KR101101011B1 - A composition comprising novel +-decursin-structural isomer synthesis derivative for treating and preventing atopic dermatitis disease - Google Patents

Abstract

The present invention relates to (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano, which is a structural isomer of (+)-decursinol isolated from Angelica gigas [2,3- g] coumarin ((8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin) and (6s) -6-hydroxy-7,7-dimethyl-5, 6-dihydropyrano [3,2-f] coumarin ((6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano [3,2-f] coumarin) was prepared and synthesized. Newly constructed (+)-decursin-structural isomeric derivative compounds, which are precursors, secrete MCP-1, IL-6 and IL-8, which show an atopic dermatitis response induced by ticks in EoL-1 cells. By effectively inhibiting the composition, the composition comprising the same can be usefully used as a pharmaceutical composition and health functional food for the prevention and treatment of atopic dermatitis diseases.

Angelica gigas, (+)-decursinol, atopic dermatitis

Description

A composition for the treatment and prophylaxis of atopic dermatitis diseases comprising a new [+]-decurin-structural isomer synthesis derivative [A composition comprising novel (+)-decursin derivative for treating and preventing atopic dermatitis disease}

The present invention relates to (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano, which is a structural isomer of (+)-decursinol isolated from Angelica gigas [2,3- g] coumarin ((8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin) and (6s) -6-hydroxy-7,7-dimethyl-5, 6-dihydropyrano [3,2-f] coumarin ((6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano [3,2-f] coumarin) was prepared and synthesized. The present invention relates to a composition comprising, as an active ingredient, (+)-decurin-structure isomer derivative compounds having a novel structure as precursors.

[1] Hanifin JM et al., Guidelines of care for atopic dermatitis. J. Am Acad. Dermatol., 50, pp 391-404, 2004.

[2] Williams HC., Clinical practice. Atopic dermatitis. N. Engl. J. Med., 352 , pp 2314-24, 2005.

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.

Colloff MJ., Exposure to house dust mites in homes of people with atopic dermatitis. Br. J. Dermatol., 127 , pp 322-327, 1992.

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.

Kino T et al., Tissue-specific glucocorticoid resistance hypersensitivity syndromes: multifactorial states of clinical importance. J. Allergy Clin. Immunol., 109 , pp 609-613, 2002.

Lu B et al., Abnorm alities in monocyte recruitment and cytokine expression in monocyt e chemoattractant protein 1-deficient mice. J. Exp. Med., 187 , pp 601-608, 1998.

Karpus WJ et al., MIP-1 alpha and MCP-1 differentially regulate acute and relapsing autoimmune encephalomy elitis asell as Th1 / Th2 lymphocyte differentiation. J. Leukoc. Biol., 62 , pp 681-687, 1997.

9 Harada A et al., Essential involvement of interleukin-8 (IL-8) in acute inflammation. J, Leukoc, Biol ,, 56 , pp 559-564, 1994.

[10] 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 , pp313-316, 1996

12, Chi, H. J and Kim HS: Studies on the components of Umbelliferae Plants in Korea. Kor. J. Pharmacogn ., 1 , pp. 25, 1970.

[13] Bae, EA et al., Anti-Helicobacter pylori activity of herbal medicines. Biol Pharm Bull . 21 , pp. 990, 1998.

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.

[Document 15] Korean Registered Patent: 10-2007-18057

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 of atopic dermatitis has been increasing rapidly in Korea and around the world. However, only the most popular drug treatments have been carried out since no treatment has been developed to 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 , pp227-237, 2003). In particular, the incidence of atopic dermatitis in proportion to the amount exposed to house dust mites (Colloff MJ., Exposure to house dust mites in homes of people with atopic dermatitis.Br . J. Dermatol., 127 , pp322-327, (1992) and significant 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.Peatr . 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 this steroid resistance, it is usually a serious problem, a complication caused by treatment, and a high cost of treatment, and it is a task to identify the mechanism of steroid resistance as soon as possible (Kino T et al., Tissue-specific glucocorticoid resistance). hypersensitivity syndromes: multifactorial states of clinical importance.J. Allergy Clin.Imunmun ., 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 monocyte 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), induced bronchial hypersensitivity by IL-8 and increased in allergic rhinitis or bronchial 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 , pp313-316, 1996) .

(+)-Decursin (decursin) is a substance that has been attracting attention since it exhibits various activities including anticancer activity recently.

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 different activities are (+)-such as (+)-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, (+)-decursin has been shown to inhibit IL-8, MCP-1, and TNF-a, which are cytokines that induce inflammatory responses by inhibiting NF-kB in macrophage, an inflammatory mediator. 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).

In addition, the inventors have synthesized novel (+)-decusrin derivatives of ester forms of various structures that do not exist in Angelica vulgaris using (+)-decursinol as a starting material and their As a result of measuring the anti-atopic effect, it was confirmed that the use as atopic dermatitis treatment by confirming the excellent atopic inhibitory effect has been notified a patent decision (Korea Patent Registration: 10-2007-18057).

Thus, the present inventors found that (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3], which is a structural isomer of (+)-decursinol isolated from Angelica gigas -g] coumarin ((8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin) and (6s) -6-hydroxy-7,7-dimethyl-5 , 6-6-dihydropyrano [3,2-f] coumarin ((6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano [3,2-f] coumarin) was prepared and synthesized. The novel (+)-decursin-structure isomer derivative compounds, which are used as precursors, of MCP-1, IL-6 and IL-8 exhibiting atopic dermatitis response induced by ticks in EoL-1 cells. As a result of measuring the amount of secretion, the present invention was completed by confirming an excellent atopy inhibitory effect.

In order to achieve the above object, a (+)-decursin-structural isomer synthetic derivative of a novel structure represented by the following general formula (I) synthesized using the structural isomer of (+)-decursinol as a precursor (decursin-structural isomer synthesis derivative) or a pharmaceutically acceptable salt thereof:

(I)

(I)

In this formula,

R ₁ is one or more substituents selected from the group consisting of C ₁ to C ₂₀ alkyl groups, C ₂ to C ₂₀ alkenyl groups, C ₂ to C ₂₀ alkynyl groups and A substituents unsubstituted or substituted with one or more R ′, wherein R ′ is a substituent selected from a halogen atom, a nitro group, an amine group or a C ₁ to C ₄ lower alkyl group;

Where A substituent is

Wherein R '' is one or more substituents optionally substituted at o, m, and p positions, and hydrogen atom, hydroxy group, acetate group, halogen atom, C ₁ to C ₄ lower alkyl group, C ₁ to C ₄ lower alkoxy group At least one substituent selected from the group consisting of C ₁ to C ₄ lower alkyl esters and C ₁ to C ₄ lower alkyl carboxy groups;

) 은 이중결합 또는 단일결합을 의미한다. n is an integer from 0 to 4, (

) Means a double bond or a single bond.

In a preferred group of compounds of the formula (I) compounds R ₁ is a halogen atom or a C ₁ to C ₄ lower substituted with an alkyl group or an unsubstituted C ₁ to C ₁₀ alkyl group, C ₂ to C ₁₀ alkenyl, C ₂ to A substituent selected from the group consisting of a C ₁₀ alkynyl group and an A substituent, wherein R '' of the A substituent is a hydrogen atom, a hydroxy group, an amine group, a halogen atom, a methyl group, an ethyl group, or a methoxy group substituted at o, m, and p positions At least one substituent selected from a period, an ethoxy group, a nitro group or an acetyl group; n is a group of compounds having an integer of o or 1, more preferably R ₁ is at least one substituent 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, p position Substituted or unsubstituted A substituent; n is a group of compounds that is an integer of o or 1;

In addition, in order to achieve the above object, (+)-decursin-structural isomer synthetic derivative of a novel structure represented by the following general formula (II) synthesized using the structural isomer of (+)-decursinol as a precursor (decursin) -structural isomer synthesis derivative) or a pharmaceutically acceptable salt thereof:

(Ⅱ)

(Ⅱ)

In this formula,

R ₂ is one or more substituents selected from the group consisting of C ₁ to C ₂₀ alkyl groups, C ₂ to C ₂₀ alkenyl groups, C ₂ to C ₂₀ alkynyl groups and A substituents unsubstituted or substituted with one or more R ′, wherein R ′ is a substituent selected from a halogen atom, a nitro group, an amine group or a C ₁ to C ₄ lower alkyl group;

Where A substituent is

Wherein R '' is one or more substituents optionally substituted at o, m, and p positions, and hydrogen atom, hydroxy group, acetate group, halogen atom, C ₁ to C ₄ lower alkyl group, C ₁ to C ₄ lower alkoxy group At least one substituent selected from the group consisting of C ₁ to C ₄ lower alkyl esters and C ₁ to C ₄ lower alkyl carboxyl groups;

) 은 이중결합 또는 단일결합을 의미한다. n is an integer from 0 to 4, (

) Means a double bond or a single bond.

In a preferred group of compounds of the general formula (Ⅱ) compound is R ₂ is a halogen atom or a C ₁ to C ₄ lower substituted with an alkyl group or an unsubstituted C ₁ to C ₁₀ alkyl group, C ₂ to C ₁₀ alkenyl, C ₂ to A substituent selected from the group consisting of a C ₁₀ alkynyl group and an A substituent, wherein R '' of the A substituent is a hydrogen atom, a hydroxy group, an amine group, a halogen atom, a methyl group, an ethyl group, or a methoxy group substituted at o, m, and p positions At least one substituent selected from a period, an ethoxy group, a nitro group or an acetyl group; n is a group of compounds having an integer of o or 1, and more preferably, R ₂ is one or more substituents selected from hydrogen, hydroxy, methyl, ethyl, methoxy, ethoxy or acetyl group substituted at o, m and p positions. Substituted or unsubstituted A substituent; n is a group of compounds that is an integer of o or 1;

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

(3s) -3-methyl-but-2tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3-yl-ester (LM-1), (3s) -2-methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] chrome Men-3-yl-ester (LM-2), (3s) -3- (3,4-dimethoxy-phenyl) -acrylic acid-2,2-dimethyl-7oxo-3,4-dihydro-2H- Pyrano [2,3-g] chromen-3-yl-ester (LM-3), (3s) -3-methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3, 4-dihydro-2H-pyrano [3,2-f] chromen-3-yl-ester (LS-1) or (3s) -2-methyl-but-2-tenophosphoric acid-2,2- Dimethyl-7oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen-3-yl-ester (LS-2).

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

In addition, bases can 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 above compounds of formula (I) or (II) include salts of acidic or basic groups which may be present in compounds of formula (I) or (II) unless otherwise indicated. . 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, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, 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 compound of Formula (I) or (II), which may be chemically synthesized by the method shown in Schemes below, 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 5. Can be. Some compounds of the present invention were synthesized according to procedures not included in the scope of Schemes 1-5, and detailed synthesis procedures for these compounds are described in their respective examples.

Scheme 1 represents a five step preparation process for preparing commercial compounds or compounds synthesized by known methods.

In the first step, hydroquinone is dissolved in 85% formic acid, 2-methyl-3-butene-2-ol is added, and the reaction is performed by heating and refluxing at about 70 to 130 ° C., preferably at 90 to 110 ° C. do. The reaction time may be carried out for 1 to 10 hours, preferably after stirring for 2 to 6 hours, the reaction solution is cooled to room temperature, and then concentrated to obtain a residue obtained by silica gel column separation through 6-hydroxy-2,2-. Dimethyl chromen (2) can be prepared. In the second step, 6-hydroxy-2,2-dimethyl chromen (2) is dissolved in ethyl propiolate, and zinc chloride is added thereto, about 90 to 150 캜, preferably The reaction is carried out while heating to reflux at about 100 to 120 ℃. After stirring for 1 to 5 hours, preferably 2 to 4 hours, the reaction mixture was cooled to room temperature, and the residue obtained by concentrating the residue was purified by silica gel column separation to obtain 7,7-dimethyl-8,9-dihydro, respectively. -7H-pyrano [2,3-g] chromen-2-one (3a) and 7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-2 -On (3b) can be prepared. In the third step, 7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3-g] chromen-2-one (3a) is dissolved in benzene to give 2,3-dichloro-5, 6-dicyano-1,4-benzoquinone (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) was added thereto, followed by heating under reflux to carry out the reaction. The reaction time should be stirred for 40 to 160 hours, preferably after stirring for 60 to 120 hours, the reaction solution is cooled to room temperature and concentrated to obtain the residue obtained by silica gel column separation 7,7-dimethyl-7H-pyrano [2,3-g] chromen-2-one (4) can be prepared. In the fourth step, 7,7-dimethyl-7H-pyrano [2,3-g] chromen-2-one (4) is dissolved in acetonitrile solution (S, S)-(+), N, N '-Bis (3,5-di-tet butyl salicyridine) -1,2-cyclohexanediamino manganese (III) chloride ((S, S)-(+), N, N'-Bis (3 , 5-di-tert-butyl-salicylidene) -1,2-cyclohexane-diaminomanganese (III) chloride, and then sodium tetraborate decahydrate was added to 0.4 mM ethylene diamine tetrasodium disodium salt solution. Dissolve tetra butylammonium bisulfate in buffer in (ethylene diamine tetraacetic acid disodium salt solution). The mixture was cooled to -20 to 0 ° C, preferably 0 ° C, and then 1,1,1-trifluoroacetone was added and oxone was 0.4 mM ethylene diamine. The solution dissolved in ethylene diamine tetraacetic acid disodium salt solution and sodium bicarbonate solution are slowly added while stirring, and then the reaction is performed at -20 to 0 ° C, preferably 0 ° C. The reaction time is stirred for 1 to 2 hours, preferably about 1 hour, the reaction solution is treated with water and extracted with ethyl ether to concentrate the residue obtained by silica gel column separation (8s, 9s) -8,9 Epoxy-7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3 g] chromen-one (5) can be prepared. Since the product of the fourth stage is unstable, the reaction proceeds to the next stage. In the fifth step, (8s, 9s) -8,9-epoxy-7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3g] chromen-one (5) was added to tetrahydrofuran. After dissolution, sodium cyanoborohydride and boron trifluoride diethyl etherate were added thereto, and the reaction was performed at -20 to 30 ° C, preferably 0 ° C, and then at room temperature. . The reaction time is stirred at 0 ° C. for 0.5 to 5 hours, preferably 0.5 to 1.5 hours, and at room temperature for 0 to 5 hours, preferably 1 to 2 hours, and then the reaction solution is treated with saturated sodium hydrogencarbonate and then acetic acid. The residue obtained by extracting with ethyl and concentrating the organic layer was purified by silica gel column separation (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin (1) Can be prepared.

Scheme 2 shows a one step process for preparing a commercial compound or a compound synthesized by known methods.

In the first step, 3,3-dimethylacrylic acid and angelic acid were dissolved in dichloromethane, respectively, 1,3-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP (8s) -8-hydroxy- The reaction is carried out with 7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin (1) The reaction temperature is not particularly limited but is 10 to 50 ° C, preferably 30 to 45 ° C. The reaction time was stirred for 30 to 70 hours, preferably 40 to 60 hours, and the filtrate was concentrated under reduced pressure, and the obtained residue was separated by silica gel column separation (3s) -3-methyl-but-2tenophosphate-2. , 2-Dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3-yl-ester (LM-1) and (3s) -2-methyl-part- 2-Tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3-yl-ester (LM-2) may be prepared. have.

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

In the first step, 3,4-dimethoxycinnamic acid is dissolved in dichloromethane and 1,3-dicyclo hexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP), (8s) -8-hydroxy- 7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin (1) was added thereto and the reaction was carried out. Although reaction temperature is not specifically limited, 20-40 degreeC, Preferably it is normal temperature or 40 degreeC, The reaction time is stirred for 10 to 48 hours, Preferably it is about 20 to 40 hours. The filtrate was concentrated under reduced pressure and the obtained residue was purified by (3s) -3- (3,4-dimethoxy-phenyl) -acrylic acid-2,2-dimethyl-7oxo-3,4-dihydro-2H- by silica gel column separation. Pyrano [2,3-g] chromen-3-yl-ester (LM-3) can be prepared.

Scheme 4 represents a five step preparation process for preparing commercial compounds or compounds synthesized by known methods.

In the first step, hydroquinone is dissolved in 85% formic acid, 2-methyl-3-butene-2-ol is added, and the reaction is performed by heating and refluxing at about 70 to 130 ° C., preferably at 90 to 110 ° C. do. The reaction time may be carried out for 1 to 10 hours, preferably after stirring for 2 to 6 hours, the reaction solution is cooled to room temperature, and then concentrated to obtain a residue obtained by silica gel column separation through 6-hydroxy-2,2-. Dimethyl chromen (2) can be prepared. In the second step, 6-hydroxy-2,2-dimethyl chromen (2) is dissolved in ethyl propiolate, and zinc chloride is added thereto, about 90 to 150 캜, preferably The reaction is carried out while heating to reflux at about 100 to 120 ℃. After stirring for 1 to 5 hours, preferably 2 to 4 hours, the reaction mixture was cooled to room temperature, and the residue obtained by concentrating the residue was purified by silica gel column separation to obtain 7,7-dimethyl-8,9-dihydro, respectively. -7H-pyrano [2,3-g] chromen-2-one (3a) and 7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-2 -On (3b) can be prepared. In the third step, 7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-2-one (3b) is dissolved in benzene to give 2,3-dichloro-5, 6-dicyano-1,4-benzoquinone (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) was added thereto, followed by heating under reflux to carry out the reaction. The reaction time is stirred for 40 to 160 hours, preferably 60 to 120 hours, the reaction solution is cooled to room temperature and concentrated to obtain the residue obtained by silica gel column separation, respectively 7,7-dimethyl-7H-pyrano [3 , 2-f] chromen-2-one (9) can be prepared. In the fourth step, 7-dimethyl-7H-pyrano [3,2-f] chromen-2-one (9) is dissolved in acetonitrile solution and (S, S)-(+), N, N'- Bis (3,5-di-tet butyl salicyridine) -1,2-cyclohexane diamino manganese (III) chloride ((S, S)-(+), N, N'-Bis (3,5 -di-tert-butyl- salicylidene) -1,2-cyclohexane-diaminomanganese (III) chloride, followed by a sodium tetraborate decahydrate solution of 0.4 mM ethylene diamine tetrasodium disodium salt (ethylene Dissolve tetra butylammonium bisulfate in buffer in diamine tetraacetic acid disodium salt solution. The mixture was lowered to -20 to 0 ° C., preferably 0 ° C., and then 1,1,1-trifluoroacetone was added so that oxone was 0.4 mM of ethylene. Slowly add the solution dissolved in ethylene diamine tetraacetic acid disodium salt solution and sodium bicarbonate solution while stirring, and at -20 to 0 ℃, preferably 0 ℃, the reaction time is 0.5 to After stirring for 5 hours, preferably 1 to 2 hours, the reaction solution was treated with water, extracted with ethyl ether, and the residue obtained by concentrating the organic layer was separated through silica gel column separation (5s, 6s) -5,6-epoxy-7. , 7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-one (10) can be prepared. Since the product of the fourth stage is unstable, the reaction proceeds to the next stage. In the fifth step, (5s, 6s) -5,6-epoxy-7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-one (10) was converted to tetrahydro After dissolving in furan, sodium cyanoborohydride and boron trifluoride diethyl etherate were added thereto, and the reaction was performed at -20 to 30 ° C, preferably 0 ° C. Perform on The reaction time is stirred at 0 ° C. for 0.5 to 5 hours, preferably 0.5 to 1.5 hours, and at room temperature for 0 to 2 hours, preferably 1 to 2 hours, after treating the reaction solution with saturated sodium hydrogencarbonate. The residue obtained by extracting with ethyl acetate and concentrating the organic layer was purified by silica gel column separation (6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano [3,2-f] coumarin (11 ) Can be prepared.

Scheme 5 shows a one-step process for preparing a commercial compound or a compound synthesized by known methods.

In the first step, 3,3-dimethylacrylic acid and angelic acid were dissolved in dichloromethane, respectively, and N- (3-dimethylaminopropyl) -N'-ethylcarbovoamide hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP). ), (6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano [3,2-f] coumarin (11) is added and the reaction is carried out. Although reaction temperature is not specifically limited, 10-40 degreeC, Preferably it is 20-40 degreeC, The reaction time was stirred for 30 to 70 hours, Preferably it is about 40 to 60 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column separation to obtain (3s) -3-methyl-but-2-tenophosphate-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano. [3,2-f] chromen-3-yl-ester (LS-1) and (3s) -2-methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4- Dihydro-2H-pyrano [3,2-f] chromen-3-yl-ester (LS-2) can be prepared.

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

Accordingly, the present invention provides a (+)-decursin-structural isomer synthesis derivative of the novel structure represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof It provides a pharmaceutical composition for the prevention and treatment of atopic dermatitis diseases containing as an active ingredient.

The composition comprising the compound of formula (I) or (II) of the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods.

Examples of carriers, excipients and diluents that can be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The compositions comprising the compounds of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories, or sterile injectable solutions, respectively, according to conventional methods. Can be used.

More specifically, when formulating the composition, it can be prepared using a diluent or an excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and the like. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, sucrose, etc. ), Lactose, gelatin and the like can be mixed. In addition to simple excipients, lubricants such as magnesium stearate and talc may 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 sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried 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 0.001 ~ 100 mg / kg divided 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 may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.

The present invention relates to a (+)-decursin-structural isomer synthesis derivative compound of the novel structure represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof. It provides a health functional food for improvement for the prevention and treatment of atopic dermatitis disease.

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 to 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 Can be added in a ratio 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 include 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 Sugar, 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. In addition, the compositions of the present invention may contain fruit flesh 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 in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.

As described above, the (+)-decursin-structural isomer synthesis derivative compounds of the present invention are MCP-1, IL- showing an atopic dermatitis response induced by ticks in EoL-1 cells. 6 and effectively inhibit the amount of IL-8 can provide a pharmaceutical composition and health functional food for the prevention and treatment of atopic dermatitis diseases.

Hereinafter, the present invention will be described in detail with reference to 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), an optical meter (Polarimeter, JASCO DIP-370, Japan) was used. 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 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. (3s) -3-Methyl-but-2tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3 -Yl-ester (6) ((3s) -3methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3 -yl-ester)

1-1. Preparation of 6-hydroxy-2,2-dimethyl chroman (2) (6-hydroxy-2,2-dimethyl chroman) intermediate

As shown in the reaction scheme, hydroquinone (hydroquinone, 220 g, 1.998 mol) was dissolved in 500 ml of 85% formic acid in a round flask, 2-methyl-3-butene-2-ol (109 ml, 1.043 mol) was added thereto, and then 100 ° C. It was refluxed while stirring for about 4 hours. The reaction solution was cooled, poured into 2000 ml of water, neutralized with NaHCO ₃ to PH 7-8, extracted three times with 800 ml of ethyl acetate, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give 6-hydride with silica gel column separation. 61.33 g of oxy-2,2-dimethyl chromen (2) was obtained.

Yield: 33%;

Reddish brown crystals;

R _f = 0.50 (n-Hexane: ethylacetate = 2: 1);

mp = 72-73 ° C .;

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 6.645-6.555 (m, 3H), 6.352 (s, OH), 2.654 (t, J = 6.8, 2H), 1.736 (t, J = 6.8, 2H), 1.29 7 (s, 6H);

MS ( m / z ) 179.4 (M + H) ⁺ .

1-2. 7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3-g] chromen-2-one (3a) (7,7-dimethyl-8,9-dihydro-7H-pyrano [ 2,3-g] chromen-2-one) and 7,7-dimethyl-5.6-dihydro-7H-pyrano [3,2-f] chromen-2-one (3b) (7,7-dimethyl Preparation of -5,6-dihydro-7H-pyrano [3,2-f] chromen-2-one) intermediates

As shown in the reaction scheme, 6-hydroxy-2,2-methylchrome (2) (50 g, 0.281 mol) was added to an intermediate compound prepared in the same manner as in Example 1-1 in a round flask. After dissolving in the pilate (ethyl propiolate, 42.8ml, 0.421mol), zinc chloride (38.5g, 0.282mol) was added thereto, and the mixture was refluxed while stirring at 110 ° C for 1.5 hours. 5% aqueous hydrogen chloride solution was added to the reaction solution, followed by extraction with ethyl acetate and concentrated under reduced pressure to obtain 7,7-dimethyl-8,9-dihydro-7H-pyranochrome [2,3-g] with physical properties through silica gel column separation. 8.41 g of men-2-one (3a) and 17.5 g of 7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-2-one (3b) were obtained.

Compound: 7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3-g] chromen-2-one (3a)

Yield: 13%;

White solid;

R _f = 0.46 (n-Hexane: ethylacetate = 3: 2);

mp = 138-139 ° C .;

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.594 (d, J = 9.52 1H), 7.052 (s, 1H), 6.850 (s, 1H), 6.356 (d, J = 9.52, 1H), 2.885 (t, J = 6.70 2H), 1.845 (t, J = 6.70, 2H), 1.3489 (s, 6H);

MS ( m / z ) 231.4 (M + H) ⁺ .

Compound: 7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-2-one (3b)

Yield: 27.1%;

Light yellow solid;

R _f = 0.33 (n-Hexane: ethylacetate = 3: 2);

mp = 135.5-136.5 ° C .;

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.860 (d, J = 9.76 1H), 7.120 (d, J = 9.00 1H), 6.991 (d, J = 9.04 1H), 6.442 (d, J = 9.76, 1H ), 2.905 (t, J = 6.82 2H), 1.895 (t, J = 6.84, 2H), 1.350 (s, 6H);

MS ( m / z ) 231.4 (M + H) ⁺ .

1-3. 7,7-dimethyl-7H-pyrano [2,3-g] chromen-2-one (4) (7,7-dimethyl-7H-pyrano [2,3-g] chromen-2-one) intermediate Manufacture

As shown in the above scheme, the intermediate compound prepared in the same manner as in Example 1-2 was placed in a round flask with 7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3-g] chromen. 2-one (3a) (5.5 g, 23.8 mmol) was added to dissolve in 500 ml of benzene, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10.9 g, 48.0 mmol) was added. It was refluxed while stirring for 80 hours. The reaction solution was treated with saturated NaHSO ₃ , extracted with diethyl ether, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by silica gel column separation to obtain 7,7-dimethyl-7H-pyrano [2,3-g]. ] 4.7 g of chroman-2-one (4) was obtained.

Yield: 86.5%;

Light yellow solid;

R _f = 0.49 (n-Hexane: ethylacetate = 3: 2);

mp = 124-125 ° C .;

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.578 (d, J = 9.60, 1H), 6.947 (s, 1H), 6.832 (s, 1H), 6.371 (t, J = 10.2, 2H), 5.840 (d , J = 10.00 1H), 1.451 (s, 6H);

MS ( m / z ) 229.3 (M + H) ⁺ .

1-4. (8s, 9s) -8,9-epoxy-7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3g] chromen-one (5) ((8s, 9s) -8, Preparation of 9-epoxy-7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3-g] chromen-2-one) intermediate

As shown in the above scheme, the intermediate compound prepared in the same manner as in Example 1-3 was placed in a round flask with 7,7-dimethyl-7H-pyrano [2,3-g] chromen-2-one (4). (987.9 mg, 4.33 mmol) was added and dissolved in 50 ml of acetonitrile solution, and then (S, S)-(+), N, N'-bis (3,5-di-tet butyl salicyridine) -1 at room temperature. , 2-cyclohexanediamino manganese (III) chloride (57mg, 0.09mmol) was added, and then sodium tetraborate decahydrate was added to 0.4mM ethylene diamine tetraacetic acid disodium solution. 35 ml of a solution of tetra butylammonium bisulfate was added to the buffer solution in salt solution. After cooling the mixture to 0 ° C., 1,1,1-trifluoroacetone (0.5 ml) was added, and thus oxone (10.25 g, 16.61 mmol) in 0.4 mM ethylene diamine tetraacid disodium salt solution (50 ml). The solution to which the solution was added and 50 ml of sodium bicarbonate (3 g, 35.7 mmol) aqueous solution were slowly added while stirring, and the reaction was stirred at 0 ° C. for 1 hour. The reaction mixture was treated with water, extracted with diethyl ether, the organic layer was dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (8s, 9s) -8,9-epoxy-7,7-dimethyl- having physical properties through separation of a silica girl column. 545.7 mg of 8,9-dihydro-7H-pyrano [2,3g] chromen-one (5) was obtained.

Yield: 51.6%;

Light yellow solid;

R _f = 0.31 (n-Hexane: ethylacetate = 3: 2);

mp = 120-121;

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.606 (d, J = 9.52, 1H), 7.344 (s, 1H), 6.902 (s, 1H), 6.417 (d, J = 9.52, 1H), 3.966 (d , J = 4.4, 1H), 3.553 (d, J = 4.4 1H), 1.600 (s, 3H), 1.260 (s, 3H);

MS ( m / z ) 245.2 (M + H) ⁺ ;

[a] _D ²⁵ = 11.2 (c 3, CHCl ₃ ).

1-5. (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin (1) ((8s) -8-hydroxy-7,7-dimethyl-8 , 9-dihydropyrano [2,3-g] coumarin)

As shown in the scheme, the intermediate compound prepared in the same manner as in Example 1-4 was placed in a round flask with (8s, 9s) -8,9-epoxy-7,7-dimethyl-8,9-dihydro-6H. -Pyrano [2,3g] chromen-on (5) (420.3mg, 1.72mmol) was added and dissolved in tetrahydrofuran (90ml), sodium cyanobromide hydride (132mg, 2.1mmol) and borontrifluoride Diethyl acrylate (216 mg, 1.52 mmol) was added thereto, the reaction was performed at 0 ° C., and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was treated with saturated NaHCO ₃ , extracted with ethyl acetate, the organic layer was concentrated under reduced pressure, and the physical properties were determined by silica gel column separation (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3]. 315.3 mg of -g] coumarin (1) was obtained.

Yield: 74.4%;

White solid

R _f = 0.26 (n-Hexane: ethylacetate = 1: 1);

mp = 161.5-162.5 ° C .;

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.587 (d, J = 9.60, 1H), 7.043 (s, 1H), 6.898 (s, 1H), 6.341 (d, J = 9.60, 1H), 3.868 (t , J = 5.2, 1H), 3.163 (dd, J = 4.8, 11.2, 1H), 2.891 (dd, J = 5.6, 11.6, 1H), 1.381 (s, 3H), 1.335 (s, 3H);

MS ( m / z ) 247.4 (M + H) ⁺ ;

[a] _D ²⁵ = 30.2 (c 0.5, CHCl ₃ ).

No. matter Compound Molecular Weight structure One 2 6-hydroxy-2,2-dimethyl chroman 178.23

2 3a 7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3-g] chromen-2-one 230.26

3b 7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-2-one
230.26

3 4 7,7-dimethyl-7H-pyrano [2,3-g] chromen-2-one 228.24

4 5 (8s, 9s) -8,9-epoxy-7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3-g] chromen-2-one 244.24

5 One (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin 246.26

1-6. (3s) -3-methyl-but-2tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3-yl-ester (6) ((3s) -3methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3-yl-ester Manufacturing

As shown in the scheme, 3,3-dimethylacrylic acid (34 mg, 0.34 mmol) was added to a round flask with the intermediate compound prepared in the same manner as in Example 1-5, and dissolved with 10 ml of dichloromethane. Cyclohexylcarbodiimide (101 mg, 0.49 mmol) and 4-dimethylaminopyridine (30 mg, 0.246 mmol) and (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2, 3-g] Coumarin (1) (60.5 mg, 0.265 mmol) was added and refluxed with stirring at 38 ° C. for 48 hours. The reaction mixture was concentrated under reduced pressure to obtain (3s) -3-methyl-but-2tenophosphate-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2] having physical properties through a silica gel column. 57.7 mg of, 3-g] chromen-3-yl-ester (LM-1) was used as a sample for the experimental example.

Yield: 66.3%;

White solid

R _f = 0.49 (n-Hexane: ethylacetate = 2: 1);

mp = 117-118 ° C .;

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.605 (d, J = 9.60, 1H), 7.034 (s, 1H), 6.920 (s, 1H), 6.365 (d, J = 9.60, 1H), 5.665 (s , 1H), 5.078 (t, J = 5.00, 1H), 3.25 (dd, J = 6, 18.0, 1H), 2.897 (dd, J = 4.4, 18.0, 1H), 2.154 (s, 3H), 1.881 (s, 3H), 1.548 (s, 6H);

MS ( m / z ) 329.3 (M + H) ⁺ ;

[a] _D ²⁵ = 12.1 (c 3, CHCl ₃ ).

Example 2. (3s) -cis-2-methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] chrome Men-3-yl-ester (7) ((3s) -2-methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [2,3- g] chromen-3-yl-ester)

As shown in the reaction scheme, the intermediate compound prepared in the same manner as in Example 1-5 was added angelic acid (25 mg, 0.25 mmol) to a round flask, dissolved in 10 ml of dichloromethane, and then 1,3-dicyclohexylcarbodie. Mead (49 mg, 0.237 mmol) and 4-dimethylaminopyridine (17 mg, 0.139 mmol) with (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] Add coumarin (1) (28.8 mg, 0.117 mmol) and reflux with stirring at 38 ° C. for 58 hours. The reaction mixture was concentrated under reduced pressure and (3s) -2-methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [ 26.4 mg of 2,3-g] chromen-3-yl-ester (LM-2) was obtained and used as a sample for the experimental example.

Yield: 68.7%;

White solid

R _f = 0.50 (n-Hexane: ethylacetate = 2: 1);

mp = 106-107 ° C .;

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.610 (d, J = 9.60, 1H), 7.034 (s, 1H), 6.930 (s, 1H), 6.82 (g, J = 4.2, 1H), 6.371 (d , J = 9.60, 1H), 5.086 (t, J = 5.2, 1H), 3.267 (dd, J = 4.8, 18.4, 1H), 2.914 (dd, J = 5.4, 18.2, 1H), 1.766 (d, J = 7.2 3H), 1.588 (s, 3H), 1.356 (d, J = 6.4, 6H).

MS ( m / z ) 329.3 (M + H) ⁺ ;

[a] _D ²⁵ = 8.7 (c 1, CHCl ₃ ).

Example 3. (3s) -3- (3,4-Dimethoxy-phenyl) -acrylic acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] Chromen-3-yl-ester (8) ((3s) -3- (3,4-dimethoxy-phenyl) -acrylicacid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [ 2,3-g] chromen-3-yl-ester)

As shown in the scheme, 3,4-dimethoxycinnamic acid (208mg, 0.999 mmol) was added to a round flask with the intermediate compound prepared in the same manner as in Example 1-5, and dissolved in 20ml of dichloromethane. Dicyclohexylcarbodiimide (289.2 mg, 0.1.402 mmol) and 4-dimethylaminopyridine (57.4 mg, 0.47 mmol) and (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydro Pyrano [2,3-g] coumarin (1) (150.3 mg, 0.659 mmol) was added thereto and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure to obtain ((3s) -3- (3,4-dimethoxy-phenyl) -acrylic acid-2,2-dimethyl-7oxo-3,4-dihydro-2H having physical properties through a silica gel column. 235.6 mg of pyrano [2,3-g] chromen-3-yl-ester (LM-3) was obtained and used as a sample for the experimental example.

Yield: 81.9%;

White solid;

R _f = 0.42 (n-Hexane: ethylacetate = 3: 2);

mp = 182-183 ° C .;

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.641 (d, J = 9.2, 1H), 7.609 (d, J = 2.8, 1H), 7.081 (dd, J = 1.8, 5.2, 1H), 7.062 (s, 1H), 7.020 (d, J = 1.6, 1H), 6.958 (s, 1H), 6.848 (d, J = 8.4, 1H), 6.376 (d, J = 9.2, 1H), 6.292 (d, J = 15.6 , 1H), 5.20. (t, J = 4.8, 1H), 3.899 (d, J = 6.0 6H), 3.304 (dd, J = 5.2, 18.0, 1H), 2.980 (dd, J = 4.4, 18.0, 1H), 1.419 (s, 3H), 1.370 (s, 3H);

MS ( m / z ) 436.9 (M + H) ⁺ ;

[a] _D ²⁵ = 37.9 (c 2, CHCl ₃ ).

No. matter Compound Molecular Weight structure 6 LM-1 (3s) -3methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3-yl-ester 328.36

7 LM-2 (3s) -2-methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3-yl-ester 328.36

8 LM-3 (3s) -3- (3,4-dimethoxy-phenyl) -acrylicacid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3-yl- ester 436.45

Example 4 (3s) -3-Methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen- 3-yl-ester (12) ((3S) -3-methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen-3-yl-ester)

4-1. 7,7-dimethyl-7H-pyrano [3,2-f] chromen-2-one (9) (7,7-dimethyl-7H-pyrano [3,2-f] chromen-2-one) intermediate Manufacture

As shown in the above scheme, the intermediate compound prepared in the same manner as in Example 1-2 was placed in a round flask with 7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen. 2-one (3b) (9.44 g, 50.0 mmol) was added to dissolve in 500 ml of benzene, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (24.1 g, 106.2 mmol) was added. It was refluxed with stirring for 5 days. The reaction solution was treated with saturated NaHSO ₃ , extracted with diethyl ether, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 7,7-dimethyl-7H-pyrano [3,2-f] having physical properties through silica gel column separation. ] 4.44 g of chroman-2-one (9) was obtained.

Yield: 47.5%;

Light yellow solid;

R _f = 0.452 (n-Hexane: ethylacetate = 3: 2);

mp = 118-119 ° C .;

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.910 (d, J = 9.76, 1H), 7.103 (d, J = 9.04, 1H), 6.986 (d, J = 9.00, 1H), 6.683 (d, J = 10.04, 1H), 6.439 (d, J = 9.76, 1H), 5.839 (d, J = 10.00, 1H), 1.456 (s, 6H);

MS ( m / z ) 229.3 (M + H) ⁺ .

4-2. (5s, 6s) -5,6-epoxy-7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-on (10) ((5s, 6s)- Preparation of 5,6-epoxy-7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-2-one) intermediate

As shown in the above scheme, the intermediate compound prepared in the same manner as in Example 4-1 was placed in a round flask with 7-dimethyl-7H-pyrano [3,2-f] chromen-2-one (9) (1.01). g, 4.425 mmol), dissolved in 50 ml of acetonitrile solution, and then (S, S)-(+), N, N'-bis (3,5-di-tet butyl salicyridine) -1,2 at room temperature. Add cyclohexanediamino manganese (III) chloride (320.1mg, 0.504mmol), and then add sodium tetraborate decahydrate to 0.4mM ethylene diamine tetraacetic acid disodium salt. 35 ml of a solution of tetra butylammonium bisulfate was added to the buffer solution. After the mixture was cooled to 0 ° C., 1,1,1-trifluoroacetone (0.5 ml) was added thereto, and oxone (15 g, 24.3 mmol) was added to 0.4 mM ethylene diamine tetrasodium disodium salt solution (50 ml). Slowly add the added solution and 50 ml of sodium bicarbonate (3 g, 35.7 mmol) aqueous solution with stirring, and react with stirring at 0 ° C. for 1.5 hours. The reaction mixture was treated with water, extracted with diethyl ether, the organic layer was dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (5s, 6s) -5,6-epoxy-7,7-dimethyl- having physical properties through separation of a silica gal column. 549 mg of 5,6-dihydro-7H-pyrano [3,2-f] chromen-one (10) was obtained.

Yield: 50.8%;

Light yellow semisolid;

R _f = 0.21 (n-Hexane: ethylacetate = 3: 2);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 8.069 (d, J = 10.00, 1H), 7.230 (d, J = 9.04, 1H), 7.017 ((d, J = 9.00, 1H), 6.522 (d, J = 9.76, 1H), 4.273 (d, J = 4.36, 1H), 3.594 (d, J = 4.36, 1H), 1.606 (s, 3H), 1.292 (s, 3H);

MS ( m / z ) 245.2 (M + H) ⁺ ;

[a] _D ²⁵ = 5.5 (c 6, CHCl ₃ ).

4-3. (6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano [3,2-f] curin (11) ((6s) -6-hydroxy-7,7-dimethyl-5 , 6-dihydropyrano [3,2-f] coumarin) intermediates

As shown in the reaction scheme, the intermediate compound prepared in the same manner as in Example 4-2 was placed in a round flask with (6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano [3,2]. -f] Add coumarin (11) (549 mg, 2.25 mmol) and dissolve in tetrahydrofuran (100 ml) to dissolve sodium cyanobromide (183 mg, 2.91 mmol) and borontrifluoride diethyl etherate (320 mg, 2.26). mmol) and the reaction was carried out at 0 ° C., followed by stirring at room temperature for 2 hours. The reaction mixture was treated with saturated NaHCO ₃ , extracted with ethyl acetate, the organic layer was concentrated under reduced pressure, and the physical properties were determined by (6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano using silica gel column separation. 455.2 mg of [3,2-f] coumarin (11) was obtained and used as a sample for the experimental example.

Yield: 82.2%;

White solid

R _f = 0.23 (n-Hexane: ethylacetate = 1: 1);

mp = 167-168 ° C .;

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.798 (d, J = 9.76, 1H), 7.128 (d, J = 9.04, 1H), 7.034 (d, J = 9.00, 1H), 6.427 (d, J = 9.76, 1H), 3.924 (s, 1H), 3.150 (dd, J = 5.12, 16.84, 1H), 2.920 (dd, J = 5.64, 17.08, 1H), 1.379 (s, 3H), 1.340 (s, 3H );

MS ( m / z ) 247.4 (M + H) ⁺ ;

[a] _D ²⁵ = 3.9 (c 5, CHCl ₃ ).

No. matter Compound Molecular Weight structure 9 9 7,7-dimethyl-7H-pyrano [3,2-f] chromen-2-one 228.24

10 10 (5s, 6s) -5,6-epoxy-7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-2-one 244.24

11 11 (6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano [3,2-f] coumarin 246.26

4-4. (3s) -3-methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen-3-yl- Ester (12) ((3S) -3-methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen-3- yl-ester)

As shown in the scheme, 3,3-dimethylacrylic acid (69 mg, 0.69 mmol) was added to a round flask in the same manner as in Example 4-3, and dissolved in 10 ml of dichloromethane. Dimethylaminopropyl) -N'-ethylcarbodiamide hydrochloride (EDC) (151 mg, 1.01 mmol) and 4-dimethylaminopyridine (26.3 mg, 0.215 mmol) and (6s) -6-hydroxy-7,7- Dimethyl-5,6-dihydropyrano [3,2-f] coumarin (11) (50.8 mg, 0.206 mmol) was added thereto, and the reaction proceeded while stirring at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and (3s) -3-methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [ 36.7 mg of 3,2-f] chromen-3-yl-ester (LS-1) was obtained and used as a sample for the experimental example.

Yield: 66.3%;

Colorless semisolid

R _f = 0.38 (n-Hexane: ethylacetate = 2: 1);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.769 (d, J = 9.76, 1H), 7.151 (d, J = 9.04, 1H), 7.048 (d, J = 9.28, 1H), 6.435 (d, J = 9.76, 1H), 5.687 (s, 1H), 5.114 (t, J = 5.4, 1H), 3.257 (dd, J = 5.36, 17.32, 1H), 2.930 (dd, J = 5.12, 17.32, 1H), 2.168 (s, 3H), 1.892 (s, 3H), 1.352 (d, J = 8.04, 6H);

MS ( m / z ) 329.3 (M + H) ⁺ ;

[a] _D ²⁵ = 18.3 (c 3, CHCl ₃ ).

Example 5. (3s) -2-Methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen- 3-yl-ester (13) ((3S) -2-methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen-3-yl-ester)

As shown in the reaction scheme, the intermediate compound prepared in the same manner as in Example 4-3 was added angelic acid (150.9 mg, 1.507 mmol) to a round flask, dissolved in 15 ml of dichloromethane, and then N- (3-dimethylaminopropyl). ) -N'-ethylcarbodiamide hydrochloride (EDC) (250 mg, 1.304 mmol) and 4-dimethylaminopyridine (50.7 mg, 0.415 mmol) and ((6s) -6-hydroxy-7,7-dimethyl- 5,6-Dihydropyrano [3,2-f] coumarin (11) (106 mg, 0.43 mmol) was added thereto, and the mixture was refluxed under stirring at room temperature for 72 hours.The reaction mixture was concentrated under reduced pressure to obtain physical properties through a silica gel column. (3s) -2-Methyl-but-2-tenophosphate-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen-3-yl- 87 mg of ester (LS-2) was obtained and used as a sample of an experiment example.

Yield: 61%;

Colorless semisolid

R _f = 0.357 (n-Hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.774 (d, J = 9.76, 1H), 7.149 (d, J = 9.00, 1H), 7.056 (d, J = 9.04, 1H), 6.854 (q, J = 7.04, 1H), 6.434 (d, J = 10.0, 1H), 5.120 (t, J = 5.4, 1H), 3.291 (dd, J = 5.36, 17.32, 1H), 2.943 (dd, J = 5.38, 17.34, 1H), 1.824 (s, 3H), 1.784 (d, J = 7.08, 3H), 1.367 (d, J = 6.12, 6H)

MS ( m / z ) 329.3 (M + H) ⁺

[a] _D ²⁵ = 25.8 (c 5, CHCl ₃ ).

No. matter Compound Molecular Weight structure 12 LS-1 (3S) -3-methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen-3-yl-ester 328.36

13 LS-2 (3S) -2-methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen-3-yl-ester 328.36

Experimental Example 1. Determination of the effect of (+)-decurin-ether derivatives on mite-induced MCP-1 / IL-6 / IL-8 secretion in EoL-1

In order to measure the ELISA of the decursin-ether derivatives synthesized in the above Example using EoL-1 (eosinophilic leukemia cell (RCB 0641)) cells, which are human eosinophils purchased from Nippon Cell Line Bank, The experiment was performed as follows.

EoL-1 cells incubated in Reference Example 1 were plated at 24 × well plates at 2.0 × 10 ⁶ / m in RPMI (Life Technologies Inc.) containing 0.5% FBS and antibiotics (100 U / ml penicillin, 100 μg / ml streptomycin). After aliquoting, the cells were incubated for 1 hour in an incubator (37 ° C., 5% CO ₂ ). After incubation, the (+)-decursin-structure isomeric synthetic derivatives (10 μg / ml) of Examples 1 to 3 were treated for 1 hour, and then the mite (1 μg / ml) was treated for 24 hours, respectively. After treatment, the amount of monocyte chemoattractant protein-1 (MCP-1), IL-6, and IL-8 was measured in the supernatant using an ELISA kit. Is shown in Table 2 below.

matter Volume of MCP-1 (pg / ml) Amount of IL-6
(pg / ml) Amount of IL-8
(pg / ml) LM-1 22.68 23.71 6.61 LM-2 0.86 4.37 15.20 LM-3 127.23 12.92 10.36 Normal 19.50 15.55 15.52 Tick treatment group 236.77 39.50 23.64 Dexamethasone treatment group 94.50 8.32 5.52

Experimental results show that the amounts of MCP-1, IL-6 and IL-8 in the normal group of EoL-1 cells are 19.50, 15.55 and 15.52 pg / ml, whereas MCP-1, IL-6 and The amount of IL-8 was confirmed to increase to 236.77, 39.50 and 23.64 pg / ml. Treatment of dexamethasone, a positive control in the increased state by ticks, resulted in 94.50, 8.32 and 5.52 pg / ml of MCP-1, IL-6 and IL-8. -1 for 22.68, 23.71 and 6.61 pg / ml, for compound LM-2 0.86, 4.37 and 15.20 pg / ml, for compound LM-3 19.50, 15.55 and 10.36 It can be confirmed that the same effect as the dexamethasone used as a positive control group (see Table 1). In addition, no toxicity was confirmed through the MTT assay.

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

(+)-Decursin-structural isomer synthetic derivative (LM-1) 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

(+)-Decursin-structural isomer synthetic derivative (LM-2) 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

(+)-Decursin-structural isomer synthetic derivative (LM-3) 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 Injection

(+)-Decursin-structural isomer synthetic derivative (LS-1) 10 mg

Mannitol 180 mg

Sterile distilled water for injection 2974 mg

Na2HPO412H2O 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

(+)-Decursin-structural isomer synthetic derivative (LS-2) 20 mg

10 g of isomerized sugar

5 g of mannitol

Purified water

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

Formulation Example 6 Preparation of Healthy Food

(+)-Decursin-structural Isomer Synthetic Derivative (LM-1) 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

50 μg folic acid

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 mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

Formulation Example 7 Preparation of Healthy Drink

(+)-Decursin-Somer Isomer Synthesis Derivative (LM-2) 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 production method, and then stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained by sterilization in a sterilized 2 L container, sealed sterilized and then stored in the present invention For the preparation of healthy beverage compositions.

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

Claims (11)

A (+)-decursin-structural isomer synthetic derivative compound of the novel structure represented by the following general formula (I) synthesized using the structural isomer of (+)-decursinol as a precursor, or a pharmaceutically acceptable salt thereof:

(I) In this formula, R ₁ is one or more substituents selected from the group consisting of C ₁ to C ₂₀ alkyl groups, C ₂ to C ₂₀ alkenyl groups, C ₂ to C ₂₀ alkynyl groups and A substituents unsubstituted or substituted with one or more R ′, wherein R ′ is a substituent selected from a halogen atom, a nitro group, an amine group or a C ₁ to C ₄ lower alkyl group; Where A substituent is

Wherein R '' is one or more substituents optionally substituted at o, m, and p positions, and 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 one or more substituents selected from the group consisting of C ₁ to C ₄ lower alkyl carboxy groups; n is an integer from 0 to 4, (

) Means a double bond or a single bond. According to claim 1, wherein the compound of formula (I) R ₁ is a C ₁ to C ₁₀ alkyl group, C ₂ to C ₁₀ alkenyl group, C ₂ unsubstituted or substituted with a halogen atom or C ₁ to C ₄ lower alkyl group To a C ₁₀ alkynyl group and an A substituent, wherein R ″ in the A substituent is a hydrogen atom, a hydroxyl group, a halogen atom, a methyl group, an ethyl group, a methoxy group, substituted at o, m, or p positions, At least one substituent selected from an ethoxy group or an acetyl group; n is o or an integer of 1 or a pharmaceutically acceptable salt thereof. The compound of formula (I) according to claim 2, wherein R ₁ is one or more substituents selected from hydrogen, hydroxy, methyl, ethyl, methoxy, ethoxy or acetyl groups substituted at o, m and p positions Substituted or unsubstituted A substituent; n is o or an integer of 1 or a pharmaceutically acceptable salt thereof. delete (+)-Decursin-structural isomer synthetic derivative compound of the novel structure represented by the following general formula (II) synthesized using the structural isomer of (+)-decursinol as a precursor, or a pharmaceutically acceptable salt thereof:

(Ⅱ) In this formula, R ₂ is one or more substituents selected from the group consisting of C ₁ to C ₂₀ alkyl groups, C ₂ to C ₂₀ alkenyl groups, C ₂ to C ₂₀ alkynyl groups and A substituents unsubstituted or substituted with one or more R ′, wherein R ′ is a substituent selected from a halogen atom, a nitro group, an amine group or a C ₁ to C ₄ lower alkyl group; Where A substituent is

Wherein R '' is one or more substituents optionally substituted at o, m, and p positions, and 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 one or more substituents selected from the group consisting of C ₁ to C ₄ lower alkyl carboxy groups; n is an integer from 0 to 4, (

) Means a double bond or a single bond. 6. The compound of claim 5, wherein R ₂ is a C ₁ to C ₁₀ alkyl group, C ₂ to C ₁₀ alkenyl group, C _{2 which} is unsubstituted or substituted with a halogen atom or a C ₁ to C ₄ lower alkyl group. To a C ₁₀ alkynyl group and an A substituent, wherein R ″ in the A substituent is a hydrogen atom, a hydroxyl group, a halogen atom, a methyl group, an ethyl group, a methoxy group, substituted at o, m, or p positions, At least one substituent selected from an ethoxy group or an acetyl group; n is o or an integer of 1 or a pharmaceutically acceptable salt thereof. The compound of formula (II) according to claim 6, wherein R ₂ is substituted with at least one substituent selected from a hydrogen atom, a hydroxy group, a methyl group, an ethyl group, a methoxy group, an ethoxy group or an acetyl group in which R ₂ is substituted at o, m, and p positions. Or an unsubstituted A substituent; n is o or an integer of 1 or a pharmaceutically acceptable salt thereof. delete Prevention and treatment of atopic dermatitis disease containing (+)-decursin-structural isomer synthetic derivative compound of the novel structure represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient Pharmaceutical composition for. Prevention and improvement of atopic dermatitis disease containing (+)-decursin-structural isomer synthetic derivative compound of the novel structure represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient Health functional food for. The dietary supplement according to claim 10 in the form of a powder, granule, tablet, capsule or beverage.