KR100837733B1 - Composition comprising decursin derivative showing treating and preventing atopic dermatitis disease - Google Patents

Abstract

A decursin derivative compound is provided to inhibit MCP-1, IL-6 and IL-8 inducing atopic skin inflammation reaction effectively, thereby being usefully used as a pharmaceutical composition and a health functional food for preventing and treating atopic dermatitis diseases. A decursin derivative synthesized from (+)-decursinol, which is isolated from Angelica gigas, is represented by a formula(1). In the formula(1), A is H, dialkyl acryloyl or cinnamoyl where a phenyl ring is substituted or unsubstituted with R', wherein R' may be substituted at an ortho-, metha- or para position of the phenyl ring and is at least one substituent selected from the group consisting of H, hydroxy, acetate, halogen, C1-4 alkyl, C1-4 alkoxy, and C1-4 alkyl ester. A pharmaceutical composition for preventing and treating atopic diseases comprises the decursin derivative compound of the formula(1) or a pharmaceutically acceptable salt thereof as an effective ingredient.

Description

Composition comprising decursin derivative showing treating and preventing atopic dermatitis disease

     The present invention relates to a composition containing a decursin derivative (dcursin derivative) synthesized by using (+)-decursinol isolated from the Angelica gi as a precursor.

Atopic dermatitis is a chronic inflammatory skin disease with chronic recurrences, characterized by pruritus, dryness, eczema, and keratin (Hanifin JM et al., Guidelines of care for atopic dermatitis. J. Am Acad. Dermatol . , 50, pp 391-404, 2004). Recently, the incidence rate of atopic dermatitis has increased rapidly in Korea and other countries, but only symptomatic drug treatment is being carried out since there are no treatments that can fundamentally change the course of the disease (Williams HC). .,. Clinical practice. Atopic dermatitis . N. Engl. J. Med, 352, pp2314-24, 2005).

The pathogenesis of atopic dermatitis is not yet fully understood, but it has been known that atopic dermatitis is caused by a chronic inflammatory response to the skin due to a sensitive immune response (allergic reaction) to a substance (allergen) common in the environment ( Oh JW et al., Nationwide study for epidemiological change of atopic dermatitis in school aged children between 1995 and 2000 and kindergarten aged children in 2003 in Korea. Pediatr. Allergy Respir . Dis ., 13 , pp 227-237, 2003). In particular incidence (Colloff MJ. Atopic dermatitis in proportion to the amount of exposure to house dust mite as the basis, Exposure to house dust mites in homes of people with atopic dermatitis. Br. J. Dermatol., 127, pp322-327, 1992) and may be a significant correlation between the severity of atopic dermatitis (Jeon SY et al., correlation between house dust mite allergen concentrations in scalp dander and clinical severity of atopic dermatitis in children. Pediatr. Allergy Respir. Dis., 9 , pp 32-40, 1999). It is also known to reduce the severity of atopic dermatitis by reducing exposure to house dust mites in the environment.

Steroids are the most widely used and effective treatments for inflammatory diseases such as bronchial asthma. Recently, many mechanisms for steroids have been elucidated, but the mechanisms have not yet been fully understood, and some patients with bronchial asthma or rheumatoid arthritis show steroid resistance that does not respond to steroids. Although there are not many patients showing such steroid resistance, it is usually a problem to identify the mechanism of steroid resistance as soon as it is severe, suffers from complications, and is expensive. (Kino T et al., Tissue-specific glucocorticoid resistance hypersensitivity syndromes:. multifactorial states of clinical importance J. Allergy Clin . Immunol ., 109 , pp 609-613, 2002).

In chronic inflammatory reactions, many cells secrete various cytokines such as tumor growth factor-β (TGF-β), IL-4 and IL-13, which are involved in fibrosis. Cytokines increase the secretion of IL-6, which activates fibroblasts, resulting in differentiation and proliferation of many fibroblasts and overproduction of extracellular matrix, resulting in cell and tissue deformation and fibrosis .

Atopic dermatitis is treated with steroid-based drugs, but as it becomes chronic, it is a reason to show resistance to steroid agents due to the deformation and fibrosis of the above tissues. Monocyte Chemoattractant Protein-1 (MCP-1) binds to the chemokine receptor (CCR2), and mice with the MCP-1 gene removed are chemotactic for monocytes. This damage and weakened resistance to infection of certain bacteria were observed (Lu B et al., Abnorm alities in monocyte recruitment and cytokine expression in monocyt e chemoattractant protein 1-deficient mice. J. Exp . Med ., 187 , pp601-608, 1998). This phenomenon was similar to the symptoms observed in animals with the CCR2 gene removed. In addition, MCP-1 has been reported to convert helper T progenitor cells (Th0 cells) into cells that secrete helper T cell cytokines (Karpus WJ et al., MIP-1 alpha and MCP-1) in vitro. differentially regulate acute and relapsing autoimmune encephalomy elitis asell as Th1 / Th2 lymphocyte differentiation. J. Leukoc. Biol., 62, pp681-687, 1997). Intravenous injection of MCP-1 decreased IL-12 production and increased IL-4 production. This indirectly means that IgE-dependent allergic inflammation can be exacerbated.

IL-8, which is important for early inflammatory responses, is an important inflammatory chemokine secreted from airway epithelial cells (Harada A et al., Essential involvement of interleukin-8 (IL-8) in acute inflammation. J, Leukoc , Biol ,, 56 , pp559-564, 1994), bronchial hypersensitivity is induced by IL-8 appears and is increased in the allergic rhinitis or asthma disease (Fujimura M et al., Role of leukotriene B4 in bronchial hyperresponsiveness induced by interleukin 8. Eur. Respir. J., 11, pp306-311, 1998; .... Kurashima K et al, Increase of chemokine levels in sputum precedes exacerbation of acute asthma attacks J. Leukoc Biol, 59, is suppressed by the pp313-316, 1996) steroids .

     Decursin (decursin) is a substance that has been attracting attention because it shows a variety of activities, including anti-cancer activity in recent years, isolated from true Angelica.

Angelica gigas is an umbelliferae plant and refers to Korean donkeys. Young shoots are used as medicinal agents for various diseases such as edible and rooted analgesic effect, relieving kidney toxicity, and treating diabetic hypertension. (Chi, H. J and Kim HS :... Studies on the components of Umbelliferae Plants in Korea Kor J. Pharmacogn, 1, pp.25, 1970). The main components exhibiting these various activities include (+)-decursin and (+)-decursinol angelate, which are dihydropyranocoumarin-based substances. Secondary alcohol group esters of decursinol [7-hydroxy-8,8-dimethyl-7,8-dihydro- 6H- pyrano (3,2-g) chromen-2-one] (Bae, EA et al., Anti-Helicobacter pylori activity of herbal medicines. Biol Pharm Bull . 21 , pp. 990, 1998).

Recently, it has been shown that decursin inhibits the cytokines IL-8, MCP-1 and TNF-a, which induce inflammatory responses by inhibiting NF-kB in macrophage, a cell that mediates inflammatory responses (Kim). J. H et al., Decursin inhibits induction of inflammatory mediators by blocking nuclear factor-k B activation in macrophages.Molecular Pharmacology, 69 (6) , pp 1783-1790, 2006).

Therefore, the present inventors synthesized new derivatives of ester forms having various structures that do not exist in Angelica quinquefolius using (+)-decursinol as a starting material, and measured their anti-atopic effects, and thus excellent atopy inhibition. By confirming the effect, the present invention was confirmed by confirming the possibility of use as a therapeutic agent for atopic dermatitis.

 An object of the present invention for the prevention and treatment of atopic dermatitis disease containing a decursin derivative (decursin derivative) having an inhibitory effect of MCP-1, IL-6, IL-8 induced by ticks as an active ingredient It is to provide a pharmaceutical composition and dietary supplement.

 In order to achieve the above object, the present invention provides a decursin derivative compound of the novel structure represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

                         (I)

     In the above formula,

The A substituent is a hydrogen atom, a C ₁ to C ₄ alkyl group, a dialkyl acryloyl group or a cinnamoyl group in which the phenyl ring is unsubstituted or substituted with R '; Wherein R ′ is optionally substituted at o, m, p positions and is composed of a hydrogen atom, a hydroxyl group, an acetate group, a halogen atom, a C ₁ to C ₄ lower alkyl group, a lower alkoxy group and a lower alkyl ester and a lower alkyl carboxyl group At least one substituent selected from the group.

As a preferable compound group of the said general formula (I) compound, A substituent is a hydrogen atom, a methyl group, a dimethyl acryloyl group, or a phenyl ring which is unsubstituted or substituted by R ', where R' is o, m, group of compounds which are one or more substituents selected from the group consisting of hydrogen atom, methyl group, methoxy group or acetate group optionally substituted at p- position.

Most preferably, the compounds of the general formula (I) include the following compounds, and the present invention is not intended to limit the scope of the invention thereto.

8,8- dimethyl -6 H - pyrano [3,2- g] chromene-2,7-dione 7-oxime, 8,8- dimethyl -6 H - pyrano [3,2- g] chromene -2,7-dione 7- [ O- (3,3-dimethylacryloyl) -oxime], 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7- dione 7- (O-cinnamoyl-oxime), 8,8- dimethyl -6 H - pyrano [3,2- g] chromene-2,7-dione 7- [O - (4- methoxy-cinnamoyl ) -Oxime], 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione 7- [ O- (3,4-dimethoxycinnamoyl) -oxime], 8,8- dimethyl -6 H - pyrano [3,2- g] chromene-2,7-dione 7- [O - (3,4,5- trimethoxy-cinnamoyl) oxime], 8, 8-dimethyl -6 H - pyrano [3,2- g] chromene-2,7-dione 7- [O - (3- acetoxy-cinnamoyl) oxime], 8,8- dimethyl -6 H - Pyrano [3,2- g ] chromen-2,7-dione 7- [ O- (3,4-diacetoxycinnamoyl) -oxime].

The present invention also provides a decursin derivative compound having a novel structure represented by the following general formula (II) or a pharmaceutically acceptable salt thereof.

     In the above formula,

The B substituent is a 5-membered unsubstituted or substituted with a hydrogen atom, a hydroxyl group, a C ₁ to C ₄ lower alkyl group, a C ₁ to C ₆ alkoxy group or a halogen atom, a C ₁ to C ₃ lower alkyl group and a C ₁ to C ₃ lower alkoxy group At least one group selected from the group consisting of 6 membered heterocyclic groups.

In a preferred group of compounds of the general formula (Ⅱ) is a B substituent is a methyl group, a halogen atom, C ₁ - C ₃ lower alkyl groups, C ₁ - C ₃ are selected from the group of compounds which is comprised of a lower alkoxy group or a phenyl group.

Most preferably, the compounds of the general formula (II) include the following compounds, and the present invention is not intended to limit the scope of the invention thereto.

Methane sulfonic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester, benzene sulfonic acid 2,2-dimethyl -8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester.

     The compounds of the present invention represented by general formulas (I) to (II) may be prepared as pharmaceutically acceptable salts according to methods conventional in the art.

As salts are acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and acid or alcohol (eg, glycol monomethylether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.

In this case, organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like.

Bases can also be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salts, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

Pharmaceutically acceptable salts of the compounds of the general formulas (I) to (II) are salts of acidic or basic groups which may be present in the compounds of the general formulas (I) to (II) unless otherwise indicated. Include. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfates, hydrogen sulphates, phosphates, hydrogen phosphates, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, which are known in the art. It can be prepared through.

      Another object of the present invention is to provide a method for preparing the compounds of the general formulas (I) to (II), which may be chemically synthesized by the methods shown in the following schemes, but is not limited thereto. .

The following reaction schemes represent the preparation steps of the representative compounds of the present invention. The various compounds of the present invention may be prepared by small changes such as changing the reagents, solvents, and reaction sequences used in the synthesis of Schemes 1 to 4. have. Some compounds of the present invention have been synthesized according to procedures not included in the scope of Schemes 1-4, and detailed synthesis procedures for these compounds are described in their respective examples.

     Scheme (1) shows a two-step process for preparing a commercial compound or a compound synthesized by known methods.

In the first step, (+)-decurinol is dissolved in anhydrous dichloromethane, and then pyridinium chlorochromate and molecular sieve are added to the reaction. The solvent used at this time is carried out using a solvent that does not adversely affect the reaction, dichloromethane, chloroform, diethyl ether, tetrahydrofuran and the like. The reaction temperature is not particularly limited, but may be generally performed at cold to room temperature, preferably at cold temperature. The reaction time can be carried out for 30 minutes to 1 hour, preferably by stirring for 1 hour 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione (17 Get) In the second step, 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione (17) is dissolved in anhydrous ethanol, and then hydroxy ammonium chloride and pyridine are added to the reaction. Do this. In this case, the solvent used is ethanol, methanol, butanol, dichloromethane, chloroform and the like which do not adversely affect the reaction. The reaction temperature is not particularly limited, but may be generally performed at room temperature to 100 ° C, and preferably at 80 ° C. The reaction time can be carried out for 30 minutes to 1 hour, preferably by stirring for 1 hour 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione 7- The oxime 18 can be manufactured.

      Scheme (2) shows a two-step process for preparing a commercial compound or a compound synthesized by known methods.

In the first step, 3,3-dimethylacrylic acid (2a) is dissolved in anhydrous dichloromethane and oxalyl chloride is added dropwise. The solvent used at this time is carried out using a solvent that does not adversely affect the reaction, dichloromethane, chloroform, diethyl ether, tetrahydrofuran and the like. The reaction temperature is not particularly limited, but may be generally performed at cold to room temperature, preferably at cold temperature. The reaction time can be carried out for 3 to 18 hours, preferably stirred for 5 hours to prepare 3,3-dimethylacryloyl chloride (19a), in the second step (+)-dekursi The sol was dissolved in anhydrous dichloromethane, and 3,3-dimethylacryloyl chloride (19a) and pyridine were added dropwise and stirred at room temperature for 2 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column separation to obtain 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione 7- [ O- (3,3- Dimethylacryloyl) -oxime] (20a) can be prepared.

      Scheme (3) shows a two-step process for preparing a commercial compound or a compound synthesized by known methods.

In the first step, cinnamic acid is dissolved in anhydrous benzene, followed by reaction with thionyl chloride and N, N -dimethylformamide. The solvent used at this time is carried out using a solvent that does not adversely affect the reaction, dichloromethane, chloroform, diethyl ether, tetrahydrofuran and the like. The reaction temperature is not particularly limited, but may be generally performed at room temperature to 100 ° C, and preferably at 80 ° C. The reaction time may be carried out for 3 to 18 hours, preferably stirred for 5 hours to prepare cinnamoyl chloride (7a), in the second step 8,8-dimethyl-6 H -pyrano [ 3,2- g ] chromen-2,7-dione 7-oxime (18) was dissolved in pyridine and anhydrous dichloromethane, cinnamoyl chloride (7a) was added dropwise and stirred at room temperature for 2 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column separation to obtain 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione 7- ( O -cinnayl-oxime). (21a) can be manufactured.

     Scheme (4) shows a one-step preparation process for preparing commercial compounds or compounds synthesized by known methods.

In the first step, decursinol (1) and triethylamine are dissolved in anhydrous dichloromethane and reacted by dropwise addition of sulfonyl chloride. The solvent used at this time is carried out using a solvent that does not adversely affect the reaction, dichloromethane, chloroform, diethyl ether, tetrahydrofuran. The reaction temperature is not particularly limited, but may be generally performed at cold to room temperature, and preferably at room temperature. The reaction time can be carried out for 5 to 20 hours, preferably stirred for 15 hours to give 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester 16a can be prepared.

     The composition containing the general formula (I) to (II) compounds obtained by the above production method as an active ingredient, by confirming the secretion inhibitory effect of MCP-1, IL-6, IL-8 induced by the tick, atopic dermatitis It can be usefully used as a pharmaceutical composition and health functional food effective for the prevention and treatment of diseases.

Accordingly, the present invention provides a pharmaceutical composition for the prevention and treatment of atopic dermatitis diseases containing the decursin derivative compounds represented by the above general formulas (I) to (II) or a pharmaceutically acceptable salt thereof as an active ingredient. do.

 The present invention also provides a pharmaceutical composition for the prevention and treatment of atopic dermatitis diseases containing a decursin derivative compound represented by the following general formula (III) as an active ingredient.

                              (III)

       In the above formula,

R ₁ is a C ₁ to C ₂₀ alkyl group, alkenyl group, alkynyl group or A substituent which is unsubstituted or substituted with one or more R ′, wherein R ′ is a halogen atom, a nitro group, an amine group or a C ₁ to C ₄ lower group An alkyl group;

       A substituent

Wherein A ′ is a substituent optionally substituted at o, m, and p positions, and is composed of a hydrogen atom, a hydroxy group, an acetate group, a halogen atom, a C ₁ to C ₄ lower alkyl group, a lower alkoxy group, and a lower alkyl ester. At least one substituent selected from the group;

n is an integer of 0-4.

Wherein a general formula (Ⅲ) A preferred group of compounds with the R ₁ is substituted or unsubstituted with a halogen atom, or C ₁ to C ₄ lower alkyl group, C ₁ to C ₁₀ alkyl compound, an alkenyl group, an alkynyl group, or A substituents, Wherein A ′ of the A substituent is at least one substituent selected from hydrogen atom, hydroxy group, methyl group, ethyl group, methoxy group, ethoxy group or acetyl group substituted at o, m, p positions; n is a group of compounds that is an integer of o or 1;

       Most preferably, the compounds of the general formula (III) include the following compounds, and the present invention is not intended to limit the scope of the invention thereto.

3-Methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl - ester, Cis-2-methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl- Ester, trans-2-methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3- Mono-ester, 2-methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, pen- 2-Tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, but-3-tenoin Acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, phen-4-tenophosphoric acid 2,2 -Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, acetic acid 2,2-dimethyl-8-oxo-3,4 -Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, chloro-acetic acid 2,2-dimethyl-8-oxo-3,4-di Hydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, trichloroacetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pi Lano [3,2-g] chromen-3-yl-ester, pentanophosphate 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] Chromen-3-yl-ester, decanoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester , 3-phenyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4- Methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4 -Hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- ( 3,4-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen- 3-yl-ester, 3- (3,4,5-Trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-di Jethro-2H, 8H-pyrano [3,2-g] chromen-3-yl-ester, 4- (3,4,5-trihydroxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo -3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8- Oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8 -Oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (3-methoxy-phenyl) -acrylic acid 2,2-dimethyl- 8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2,3-dimethoxy-phenyl) -acrylic acid 2,2 -Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2,4-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2,5-dimethoxy-phenyl ) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H, 8H-pyrano [3,2-g] chromene-3-S 3- (2,4,5-trimethoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H, 8H-pyrano [3,2-g] chromen 3-yl-ester, 3- (4-nitro-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen 3-yl-ester, 3- (3-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chrome Men-3-yl-ester, 3- (3-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] Chromen-3-yl-ester, 3- (3,4-dihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3, 2-g] chromen-3-yl-ester, 3- (3,4-diacetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -P Lano [3,2-g] chromen-3-yl-ester, 3- (4-hydroxy-3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro -2H, 8H-pyrano [3,2-g] chromen-3-yl-ester, 3- (4-acetoxy-3-methoxy-phenyl) Methacrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H, 8H-pyrano [3,2-g] chromen-3-yl-ester, 3- (4-acetoxy -3 , 4-Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, benzo Phosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3,4,5-trihydroxy- Benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester or 3,4,5-triacetoxy Benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester.

The present invention also provides a pharmaceutical composition for the prevention and treatment of atopic dermatitis diseases containing a decursin derivative compound represented by the following general formula (IV) as an active ingredient.

      In the above formula,

C is at least one substituent selected from the group consisting of a hydrogen atom, a C ₁ to C ₄ lower alkyl group and a ketone group.

      Preferred group of compounds of the general formula (IV) compound is the C substituent is one or more group of compounds selected from a hydrogen atom or a ketone group.

      Most preferably, the compounds of the general formula (IV) include the following compounds, and the present invention is not intended to limit the scope of the invention thereto.

8,8- dimethyl -6 H - pyrano [3,2- g] chromene-2,7-dione, 8,8- dimethyl -6 H - pyrano [3,2- g] chromene-2 On.

       Compositions comprising the compounds of the general formulas (III) to (IV) of the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods.

Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

      The compositions comprising the compounds of the present invention are each formulated in the form of oral dosage forms, external preparations, suppositories, or sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., in accordance with conventional methods. Can be used.

Specifically, when formulated, it may be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid form preparations may include at least one excipient such as starch, calcium carbonate, sucrose ( sucrose), lactose, gelatin and the like can be mixed. In addition to simple excipients, lubricants such as magnesium stearate, talc can also be used. Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

       Preferred dosages of the compounds of the present invention depend on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention may be administered in an amount of 0.0001 to 100 mg / kg, preferably in an amount of 0.001 to 100 mg / kg once to several times daily. The compound of the present invention in the composition may be formulated in an amount of 0.0001 to 50% by weight based on the total weight of the total composition.

       In addition, the pharmaceutical dosage forms of the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.

       The pharmaceutical composition of the present invention can be administered to mammals such as mice, mice, livestock, humans, etc. by various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.

The present invention is an improved health for the prevention and treatment of atopic dermatitis diseases containing a decurcin derivative compound of the novel structure represented by the general formula (I) to (II) or a pharmaceutically acceptable salt thereof as an active ingredient Provide nutraceuticals.

The present invention also provides a dietary supplement for improvement for the prevention and treatment of atopic dermatitis diseases containing the decursin derivative compounds represented by the general formulas (III) to (IV) as an active ingredient.

The compounds of the present invention can be used in various ways, such as drugs, foods and beverages for the prevention and improvement of atopic dermatitis diseases. Examples of the food to which the compound of the present invention may be added include various foods, beverages, gums, teas, vitamin complexes, health supplements, and the like, and may be used in the form of powders, granules, tablets, capsules, or beverages. have.

Since the compound of the present invention has little toxicity and side effects, it is a drug that can be used safely even for long-term administration for the purpose of prevention.

The compound of the present invention may be added to food or beverage for the purpose of preventing and treating atopic dermatitis diseases. At this time, the amount of the compound in the food or beverage is generally added to the health food composition of the present invention 0.01 to 15% by weight of the total food weight, the health beverage composition is 0.02 to 30 g based on 100 ml, preferably Preferably at a rate of 0.3 to 10 g.

The health beverage composition of the present invention, in addition to containing the compound as an essential ingredient in the indicated proportions, has no particular limitation on the liquid component and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. Examples of the above-mentioned natural carbohydrates are conventional monosaccharides such as disaccharides such as glucose and fructose, such as maltose, sucrose and the like, and polysaccharides such as dextrin, cyclodextrin and the like. Sugars and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of natural carbohydrates is generally about 1-20 g, preferably about 5-12 g per 100 ml of the composition of the present invention.

In addition to the compounds of the present invention, the composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic and natural flavors, colorants and fillers (such as cheese, chocolate), pectic acid and salts thereof, alginic acid and Salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like. The compositions of the present invention may also contain pulp for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical but is generally selected from the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.

Hereinafter, the present invention will be described in detail by Examples and Experimental Examples.

        However, the following Examples and Experimental Examples are only illustrative of the present invention, and the content of the present invention is not limited to the following Examples and Experimental Examples.

Reference Example  1. Reagents and Instruments

As an analyzer, ¹ H-NMR (400 MHz) spectrometer (JNM-AL 400, JEOL Ltd., Japan), melting pointer (Melting pointer, Yamako, MD-S3, Japan), mass spectrometer (MS, PE SCIX API) 2000 MS / MS, Canada). Various reagents were used by Aldrich Chemical Co., and other solvents were used without purification of the first or higher reagents. Silica gel (Silica gel, Merck, 230-400 mesh) was used for the purification of the synthesized materials.

Reference Example 2 THP-1 Culture

Human monocyte THP-1 (human acute monocytic leukemia cell) was 2.0 × 10 ⁵ / m RPMI 1640 medium, antibiotics (penicillin 10 ⁴ U / ml, streptomycin 10 mg / ml, Amphotericin B 25 μg / ml) and 10% FBS were added thereto, and then cultured in a 37 ° C. CO ₂ incubator for 3 days.

Reference Example  3. EoL -1 culture

Human eosinophil EoL-1 (eosinophilic leukemia cell) cells at 2.0 x 10 ⁵ / m RPMI 1640 medium, antibiotics (penicillin 10 ⁴ U / ml, streptomycin 10 mg / ml, cancer cells 25 μg / ml erysine B) and 10% FBS were added thereto, followed by incubation for 3 days in a 37 ° C. CO ₂ incubator.

Example 1. 3-Methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Cromen-3-yl-ester (3a) Preparation

As shown in the reaction scheme, 3-methyl-but-2-tenophosphoric acid (410 mg, 4.06 mmol), 1,3-dicyclohexylcarbodiimide (DCC, 1.68 g, 8.12 mmol) and 4-dimethyl in a round flask Aminopyridine (DMAP, 198 mg, 1.62 mmol) was added and dissolved in anhydrous dichloromethane. (+)-Decursinol ((+)-decursinol, 1 g, 4.06 mmol) was added to the reaction mixture, which was stirred for 24 hours at room temperature. The reaction mixture was washed with dichloromethane and filtered, and the filtrate was concentrated under reduced pressure. To obtain the pure product (3a) are 3-methyl-concentrate having the following physical data was purified by silica gel column via a separate-part 2-te elderly acid 2,2-dimethyl-8-oxo-3,4-dihydro -2 H, 8 H -pyrano [3,2- g ] chromen-3-yl-ester (3a) was obtained and used as a sample for the experimental example.

Yield: 64.0%;

Semi solid;

R _f = 0.35 ( n- hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.589 (d, J = 9.6 Hz, 1H), 7.160 (s, 1H), 6.788 (s, 1H), 6.222 (d, J = 9.6 Hz, 1H), 5.663 ( s, 1H), 5.086 (t, J = 4.8 Hz, 1H), 3.197 (dd, J = 4.8, 17.2 Hz, 1H), 2.867 (dd, J = 4.8, 17.2 Hz, 1H), 2.146 (d, J = 1.0 Hz, 3H), 1.880 (d, J = 1.0 Hz, 3H), 1.384 (s, 3H), 1.365 (s, 3H);

MS ( m / z ): 329 (M + H) ⁺ _.

Example  2. Sheath -2- methyl Part-2- Tennophosphate  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (3b)

The reaction of Example 1 except that the round flask of Example 1 was replaced with cis -2-methyl-but-2-tenoic acid (2b) instead of 3-methyl-but-2-tenophosphoric acid (2a). The same process as in cis -2-methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2] g ] chromen-3-yl-ester (3b) was obtained and used as a sample for the experimental example.

Yield: 56.3%;

Oil phase;

R _f = 0.35 ( n- hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.595 (d, J = 9.2 Hz, 1H), 7.167 (s, 1H), 6.819 (qd, J = 6.8, 1.2 Hz, 1H), 6.790 (s, H), 6.223 (d, J = 9.2Hz, 1H), 5.092 (t, J = 5.4Hz, 1H), 3.214 (dd, J = 4.8, 17.2Hz, 1H), 2.888 (dd, J = 5.4, 17.2Hz, 1H ), 1.803 (d, J = 1.2 Hz, 3H), 1.767 (d, J = 6.8 Hz, 3H), 1.398 (s, 3H), 1.378 (s, 3H);

MS ( m / z ): 329 (M + H) ⁺ _.

Example  3. Trans -2- methyl Part-2- Tennophosphate  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (3c)

The reaction of Example 1 except that the round flask of Example 1 was replaced with trans -2-methyl-but-2-tenoic acid (2c) instead of 3-methyl-but-2-tenophosphoric acid (2a). The same process as described for trans -2-methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2] g ] chromen-3-yl-ester (3c) was obtained and used as a sample for the experimental example.

Yield: 43.9%;

Oil phase;

R _f = 0.48 ( n- hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.505 (d, J = 9.6 Hz, 1H), 7.074 (s, 1H), 6.743 (m, 2H), 6.154 (d, J = 9.6 Hz, 1H), 5.009 (t , J = 4.8 Hz, 1H), 3.133 (dd, J = 4.8, 17.2 Hz, 1H), 2.806 (dd, J = 4.8, 17.2 Hz, 1H), 1.784 (m, 6H), 1.352 (s, 3H) , 1.319 (s, 3 H);

MS ( m / z ): 329 (M + H) ⁺ _.

Example 4. 2-Methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Production of Chromium-3-yl-ester (3d)

The same physical properties as in Example 1 were carried out except that the round flask of Example 1 was changed to 2-methyl-acrylic acid (2d) instead of 3-methyl-but-2-tenoic acid (2a). 2-methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (3d) having It used as the sample of an experiment example.

Yield: 93.3%;

Semi Solid;

R _f = 0.52 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.565 (d, J = 9.6 Hz, 1H), 7.141 (s, 1H), 6.786 (s, 1H), 6.216 (d, J = 9.6 Hz, 1H), 6.052 (s, 1H), 5.562 (s, 1H), 5.076 (t, J = 5.2 Hz, 1H), 3.209 (dd, J = 4.8, 16.8 Hz, 1H), 2.883 (dd, J = 5.6, 17.2 Hz, 1H), 1.903 (s, 3H), 1.384 (s, 3H), 1.370 (s, 3H);

MS ( m / z ): 315 (M + H) ⁺ _.

Example  5. Pen-2- Tennophosphate  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (3e)

The same procedure as in Example 1 was carried out except that the round flask of Example 1 was changed to phen-2-tenophosphoric acid (2e) instead of 3-methyl-but-2-tenoic acid (2a). Phen-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester having the following physical properties 3e) was obtained and used as a sample of the experimental example.

Yield: 92.1%;

Oil phase;

R _f = 0.40 ( n- hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.58 (d, J = 9.6 Hz, 1 H), 7.151 (s, 1 H), 7.028 (m, 1 H), 6.798 (s, 1 H), 6.223 (d, J = 9.6 Hz , 1H), 5.803 (d, J = 15.6 Hz, 1H), 5.111 (t, J = 4.8 Hz, 1H), 3.204 (dd, J = 4.8, 17.2 Hz, 1H), 2.882 (dd, J = 4.8, 17.2 Hz, 1H), 2.197 (m, 2H), 1.390 (s, 3H), 1.366 (s, 3H), 1.049 (t, J = 7.6 Hz, 3H);

MS ( m / z ): 329 (M + H) ⁺ _.

Example 6. But-3-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g Preparation of Chromen-3-yl-ester (3f)

The same procedure as in Example 1 was carried out except that the round flask of Example 1 was replaced with 3--3-enonoic acid (2f) instead of 3-methyl-but-2-enonoic acid (2a). But-3-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester having the following physical properties 3f) was obtained and used as a sample of the experimental example.

Yield: 90.2%;

Semi Solid;

R _f = 0.65 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.584 (d, J = 9.6 Hz, 1H), 7.154 (s, 1H), 6.793 (s, 1H), 6.232 (d, J = 9.6 Hz, 1H), 5.866 (m , 1H), 5.176 (m, 2H), 5.063 (t, J = 4.8 Hz, 1H), 3.190 (dd, J = 4.8, 17.2 Hz, 1H), 3.096 (m, 2H), 2.856 (dd, J = 5.2, 17.2 Hz, 1H), 1.373 (s, 3H), 1.355 (s, 3H);

MS ( m / z ): 315 (M + H) ⁺ _.

Example  7. Pen-4- Tennophosphate  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (3 g)

The same procedure as in Example 1 was carried out except that the round flask of Example 1 was changed to phen-4-tenophosphoric acid (2 g) instead of 3-methyl-but-2-tenophosphoric acid (2a). Phen-4-tenoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl- having the following physical properties Ester (3 g) was obtained and used as a sample of an experiment example.

Yield: 81.0%;

Oil phase;

R _f = 0.51 ( n- hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.580 (d, J = 9.6 Hz, 1 H), 7.146 (s, 1 H), 6.792 (s, 1 H), 6.231 (d, J = 9.6 Hz, 1 H), 5.790 (m , 1H), 5.056-4.957 (m, 3H), 3.178 (dd, J = 4.8, 17.2 Hz, 1H), 2.837 (dd, J = 5.2, 17.2 Hz, 1H), 2.433 (m, 2H), 2.356 ( t, J = 6.4 Hz, 2H), 1.374 (s, 3H), 1.352 (s, 3H);

MS ( m / z ): 329 (M + H) ⁺ _.

Example 8 Acetic Acid 2,2-Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Preparation of chromen-3-yl-ester (3h)

The acetic acid 2 having the following physical properties was carried out in the same manner as in the reaction of Example 1, except that the round flask of Example 1 was changed to acetic acid (2h) instead of 3-methyl-but-2-tenophosphoric acid (2a). , 2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (3h) was obtained and used as a sample for the experimental example.

Yield: 89.8%;

Solid phase;

m.p 125-126 ° C .;

R _f = 0.38 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.579 (d, J = 9.6 Hz, 1H), 7.153 (s, 1H), 6.791 (s, 1H), 6.229 (d, J = 9.6 Hz, 1H), 5.050 (t , J = 4.8 Hz, 1H), 3.184 (dd, J = 4.0, 17.2 Hz, 1H), 3.004 (dd, J = 4.8, 17.4 Hz, 1H), 2.041 (s, 3H), 1.422 (s, 3H) , 1.378 (s, 3H);

MS ( m / z ): 289 (M + H) ⁺ _.

Example  9. Chloro Acetic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (3i)

The same procedure as in Example 1 was carried out except that the round flask of Example 1 was changed to chloro-acetic acid (2i) instead of 3-methyl-but-2-tenophosphoric acid (2a) to have the following physical properties. Chloro-acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (3i) was obtained as a sample of the experimental example. Used.

Yield: 96.2%;

Solid phase;

m.p 147-148 ° C .;

R _f = 0.46 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.579 (d, J = 9.6 Hz, 1H), 7.160 (s, 1H), 6.794 (s, 1H), 6.235 (d, J = 9.6 Hz, 1H), 5.128 (t , J = 4.8 Hz, 1H), 4.088 (d, J = 14.8 Hz, 1H), 4.031 (d, J = 14.8 Hz, 1H), 3.229 (dd, J = 4.8, 17.2 Hz, 1H), 2.907 (dd , J = 4.8, 17.2 Hz, 1H), 1.400 (s, 3H), 1.375 (s, 3H);

MS ( m / z ): 323 (M + H) ⁺ _.

Example 10. Trichloro-acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Preparation of Chromium-3-yl-ester (5a)

(+)-Decursinol (1, 20 mg, 0.081 mmol) was added to a 100 mL round flask and dissolved with anhydrous dichloromethane (20 mL), followed by pyridine (13.1 μl, 0.162 mmol) and trichloroacetyl chloride (4a). ) Was added dropwise and stirred at room temperature for 2 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column separation to give trichloro-acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- having the following physical properties. g ] chromen-3-yl-ester (5a) was obtained and used as a sample for the experimental example.

Yield: 87.5%;

Semi Solid;

R _f = 0.60 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.578 (d, J = 9.6 Hz, 1H), 7.178 (s, 1H), 6.185 (s, 1H), 6.245 (d, J = 9.6 Hz, 1H), 5.138 (t , J = 5.2 Hz, 1H), 3.292 (dd, J = 4.8, 16.8 Hz, 1H), 2.999 (dd, J = 5.2, 17.2 Hz, 1H), 1.450 (s, 3H), 1.435 (s, 3H) ;

MS ( m / z ): 392 (M + H) ⁺ _.

Example 11.pentanophosphate 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Production of chromen-3-yl-ester (5b)

The same procedure as in Example 10 was carried out except that the round flask of Example 10 was changed to pentanoyl chloride (4b) instead of trichloroacetyl chloride (4a). 2,2-pentanophosphate having the following physical properties Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (5b) was obtained and used as a sample for the experimental example.

Yield: 90.7%;

Oil phase;

R _f = 0.39 ( n- hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.576 (d, J = 9.6 Hz, 1H), 7.145 (s, 1H), 6.788 (s, 1H), 6.224 (d, J = 9.6 Hz, 1H), 5.044 (t , J = 5.2 Hz, 1H), 3.180 (dd, J = 4.8, 16.8 Hz, 1H), 2.837 (dd, J = 4.8, 16.8 Hz, 1H), 2.313 (t, J = 7.6 Hz, 2H), 1.580 (m, 2H), 1.372 (s, 3H), 1.355 (s, 3H), 1.377-1.256 (m, 2H), 0.876 (t, J = 7.2 Hz, 3H);

MS ( m / z ): 329 (M + H) ⁺ _.

Example  12. Decanoic acid  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (5c)

The same procedure as in Example 10 was carried out except that the round flask of Example 10 was replaced with decanoyl chloride (4c) instead of trichloroacetyl chloride (4a). Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (5c) was obtained and used as a sample for the experimental example.

Yield: 93.0%;

Oil phase;

R _f = 0.49 ( n- hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.574 (d, J = 9.2 Hz, 1H), 7.143 (s, 1H), 6.788 (s, 1H), 6.227 (d, J = 9.2 Hz, 1H), 5.043 (t , J = 4.8 Hz, 1H), 3.178 (dd, J = 4.8, 16.8 Hz, 1H), 2.839 (dd, J = 4.8, 17.2 Hz, 1H), 2.323 (t, J = 8.0 Hz, 2H), 1.615 (m, 2H), 1.406 (s, 3H), 1.373 (s, 3H), 1.336-1.256 (m, 12H), 0.888 (t, J = 7.2 Hz, 3H);

MS ( m / z ): 331 (M + H) ⁺ _.

Example 13. 3-phenyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Chrome-3-yl-ester (8a) Preparation

Step 1.

Cinnamic acid (6a, 1.81 g, 12.2 mmol) was added to a completely dried 100 mL round flask and dissolved in anhydrous benzene (20 mL). N, N -dimethylformamide (2 drops) and thionyl chloride (SOCl ₂ , 4.44 ml, 60.9 mmol) were added thereto, and the mixture was refluxed at 70-80 degrees for 5 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to synthesize cinnamoyl chloride (7a), which was dissolved in anhydrous dichloromethane and applied to the next step.

Step 2.

(+)-Decursinol (1, 2g, 8.12mmol) was added to a 100ml round flask, dissolved in anhydrous dichloromethane (100ml), pyridine (1.97ml, 24.4mmol) and anhydrous dichloromethane (30ml Cinnamoyl chloride (7a) dissolved in) was added dropwise, followed by stirring at room temperature for 2 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column separation to obtain 3-phenyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2]. g ] chromen-3-yl-ester (8a) was obtained and used as a sample for the experimental example.

Yield: 49.3%;

Solid phase;

m.p 136-137 ° C .;

R _f = 0.40 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (acetone-d ₆ ): δ ppm 7.882 (d, J = 9.6 Hz, 1H), 7.707 (m, 3H), 7.433 (m, 4H), 6.754 (s, 1H), 6.568 (d, J = 16.0 Hz, 1H), 6.212 (d, J = 9.2 Hz, 1H), 5.240 (t, J = 4.6 Hz, 1H), 3.344 (dd, J = 4.6, 17.6 Hz, 1H), 2.991 (dd, J = 4.4, 17.6 Hz, 1H), 1.436 (s, 3H), 1.424 (s, 3H);

MS ( m / z ): 377 (M + H) ⁺ _.

Example  14. 3- (4- Methoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (8b)

The same physical properties as in Example 13 were followed except that the 100 ml round flask completely dried in the first step of Example 13 was changed to 4-methoxy cinnamic acid (6b) instead of cinnamic acid (6a). 3- (4-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl- The ester 8b was obtained and used as a sample of an experiment example.

Yield: 91.2%;

Solid phase;

m.p 68 ° C .;

R _f = 0.20 ( n- hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.631 (d, J = 16.0 Hz, 1H), 7.583 (d, J = 9.2 Hz, 1H), 7.450 (d, J = 8.4 Hz, 1H), 7.170 (s, 1H ), 6.882 (d, J = 8.8 Hz, 2H), 6.829 (s, 1H), 6.282 (d, J = 16.0 Hz, 1H), 6.231 (d, J = 9.2 Hz, 1H), 5.188 (t, J = 4.8Hz, 1H), 3.828 ( s, 3H), 3.238 (dd, J = 4.4, 17.6Hz, 1H), 2.934 (dd, J = 4.4, 17.6Hz, 1H), 1.433 (s, 3H), 1.391 (s, 3H); MS ( m / z ): 407 (M + H) ⁺ _.

Example 15 3- (4-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Preparation of chromen-3-yl-ester (8c)

3- (4-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen- in a 100 ml round flask Add 3-yl-ester (8b, 100mg, 0.246mmol), dissolve in anhydrous dichloromethane (20ml), add 1M boron tribromide solution (1M BBr ₃ in MC, 2.46ml, 2.46mmol) dropwise, and then room temperature Stirred for 2 h. The reaction mixture was poured into iced water (200 ml), stirred for 10 minutes, extracted with ethyl acetate, and dehydrated with anhydrous forget-me-not and concentrated under reduced pressure. The obtained residue was subjected to silica gel column separation to obtain 3- (4-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3, 2- g ] chromen-3-yl-ester (8c) was obtained and used as a sample for the experimental example.

Yield: 82.3%;

Solid phase;

m.p 104 ° C .;

R _f = 0.32 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.608 (m, 2H), 7.401 (d, J = 8.8 Hz, 2H), 7.174 (s, 1H), 6.841 (m, 2H), 6.252 (m, 2H), 5.825 (s, OH), 5.187 ( t, J = 4.6Hz, 1H), 3.237 (dd, J = 4.6, 17.6Hz, 1H), 2.935 (dd, J = 4.6, 17.6Hz, 1H), 1.432 (s, 3H), 1.387 (s, 3H);

MS ( m / z ): 393 (M + H) ⁺ _.

Example  16. 3- (3,4- Dimethoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (8d)

The same process as in Example 13 was carried out except that the 100 mL round flask completely dried in the first step of Example 13 was changed to 3,4-dimethoxy cinnamic acid (6d) instead of cinnamic acid (6a). 3- (3,4-Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen- having physical properties 3-yl-ester (8d) was obtained and used as a sample for the experimental example.

Yield: 45.8%

Solid phase;

m.p 83 ° C .;

R _f = 0.35 ( n- hexane: ethyl acetate = 11);

¹ H NMR (CDCl ₃ ): δ ppm 7.608 (m, 2H), 7.178 (s, 1H), 7.080 (dd, J = 8.4, 2.0 Hz, 1H), 7.016 (d, J = 2.0 Hz, 1H), 6.848 (m, 2H), 6.256 (dd, J = 14.4, 9.6 Hz, 2H), 5.200 (t, J = 4.4 Hz, 1H), 3.916 (s, 3H), 3.908 (s, 3H), 3.230 (dd, J = 4.4, 16.8 Hz, 1H), 2.965 (dd, J = 4.4, 16.8 Hz, 1H), 1.446 (s, 3H), 1.392 (s, 3H);

MS ( m / z ): 437 (M + H) ⁺ _.

Example 17. 3- (3,4,5-Trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Preparation of chromen-3-yl-ester (8e)

The same process as in Example 13 was carried out except that the 100 mL round flask completely dried in the first step of Example 13 was changed to 3,4,5-trimethoxy cinnamic acid (6e) instead of cinnamic acid (6a). 3- (3,4,5-trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2] having the following physical properties g ] chromen-3-yl-ester (8e) was obtained and used as a sample for the experimental example.

Yield: 52.9%;

Solid phase;

m.p 87 ° C .;

R _f = 0.23 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.607 (d, J = 5.6 Hz, 1H), 7.575 (s, 1H), 7.184 (s, 1H), 6.840 (s, 1H), 6.722 (s, 2H), 6.322 (d, J = 16.0 Hz, 1H), 6.240 (d, J = 9.2 Hz, 1H), 5.208 (t, J = 4.4 Hz, 1H), 3.904 (s, 9H), 3.254 (dd, J = 4.4, 16.8 Hz, 1H), 2.951 (dd, J = 4.4, 16.8 Hz, 1H), 1.452 (s, 3H), 1.395 (s, 3H);

MS ( m / z ): 467 (M + H) ⁺ _.

Example  18. 3- (3,4,5- Trihydroxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (8f)

In Example 15 above, in a 100 ml round flask, 3- (4-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] 3- (3,4,5-trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, instead of chroman-3-yl-ester (8b) , Except for changing to 8H -pyrano [3,2- g ] chromen-3-yl-ester (8e), the same process as in Example 15 was carried out to provide 3- (3,4,5- having the following physical properties. Trihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (8f) Obtained and used as a sample of an experiment example.

Yield: 18.2%;

White solid;

m.p 144 ° C .;

R _f = 0.44 (chloroform: methanol = 5: 1);

¹ H NMR (acetone-d ₆ ): δ ppm 7.849 (d, J = 9.6 Hz, 1H), 7.453 (m, 2H), 6.737 (s, 1H), 6.720 (s, 2H), 6.204 (m, 2H) 5.195 (t, J = 4.8 Hz, 1H), 3.310 (dd, J = 16.8, 4.8 Hz, 1H), 2.937 (dd, J = 16.8, 4.8 Hz, 1H), 1.417 (s, 6H);

MS ( m / z ): 425 (M + H) ⁺ _.

Example 19. 3- (2-Methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Preparation of Chromium-3-yl-ester (8 g)

The following physical properties were carried out in the same manner as in Example 13 except that the 100 ml round flask completely dried in the first step of Example 13 was changed to 2-methoxy cinnamic acid (6 g) instead of cinnamic acid (6a). 3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl- Ester (8g) was obtained and used as a sample of an experiment example.

Yield: 81.8%;

White solid;

m.p 72 ° C .;

R _f = 0.48 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.996 (d, J = 16.4 Hz, 1H), 7.589 (d, J = 9.6 Hz, 1H), 7.472 (d, J = 6.4 Hz, 1H), 7.352 (t, J = 7.8 Hz, 1H), 7.173 (s, 1H), 6.960-6.895 (m, 2H), 6.804 (s, 1H), 6.508 (d, J = 16.0 Hz, 1H), 6.235 (d, J = 9.6 Hz , 1H), 5.194 (t, J = 5.0 Hz, 1H), 3.871 (s, 3H), 3.242 (dd, J = 5.0, 17.2 Hz, 1H), 2.942 (dd, J = 5.0, 17.2 Hz, 1H) , 1.437 (s, 3H), 1.396 (s, 3H).

Example  20. 3- (2-hydroxy- Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H -blood Llan [3,2- g ] Preparation of Chromen-3-yl-ester (8h)

In Example 15 above, in a 100 ml round flask, 3- (4-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] 3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [instead of chroman-3-yl-ester (8b) Except for changing to 3,2- g ] chromen-3-yl-ester (8g), the same process as in Example 15 was carried out to give 3- (2-hydroxy-phenyl) -acrylic acid 2, 2-Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (8h) was obtained and used as a sample for the experimental example.

Yield: 58.5%;

White solid;

m.p 106 ° C .;

R _f = 0.39 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (acetone-d ₆ ): δ ppm 8.001 (d, J = 16.4 Hz, 1H), 7.851 (d, J = 9.2 Hz, 1H), 7.613 (d, J = 7.6 Hz, 1H), 7.434 (s , 1H), 7.253 (t, J = 6.8 Hz, 1H), 6.954 (d, J = 8.4 Hz, 1H), 6.883 (t, J = 7.4 Hz, 1H), 6.741 (s, 1H), 6.614 (d , J = 16.0 Hz, 1H), 6.203 (d, J = 9.6 Hz, 1H), 5.233 (t, J = 4.4 Hz, 1H), 3.332 (dd, J = 4.4, 17.6 Hz, 1H), 2.984 (dd , J = 4.4, 17.6 Hz, 1H), 2.913 (d, J = 12.0 Hz, OH), 1.432 (s, 3H), 1.421 (s, 3H);

MS ( m / z ): 393 (M + H) ⁺ _.

Example 21. 3- (3-Methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Preparation of chromen-3-yl-ester (8i)

The same physical properties as in Example 13 were followed except that the 100 ml round flask completely dried in the first step of Example 13 was changed to 3-methoxy cinnamic acid (6i) instead of cinnamic acid (6a). 3- (3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl- Ester 8i was obtained and used as a sample of an experiment example.

Yield: 90.9%;

White solid;

m.p 72 ° C .;

R _f = 0.51 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.644 (d, J = 16.0 Hz, 1H), 7.584 (d, J = 9.6 Hz, 1H), 7.282 (t, J = 8.4 Hz, 1H), 7.175 (s, 1H) ), 7.088 (d, J = 8.0 Hz, 1H), 6.932 (dd, J = 4.0, 8.4 Hz, 1H), 6.835 (s, 1H), 6.403 (d, J = 15.6 Hz, 1H), 6.236 (d , J = 9.6 Hz, 1H), 5.199 (t, J = 4.8 Hz, 1H), 3.813 (s, 3H), 3.248 (dd, J = 4.8, 17.2 Hz, 1H), 2.943 (dd, J = 4.8, 17.2 Hz, 1H), 1.440 (s, 3H), 1.394 (s, 3H);

MS ( m / z ) 407 (M + H) ⁺ .

Example  22. 3- (2,3- Dimethoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (8j)

The same process as in Example 13 was carried out except that the 100 mL round flask completely dried in the first step of Example 13 was changed to 2,3-dimethoxy cinnamic acid (6j) instead of cinnamic acid (6a). 3- (2,3-Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen- having physical properties 3-yl-ester (8j) was obtained and used as a sample for the experimental example.

Yield: 25.0%;

White solid;

m.p 149 ° C .;

R _f = 0.43 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 8.021 (d, J = 16.0 Hz, 1H), 7.585 (d, J = 9.6 Hz, 1H), 7.174 (s, 1H), 7.121 (d, J = 6.8 Hz, 1H ), 7.032 (t, J = 8.0 Hz, 1H), 6.939 (d, J = 8.8 Hz, 1H), 6.829 (s, 1H), 6.449 (d, J = 16.8 Hz, 1H), 6.232 (d, J = 9.6 Hz, 1H), 5.192 (t, J = 4.8 Hz, 1H), 3.868 (s, 3H), 3.832 (s, 3H), 3.249 (dd, J = 4.8, 17.2 Hz, 1H), 2.945 (dd , J = 4.8, 17.2 Hz, 1H), 1.435 (s, 3H), 1.400 (s, 3H);

MS ( m / z ) 437 (M + H) ⁺ .

Example 23. 3- (2,4-Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Preparation of chromen-3-yl-ester (8k)

The same process as in Example 13 was carried out except that the 100 mL round flask completely dried in the first step of Example 13 was changed to 2,4-dimethoxy cinnamic acid (6k) instead of cinnamic acid (6a). 3- (2,4-Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen- having physical properties 3-yl-ester (8k) was obtained and used as a sample for the experimental example.

Yield: 25.0%;

White solid;

m.p 149 ° C .;

R _f = 0.43 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 8.021 (d, J = 16.0 Hz, 1H), 7.585 (d, J = 9.6 Hz, 1H), 7.174 (s, 1H), 7.121 (d, J = 6.8 Hz, 1H ), 7.032 (t, J = 8.0 Hz, 1H), 6.939 (d, J = 8.8 Hz, 1H), 6.829 (s, 1H), 6.449 (d, J = 16.8 Hz, 1H), 6.232 (d, J = 9.6 Hz, 1H), 5.192 (t, J = 4.8 Hz, 1H), 3.868 (s, 3H), 3.832 (s, 3H), 3.249 (dd, J = 4.8, 17.2 Hz, 1H), 2.945 (dd , J = 4.8, 17.2 Hz, 1H), 1.435 (s, 3H), 1.400 (s, 3H);

MS ( m / z ): 437 (M + H) ⁺ .

Example  24. 3- (2,5- Dimethoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (8l)

The same process as in Example 13 was carried out except that the 100 ml round flask completely dried in the first step of Example 13 was changed to 2,5-dimethoxy cinnamic acid (6l) instead of cinnamic acid (6a). 3- (2,5-Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen- having physical properties 3-yl-ester (8 l) was obtained and used as a sample for the experimental example.

Yield: 38.7%;

Light yellow solid;

m.p 77 ° C .;

R _f = 0.46 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.983 (d, J = 16.0 Hz, 1H), 7.592 (d, J = 10.4 Hz, 1H), 7.178 (s, 1H), 7.001 (d, J = 2.8 Hz, 1H ), 6.912 (dd, J = 2.8, 8.8 Hz, 1H), 6.849-6.827 (m, 2H), 6.471 (d, J = 16.4 Hz, 1H), 6.237 (d, J = 9.2 Hz, 1H), 5.196 (t, J = 4.8 Hz, 1H), 3.824 (s, 3H), 3.768 (s, 3H), 3.245 (dd, J = 4.8, 17.2 Hz, 1H), 2.945 (dd, J = 4.8, 17.2 Hz, 1H), 1.441 (s, 3H), 1.396 (s, 3H);

MS ( m / z ): 437 (M + H) ⁺ .

Example 25. 3- (2,4,5-Trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Cromen-3-yl-Ester (8m) Preparation

The same process as in Example 13 was carried out except that the 100 ml round flask completely dried in the first step of Example 13 was replaced with 2,4,5-trimethoxy cinnamic acid (6m) instead of cinnamic acid (6a). 3- (2,4,5-trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2 having the following physical properties g ] chromen-3-yl-ester (8m) was obtained and used as a sample for the experimental example.

Yield: 33.5%;

Yellow solid;

m.p 93 ° C .;

R _f = 0.29 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.986 (d, J = 13.6 Hz, 1H), 7.586 (d, J = 9.6 Hz, 1H), 7.173 (s, 1H), 6.966 (s, 1H), 6.833 (s , 1H), 6.478 (s, 1H), 6.325 (d, J = 16.0 Hz, 1H), 6.232 (d, J = 9.2 Hz, 1H), 5.196 (t, J = 4.8 Hz, 1H), 3.922 (s , 3H), 3.855 (s, 3H), 3.840 (s, 3H), 3.238 (dd, J = 4.8, 17.2 Hz, 1H), 2.940 (dd, J = 4.8, 17.2 Hz, 1H), 1.443 (s, 3H), 1.393 (s, 3H);

MS ( m / z ): 483 (M + H) ⁺ .

Example  26.3- (4-nitro- Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (8n)

The same procedure as in Example 13 was carried out except that the 100 ml round flask completely dried in the first step of Example 13 was changed to 4-nitro cinnamic acid (6n) instead of cinnamic acid (6a) to have the following physical properties. 3- (4-Nitro-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester ( 8n) was obtained and used as a sample for the experimental example.

Yield: 65.7%;

Light yellow solid;

m.p 193 ° C .;

R _f = 0.42 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 8.237 (d, J = 8.8 Hz, 2H), 7.727-7.623 (m, 3H), 7.598 (d, J = 9.2 Hz, 1H), 7.218 (s, 1H), 6.840 (s, 1H), 6.560 (d, J = 11.2 Hz, 1H), 6.248 (d, J = 9.6 Hz, 1H), 5.225 (t, J = 4.8 Hz, 1H), 3.272 (dd, J = 4.8, 17.2 Hz, 1H), 2.958 (dd, J = 4.8, 17.2 Hz, 1H), 1.449 (s, 3H), 1.403 (s, 3H);

MS ( m / z ) 422 (M + H) ⁺ .

Example 27. 3- (3-Hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Production of Chromium-3-yl-ester (11a)

Step 1.

       As shown in the reaction scheme, acetic anhydride (11.5 ml, 25.6 mmol) was added to a 100 ml round flask, and 3-hydroxy cinnamic acid (9a, 2 g, 12.8 mmol) and pyridine (10 ml, excess) were added thereto. It was stirred at room temperature for one day and then concentrated under reduced pressure. The concentrate was subjected to silica gel column separation to obtain 3-acetoxy cinnamic acid (9b), a portion of which was applied to step 2.

Step 2. 3

The same procedure as in Example 13 was carried out except that the 100 ml round flask completely dried in the first step of Example 13 was changed to 3-acetoxy cinnamic acid (9b) instead of cinnamic acid (6a). 3-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (11b) Was obtained and applied to the next step.

Step 4.

3- (3-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (11b, 1.8 g) was dissolved in acetone (60 mL) and then 3N HCl (20 mL) was added dropwise. It was refluxed at 50-60 degrees for 12 hours, and then cooled to room temperature and concentrated under reduced pressure. The concentrated solution was dissolved in ethyl acetate and distilled water and separated. The ethyl acetate layers were collected, dehydrated with anhydrous forget-me-not, and concentrated under reduced pressure. The concentrate was purified by silica gel column separation to obtain 3- (4-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2]. g ] chromen-3-yl-ester (11a) was obtained and used as a sample for the experimental example.

Yield: 88.1%;

Solid phase;

m.p 105 ° C .;

R _f = 0.21 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (acetone-d ₆ ): δ ppm 7.863 (d, J = 9.2 Hz, 1H), 7.622 (d, J = 15.6 Hz, 1H), 7.442 (s, 1H), 7.252 (t, J = 7.8 Hz , 1H), 7.168 (d, J = 7.6 Hz, 1H), 7.111 (s, 1H), 6.915 (d, J = 8.4 Hz, 1H), 6.751 (s, 1H), 6.489 (d, J = 16.0 Hz , 1H), 6.213 (d, J = 9.6 Hz, 1H), 5.229 (t, J = 4.6 Hz, 1H), 3.337 (dd, J = 4.2, 17.2 Hz, 1H), 2.987 (dd, J = 4.4, 17.6 Hz, 1H), 1.432 (s, 3H), 1.422 (s, 3H);

MS ( m / z ): 393 (M + H) ⁺ _.

Example  28. 3- (3- Acetoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (11b)

Steps 1, 2, 3.

3- (3-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro having the following physical properties by performing the same process as in the first, second and third steps of Example 27 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (11b) was obtained and used as a sample for the experimental example.

Yield: 87.0%;

Solid phase;

m.p 181 ° C .;

R _f = 0.31 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (acetone-d ₆ ): δ ppm 7.840 (d, J = 9.6 Hz, 1H), 7.684 (d, J = 16.0 Hz, 1H), 7.558 (d, J = 7.6 Hz, 1H), 7.451 ( m, 3H), 7.180 (dd, J = 2.4, 7.6 Hz, 1H), 6.737 (s, 1H), 6.574 (d, J = 15.6 Hz, 1H), 6.198 (d, J = 9.6 Hz, 1H), 5.232 (t, J = 4.4 Hz, 1H), 3.336 (dd, J = 4.2, 17.6 Hz, 1H), 2.984 (dd, J = 4.8, 17.6 Hz, 1H), 2.258 (s, 3H), 1.430 (s , 3H), 1.422 (s, 3H);

MS ( m / z ): 435 (M + H) ⁺ _.

Example 29. 3- (3,4-Dihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Preparation of chromen-3-yl-ester (11c)

1-4 of Example 27 except that in the first step of Example 27 it was replaced with 3,4-dihydroxy cinnamic acid (9c, 7g, 38.9mmol) instead of 3-hydroxy cinnamic acid (9a). 3- (3,4-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3] having the following physical properties , 2- g ] chromen-3-yl-ester (11c) was obtained and used as a sample for the experimental example.

Yield 93.2%;

Solid phase;

m.p 115 ° C .;

R _f = 0.36 ( n- hexane: ethyl acetate = 1: 2);

¹ H NMR (CDCl ₃ ): δ ppm 7.618 (d, J = 8.8 Hz, 1H), 7.549 (d, J = 16.0 Hz, 1H), 7.181 (s, 1H), 7.068 (s, 1H), 6.948 (dd) , J = 1.6, 8.4 Hz, 1H), 6.870 (d, J = 8.0 Hz, 1H), 6.821 (s, 1H), 6.223 (m, 2H), 5.179 (t, J = 4.6 Hz, 1H), 3.231 (dd, J = 4.6, 17.6 Hz, 1H), 2.935 (dd, J = 4.6, 17.6 Hz, 1H), 1.428 (s, 3H), 1.379 (s, 3H);

MS ( m / z ): 409 (M + H) ⁺ _.

Example  30. 3- (3,4- Diacetoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (11d)

Steps 1, 2, 3.

Except for changing to 3-hydroxy cinnamic acid (9a) instead of 3,4-dihydroxy cinnamic acid (9c, 7g, 38.9 mmol) in the first step of Example 27, except that 3- (3,4-Diacetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano having the following physical properties 3,2- g ] chromen-3-yl-ester (11d) was obtained and used as a sample for the experimental example.

Yield: 84.5%;

Solid phase;

m.p 92 ° C .;

R _f = 0.27 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.613 (d, J = 8.4 Hz, 1H), 7.581 (d, J = 2.0 Hz, 1H), 7.389-7.339 (m, 2H), 7.256-7.179 (m, 2H ), 6.823 (s, 1H), 6.358 (d, J = 16.0, 1H), 6.232 (d, J = 9.2 Hz. 1H), 5.190 (t, J = 4.6 Hz, 1H), 3.244 (dd, J = 4.6, 17.6 Hz, 1H), 2.932 (dd, J = 4.6, 17.6 Hz, 1H), 2.293 (s, 3H), 2.290 (s, 3H), 1.425 (s, 3H), 1.389 (s, 3H);

MS ( m / z ): 493 (M + H) ⁺ _.

Example  31. 3- (4-hydroxy-3- Methoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (11e)

Except for changing to 3-hydroxy cinnamic acid (9a) instead of 3-hydroxy-3-methoxy cinnamic acid (9e, 5g, 25.7 mmol) in the first step of Example 27, the first embodiment of Example 27 3- (4-hydroxy-3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H having the following physical properties by the same process as in step -4 -Pyrano [3,2- g ] chromen-3-yl-ester (11e) was obtained and used as a sample for the experimental example.

Yield: 91.8%;

Solid phase;

m.p 102 ° C .;

R _f = 0.32 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (acetone-d ₆ ): δ ppm 7.843 (d, J = 9.6 Hz, 1H), 7.616 (d, J = 16.0 Hz, 1H), 7.424 (s, 1H), 7.357 (s, 1H), 7.123 (dd, J = 2.0, 8.0 Hz, 1H), 6.851 (d, J = 8.4 Hz, 1H), 6.740 (s, 1H), 6.387 (d, J = 15.6 Hz, 1H), 6.198 (d, J = 9.6 Hz, 1H), 5.221 (t, J = 4.6 Hz, 1H), 3.895 (s, 3H), 3.321 (dd, J = 4.6, 17.2 Hz, 1H), 2.963 (dd, J = 4.4, 17.6 Hz , 1H), 1.421 (s, 3H), 1.413 (s, 3H);

MS ( m / z ): 423 (M + H) ⁺ _.

Example  32. 3- (4- Acetoxy -3- Methoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (11f)

Steps 1, 2, 3.

Except for changing to 3-hydroxy cinnamic acid (9a) instead of 3-hydroxy-3-methoxy cinnamic acid (9e, 5g, 25.7 mmol) in the first step of Example 27, the first embodiment of Example 27 3- (4-acetoxy-3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H having the following physical properties by the same process as in step -3 -Pyrano [3,2- g ] chromen-3-yl-ester (11f) was obtained and used as a sample for the experimental example.

Yield: 42.4%;

Solid;

m.p 98 ° C .;

R _f = 0.40 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (acetone-d ₆ ): δ ppm 7.843 (d, J = 9.6 Hz, 1H), 7.679 (d, J = 16.0 Hz, 1H), 7.480 (s, 1H), 7.428 (s, 1H), 7.247 (d, J = 8.4 Hz, 1H), 7.095 (d, J = 8.4 Hz, 1H), 6.742 (s, 1H), 6.568 (d, J = 16.0 Hz, 1H), 6.200 (d, J = 9.6 Hz , 1H), 5.243 (t, J = 4.4 Hz, 1H), 3.872 (s, 3H), 3.338 (dd, J = 4.4, 17.6 Hz, 1H), 2.982 (dd, J = 4.4, 17.6, 1H), 2.242 (s, 3H), 1.428 (s, 3H), 1.418 (s, 3H);

MS ( m / z ): 465 (M + H) ⁺ _.

Example 33. 3- (4-acetoxy-3,5-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Preparation of Chromium-3-yl-ester (11 g)

Steps 1, 2, 3.

Except for changing to 3-hydroxy cinnamic acid (9a) instead of 3-hydroxy-3,5-dimethoxy cinnamic acid (9e, 500 g, 2.23 mmol) in the first step of Example 27, 3- (4-acetoxy-3,5-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro having the following physical properties by the same process as in step 1-3 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (11 g) was obtained and used as a sample for the experimental example.

Yield: 10.8%;

Solid;

m.p 121 ° C .;

R _f = 0.42 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.614 (d, J = 9.2 Hz, 1H), 7.582 (d, J = 2.4 Hz, 1H), 7.189 (s, 1H), 6.826 (s, 1H), 6.739 (s , 2H), 6.362 (d, J = 16.0 Hz, 1H), 6.227 (d, J = 9.2 Hz, 1H), 5.211 (t, J = 4.8 Hz, 1H), 3.801 (s, 6H), 3.255 (dd , J = 4.8, 18.0 Hz, 1H), 2.935 (dd, J = 4.8, 18.0 Hz, 1H), 2.331 (s, 3H), 1.451 (s, 3H), 1.397 (s, 3H);

MS ( m / z ): 495 (M + H) ⁺ _.

Example  34. Benzoic acid  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester 14a

Step 2. 3

The same procedure as in Example 13 was carried out except that the 100 ml round flask completely dried in the first step of Example 13 was replaced with benzoic acid (12a) instead of cinnamic acid (6a). -8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (14a) was obtained and used as a sample for the experimental example.

Yield 93.2%;

Semi solid;

R _f = 0.52 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.972 (d, J = 9.6 Hz, 2H), 7.557 (m, 2H), 7.417 (t, J = 7.8 Hz, 2H), 7.166 (s, 1H), 6.845 ( s, 1H), 6.227 (d, J = 9.6 Hz, 1H), 5.296 (t, J = 4.8 Hz, 1H), 3.300 (dd, J = 4.4, 17.6 Hz, 1H), 3.004 (dd, J = 4.8 , 17.6 Hz, 1H), 1.474 (s, 3H), 1.428 (s, 3H);

MS ( m / z ): 351 (M + H) ⁺ _.

Example  35. 3,4,5- Trihydroxy - Benzoic acid  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester 14b

Step 1.

       As shown in the reaction scheme of Example 34, acetic anhydride (11.5 ml, 25.6 mmol) and 3,4,5-trihydroxy benzoic acid (12b, 3 g, 17.6 mmol) were added and dissolved in a 100 ml round flask. -3 drops of concentrated sulfuric acid were added dropwise. The reaction mixture was refluxed at 80 degrees for 10 minutes and then cooled to room temperature. It was stirred while pouring 30 times (volume ratio) of ice water in the reaction mixture, and the crystals were filtered after standing at room temperature for 2 hours. The white crystals on the filter paper were washed with distilled water, which was dried at 40 ° C. for 12 hours to obtain 3,4,5-triacetoxy benzoic acid (12c), a portion of which was applied to Step 2.

Step 2, 3.

Except for changing to 3,4,5-triacetoxy-benzoic acid (12c, 5g, 0.017mmol) instead of cinnamic acid (6a) in a 100 ml round flask completely dried in the first step of Example 13 3,4,5-triacetoxy-benzophosphate 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] Chromen-3-yl-ester (14c) was obtained and part of it was subjected to the next step.

Step 4.

In the fourth step of Example 27, 3- (3-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] 3,4,5-triacetoxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3] instead of chromen-3-yl-ester (11b) [3] , 2-g] chromen-3-yl-ester (14c, 1.8g, 3.43mmol) was subjected to the same process as in Step 4 of Example 27 except for changing to 3,4,5- having the following physical properties 1.5 g of trihydroxybenzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (14b) Obtained and used as a sample of an experiment example.

Yield: 98.7%;

Solid phase;

m.p 138 ° C .;

R _f = 0.22 ( n- hexane: ethyl acetate = 1: 2);

¹ H NMR (CDCl ₃ ): δ ppm 7.674 (d, J = 9.2 Hz, 1H), 7.242 (s, 1H), 7.132 (s, 2H), 6.782 (s, 1H), 6.228 (d, J = 9.2 Hz, 1H), 5.215 (t, J = 4.8 Hz, 1H), 3.284 (dd, J = 4.2, 17.6 Hz, 1H), 2.981 (dd, J = 4.6, 17.6 Hz, 1H), 1.443 (s, 3H ), 1.413 (s, 3 H);

MS ( m / z ): 399 (M + H) ⁺ _.

Example 36. 3,4,5-triacetoxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Production of chromen-3-yl-ester (14c)

3,4,5-triacetoxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H was carried out in the same manner as in the first, second, and third steps of Example 35. -Pyrano [3,2- g ] chromen-3-yl-ester (14c) was obtained and used as a sample for the experimental example.

Yield: 28.8%;

Solid phase;

m.p 97 ° C .;

R _f = 0.44 ( n- hexane: ethyl acetate = 1: 2);

¹ H NMR (acetone-d ₆ ) δ ppm 7.848 (d, J = 9.6 Hz, 1H), 7.740 (s, 2H), 7.435 (s, 1H), 6.765 (s, 1H), 6.209 (d, J = 9.6 Hz, 1H), 5.359 (t, J = 4.4, 17.6 Hz, 1H), 3.403 (dd, J = 4.2, 17.6 Hz, 1H), 3.123 (dd, J = 4.4, 17.6 Hz, 1H), 2.317 (s , 3H), 2.283 (m, 6H), 1.479 (s, 3H), 1.457 (s, 3H);

MS ( m / z ): 525 (M + H) ⁺ _.

Example  37. Methane Sulfonic acid  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester 16a

As shown in the reaction scheme, decurcinol ( 1 , 20mg, 0.081mmol) and triethylamine (TEA, 34µl, 0.24mmol) were added to a 100 ml round flask, and dissolved in anhydrous dichloromethane (5 ml). Methane sulfonyl chloride (31 μl, 0.406 mmol) is added dropwise in the phase. After stirring for 15 hours at room temperature, about half of the filtrate was concentrated under reduced pressure at room temperature, and then methane sulfonic acid 2,2-dimethyl-8-oxo-3,4-dihydro- having the following physical properties through silica gel column separation. 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (16a) was obtained and used as a sample for the experimental example.

Yield: 91.2%;

Solid phase;

m.p 174 ° C;

R _f = 0.32 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ) δppm 7.591 (d, J = 9.6Hz, 1H), 7.197 (s, 1H), 6.786 (s, 1H), 6.244 (d, J = 9.6Hz, 1H), 4.884 (t, J = 4.8 Hz, 1 H), 3.293 (dd, J = 4.8, 17.6 Hz, 1 H), 3.179 (dd, J = 4.8, 17.6 Hz, 1 H), 3.067 (s, 3 H),

1.456 (s, 3 H), 1.407 (s, 3 H);

MS ( m / z ): 325 (M + H) ⁺ _.

Example 38. Benzene Sulphonic Acid 2,2-Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Cromen-3-yl-ester (16b) Preparation

Except for changing from methane sulfonyl chloride (15a) to benzene sulfonyl chloride (15b) in Example 37, the same process as in Example 37 was carried out to give benzene sulfonic acid 2,2-dimethyl-8- having the following physical properties. Oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (16b) was obtained and used as a sample for the experimental example.

Yield: 36.2%;

Solid phase;

m.p 64 ° C .;

R _f = 0.21 ( n- hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ ) δ ppm 7.907 (d, J = 7.6 Hz, 2H), 7.682 (m, 1H), 7.567 (m, 3H), 7.085 (s, 1H), 6.744 (s, 1H), 6.236 ( d, J = 9.2 Hz, 1H), 4.706 (t, J = 5.2 Hz, 1H), 3.173 (dd, J = 5.2, 18.0 Hz, 1H), 3.036 (dd, J = 5.2, 18.0 Hz, 1H), 1.283 (s, 3 H), 1.245 (s, 3 H);

MS ( m / z ): 387 (M + H) ⁺ _.

Example  39. 8,8-dimethyl-6 H - Pyrano [3,2- g ] Chrome -2,7- Dion (17)  Produce

Pyridinium chlorochromate (PCC, 1.74g, 8.12mmol) and molecular sieve 4Å (molecular sieve 4Å, 2g, wt / wt = 2/1) were added to a 100ml round flask with anhydrous dichloromethane (150ml). After melting, the mixture was placed on an ice bath in water and stirred for 5 minutes. Decurinol (1, 1g, 4.06mmol) was added thereto and stirred at 0 ° C for 1 hour. About half of the filtrate was concentrated under reduced pressure at room temperature, followed by silica gel column separation to obtain 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione (17) having the following physical properties. g was obtained and used as a sample of an experiment example.

Yield: 41.9%;

Yellow solid phase;

m.p: 165 ° C;

R _f = 0.47 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.642 (d, J = 9.6 Hz, 1H), 7.229 (s, 1H), 6.969 (s, 1H), 6.313 (d, J = 9.6 Hz, 1H), 3.660 ( s, 2H), 1.453 (s, 6H);

MS ( m / z ): 245 (M + H) ⁺ _.

Example  40. 8,8-dimethyl-6 H - Pyrano [3,2- g ] Chrome -2,7- Dion  7- Oxime  Preparation of Synthesis 18

In a 100 ml round flask, 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione (17, 788 mg, 3.23 mmol) was dissolved in anhydrous ethanol (20 ml). , Hydroxyammonium chloride (NH ₄ OHCl, 336mg, 4.85mmol) and pyridine (391μl, 4.85mmol) were added. A reflux tube was installed in the reaction flask, followed by stirring for 1 hour while warming to 80 ° C. The reaction solution was cooled to room temperature, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from hexane and ethyl acetate and filtered while washing with hexane. The crystallized material was subjected to silica gel column separation to obtain 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione 7-oxime (18) having the following physical properties. Used as.

Yield: 83.0%;

Light yellow solid phase;

m.p: 217 ° C;

R _f = 0.30 ( n- hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.614 (d, J = 9.6 Hz, 1H), 7.253 (s, 1H), 6.858 (s, 1H), 6.277 (d, J = 9.6, 1H), 3.851 (s , 2H), 1.525 (s, 6H);

MS ( m / z ): 260 (M + H) ⁺ _.

Example  41.8,8-dimethyl-6 H - Pyrano [3,2- g ] Chrome -2,7- Dion  7- [ O -(3,3-dimethylacryloyl)- Oxime] Preparation of 20a

Step 1.

In a fully dried 50 μl round flask, 3,3-dimethylacrylic acid (2a, 3,3-dimethylacrylic acid, 100 mg, 0.999 mmol) was dissolved in anhydrous dichloromethane (3 mL), and a nitrogen balloon was attached and stirred in a water ice bath. Oxalyl chloride (oxalyl chloride, 356.8 μl, 3.996 mmol) was added dropwise thereto, followed by stirring at 0 ° C. for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to synthesize 3,3-dimethylacryloyl chloride (19a), which was dissolved in anhydrous dichloromethane and applied to the next step.

Step 2.

Into a 100 µl round flask, add 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione 7-oxime (18, 103.5 mg, 0.399 mmol) and anhydrous dichloromethane (30 Ml), 3,3-dimethylacryloyl chloride (19a) dissolved in pyridine (96.9 µl, 1.197 mmol) and anhydrous dichloromethane (20 ml) was added dropwise, followed by stirring at room temperature for 2 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column separation to obtain 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione 7- [ O- ( 3,3-dimethylacryloyl) -oxime] (20a) was obtained and used as a sample for the experimental example.

Yield: 66.8%;

Yellow solid phase;

m.p: 147 ° C;

R _f = 0.26 ( n- hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.612 (d, J = 9.4 Hz, 1H), 7.243 (s, 1H), 6.885 (s, 1H), 6.288 (d, J = 9.4 Hz, 1H), 5.830 ( s, 1H), 3.914 (s, 2H), 2.254 (s, 3H), 1.991 (s, 3H), 1.620 (s, 6H);

MS ( m / z ): 342 (M + H) ⁺ _.

Example 42. 8,8-Dimethyl-6 H -Pyrano [3,2- g ] Chrome-2,7-Dion 7- ( O Cinnamoyl-oxime) (21a)

Step 1.

Cinnamic acid (6a, cinnamic acid, 85.7 mg, 0.579 mmol) was added to a completely dried 100 ml round flask and dissolved in anhydrous benzene (6 ml). N, N -dimethylformamide (2 drops) and thionyl chloride (SOCl ₂ , 211 μl, 2.893 mmol) were added thereto, and the mixture was refluxed at 70-80 degrees for 5 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to synthesize cinnamoyl chloride (7a), which was dissolved in anhydrous dichloromethane and applied to the next step.

Step 2.

Into a 100 mL round flask was placed 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione 7-oxime (18, 100 mg, 0.386 mmol) and anhydrous dichloromethane (30 mL ), Cinnamoyl chloride (7a) dissolved in pyridine (93.6µl, 1.158mmol) and anhydrous dichloromethane (20ml) was added dropwise, followed by stirring at room temperature for 2 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column separation to obtain 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione 7- ( O -cinna) having the following physical properties. Mole-oxime) (21a) was obtained and used as a sample of an experiment example.

Yield: 60.7%;

White solid phase;

m.p: 175 ° C;

R _f = 0.44 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.867 (d, J = 16.0 Hz, 1H), 7.609 (m, 3H), 7.436 (m, 3H), 7.279 (s, 1H), 6.912 (s, 1H), 6.614 (d, J = 16.0 Hz, 1H), 6.304 (d, J = 9.4 Hz, 1H), 3.999 (s, 2H), 1.654 (s, 6H);

MS ( m / z ): 390 (M + H) ⁺ _.

Example 43. 8,8-Dimethyl-6 H -Pyrano [3,2- g ] Chrome-2,7-Dion 7- [ O -(4-methoxycinnamoyl) -oxime] (21b)

The same physical properties as in Example 42 were carried out except that the 100 ml round flask completely dried in the first step of Example 42 was changed to 4-methoxy cinnamic acid (6b) instead of cinnamic acid (6a). with 8,8- dimethyl -6 H - pyrano [3,2- g] chromene-2,7-dione 7- [O - (4- methoxy-cinnamoyl) oxime] obtained an experimental example (21b) Used as a sample.

Yield: 62.4%;

White solid phase;

m.p: 175 ° C;

R _f = 0.39 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.820 (d, J = 16.0 Hz, 1H), 7.625 (d, J = 9.6 Hz, 1H), 7.546 (d, J = 8.8 Hz, 2H), 7.278 (s, 1H), 6.942 (d, J = 8.8 Hz, 2H), 6.908 (s, 1H), 6.476 (d, J = 16.0 Hz, 1H), 6.302 (d, J = 9.6 Hz, 1H), 3.994 (s, 2H), 3.865 (s, 3H), 1.650 (s, 6H);

MS ( m / z ): 420 (M + H) ⁺ _.

Example  44. 8,8-dimethyl-6 H - Pyrano [3,2- g ] Chrome -2,7- Dion  7- [ O -(3,4- Dimethoxycinnamoyl )- Oxime ] Synthesis (21d)

The same procedure as in Example 42 was performed except that the 100 ml round flask completely dried in the first step of Example 42 was changed to 3,4-dimethoxy cinnamic acid (6d) instead of cinnamic acid (6a). having the following physical data 8,8- dimethyl -6 H - pyrano [3,2- g] chromene-2,7-dione 7- [O - (3,4- dimethoxy-cinnamoyl) oxime] (21d) It was obtained and used as a sample of the experimental example.

Yield: 56.0%;

Light yellow solid phase;

m.p: 202 ° C;

R _f = 0.26 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.801 (d, J = 16.0 Hz, 1H), 7.615 (d, J = 9.4 Hz, 1H), 7.275 (s, 1H), 7.184 (dd, J = 8.4, 2.0 Hz, 1H), 7.100 (d, J = 2.0 Hz, 1H), 6.904 (m, 2H), 6.459 (d, J = 16.0 Hz, 1H), 6.298 (d, J = 9.4 Hz, 1H), 3.999 ( s, 2H), 3.948 (s, 3H), 3.940 (s, 3H), 1.651 (s, 6H);

MS ( m / z ): 450 (M + H) ⁺ _.

Example 45 8,8-dimethyl-6 H -Pyrano [3,2- g ] Chrome-2,7-Dion 7- [ O -(3,4,5-trimethoxycinnamoyl) -oxime] (21e)

The same process as in Example 42 was carried out except that the 100 ml round flask completely dried in the first step of Example 42 was changed to 3,4,5-trimethoxy cinnamic acid (6e) instead of cinnamic acid (6a). carried out to 8,8- dimethyl -6 H having the following physical-pyrano [3,2- g] chromene-2,7-dione 7- [O - (3,4,5- trimethoxy-cinnamoyl) -Oxime] (21e) was obtained and used as a sample for an experimental example.

Yield: 72.8%;

Yellow solid phase;

m.p: 175 ° C;

R _f = 0.24 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.776 (d, J = 16.0 Hz, 1H), 7.617 (d, J = 9.4 Hz, 1H), 7.277 (s, 1H), 6.912 (s, 1H), 6.814 ( s, 2H), 6.487 (d, J = 16.0 Hz, 1H), 6.303 (d, J = 9.4 Hz, 1H), 4.005 (s, 2H), 3.923 (s, 9H), 1.653 (s, 6H);

MS ( m / z ): 480 (M + H) ⁺ _.

Example  46. 8,8-dimethyl-6 H - Pyrano [3,2- g ] Chrome -2,7- Dion  7- [ O -(3- Acetoxy Cinnamo )- Oxime (22a) Preparation

Step 1.

      The same process as in the first step of Example 27 was carried out to obtain 3-acetoxy cinnamic acid (9b), a portion of which was applied to step 2.

Step 2, Step 3.

The same process as in Example 42, except that the 100 ml round flask completely dried in the first step of Example 42 was replaced with 3-acetoxy cinnamic acid (9b) instead of cinnamic acid (6a). pyrano [3,2- g] chromene-2,7-dione 7-8,8- dimethyl -6 H having the following physical data and to perform a [O - (3- acetoxy-cinnamoyl) - oxime ( 22a) was obtained and used as a sample of an experiment example.

Yield: 91.5%;

Yellow solid phase;

m.p: 160 ° C;

R _f = 0.47 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.823 (d, J = 16.0 Hz, 1H), 7.625 (d, J = 9.4 Hz, 1H), 7.443 (d, J = 2.4 Hz, 2H), 7.342 (s, 1H), 7.282 (s, 1H), 7.164 (m, 1H), 6.905 (s, 1H), 6.591 (d, J = 16 Hz, 1H), 6.301 (d, J = 9.4 Hz, 1H), 3.989 (s , 2H), 2.325 (s, 3H), 1.649 (s, 6H);

MS ( m / z ): 448 (M + H) ⁺ _.

Example  47. 8,8-dimethyl-6 H - Pyrano [3,2- g ] Chrome -2,7- Dion  7- [ O -(3,4- Diacetoxy cinnamoyl )- Oxime ] 22b

Step 1.

      Except for changing to 3-hydroxy cinnamic acid (9a) instead of 3,4-dihydroxy cinnamic acid (9c, 7g, 38.9mmol) in the first step of Example 27 and the first step of Example 27 The same process was followed to obtain 3,4-diacetoxy cinnamic acid (9d), a portion of which was applied to step 2.

Step 2, Step 3.

Steps 1-2 of Example 42 except that the 100 ml round flask completely dried in the first step of Example 42 was replaced with 3,4-diacetoxy cinnamic acid (9d) instead of cinnamic acid (6a). 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione 7- [ O- (3,4-diacetoxy cinna) having the following physical properties Mole) -oxime] (22b) was used as a sample for the experimental example.

Yield: 77.1%;

White solid phase;

m.p: 192 degreeC;

R _f = 0.23 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.794 (d, J = 16.4 Hz, 1H), 7.625 (d, J = 9.4 Hz, 1H), 7.462 (m, 2H), 7.268 (m, 2H), 6.907 ( s, 1H), 6.544 (d, J = 16.4 Hz, 1H), 6.303 (d, J = 9.4 Hz, 1H), 3.947 (s, 2H), 2.308 (s, 3H), 2.298 (s, 3H), 1.647 (s, 6 H);

MS ( m / z ): 506 (M + H) ⁺ _.

Example  48.8,8-dimethyl-6 H - Pyrano [3,2- g ] Chrome Preparation of 2-one (23)

Decurinol (1, 100mg, 0.406mmol) and triphenyl phosphine (213mg, 0.821mmol) 0 were added to a 100ml round flask, and dissolved in carbon tetrachloride (4ml) and acetonitrile (4ml). At reflux for 2 h. After about half of the filtrate was concentrated under reduced pressure, 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2-one (23) having the following physical properties was obtained through silica gel column separation. Used as a sample.

Yield: 95.6%;

White solid phase;

m.p: 124 ° C;

R _f = 0.69 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm; 7.576 (d, J = 9.2 Hz, 1H), 7.045 (s, 1H), 6.724 (s, 1H), 6.339 (d, J = 10.0 Hz, 1H), 6.219 (d, J = 9.6 Hz, 1H), 5.688 (d, J = 9.6 Hz, 1H), 1.468 (s, 6H);

MS ( m / z ): 229 (M + H) ⁺ _.

Experimental Example  One. THP -1 to mite ( mite) Induced by MCP -One/ IL -6 / IL - At eight minutes  Affectionate Decursin  Influence of Derivatives

ELISA kit company to measure the ELISA of the decursin derivatives synthesized in the above example using human acute monocytic leukemia cell line (THP-1) purchased from the American Cell Line Bank. Experiments were performed as follows using the manual of BD bioscience.

THP-1 cells cultured in Reference Example 1 were dispensed in a 24 well plate at 2.0 × 10 ⁶ / m in RPMI containing 0.5% FBS and incubated in an incubator (37 ° C., 5% CO ₂ ) for 16 hours. After incubation, treatment with decursin derivatives (10 μg / ml) for 1 hour followed by HDE (1 μg / ml) for 24 hours, followed by monocyte chemoattractant protein-1 (monocyte) in supernatant using ELISA. The amount of chemoattractant protein-1, MCP-1), IL-6, IL8 was measured, and the experimental results are shown in Table 12 and Table 13.

As a result, the amount of MCP-1, IL-6 and IL-8 in the normal group of THP-1 cells was 31, 19 and 181 pg / ml. The amount of 8 was found to increase to 342, 148 and 2319 pg / ml. Treatment with dexamethasone, a positive control in the increased state by ticks, showed that the amounts of MCP-1, IL-6 and IL-8 were reduced to 29, 18 and 132 pg / ml, almost equivalent to those of the normal group. . Meanwhile, 3d, 11a, 11c-f, 14c, 16a, and 23 of the deucine derivatives synthesized reduced the amount of MCP-1 to approximately the same level as the dexamethasone treated group, and 3d, 11a, 11c, 14c , 16a and 23 , reduced the amount of IL-6 to approximately the same level as the dexamethasone treated group. In addition, substances 3d and 11c reduced the amount of IL-8 to about the same level as the dexamethasone treated group. Taken together, the 3d, 11c, 11d, 18 and 23 material was found to reduce the overall amount of MCP-1, IL-6 and IL-8.

Experimental Example  2. EoL -1 to mite ( mite Induced by MCP -One/ IL -6 / IL - At eight minutes  Affectionate Decursin  Influence of Derivatives

     Manual of BD bioscience, an ELISA kit manufacturer, for measuring ELISA of decursin derivatives synthesized in the above example using human eosinophil EoL-1 (eosinophilic leukemia cell) cells purchased from Bank of Japan The experiment was performed as follows.

The EoL-1 cells cultured in Reference Example 2 were dispensed into a 24 well plate at 2.0 × 10 ⁶ / m in RPMI containing 0.5% FBS, and then cultured in an incubator (37 ° C., 5% CO ₂ ) for 16 hours. After incubation, treatment with decursin derivatives (10 μg / ml) for 1 hour followed by HDE (1 μg / ml) for 24 hours, followed by monocyte chemoattractant protein-1 (monocyte) in supernatant using ELISA. The amount of chemoattractant protein-1, MCP-1), IL-6, IL8 was measured, and the experimental results are shown in Tables 14 and 15 below.

The experimental results showed that the amounts of MCP-1, IL-6 and IL-8 in the normal group of EoL-1 cells were 91, 73 and 403 pg / ml, whereas MCP-1, IL-6 and It was confirmed that the amount of IL-8 was increased to 247, 281 and 812 pg / ml. Treatment of dexamethasone, a positive control, in the increased condition by ticks, reduced the amount of MCP-1, IL-6 and IL-8 to 73, 69, and 361 pg / ml, almost equivalent to that of the normal group. . On the other hand, 3d, 11a-e, 14b-c, 18 and 23 of the deucine derivatives synthesized reduced the amount of MCP-1 to approximately the same level as the dexamethasone treatment group, and dexamethasone 3d and 11c The amount of IL-6 was reduced to about the same level as the treatment group. In addition , substances 3d, 11c and 28 reduced the amount of IL-8 to about the same level as the dexamethasone treated group. Taken together, the 3d, 11c and 23 material was confirmed to reduce the overall amount of MCP-1, IL-6 and IL-8.

      Examples of the formulation of the composition are described below, but are not intended to limit the present invention but to explain in detail only.

Formulation Example 1 Preparation of Powder

Decursinol derivative (11c) 20 mg

Lactose 100 mg

Talc 10 mg

     The above ingredients are mixed and filled in an airtight cloth to prepare a powder.

Formulation Example 2 Preparation of Tablet

Decursinol derivative (11c) 10 mg

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

     After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.

Formulation Example 3 Preparation of Capsule

Decursinol derivative (11c) 10 mg

3 mg of crystalline cellulose

Lactose 14.8 mg

Magnesium Stearate 0.2 mg

    According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.

Formulation example  4. Preparation of Injectables

Decursinol derivative (11c) 10 mg

Mannitol 180 mg

Sterile distilled water for injection 2974 mg

Na ₂ HPO ₄ 12H ₂ O 26 mg

     According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).

Formulation Example 5 Preparation of Liquid

Decursinol derivative (11c) 20 mg

10 g of isomerized sugar

5 g of mannitol

Purified water

      According to the conventional method of preparing a liquid solution, each component is added to the purified water to dissolve it, the lemon flavor is added appropriately, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by the addition of purified water, and then filled in a brown bottle. The solution is prepared by sterilization.

Formulation Example 6 Preparation of Healthy Food

Decursinol derivative (11c) 1000 mg

Vitamin mixture proper amount

70 μg of Vitamin A Acetate

Vitamin E 1.0 mg

Vitamin B1 0.13 mg

Vitamin B2 0.15 mg

Vitamin B6 0.5 mg

0.2 μg of vitamin B12

Vitamin C 10 mg

10 μg biotin

Nicotinic Acid 1.7 mg

Folate 50 ㎍

Calcium Pantothenate 0.5mg

Mineral mixture

Ferrous Sulfate 1.75 mg

Zinc Oxide 0.82 mg

Magnesium carbonate 25.3 mg

Potassium monophosphate 15 mg

Dibasic calcium phosphate 55 mg

Potassium Citrate 90 mg

Calcium Carbonate 100 mg

Magnesium chloride 24.8 mg

     Although the composition ratio of the above-mentioned vitamin and mineral mixtures is mixed with a component suitable for a health food in a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health food manufacturing method. The granules may be prepared and used for preparing a health food composition according to a conventional method.

Formulation Example 7 Preparation of Healthy Drink

Decursinol derivative (11c) 1000 mg

Citric acid 1000 mg

100 g oligosaccharides

Plum concentrate 2 g

1 g of taurine

Add 900 ml of purified water

     After mixing the above components according to a conventional healthy beverage manufacturing method, and then stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 L container, sealed and sterilized and then refrigerated and stored in the present invention For the preparation of healthy beverage compositions.

     Although the composition ratio is a composition suitable for a preferred beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, use purpose.

As described above, the decursin derivative compounds of the present invention exhibit the secretion amounts of MCP-1, IL-6 and IL-8, which show atopic dermatitis response induced by ticks in THP-1 or EoL-1 cells. Effectively inhibiting it can provide a pharmaceutical composition and health functional food for the prevention and treatment of atopic dermatitis diseases.

Claims (16)

     A decursin derivative compound having a novel structure represented by the following general formula (I) synthesized by using (+)-decursinol isolated from a real Angelica as a precursor and a pharmaceutically acceptable salt thereof:

                             (I)        In the above formula, The A substituent is a hydrogen atom, a dialkyl acryloyl group or a cinnamoyl group in which the phenyl ring is unsubstituted or substituted with R '; Wherein R ′ is optionally substituted at o, m, and p positions, and is hydrogen atom, hydroxy group, acetate group, halogen atom, C ₁ to C ₄ lower alkyl group, C ₁ to C ₄ lower alkoxy group and C ₁ to C ₄ At least one substituent selected from the group consisting of lower alkyl esters. According to claim 1, wherein the general formula (I) compound A substituent is a hydrogen atom, a methyl group, dimethyl acryloyl group or a phenyl ring is a cinnamoyl group unsubstituted or substituted with R ', wherein R' is o, m and a compound which is a hydrogen atom, a methyl group, a methoxy group or an acetate group substituted at the p- position, and its salt. The method of claim 1 wherein the general formula (I) compound is 8,8- dimethyl -6 H - pyrano [3,2- g] chromene-2,7-dione 7-oxime, 8,8- dimethyl- 6 H -pyrano [3,2- g ] chromen-2,7-dione 7- [O- (3,3-dimethylacryloyl) -oxime], 8,8-dimethyl-6 H -pyrano [3,2- g] chromene-2,7-dione 7- (O-cinnamoyl-oxime), 8,8- dimethyl -6 H - pyrano [3,2- g] chromene -2,7 -dione 7- [O - (4- methoxy-cinnamoyl) oxime], 8,8- dimethyl -6 H - pyrano [3,2- g] chromene-2,7-dione 7- [O- (3,4-dimethoxycinnamoyl) -oxime], 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione 7- [ O- (3,4, 5-trimethoxy cinnamoyl) oxime], 8,8- dimethyl -6 H - pyrano [3,2- g] chromene-2,7-dione 7- [O - (3- acetoxy-cinnamoyl ) -Oxime] or 8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2,7-dione 7- [ O- (3,4-diacetoxycinnamoyl) -oxime] Compounds and salts thereof.  A pharmaceutical composition for the prevention and treatment of atopic diseases comprising as an active ingredient a decursin derivative compound having a novel structure represented by general formula (I) of claim 1 or a pharmaceutically acceptable salt thereof. 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester, benzene sulfonic acid 2,2-dimethyl-8- Oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester compound and pharmaceutically acceptable salts thereof. delete delete The 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester, benzene sulfonic acid 2,2-dimethyl of claim 5 Atopic dermatitis, comprising as an active ingredient a -8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester compound or a pharmaceutically acceptable salt thereof Pharmaceutical compositions for the prevention and treatment of diseases. A pharmaceutical composition for the prevention and treatment of atopic dermatitis diseases containing a decursin derivative compound represented by the following general formula (III) as an active ingredient:

                              (III)      In the above formula, R ₁ is a C ₁ to C ₁₀ alkyl group, a C ₂ to C ₁₀ alkenyl group or an A substituent which is unsubstituted or substituted with a halogen atom or a C ₁ to C ₄ lower alkyl group, A substituent

Wherein A 'is optionally substituted at o, m, and p positions; At least one substituent selected from the group consisting of a hydrogen atom, a hydroxy group, an acetate group, a halogen atom, a C ₁ to C ₄ lower alkyl group, a C ₁ to C ₄ lower alkoxy group and a C ₁ to C ₄ lower alkyl ester; n is an integer from o to 4; The compound according to claim 9, wherein R ₁ is a C ₁ to C ₁₀ alkyl group, C ₂ to C ₁₀ alkenyl group or A which is unsubstituted or substituted with a halogen atom or a C ₁ to C ₄ lower alkyl group. Wherein A ′ of the A substituent is one or more substituents selected from a hydrogen atom, a hydroxy group, a methyl group, an ethyl group, a methoxy group, an ethoxy group or an acetyl group substituted in the o, m, and p positions; n is a pharmaceutical composition wherein the compound is an integer of o or 1. 10. The compound of claim 9, wherein the general formula (III) compound is 3-methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3]. , 2-g] chromen-3-yl - ester, cis-2-methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, trans-2-methyl-but-2-tenophosphate 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H- Pyrano [3,2-g] chromen-3-yl-ester, 2-methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2 -g] chromen-3-yl-ester, phen-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chrome Men-3-yl-ester, but-3-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3- Yl-ester, phen-4-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, a-ethyl 2,2-dimethyl-8-oxo-3,4-dihydro-2H, 8H-pyrano [3,2-g] chromen-3-yl Grounds, chloro-ethyl, 2,2-dimethyl-8-oxo-3,4-dihydro-2H, 8H-to ester, trichloromethyl-pyrano [3,2-g] chromen-2-yl acetate, 2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, pentanoic acid 2,2-dimethyl-8-oxo- 3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, decanoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H , 8H -pyrano [3,2-g] chromen-3-yl-ester, 3-phenyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [ 3,2-g] chromen-3-yl-ester, 3- (4-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -P Lano [3,2-g] chromen-3-yl-ester, 3- (3,4-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H-pyrano [3,2-g] chromen-3-yl-ester, 3- (3,4,5-trimethoxy City-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H, 8H-pyrano [3,2-g] chromen-3-yl-ester, 3- (3, 4,5-Trihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester , 3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl- Ester, 3- (2-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl Ester, 3- (3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3- Mono-ester, 3- (2,3-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen 3-yl-ester, 3- (2,4-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g ] Crommen-3-yl-ester, 3- (2,5-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-di Jethro-2H, 8H-pyrano [3,2-g] chromen-3-yl-ester, 3- (2,4,5-trimethoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo -3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4-nitro-phenyl) -acrylic acid 2,2-dimethyl-8-oxo -3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (3-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8- Oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (3-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8 -Oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (3,4-dihydroxy-phenyl) -acrylic acid 2,2 -Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (3,4-diacetoxy-phenyl)- Acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4-hydroxy-3- methoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H, 8H-pyrano [3,2-g] chroman 3-yl-ester, 3- (4-acetoxy-3-methoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H, 8H-pyrano [3, 2-g] chromen-3-yl-ester, 3- (4-acetoxy-3,4-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2-g] chromen-3-yl-ester, benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3, 2-g] chromen-3-yl-ester, 3,4,5-trihydroxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3 , 2-g] chromen-3-yl-ester or 3,4,5-triacetoxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [ A pharmaceutical composition that is 3,2-g] chromen-3-yl-ester. A pharmaceutical composition for the prevention and treatment of atopic dermatitis diseases containing a decursin derivative compound represented by the following general formula (IV) as an active ingredient:

       In the above formula, C is at least one substituent selected from the group consisting of a hydrogen atom and a ketone group. delete The method of claim 12, wherein the general formula (Ⅳ) compound is 8,8- dimethyl -6 H - pyrano [3,2- g] chromene-2,7-dione or 8,8- dimethyl -6 H - A pharmaceutical composition that is pyrano [3,2- g ] chromen-2-one. A dietary supplement for the prevention and improvement of atopic dermatitis diseases comprising the decursinol derivative compound of claim 1, 5, 9 and 12 as an active ingredient. delete