may be made to the Food Code or the Food Additive Code.

The composition for anti-inflammation of the present invention and the like may be regarded as a pharmaceutical composition in another specific embodiment.

The pharmaceutical composition of the present invention may be prepared into oral formulations or parenteral formulations according to the route of administration by conventional methods known in the art, including pharmaceutically acceptable carriers in addition to the active ingredient. The term " pharmaceutically acceptable " as used herein means that the application (prescribing) subject does not have the above-mentioned toxicity that is adaptable without inhibiting the activity of the active ingredient.

When the pharmaceutical composition of the present invention is prepared into an oral formulation, it may be formulated into powder, granules, tablets, pills, sugar tablets, capsules, solutions, gels, syrups, suspensions, wafers And the like. Examples of suitable pharmaceutically acceptable carriers include sugars such as lactose, glucose, sucrose, dextrose, sorbitol, mannitol, xylitol, starch such as corn starch, potato starch and wheat starch, cellulose, methylcellulose, ethylcellulose, Cellulose derivatives such as sodium carboxymethyl cellulose and hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, magnesium stearate, mineral oil, malt, gelatin, talc, And the like. In case of formulation, a diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and / or an excipient may be formulated according to need.

When the pharmaceutical composition of the present invention is prepared into a parenteral dosage form, it may be formulated in the form of an injection, transdermal drug delivery, nasal aspirate and suppository together with a suitable carrier according to methods known in the art. Examples of suitable carrier in the case of formulation with an injectable preparation include sterilized water, ethanol, polyol such as glycerol and propylene glycol, or a mixture thereof. Preferably, the carrier is selected from the group consisting of Ringer's solution, phosphate buffered saline containing triethanolamine, Water, or isotonic solution such as 5% dextrose may be used. When formulated with a transdermal drug, it can be formulated in the form of an ointment, a cream, a lotion, a gel, a solution for external use, a pasta, a liniment, or an air-roll. The nasal inhalant may be formulated in the form of an aerosol spray using a suitable propellant such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, etc. When formulated as a suppository, witepsol, tween 61, polyethylene glycols, cacao butter, laurin, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, and sorbitan fatty acid esters.

The formulation of pharmaceutical compositions is well known in the art and can be specifically described in Remington ' s Pharmaceutical Sciences (19th ed., 1995). This document is considered part of this specification.

The preferred dosage of the pharmaceutical composition of the present invention is 0.001 mg / kg to 10 g / kg per day, preferably 0.001 mg / kg to 1 g / day, depending on the patient's condition, body weight, sex, age, / kg &lt; / RTI &gt; The administration can be carried out once or several times a day. Such dosages should in no way be construed as limiting the scope of the invention.

In another specific embodiment, the composition for anti-inflammation of the present invention can be identified as a cosmetic composition. When the anti-inflammatory composition of the present invention is identified as a cosmetic composition, its use can be understood as a relief of inflammatory skin irritation.

The cosmetic composition of the present invention may contain, in addition to its active ingredient, conventional additives such as stabilizers, solubilizing agents, surfactants, vitamins, colorants and antioxidants, and carriers commonly used in cosmetic compositions.

The cosmetic composition of the present invention can be prepared into any of the formulations conventionally produced in the art and can be used in the form of solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, , Oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto. More specifically, it can be manufactured in the form of a soft lotion, a nutritional lotion, a nutritional cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray or a powder.

When the formulation of the present invention is a paste, cream or gel, an animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component .

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In the case of a spray, in particular, / Propane or dimethyl ether.

When the formulation of the present invention is a solution or an emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.

In the case where the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.

When the formulation of the present invention is an interfacial active agent-containing cleansing, the carrier component is selected from aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters.

The cosmetic composition of the present invention can be manufactured according to a method for producing a cosmetic composition which is conventionally performed in the art, except that it contains the active ingredient exhibiting anti-inflammatory activity and the like.

INDUSTRIAL APPLICABILITY As described above, the present invention can provide an antiinflammatory composition using a method for producing a picnic acid derivative and a derivative thereof. The composition of the present invention can be commercialized as food, medicine or cosmetics.

[Fig. 1] is a diagram showing a reaction formula for producing ketoxime (5a), which is a stepwise step compound for generating phentolinone.
[Figure 2] is a diagram showing an acylation reaction formula of ketoxime (5a) using para-anisaldehyde (6a) as a substrate and reactant (7a).
[Figure 3] shows the reaction conditions for the production of the reactant 7a.
[Fig. 4] is a drawing showing the synthesis reaction formula of picinone derivatives by CH acylation and hydrolysis.

Hereinafter, the present invention will be described with reference to Examples and Experimental Examples. However, the scope of the present invention is not limited to these examples and experimental examples.

< Example > Pincheon  a( Penchinone  A) and derivatives

1. Manufacturing Method

The synthesis of the picnicone-A of the present invention proceeded while generating ketoxime (5a), an intermediate step reaction product. The process and the structure of the compound are shown in Fig.

<Compound 2>

The phenol with ortho-allyl group (compound 2) was obtained in a yield of 71% during the two steps of allylation of p-hydroxyacetophenone (compound of formula 1) followed by rearrangement of Clizene.

Specifically, para-hydroxyacetophenone (1) (2.7 g, 20 mmol, 100 mol%), K ₂ CO ₃ (5.5 g, 40 mmol, 200 mol%) and MeCN (20 mL) were added to a dry round bottom flask (100 mL) and allyl bromide (2.1 mL, 24 mmol, 120 mol%) was added. The reaction mixture was stirred at 60 &lt; 0 &gt; C for 6 hours. The resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with saturated NH4Cl solution (2 x 60 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes / EtOAc = 2: 1) to give 1- (4- (allyloxy) phenyl) ethan- 1-one (3.5 g, 99%) as a colorless oil . Then, 1- (4- (allyloxy) phenyl) ethan-1-one (2.8 g, 16 mmol, 100 mol%) was stirred in o-xylene (16 mL) at 220 ° C for 18 hours. The resulting mixture was cooled to room temperature, diluted with EtOAc (20 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes / EtOAc = 6: 1) to give compound 2 (2.0 g, 71%) as a white solid.

<Compound 3>

The olefin transfer of compound 2 was carried out by treatment of KOtBu to give an internal olefin (compound 3) with a ratio of E: Z = 5: 1 in 95% yield.

KOtBu (4.5 g, 40 mmol, 400 mol%) was added to the round bottom flask (100 mL) which was dried in an oven under the air at room temperature. Compound 2 (1.8 g, 10 mmol, 100 mol%) and THF (40 mL) The reaction mixture was stirred at 80 &lt; 0 &gt; C for 8 hours. The resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with saturated NH4Cl solution (2 × 60 mL), and dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes / EtOAc = 5: 1) to give compound 3 (1.7 g, 95%) as a white solid.

<Compound 4>

The reaction product, compound 3, was reacted with hydroxylamine hydrochloride to produce p-hydroxy ketoxime (compound 4).

Specifically, Compound 3 (1.1 g, 6 mmol, 100 mol%), O-methyl hydroxylamine hydrochloride (0.6 g, 7.2 mmol, 120 mol%) and NaOAc (0.98 g, 12 mmol, 200 mol%) were added to a dried round bottom flask ) And MeOH (12 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The resulting mixture was extracted with EtOAc (60 mL). The organic layer was washed with saturated NH ₄ Cl solution (2 x 30 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes / EtOAc = 15: 1) to give compound 4 (1.08 g, 87%) as a white solid.

<Compound 5>

Acetylated to give a mixture of trans-product 5a (71%) and cis-product 5b (14%).

Specifically, 4 (0.62 g, 3 mmol, 100 mol%), acetyl chloride (0.94 g, 12 mmol, 400 mol%) and N, N-diisopropylethylamine (0.94 g, 12 mmol, 400 mol) were added to a dried round bottom flask %) Was added and CH ₂ Cl ₂ (6 mL) was added at room temperature. The reaction mixture was stirred at 60 &lt; 0 &gt; C for 6 hours. The resulting mixture was extracted with EtOAc (30 mL). The organic layer was washed with saturated NH ₄ Cl solution (2 x 20 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes / EtOAc = 20: 1) to give a separable mixture of 5a (0.53 g, 71%) and 5b (0.11 g, 14%), respectively.

<Compound 7a-7g>

A ketoxime-directed catalytic oxidative acylation of 5a was performed using para-anisaldehyde (6a) as a model substrate to produce compound 7a (Fig. 2). 7a, the optimal reaction conditions were investigated by varying the catalyst, additive, solvent, etc. The results are shown in FIG.

As shown in item 1 of [Figure 3], the coupling reaction between 5a and 6a was not observed when the cation Rh (III) was used as a catalyst. It was also confirmed that the conversion efficiency was low even when Ag ₂ CO ₃ , which is an external oxidizing agent, was treated (items 2 and 3 in [FIG. 3]). The product 7a was obtained in a yield of 38% using the Pd (II) catalyst and the TBHP oxidant (item 4 in [Figure 3]) and when the amount of TBHP was increased to 3 equivalents, The yield (51%) was confirmed (items 5 and 6 in [Figure 3]). The addition of additives and Pd salt was not effective in improving the yield (items 7 and 8 of [Figure 3]), but when the Pd (OAc) ₂ was increased to 10 mol%, the reactivity increased and the yield of 7a increased to 61% (Item 9 in FIG. 3). Various solvents were also screened and DCE solvent was most effective (items 10-12 of FIG. 3). In addition, a control experiment with modified temperature and substrate concentrations was performed, but no yield improvement was observed as shown in items 13 and 14 of [Figure 3]. On the other hand, the CH acylation reaction of phenol compound 4 was also carried out under various reaction conditions, but formation of the corresponding product was not observed due to interference of hydroxy and olefin functional groups with respect to the center of Pd (II).

Compound 7a was prepared using the optimal reaction conditions searched through the above procedure. Specifically, 5a (98.9 mg, 0.4 mmol, 100 mol%), Pd (OAc) ₂ (9.0 mg, 0.04 mmol, 10 mol%), TBHP (0.24 mL, 1.2 mmol, 300 mol% 5M in decane) and p-anisaldehyde (6a) (163.4 mg, 1.2 mmol, 300 mol%) and DCE (2 mL) were added at room temperature. The reaction mixture was stirred at 80 &lt; 0 &gt; C for 20 hours and the resulting mixture was extracted with EtOAc (30 mL). The organic layer was washed with saturated NH ₄ Cl solution (2 x 15 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes / EtOAc = 10: 1) to give compound 7a (93.1 mg) in 61% yield.

Various allylic aldehydes 6b-6g were reacted with ketoxime 5a using optimal reaction conditions. The reaction scheme and the structure of the compound are shown in Fig.

para-OH-substituted benzaldehyde; 6b showed moderate reactivity, yielding bialyl ketone (7b) in 51% yield. The acylation reaction of meta-substituted benzaldehydes (6c and 6d) showed relatively low reactivity under current reaction conditions (7c and 7d). In addition, the 3,4-disubstituted substituent (6e) underwent C-H acylation to give the desired product 7e in 34% yield. The ortho-hydroxylbenzaldehyde (6f) produced 7f with a low yield (21%). The reaction conditions were also successfully applied to highly substituted benzaldehyde (6 g), yielding 7 g of the synthetic precursor of phentinone.

<Compounds 8a-8g>

Acid catalyzed hydrolysis of all acylated compounds 7a-7g was performed to make picnic acid and its structural analogs (Figure 4). The acetyl and imine moieties were readily removed in a MeOH / acetone solvent using 0.5 M HCl at 80 &lt; 0 &gt; C and 8a-8g of the corresponding product were produced in good yields. The reaction formulas and the structural formulas of the compounds are shown in FIG. The spectroscopic data (1 H NMR and &lt; 13 &gt; C NMR) and physical properties of pliquinone (8 g) were in complete agreement with the reported values.

Specifically, compound 7a (76.3 mg, 0.2 mmol, 100 mol%) was added to a dried suture tube and 0.5 M HCl (1 mL) and MeOH / acetone (1 mL, 1: 1) were added. The reaction mixture was then stirred at 80 &lt; 0 &gt; C for 4 hours. The reaction mixture was cooled to room temperature and the reaction was terminated by the addition of saturated NaHCO3 solution (1 mL), adjusted to pH 7 and extracted with EtOAc (2 x 10 mL). The organic layer is MgSO ₄ Lt; / RTI &gt; and concentrated in vacuo via filtration. The residue was purified by flash column chromatography (n-hexanes / EtOAc = 3: 1) to give 32.9 mg of compound 8a in 53% yield.

2. Identification of compounds

The characteristics of the compounds 2 to 5b according to the step of preparing the puchinone A synthesized in the present invention are as follows.

<Compound 2>

1- (3-Allyl-4-hydroxyphenyl) ethan-1-one

2.0 g (71%); white solid; mp = 115.8-116.4 ^o C; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.79-7.76 (m, 2H), 7.04 (s, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.05-5.98 (d, 1H), 5.16- 5.13 (m, 2H), 3.45 (d, J = 6.3 Hz, 2H), 2.57 (s, 3H); ^{13 C NMR (100 MHz, CDCl} 3) δ 198.1, 159.2, 135.7, 131.3, 129.9, 129.2, 126.0, 116.7, 115.4, 34.6, 26.2; IR (KBr) υ 3078, 2933, 1672, 1655, 1595, 1508, 1422, 1358, 1273, 1172, 1120 1017, 996, 962, 919, 833 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C ₁₁ H ₁₃ O ₂ [M + H] ⁺ 177.0910, found 177.0905.

<Compound 3>

1- (4-Hydroxy-3- (prop-1-en-1-yl) phenyl) ethan-

1.7 g (95%, E: Z = 5: 1); white solid; mp = 107.3-109.1 ^o C; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.98 (s, 1H), 7.72 (dd, J = 8.4, 1.7 Hz, 1H), 7.64-7.61 (m, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 15.9 Hz, 1H), 6.35-6.26 (m, 1H), 2.58 (s, 3H), 1.90 (d, J = 6.5 Hz, 3H); ^{13 C NMR (100 MHz, CDCl} 3) δ 198.5, 157.8, 129.7, 128.9, 128.8, 128.3, 125.3, 124.6, 115.6, 26.2, 18.8; IR (KBr) υ 3282, 3041, 2964, 1651, 1583, 1505, 1421, 1357, 1302, 1274, 1254, 1202, 1125, 1073, 968, 890, 824, 771 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C 11 H 13 O 2 [M + H] + 177.0910, found 177.0909.

<Compound 4>

(Z) -1- (4-Hydroxy-3 - ((E) -prop-1-en-1-yl) phenyl) ethan-

1.08 g (87%, E: Z = 5: 1); white solid; mp = 105.8-107.3 ^o C; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.57 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 16.0 Hz (M, IH), 6.27-6.18 (m, IH), 5.82 (br s, IH), 3.97 (s, 3H), 2.20 (s, 3H), 1.89 (d, J = 6.4 Hz, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 154.7, 153.4, 131.6, 128.8, 125.8, 125.3, 125.1, 123.8, 115.6, 61.7, 18.8, 12.7; IR (KBr) ν 3323, 3037, 2936, 2818, 1654, 1595, 1504, 1435, 1366, 1315, 1274, 1221, 1177, 1120, 1049, 968, 913, 876, 821, 770 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C ₁₂ H ₁₆ NO ₂ [M + H] ⁺ 206.1176, found 205.1173.

<Compound 5a>

4 - ((E) -1- (Methoxyimino) ethyl) -2 - ((E) -prop-1-en-

0.53 g (71%, E-isomer); colorless oil; ^{1 H NMR (700 MHz, CDCl} 3) δ 7.76 (d, J = 2.1 Hz, 1H), 7.48 (dd, J = 8.4, 2.1 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 16.1, 2.1 Hz, 1H), 6.32-6.27 (m, 1H), 3.99 (s, 3H), 2.33 , 2.1 Hz, 3H); ¹³ C { ¹ H} NMR (175 MHz, CDCl ₃ ) δ 169.2, 153.9, 147.9, 134.5, 130.3, 129.0, 125.3, 124.3, 124.1, 122.4, 61.9, 20.9, 18.8, 12.6; IR (KBr)? 3036, 2937, 2817, 1759, 1654, 1603, 1487, 1441, 1367, 1318, 1263, 1197, 1169, 1116, 1046, 1009, 963, 906, 869, 832, 756 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C 14 H 18 NO 3 [M + H] ⁺ 248.1281, found 248.1280.

<Compound 5b>

4 - ((E) -1- (Methoxyimino) ethyl) -2 - ((Z) -prop-1-enyl) phenyl acetate

0.11 g (14%, Z-isomer); colorless oil; ^{1 H NMR (700 MHz, CDCl} 3) δ 7.57 (d, J = 2.1 Hz, 1H), 7.55 (dd, J = 8.4, 2.1 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 11.2, 1.4 Hz, 1H), 5.90-5.86 (s, 3H), 2.98 , 2.1 Hz, 3H); ^{13 C {1 H} NMR (} 175 MHz, CDCl 3) δ 169.0, 153.8, 147.0, 134.1, 130.2, 129.4, 128.1, 125.6, 124.1, 122.2, 61.9, 20.8, 14.5, 12.6; IR (KBr) υ 3038, 2935, 2816, 1759, 1651, 1605, 1485, 1440, 1351, 1311, 1258, 1197, 1169, 1113, 1035, 1008, 959, 902, 874, 824, 751 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C 14 H 18 NO 3 [M + H] + 248.1281, found 248.1280.

The characteristics of reactants 7a-7g as a result of the ketoxime-directed catalytic oxidative acylation of 5a synthesized through the above reaction are as follows.

<Compound 7a>

E) -prop-1-en-1-yl) phenyl acetate (prepared as described in Example 1).

93.1 mg (61%); orange sticky oil; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.73 (dt, J = 9.6, 2.8 Hz, 2H), 7.58 (s, 1H), 7.12 (s, 1H), 6.88 (dt, J = 9.7, 2.8 Hz, 2H), 6.45-6.33 (s, 3H), 3.85 (s, 3H), 3.72 ); 13 C NMR (100 MHz, CDCl ₃ ) δ 194.7, 168.9, 163.3, 154.1, 146.9, 137.9, 134.7, 132.2, 131.9, 130.6, 130.5, 126.3, 123.6, 123.5, 113.5, 61.7, 55.4, 20.8, 18.9, 15.1; IR (KBr) ν 2958, 2937, 2841, 1762, 1718, 1658, 1598, 1575, 1509, 1458, 1420, 1368, 1316, 1255, 1197, 1170, 1154, 1125, 1042, 965, 910, 872, 847 , 775, 738 cm &lt; ^{-1 &} gt ;; HRMS (orbitrap, ESI) calcd for C 22 H 24 NO 5 [M + H] + 382.1649, found 382.1652.

<Compound 7b>

Synthesis of 5- (4-hydroxybenzoyl) -4 - ((E) -1- (methoxyimino) ethyl) -2 - ((E) -prop-

74.9 mg (51%); white solid; mp = 132.0-133.6 ^o C; ^{1 H NMR (700 MHz, CD} 3 OD) δ 7.69 (s, 1H), 7.59 (d, J = 9.1 Hz, 2H), 7.10 (s, 1H), 6.80 (d, J = 8.4 Hz, 2H), 2H), 3.66 (s, 3H), 2.33 (s, 3H), 2.03 (s, 3H), 1.93 (dd, J = 3.5, 0.7 Hz, 3H); 13 C {1H} NMR (175 MHz, CD ₃ OD) δ 197.2, 170.7, 163.8, 155.5, 148.5, 139.4, 135.7, 133.6, 131.9, 130.5, 127.2, 124.6, 124.5, 116.1, 61.9, 20.6, 19.1, 14.9; IR (KBr) v 3341, 2934, 2855, 1763, 1650, 1599, 1582, 1511, 1437, 1368, 1317, 1274, 1195, 1166, 1153, 1125, 1040, 1008, 964, 911, 871, 850, 776 , 736 cm- ¹ ; HRMS (orbitrap, ESI) calcd for C ₂₁ H ₂₂ NO ₅ [M + H] ⁺ 368.1492, found 368.1493.

<Compound 7c>

5 - (3-Methoxybenzoyl) -4 - ((E) -1- (methoxyimino) ethyl) -2 - ((E) -prop-

74.8 mg (49%); brown sticky oil; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.58 (s, 1H), 7.34 (q, J = 2.5 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.23 (dt, J = 7.6, 2H), 3.82 (s, 3H), 3.72 (s, 3H, &lt; RTI ID = 0.0 & ), 2.33 (s, 3H), 2.02 (s, 3H), 1.93 (d, J = 5.0 Hz, 3H); ¹³ C ( ¹ H) NMR (100 MHz, CDCl ₃ ) 隆 195.6, 168.8, 159.6, 154.0, 147.0, 139.2, 137.5, 134.9, 132.6, 130.8, 129.2, 126.2, 124.0, 123.5, 122.4, 119.5, , 55.4, 20.8, 18.9, 14.9; IR (KBr) υ 2930, 1769 , 1721, 1692, 1668, 1584, 1535, 1486, 1458, 1429, 136, 1319, 1270, 1193, 1151, 1119, 1043, 964, 875, 799, 758, 735 cm - ¹ ; HRMS (orbitrap, ESI) calcd for C 22 H 24 NO 5 [M + H] + 382.1649, found 382.1654.

<Compound 7d>

Synthesis of 5- (3-hydroxybenzoyl) -4 - ((E) -1- (methoxyimino) ethyl) -2 - ((E) -prop-

58.8 mg (40%); white solid; mp = 129.0-130.2 ^o C; ^{1 H NMR (700 MHz, CD} 3 OD) δ 7.71 (s, 1H), 7.24 (t, J = 7.9 Hz, 1H), 7.15 (s, 1H), 7.09-7.07 (m, 2H), 6.97 (ddd 3H), 2.02 (s, 3H), 1.93 (d, J = 4.7 (m, 2H) Hz, 3H); ^{13 C {1 H} NMR (} 175 MHz, CD 3 OD) δ 198.2, 170.7, 158.8, 155.2, 148.7, 140.6, 139.2, 135.9, 134.1, 132.1, 130.5, 126.9, 124.7, 124.6, 121.6, 121.1, 116.5, 62.0, 20.6, 19.0, 14.6; IR (KBr) υ 3385, 2935 , 2856, 1768, 1651, 1596, 1564, 1553, 1485, 1446, 1368, 1317, 1282, 1194, 1143, 1120, 1043, 1009, 964, 874, 818, 764 cm - ¹ ; HRMS (orbitrap, ESI) calcd for C ₂₁ H ₂₂ NO ₅ [M + H] ⁺ 368.1492, found 368.1495.

<Compound 7e>

(E) -prop-1-en-1-yl) phenyl acetate as a colorless powder.

54.1 mg (34%); red sticky oil; ¹ H NMR (400 MHz, CD ₃ OD)? 7.69 (s, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.15 (dd, J = 8.2, 1.9 Hz, 1H) ), 6.80 (d, J = 8.2 Hz, 1H), 6.50-6.49 (m, 2H), 3.85 (s, 3H) , 1.93 (d, J = 4.8 Hz, 3H); ^{13 C {1 H} NMR (} 100 MHz, CD 3 OD) δ 195.1, 168.8, 153.7, 151.4, 147.0, 146.4, 137.2, 133.9, 131.6, 130.0, 128.7, 125.3, 124.3, 122.7, 122.6, 113.7, 111.2, 60.0, 54.3, 18.6, 17.1, 13.1; IR (KBr) v 3404, 2936, 28525, 1762, 1652, 1589, 1510, 1459, 1427, 1369, 1278, 1195, 1145, 1119, 1042, 965, 916, 874, 781 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C 22 H 24 NO 6 [M + H] + 398.1598, found 398.1600.

<Compound 7f>

Synthesis of 5- (2-hydroxybenzoyl) -4 - ((E) -1- (methoxyimino) ethyl) -2 - ((E) -prop-

30.9 mg (21%); yellow sticky oil; ^{1 H NMR (400 MHz, CDCl} 3) δ 11.86 (s, 1H), 7.62 (s, 1H), 7.43 (ddd, J = 15.6, 8.7, 1.7 Hz, 1H), 7.23 (dd, J = 8.9, 2.5 J = 15.1, 8.1, 1.0 Hz, 1H), 6.46-6.35 (m, 2H), 6.99 (dd, J = , 3.67 (s, 3H), 2.34 (s, 3H), 2.08 (s, 3H), 1.94 (d, J = 5.1 Hz, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 201.6, 168.8, 162.3, 152.7, 147.1, 136.3, 135.9, 133.6, 132.4, 132.1, 130.8, 125.9, 123.5, 123.1, 120.4, 118.8, , 20.8, 18.9, 13.9; IR (KBr) υ 2965, 2936 , 2818, 1765, 1630, 1612, 1484, 1446, 1367, 1331, 1294, 1243, 1192, 1149, 1130, 1112, 1046, 1009, 965, 912, 874, 835 cm - ¹ ; HRMS (orbitrap, ESI) calcd for C 21 H 22 NO 5 [M + H] + 368.1492, found 368.1508.

<Compound 7g>

Synthesis of 5- (2,4-Dihydroxy-3-methoxybenzoyl) -4 - ((E) -1- (methoxyimino) ethyl) -2 - ((E) -prop-

29.8 mg (18%); yellow sticky solid; ^{1 H NMR (700 MHz, CD} 3 OD) δ 7.72 (s, 1H), 7.11 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 2.1 Hz, 2H), (S, 3H), 2.33 (s, 3H), 2.09 (s, 3H), 1.93 (d, J = 4.9 Hz, 3H) ); ¹³ C ( ¹ H) NMR (175 MHz, CD ₃ OD) δ 201.9, 170.7, 158.6, 158.4, 154.8, 148.6, 138.1, 136.1, 134.9, 133.7, 132.0, 130.1, 127.1, 124.5, 124.1, 115.7, 108.9, 62.0, 60.8, 20.6, 19.1, 14.3; IR (KBr) ν 3396, 2922, 2852, 1754, 1614, 1503, 1431, 1367, 1328, 1291, 1242, 1193, 1157, 1131, 1090, 1040, 1006, 963, 934, 872, 793 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C 22 H 24 NO 7 [M + H] + 414.1547, found 414.1554.

Hydrolysis of the acylated compounds 7a-7g was carried out to produce phenttonone and its derivatives, and the characteristics of reactants 8a-8g were as follows.

<Compound 8a>

(E) -1- (4-Hydroxy-2- (4-methoxybenzoyl) -5- (prop-1-en- 1- yl) phenyl) ethan-

32.9 mg (53%); white solid; mp = 177.2-178.6 ^o C; ^{1 H NMR (400 MHz, CD} 3 OD) δ 8.04 (s, 1H), 7.65 (dt, J = 9.7, 2.8 Hz, 2H), 6.94 (dt, J = 7.2, 2.8 Hz, 2H), 6.74-6.70 (m, 1H), 6.68 (s, 1H), 6.53-6.48 (m, 1H), 3.84 (s, 3H), 2.47 (s, 3H), 1.94 (dd, J = 6.5, 1.6 Hz, 3H); ^{13 C {1 H} NMR (} 100 MHz, CD 3 OD) δ 199.1, 199.0, 165.2, 159.5, 142.6, 132.5, 132.3, 131.3, 130.5, 129.8, 129.6, 129.2, 127.1, 125.9, 115.9, 114.7, 56.0, 26.8, 19.1; IR (KBr) ν 3295, 2926, 2841, 1671, 1595, 1570, 1509, 1420, 1359, 1302, 1256, 1170, 1150, 1129, 1025, 961, 898, 846, 771, 738 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C ₁₉ H ₁₉ O ₄ [M + H] &lt; ⁺ &gt; 311.1278, found 311.1290.

<Compound 8b>

(E) -1- (4-Hydroxy-2- (4-hydroxybenzoyl) -5- (prop-1-en-1-yl) phenyl) ethan-

42.2 mg (71%); white solid; mp = 233.1-234.9 ^o C; ^{1 H NMR (400 MHz, CD} 3 OD) δ 8.02 (s, 1H), 7.58 (dt, J = 9.5, 2.7 Hz, 2H), 6.77 (dt, J = 9.5, 2.7 Hz, 2H), 6.74-6.99 (m, 1H), 6.67 (s, 1H), 6.54-6.45 (m, 1H), 2.47 (s, 3H), 1.93 (dd, J = 6.5, 1.6 Hz, 3H); ¹³ C { ¹ H} NMR (100 MHz, CD ₃ OD) δ 199.2, 199.1, 163.8, 159.5, 142.7, 132.9, 130.5, 130.1, 129.5, 129.1, 127.1, 126.0, 116.1, 116.0, 26.9, 19.1; IR (KBr) ν 2924, 2852, 1773, 1636, 1599, 1562, 1414, 1359, 1312, 1260, 1195, 1166, 1129, 1051, 965, 914, 871, 773, 708 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C 18 H 17 O 4 [M + H] + 297.1121, found 297.1122.

<Compound 8c>

(E) -1- (4-Hydroxy-2- (3-methoxybenzoyl) -5- (prop-1-en-1-yl) phenyl) ethan-

24.9 mg (40%); brown sticky oil; ^{1 H NMR (700 MHz, CD} 3 OD) δ 8.04 (s, 1H), 7.30 (t, J = 1.5 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.12-7.10 (m, 2H 3H), 2.46 (s, 3H), 1.94 (dd, 1H), 6.72 (dd, J = J = 6.5, 1.7 Hz, 3H); ^{13 C {1 H} NMR (} 175 MHz, CD 3 OD) δ 199.6, 199.1, 161.2, 159.7, 142.4, 139.9, 130.5, 129.6, 129.3, 127.4, 125.9 (two-carbon overlap), 122.9, 120.1, 116.0, 114.1, 55.8, 26.6, 19.1; IR (KBr) υ 3274, 2923 , 2854, 1670, 1595, 1581, 1566, 1485, 1452, 1428, 1415, 1359, 1300, 1267, 1220, 1180, 1122, 1036, 968, 902, 877, 799 cm - ¹ ; HRMS (orbitrap, ESI) calcd for C 19 H 19 O 4 [M + H] + 311.1278, found 311.1289.

<Compound 8d>

(E) -1- (4-Hydroxy-2- (3-hydroxybenzoyl) -5- (prop-1-en-1-yl) phenyl) ethan-

26.6 mg (45%); white solid; mp = 215.0-216.5 ^o C; ^{1 H NMR (400 MHz, CD} 3 OD) δ 8.04 (s, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.12-7.08 (m, 2H), 6.95 (ddd, J = 11.5, 8.0, 1H), 6.74 (s, 1H), 6.70 (s, 1H) ); ^{13 C {1 H} NMR (} 100 MHz, CD 3 OD) δ 197.9, 197.1, 157.7, 156.7, 140.5, 137.8, 128.5, 128.4, 127.6, 127.2, 125.3, 124.0, 119.5, 119.1, 114.3, 114.0, 24.6, 17.1; IR (KBr) ν 2957, 2927, 2854, 2366, 2325, 1769, 1649, 1597, 1559, 1448, 1361, 1269, 1199, 1129, 1047, 973, 832 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C 18 H 17 O 4 [M + H] + 297.1121, found 297.1129.

<Compound 8e>

(E) -1- (4-Hydroxy-2- (4-hydroxy-3-methoxybenzoyl) -5- (prop-1-en- 1- yl) phenyl) ethan-

35.9 mg (55%); white solid; mp = 168.4-169.9 ^o C; ¹ H NMR (400 MHz, CD ₃ OD)? 8.02 (s, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.01 (dd, J = 8.2, 1.9 Hz, 1H), 6.76-6.70 2H), 6.69 (s, 1H), 6.53-6.47 (m, 1H), 3.87 (s, 3H), 2.47 (s, 3H), 1.94 (dd, J = 6.6, 1.6 Hz, 3H); ^{13 C {1 H} NMR (} 100 MHz, CD 3 OD) δ 197.3, 197.0, 157.4, 151.3, 147.1, 140.5, 128.5, 128.4, 127.7, 127.2, 125.1, 124.3, 124.0, 114.1, 113.5, 110.3, 54.3, 24.9, 17.1; IR (KBr) v 3311, 2957, 2924, 2853, 1650, 1590, 1512, 1461, 1427, 1360, 1298, 1275, 1210, 1121, 1029, 970, 903, 781 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C 19 H 19 O 5 [M + H] + 327.1227, found 327.1239.

<Compound 8f>

(E) -1- (4-Hydroxy-2- (2-hydroxybenzoyl) -5- (prop-1-en-1-yl) phenyl) ethan-

36.3 mg (61%); white solid; mp = 100.7-102.6 ^o C; ^{1 H NMR (400 MHz, CD} 3 OD) δ 8.07 (s, 1H), 7.44 (ddd, J = 15.6, 10.0, 1.7 Hz, 1H), 7.04 (dd, J = 7.9, 1.6 Hz, 1H), 6.95 (dd, J = 8.4, 0.8 Hz, 1H), 6.77-6.71 (m, 2H), 6.70 (s, = 6.6, 1.6 Hz, 3H); ¹³ C ( ¹ H) NMR (100 MHz, CD ₃ OD)? 203.2, 196.7, 161.3, 158.1, 138.7, 134.9, 131.2, 128.7, 127.4, 126.7, 125.5, 123.9, 119.5, 117.9, 116.7, 113.8, 24.5, 17.1; IR (KBr) υ 3236, 3063, 2914, 1627, 1600, 1566, 1484, 1448, 1413, 1359, 1331, 1305, 1267, 1242, 1217, 1159, 1034, 965, 906, 874, 814, 755, ^-1 ; HRMS (orbitrap, ESI) calcd for C 18 H 17 O 4 [M + H] + 297.1121, found 297.1133.

<Compound 8g>

(E) -1- (2- (2,4-Dihydroxy-3-methoxybenzoyl) -4-hydroxy-5- (prop-1-en-1-yl) phenyl) ethan-1-one; penchinonee

41.2 mg (60%); white solid; mp = 111.2-113.9 ^o C; ¹ H NMR (700 MHz, CD ₃ OD)? 8.05 (s, 1H), 6.72-6.70 (m, 2H), 6.68 8.4 Hz, 1H), 3.88 (s, 3H), 2.50 (s, 3H), 1.94 (dd, J = 6.3, 1.4 Hz, 3H); ^{13 C {1 H} NMR (} 175 MHz, CD 3 OD) δ 203.8, 198.9, 159.5, 158.5, 158.3, 140.7, 136.1, 130.7, 129.9, 129.3, 128.9, 127.3, 125.9, 115.9, 115.4, 108.8, 60.8, 26.8, 19.1; IR (KBr) ν 3279, 2923, 2853, 1651, 1601, 1501, 1445, 1359, 1290, 1158, 1107, 1090, 1042, 969, 812, 791 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C 19 H 19 O 6 [M + H] + 343.1176, found 343.1179.

<Experimental Example> Identification of anti-inflammatory activity

One. Experimental Method

Rat-derived RAW 264.7 macrophages were purchased from the American Type Culture Collection (ATCC) and cultured in Dulbecco's modified Eagle's medium (DMEM), 10% fetal bovine serum and 1% penicillin-streptomycin at 37 ° C in 5% CO2.

To confirm the concentration of NO, RAW264.7 cells were treated with compounds for 2 hours and then LPS (1 μg / mL) was added for an additional 24 hours. The concentration of NO in the culture supernatant was measured using the previously described assay system (please check the exact method ). The NO level was used as an indicator of NO production. 100 μL of Griess regent (1% sulfanilamide in 5% phosphoric acid, 1% α-naphthylamide in H2O) was placed in a 96-well plate and incubated at room temperature for 15 minutes and then measured at 550 nm using a Molecular Device microplate reader.

To confirm the expression of TNF-α and IL-6, RAW264.7 cells were pretreated with compounds and LPS (1 μg / mL) was added to the culture for 24 hours. The concentrations of TNF-a and IL-6 in each sample treated with the compound were measured using a DuoSet Elisa kit according to the manufacturer's instructions.

The results of the above experiments were expressed as means ± S.E.M. All experiments were performed at least three times and Student's t test (SigmaPlot) was used for comparison between groups. Multiple group comparisons of mean values were analyzed by one-way analysis (ANOVA, GraphPad program).

2. Experiment result

7-g and 7-g) synthesized for nitric oxide (NO), tumor necrosis factor alpha (TNF-a) and interleukin-6 (IL-6) Compounds 8a-8g) were evaluated [Table 1].

The anti-inflammatory effect (IC ₅₀ value (μM)) of compounds 7a-7g and 8a-8g compound NO TNF-a IL-6 compound NO TNF-a IL-6 7a 7.60 + 0.07 11.16 ± 0.06 8.68 ± 0.06 8a 4.38 + 0.02 9.16 + 0.04 7.66 ± 0.01 7b 6.26 + 0.02 8.66 + 0.07 5.60 ± 0.01 8b 5.40 ± 0.01 7.66 ± 0.01 6.53 ± 0.01 7c 2.73 ± 0.01 5.89 ± 0.01 4.26 + 0.02 8c 2.00 + 0.02 4.05 ± 0.00 2.15 + 0.03 7d 2.78 + 0.02 6.96 + 0.02 4.14 + 0.02 8d 6.21 + 0.03 6.86 ± 0.02 7.70 + - 0.01 7e 5.77 + 0.02 8.97 ± 0.07 6.88 + 0.02 8e 1.81 ± 0.01 3.77 ± 0.02 3.10 ± 0.01 7f 4.95 ± 0.01 4.32 ± 0.02 3.23 + 0.02 8f 0.94 + - 0.01 3.20 ± 0.03 2.07 ± 0.01 7g 4.16 + 0.07 6.24 + 0.02 5.96 ± 0.01 8g 1.01 + - 0.01 3.12 ± 0.01 2.10 + 0.04 Dexamethasone 1.76 + 0.02 4.52 + 0.02 3.92 ± 0.01

The detection of anti - inflammatory activity was confirmed by enzyme - linked immunosorbent assay (ELISA) in RAW264.7 cells induced by LPS. LPS derived RAW264.7 cells (control) as compared to anti-inflammatory drug, dexamethasone (dexamethasone) are commercially exhibited a 50% inhibition concentration (IC ₅₀₎ of inflammatory factors by the compound treatment was used as a positive control (IC ₅₀ value (μM): 50% inhibition concentration for NO, TNF-α, and IL-6 production. The activity of the compounds 7c, 7d, 8c and 8e-8g showed an inhibitory activity similar to the positive control dexamethasone. In particular, picchinone (8 g) and its structural analogue 8f showed better NO production inhibitory activity than the positive control (IC ₅₀ = 1.01 ± 0.01 μM for compound 8g, IC ₅₀ = 0.94 ± 0.01 μM for compound 8f).

In addition, it was confirmed that the compounds 8c and 8e-8g showed higher TNF-a and IL-6 production inhibitory activities than dexamethasone.

Claims (4)

7. An anti-inflammatory composition comprising as an active ingredient any one of the following formulas (7a) to (8g).

The method according to claim 1,
Wherein the composition is a food composition.
The method according to claim 1,
Wherein the composition is a pharmaceutical composition.
The method according to claim 1,
Wherein the composition is a cosmetic composition.

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