KR20100008808A - A composition comprising novel (+)-decursin-ether derivative for treating and preventing atopic dermatitis disease - Google Patents

Abstract

PURPOSE: A composition containing a novel (+)-decursin derivative for preventing and treating atopic dermatitis is provided to ensure higher stability than a conventional ester and suppress MCP-1[Monocyte Chemoattractant Protein-1], IL-6[interleukin-6] and IL-8. CONSTITUTION: A novel structure (+)-decursin-ether derivative compound is denoted by general formula I. A pharmaceutical composition for preventing and treating atopic dermatitis contains the (+)-decursin-ether derivative compound or its pharmaceutically acceptable salt as an active ingredient. The daily dose of the (+)-decursin-ether derivative compound is 0.0001-100 mg/kg. The functional health food also contains the (+)-decursin-ether derivative compound or its pharmaceutically acceptable salt as an active ingredient. The food is used in the form of powder, granule, tablet, capsule or beverage.

Description

A composition comprising novel (+)-decursin-ether derivative for treating and preventing atopic dermatitis disease}

The present invention is an ether form of (+)-decous, which has a more stable structure than the (+)-decursin derivative of the ester form known as a precursor using (+)-decursinol isolated from Angelica gigas. It relates to a composition containing a decursin-ether derivative as an active ingredient.

[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 2312-24, 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 , pp559-564, 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 , 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 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 . 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 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), 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 since it exhibits various activities including anticancer activity recently.

Angelica Angelica gigas ) is a plant of the umbelliferae and refers to Korean Angelica, and young shoots are used as medicines for various diseases such as edible and rooted analgesic effect, renal toxicity alleviation, and diabetic hypertension treatment (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] They are materials (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. there bar (J. Kim 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 (+)-decursinol as a starting material and synthesized new (+)-decusrin derivatives of ester forms of various structures that do not exist in Angelica gigas and their anti-atopic dermatitis. As a result of measuring the effect, it was confirmed that the excellent atopic inhibitory effect and confirmed the possibility of use as a therapeutic agent for atopic dermatitis has been notified a patent decision (Korea Patent Registration: 10-2007-18057).

However, the ester form of (+)-decursin derivatives esterified with various organic acids in the alcohol group of (+)-decurinol as described above is produced by an enzyme such as esterase present in the blood ( It has the disadvantage of being degraded into +)-decurinol.

Therefore, the present inventors synthesized (+)-decursin-ether derivatives, which are more stable structures like the ether form, than the ester form, and measured their anti-atopic effects, and thus, showed excellent atopic inhibition effect. The present invention was completed by confirming.

In order to achieve the above object, a (+)-decursin-ether derivative compound of the novel structure represented by the following general formula (I) synthesized using (+)-decursinol as a precursor or its Pharmaceutically acceptable salts:

(I)

(I)

In the above formula,

R ₁ is a C ₁ to C ₂₀ alkyl group unsubstituted or substituted with one or more R ′, C ₂ to C ₂₀ Alkenyl groups, C ₂ to C ₂₀ At least one substituent selected from the group consisting of an alkynyl group and an A substituent, 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, hydrogen atom, hydroxy group, acetate group, halogen atom, C ₁ to C ₄ lower alkyl group, C ₁ to C ₄ Lower alkoxy groups, C ₁ to C ₄ Lower alkyl esters and C ₁ to C ₄ At least one substituent selected from the group consisting of 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.

Preferred compound groups of the above general formula (I) compound include R ₁ is a C ₁ to C ₁₀ alkyl group unsubstituted or substituted with a halogen atom or a C ₁ to C ₄ lower alkyl group, C ₂ to C ₁₀ Alkenyl groups, C ₂ to C ₁₀ Alkynyl is a substituent selected from the group and the group A consisting of the substituents, where the A substituent of R '' is o, m, p of the hydrogen atoms substituted at the position, a hydroxy group, an amine group, a halogen atom, a methyl group, an ethyl group, a methoxy group, At least one substituent selected from 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;

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.

(7S) -7-methoxy-8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (3a), (7S) -8,8 -Dimethyl-7- (3-methyl-but-2-tenyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (3b), (7S)- 8,8-dimethyl-7- (2-methyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (3c), (7S) -8 , 8-dimethyl-7- (3-phenyl-propoxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (3d), (7S) -7- [3- (2-methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (7a) , (7S) -7- [3- (3-methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen- 2-one (7b), (7S) -7- [3- (4-methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2 g ] chromen-2-one (7c), (7S) -7- [3- (3,4-dimethoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -Pyrano [3,2- g ] chromen-2-one (7d), (7S) -7- [3- (2,3-dimethoxy-phenyl) -propoxy] -8,8-dimethyl -7,8-diha Draw - 6H - pyrano [3,2- g] chromen-2-one (7e), (7S) -8,8- dimethyl-7- [3- (3,4,5-trimethoxyphenyl) -Propoxy)]-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (7f), (7S) -8,8-dimethyl-7- (3-phenyl -Allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (12a) or (7S) -7- [3- (4-methoxy-phenyl) -Allyloxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (12b).

The compounds of the present invention represented by the general formula (I) 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 above compounds of formula (I) include salts of acidic or basic groups which may be present in compounds of formula (I), 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), which may be chemically synthesized by the method 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 3. Can be. Some compounds of the present invention have been synthesized according to processes not included in the scope of Schemes 1 through 3, and detailed synthesis procedures for these compounds are described in their respective examples.

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

In the first step, (+)-decurinol (Ia) is dissolved in a solvent of anhydrous N, N -dimethylformamide , and then reacted with an alkalizing agent such as sodium hydride and methane iodide. At this time, the solvent is used to perform the reaction using a solvent that does not adversely affect the reaction, such as N, N- dimethylformamide and dimethyl sulfoxide. The reaction temperature can generally be carried out at -20 ° C to -40 ° C, preferably at -20 ° C. The reaction time can be carried out for 12 to 48 hours, preferably for 24 hours. The reaction solution was concentrated by filtration over a silica gel column, followed by removing the residual solvent such as N, N -dimethylformamide under vacuum while concentrating the concentrated flask at 90-100 ° C. The obtained residue can be prepared alkoxyl (Ib) through silica gel column separation.

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

In the first step, cinnamic acid (IIa ') or propionic acid (IIa' ') substituted with R' 'is dissolved in a solvent of anhydrous tetrahydrofuran, and then reacted with a reducing agent such as lithium aluminum hydride. To prepare. At this time, the solvent used is a solvent that does not adversely affect the reaction using a solvent such as tetrahydrofuran, diethyl ether, dichloromethane and chloroform, preferably using tetrahydrofuran. The reaction temperature is generally from room temperature to 0 ° C., preferably at room temperature. The reaction time can be carried out for 2 to 24 hours, preferably for about 3 to 12 hours. Distilled water is slowly added to the reaction solution, followed by stirring until no heat is generated. Add an acid such as HCl to pH 1 to 5 and extract with an organic solvent such as dichloromethane. The filtrate was dehydrated with anhydrous forget-me-not and concentrated under reduced pressure, and the obtained residue could be prepared by silica gel column separation to prepare alcohol (IIb).

In the second step, two different methods are used to synthesize a halide such as 1- (3-bromo-propyl) -2-methoxybenzene or 1- (3-iodo-propyl) -2-methoxybenzene. It can be used for the reaction. For example, the first method is to prepare 1- (3-bromo-propyl) -2-methoxybenzene and halogen such as 3- (2-methoxyphenyl) propan-1-ol and boron tribromide. An agent is added and dissolved in a solvent such as dichloromethane to react. In this case, the solvent is used toluene, benzene, dichloromethane, chloroform, carbon tetrachloride and the like which do not adversely affect the reaction. The reaction temperature may generally be carried out at 0 ° C to room temperature, preferably at 0 ° C. The reaction time may be carried out for 30 minutes to 24 hours and preferably stirred for 2 hours to 12 hours. The residue obtained by concentrating the reaction solution under reduced pressure may prepare 1- (3-bromo-propyl) -2-methoxybenzene (IIc ') through silica gel column separation. The second method is to prepare 1- (3-iodo-propyl) -2-methoxybenzene, 3- (2-methoxyphenyl) propan-1-ol, triphenylphosphine, iodine, imidazole, etc. Solvent is dissolved in an organic solvent such as toluene and reacted. At this time, the solvent is used toluene, benzene and the like that do not adversely affect the reaction to perform the reaction. The reaction temperature can generally be carried out at 0 ℃ to room temperature, preferably at room temperature. The reaction time can be carried out for 30 minutes to 24 hours and preferably stirred for 30 minutes to 12 hours. The residue obtained by concentrating the reaction solution under reduced pressure can be prepared 1- (3-iodo-propyl) -2-methoxybenzene (IIc '') by silica gel column separation. In this step, the second method is economical and easier and safer to operate, but in the case of a substance substituted with 2-methoxy group (6a), 3-methoxy group (6b) or 4-methoxy group (6c) Since the polarity (R _f value) is almost similar to triphenylphosphine, which is a reagent for use, it is difficult to separate and purify. However, in the case of a substance substituted with 3,4-dimethoxy group (6d), 2,3-dimethoxy group (6e) or 3,4,5-trimethoxy group (6f), it is preferable to use the second method. . In the third step, (+)- decursinol (Ia) of Scheme 1 is dissolved with anhydrous N, N -dimethylformamide , and sodium hydride and 1- (3-halo-propyl) -2-methoxybenzene are dissolved. Put and react. At this time, the solvent is used to perform the reaction using a solvent that does not adversely affect the reaction, N, N- dimethylformamide, dimethyl sulfoxide and the like. The reaction temperature can generally be carried out at -20 ° C to -40 ° C, preferably at -20 ° C. The reaction time can be carried out for 12 to 48 hours, preferably for 24 hours. The reaction solution was concentrated by filtration over a silica gel column, and the concentrated flask was then heated at 90-100 ° C. to remove N, N -dimethylformamide under vacuum. The obtained residue was subjected to (7S) -7- [3- (2-methoxyphenyl) propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2 through silica gel column separation. g ] chromen-2-one (IId) can be prepared.

Scheme (3) shows a four step preparation process for preparing commercial compounds or compounds synthesized by known methods.

For example, in the first step, cinnamic acid derivative (IIIa) is dissolved in a solvent such as methanol, and then a strong acid such as concentrated sulfuric acid is added and heated to reflux. The reaction temperature is carried out at 70 ℃ to 90 ℃, preferably at 80 ℃. The reaction time can be carried out for 12-36 hours, preferably for 24 hours. After cooling the reaction solution to room temperature, the residue obtained by concentrating the silica gel column separation can be prepared through the 3-phenyl- acrylic acid methyl ester (IIIb). In the second step, 3-phenyl-acrylic acid methyl ester (IIIb) was dissolved in an organic solvent such as anhydrous dichloromethane and cooled to -78 ° C in a nitrogen-filled round flask, followed by diisobutylaluminum hydride (DIBAL-H, 1M solution in hexane) is added dropwise over 10 minutes to 2 hours, preferably 20 minutes to 1 hour. The reaction solution is cooled to 0 ° C to 25 ° C, preferably 0 ° C to 10 ° C, stirred for 30 minutes to 5 hours, preferably 30 minutes to 2 hours, and then a solvent such as methanol is added dropwise. The reaction solution is cooled to 0 ° C to 50 ° C, preferably at room temperature, stirred for 10 minutes to 2 hours, preferably 30 minutes to 1 hour, and saturated Rochelle's salt is added. The reaction solution is stirred vigorously for 30 minutes to 5 hours, preferably 1 hour to 3 hours, extracted with an organic solvent such as dichloromethane, dehydrated with anhydrous forget-me-not, and then concentrated in dark and dark. The obtained residue may be produced 3-phenyl-pro-2-phen-1-ol (IIIc) by silica gel column separation. In the third step, a brominating agent such as boron tribromide (1M solution in dichloromethane) is dissolved in an organic solvent such as dichloromethane and reacted with 3-phenyl-pro-2-phen-1-ol (IIIc). At this time, the solvent is used to perform the reaction using an organic solvent such as toluene, benzene, dichloromethane, chloroform, carbon tetrachloride, which does not adversely affect the reaction. The reaction temperature may generally be performed at -20 ° C to 50 ° C, and preferably at 0 ° C to room temperature. The reaction time can be carried out for 30 minutes to 24 hours and preferably stirred for 30 minutes to 12 hours. The reaction solution is poured into a Erlenmeyer flask containing distilled water and stirred for 10 minutes. The reaction mixture was separated with an organic solvent such as saturated sodium hydrogen carbonate and diethyl ether, and the diethyl ether layer was dehydrated with anhydrous manganese and concentrated under reduced pressure. The obtained residue can be produced (3-bromo-propenyl) -benzene (IIId) by silica gel column separation. In the fourth step, (+)-decurinol (Ia) of Scheme 1 was dissolved with anhydrous N, N -dimethylformamide , and sodium hydride and (3-bromo-propenyl) -benzene (IIId) were added thereto. React. The solvent used at this time is carried out using a solvent such as N, N -dimethylformamide, dimethyl sulfoxide, which does not adversely affect the reaction. The reaction temperature can generally be carried out at -20 ° C to -40 ° C, preferably at -20 ° C. The reaction time can be carried out for 12 to 48 hours, preferably for 24 hours . The reaction solution was concentrated by filtration over a silica gel column, and the concentrated flask was then heated at 90-100 ° C. to remove N, N -dimethylformamide under vacuum. The obtained residue was subjected to (7S) -8,8-dimethyl-7- (3-phenyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen via silica gel column separation. 2-one (IIIe) can be prepared.

The composition containing the general formula (I) obtained by the above manufacturing method as an active ingredient, by preventing the secretion inhibitory effect of MCP-1, IL-6, IL-8 induced by ticks, thereby preventing and treating atopic dermatitis diseases It can be usefully used as an effective pharmaceutical composition and health functional food.

Accordingly, the present invention provides a method for preventing and treating atopic dermatitis diseases containing a (+)-decursin-ether derivative compound or a pharmaceutically acceptable salt thereof of the novel structure represented by the above general formula (I) as an active ingredient. To provide a pharmaceutical composition for.

The composition comprising the compound of formula (I) 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, 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, 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 oils such as olive oil, injectable esters 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 improvement for the prevention and treatment of atopic dermatitis disease containing (+)-decursin-ether derivative compound of the novel structure represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Provide dietary supplements for health.

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 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. 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 from 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-ether derivative compounds of the present invention are MCP-1, IL- showing an atopic dermatitis response induced by ticks in THP-1 or 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 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), 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. 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  (7S) -7- Methoxy -8,8-dimethyl-7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (3a)

As shown in the reaction scheme, (+)-decursinol ((+)-decursinol, 1 , 100 mg, 0.41 mmol) was dissolved in anhydrous N, N -dimethylformamide (3 ml) in a round flask at -20 ° C. Cooled. Methane iodide (2a) (37.91 mg, 0.609 mmol) was added to the reaction mixture, and the mixture was stirred at -20 ° C for 24 hours. The reaction mixture was concentrated by filtration through a silica gel column, and the concentrated flask was then heated in 90-100 ° C. to remove N, N -dimethylformamide under vacuum. To obtain the pure product (3a), the concentrate was purified by silica gel column separation to obtain (7S) -7-methoxy-8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- having the following physical properties. g ] chromen-2-one (3a) 61 mg was obtained and used as a sample of an experiment example.

Yield: 28.1%;

Solid;

m.p 94 ° C .;

R _f = 0.45 ( n- hexane: ethyl acetate = 1: 1);

₁ H NMR (CDCl ₃ ): δ ppm δ 7.574 (d, J = 9.6 Hz, 1 H), 7.167 (s, 1 H), 6.759 (s, 1 H), 6.207 (d, J = 9.6 Hz, 1 H), 3.447 (s, 3H), 3.372 (dd, J = 5.2, 7.2 Hz, 1H), 3.072 (dd, J = 4.8, 16.4 Hz, 1H), 2.827 (dd, J = 7.2, 16.8 Hz, 1H), 1.388 ( s, 3H), 1.330 (s, 3H);

MS ( m / z ): 261 (M + H) ⁺ ;

+97.2(c=1, CHCl₃)

+97.2 (c = 1, CHCl ₃ )

Example  2. (7S) -8,8-dimethyl-7- (3- methyl Part-2- Tenyloxy ) -7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (3b)

The same procedure as in Example 1 was carried out except that the round flask of Example 1 was replaced with 3,3-dimethyl aryl bromide (2b) instead of methane iodide (2a) to have (7S) -8. 23.0 mg of 8-dimethyl-7- (3-methyl-but-2-tenyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (3b) Obtained and used as a sample of an experiment example.

Yield: 18.0%;

Solid;

m.p 73 ° C .;

R _f = 0.59 ( n- hexane: ethyl acetate = 1: 1);

₁ H NMR (CDCl ₃ ): δ ppm 7.571 (d, J = 9.6 Hz, 1H), 7.156 (s, 1H), 6.753 (s, 1H), 6.205 (d, J = 9.6 Hz, 1H), 5.331 ( t, J = 7.0 Hz, 1H), 4.157 (dd, J = 6.8, 12.0 Hz, 1H), 4.036 (dd, J = 7.2, 11.6 Hz, 1H), 3.490 (dd, J = 5.2, 7.6 Hz, 1H ), 3.048 (dd, J = 4.8, 16.4 Hz, 1H), 2.812 (dd, J = 7.6, 17.2 Hz, 1H), 1.750 (s, 3H), 1.673 (s, 3H), 1.403 (s, 3H) , 1.309 (s, 3 H);

MS ( m / z ): 315 (M + H) ⁺ ;

+113.9(c=1, CHCl₃)

+113.9 (c = 1, CHCl ₃ )

Example  3. (7S) -8,8-Dimethyl-7- (2- methyl - Allyloxy ) -7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (3c)

The same procedure as in Example 1 was carried out except that the round flask of Example 1 was changed to 3-bromo-2-methylpropene (2c) instead of methane iodide (2a) to have the following physical properties (7S 72 mg of 8,8-dimethyl-7- (2-methyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (3c) was obtained. It used as the sample of an experiment example.

Yield: 59.0%;

Solid;

m.p 81 ° C .;

R _f = 0.55 ( n- hexane: ethyl acetate = 1: 1);

₁ H NMR (CDCl ₃ ): δ ppm 7.577 (d, J = 9.6 Hz, 1H), 7.158 (s, 1H), 6.760 (s, 1H), 6.212 (d, J = 9.6 Hz, 1H), 4.938 ( d, J = 26.0 Hz, 2H), 4.058 (d, J = 12.0 Hz, 1H), 3.941 (d, J = 12.0 Hz, 1H), 3.521 (dd, J = 4.8, 7.6 Hz, 1H), 3.058 ( dd, J = 5.2, 16.4 Hz, 1H), 2.817 (dd, J = 7.6, 16.4 Hz, 1H), 1.758 (s, 3H), 1.420 (s, 3H), 1.331 (s, 3H);

MS ( m / z ): 301 (M + H) ⁺ ;

+121.9(c=1, CHCl₃)

+121.9 (c = 1, CHCl ₃ )

Example  4. (7S) -8,8-Dimethyl-7- (3- Phenyl - Propoxy ) -7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (3d)

The same procedure as in Example 1 was carried out except that the round flask of Example 1 was changed to 1-bromo-3-phenylpropane (2d) instead of methane iodide (2a) (7S). 48 mg of -8,8-dimethyl-7- (3-phenyl-propoxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (3d) was obtained to give an experiment. Used as an example sample.

Yield: 32.7%;

Oil phase;

R _f = 0.59 ( n- hexane: ethyl acetate = 1: 1);

₁ H NMR (CDCl ₃ ): δ ppm 7.577 (d, J = 9.2 Hz, 1H), 7.290-7.145 (m, 6H), 6.768 (s, 1H), 6.215 (d, J = 9.2 Hz, 1H), 3.655 (m, 1H), 3.433 (m, 2H), 3.033 (dd, J = 4.8, 16.4 Hz, 1H), 2.788 (dd, J = 7.2, 16.4 Hz, 1H), 2.685 (t, J = 6.4 Hz , 2H), 1.903 (q, J = 7.0 Hz, 2H), 1.445 (s, 3H), 1.371 (s, 3H);

MS ( m / z ): 365 (M + H) ⁺ ;

+33.9(c=0.5, CHCl₃)

+33.9 (c = 0.5, CHCl ₃ )

No. matter Compound Molecular Weight structure One 3a (7S) -7-Methoxy-8,8-dimethyl-7,8-dihydro- 6H- pyrano [3,2- g ] chromen-2-one 260.26

2 3b (7S) -8,8-Dimethyl-7- (3-methyl-but-2-enyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one 314.38

3 3c (7S) -8,8-Dimethyl-7- (2-methyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one 300.14

4 3d (7S) -8,8-Dimethyl-7- (3-phenyl-propoxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one 364.43

Example  5. (7 SR ) -7- [3- (2- Methoxy - Phenyl )- Propoxy ] -8,8-dimethyl-7,8- Dehydro - 6H -Pyrano [ 3,2- g ] Chrome Preparation of 2-one (7a)

Step 1.

The method shown in the scheme was synthesized in two different ways.

In the first method (Step 1-1), 2-methoxycinnamic acid (700 mg, 3.93 mmol) was dissolved in anhydrous tetrahydrofuran in a round flask, and lithium aluminum hydride (223 mg, 5.89 mmol) was added and stirred at room temperature for 6 hours. It was. Distilled water (50 ml) was slowly added to the reaction solution, followed by stirring until no heat was generated. 3N HCl was added to the reaction mixture to pH 2 and extracted with dichloromethane. The filtrate was concentrated under reduced pressure by dehydration with anhydrous forget-me-not. The concentrate was purified by silica gel column separation to obtain 200 mg of pure product 3- (2-methoxy) -propan-1-ol (5a), which was applied to the next step.

In the second method (Step 1-2), 3- (2-methoxy) propionic acid (500 mg, 2.77 mmol) was dissolved in anhydrous tetrahydrofuran in a round flask, and lithium aluminum hydride (157 mg, 4.16 mg) was added at room temperature. Stir for 6 hours. Distilled water (50 ml) was slowly added to the reaction solution, followed by stirring until no heat was generated. 3N HCl was added to the reaction mixture to pH 2 and extracted with dichloromethane. The filtrate was concentrated under reduced pressure by dehydration with anhydrous forget-me-not. The concentrate was subjected to silica gel column separation to obtain 466 mg of pure product 3- (2-methoxy) -propan-1-ol (5a), which was applied to the next step.

Step 2.

As shown in the reaction scheme, 3- (2-methoxyphenyl) -propan-1-ol (5a, 461mg, 2.77mmol) was added to a round flask and dissolved in anhydrous dichloromethane, followed by boron tribromide (water evaporation). 1M solution in dichloromethane), (104.6 μl, 1.11 mmol) was added and stirred for 2 hours. After the reaction solution was concentrated under reduced pressure, 180 mg of pure product 1- (3-bromo-propyl) -2-methoxy-benzene (6a) was obtained through silica gel column separation, which was applied to the next step.

Step 3.

The same procedure as in Example 1 was carried out except that the round flask of Example 1 was changed to 1- (3-bromo-propyl) -2-methoxy-benzene (6a) instead of methane iodide (2a). (7S) -7- [3- (2-methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g with the following physical properties ] 13.0 mg of chroman-2-one (7a) was obtained and used as a sample of an experiment example.

Yield: 8.1%;

Oil phase;

R _f = 0.56 ( n- hexane: ethyl acetate = 1: 1);

₁ H NMR (CDCl ₃ ): δ ppm 7.576 (d, J = 9.2 Hz, 1H), 7.198-7.148 (m, 2H), 7.084 (d, J = 7.2 Hz, 1H), 6.905-6.832 (m, 2H ), 6.765 (s, 1H), 6.212 (d, J = 9.6 Hz, 1H), 3.811 (s, 3H), 3.665 (m, 1H), 3.463 (m, 2H), 3.045 (dd, J = 4.8, 16.4 Hz, 1H), 2.796 (dd, J = 7.6, 16.4 Hz, 1H), 2.672 (t, J = 7.6 Hz, 2H), 1.867 (q, J = 7.0 Hz, 2H), 1.419 (s, 3H) , 1.334 (s, 3 H);

MS ( m / z ): 395 (M + H) ⁺ ;

+77.2(c=1, CHCl₃)

+77.2 (c = 1, CHCl ₃ )

Example  6. (7S) -7- [3- (3- Methoxy - Phenyl )- Propoxy ] -8,8-dimethyl-7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (7b)

In the first step of Example 5, 3-methoxycinnamic acid instead of 2-methoxycinnamic acid in the round flask of the first method, 3- (3 instead of 3- (2-methoxy) propionic acid in the round flask of the second method (7S) -7- [3- (3-methoxy-phenyl) -propoxy] -8 having the following physical properties by the same process as the reaction of Example 5 except for changing to -methoxy) propionic acid; 8.1 mg of 8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (7b) was obtained and used as a sample for the experimental example.

Yield: 5.1%;

Oil phase;

R _f = 0.59 ( n- hexane: ethyl acetate = 1: 1);

₁ H NMR (CDCl ₃ ): δ ppm 7.570 (d, J = 9.6 Hz, 1H), 7.187 (t, J = 7.6 Hz, 1H), 7.140 (s, 1H), 6.763-7.714 (m, 4H), 6.210 (d, J = 9.6 Hz, 1H), 3.799 (s, 3H), 3.662 (m, 1H), 3.442 (m, 2H), 3.033 (dd, J = 5.2, 17.2 Hz, 1H), 2.785 (dd , J = 7.2, 16.0 Hz, 1H), 2.659 (t, J = 6.0 Hz, 2H), 1.897 (q, J = 6.9 Hz, 2H), 1.409 (s, 3H), 1.333 (s, 3H);

MS ( m / z ): 395 (M + H) ⁺ ;

+24.9(c=0.3, CHCl₃)

+24.9 (c = 0.3, CHCl ₃ )

Example  7. (7S) -7- [3- (4- Methoxy - Phenyl )- Propoxy ] -8,8-dimethyl-7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (7c)

In the first step of Example 5, 4-methoxycinnamic acid instead of 2-methoxycinnamic acid in the round flask of the first method, 3- (4 instead of 3- (2-methoxy) propionic acid in the round flask of the second method (7S) -7- [3- (4-methoxy-phenyl) -propoxy] -8 having the following physical properties by the same process as the reaction of Example 5 except for changing to -methoxy) propionic acid; 7.8 mg of 8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (7c) was obtained and used as a sample for the experimental example.

Yield: 4.9%;

Oil phase;

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

₁ H NMR (CDCl ₃ ): δ ppm 7.574 (d, J = 9.6 Hz, 1 H), 7.143 (s, 1 H), 7.064 (d, J = 8.8 Hz, 2H), 6.812 (d, J = 8.8 Hz, 2H), 6.763 (s, 1H), 6.210 (d, J = 9.6 Hz, 1H), 3.648 (m, 1H), 3.427 (m, 2H), 3.030 (dd, J = 4.8, 16.8 Hz, 1H), 2.785 (dd, J = 7.6, 16.4 Hz, 1H), 2.623 (t, J = 6.4 Hz, 2H), 1.864 (q, J = 6.9 Hz, 2H), 1.407 (s, 3H), 1.335 (s, 3H );

MS ( m / z ): 395 (M + H) ⁺ ;

+79.2(c=1, CHCl₃)

+79.2 (c = 1, CHCl ₃ )

Example  8. (7S) -7- [3- (3,4- Dimethoxy - Phenyl )- Propoxy ] -8,8-dimethyl-7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (7d)

Step 1.

3,4-dimethoxycinnamic acid instead of 2-methoxycinnamic acid in the round flask of the first method in the first step of Example 5, 3 instead of 3- (2-methoxy) propionic acid in the round flask of the second method A pure product 3- (3,4-dimethoxy-)-propan-1-ol was subjected to the same process as in the first step reaction of Example 5 except that it was changed to-(3,4-dimethoxy) propionic acid. 5d) 236 mg were obtained and subjected to the next step.

Step 2.

As shown in the above scheme, triphenylphosphine (721 mg, 2.75 mmol), iodine (232 mg, 1.83 mmol), and imidazole (187 mg, 2.75 mmol) were dissolved in toluene in a round flask, followed by 3- (3,4-dimethol). Toxy) -propan-1-ol (5d) (180mg, 0.92mmol) was added thereto and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and 234 mg of pure product 1- (3-iodo-propyl) -3,4-dimethoxy-benzene (6d) was obtained through silica gel column separation, which was applied to the next step.

Step 3.

The same process as in Example 1 except that the round flask of Example 1 was replaced with 1- (3-iodo-propyl) -3,4-dimethoxy-benzene (6d) instead of methane iodide (2a). (7S) -7- [3- (3,4-dimethoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3] having the following physical properties , 2- g ] chromen-2-one (7d) 38 mg was obtained and used as a sample of an experiment example.

Yield: 22.0%;

Oil phase;

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

₁ H NMR (CDCl ₃ ): δ ppm 7.566 (d, J = 9.2 Hz, 1H), 7.138 (s, 1H), 6.788-6.760 (m, 2H), 6.694-6.681 (m, 2H), 6.205 (d , J = 9.2 Hz, 1H), 3.854 (s, 6H), 3.660 (m, 1H), 3.446 (m, 2H), 3.037 (dd, J = 4.8, 16.4 Hz, 1H), 2.788 (dd, J = 7.6, 16.8 Hz, 1H), 2.630 (dd, J = 4.8, 7.6 Hz, 2H), 1.883 (q, J = 6.9, 2H), 1.413 (s, 3H), 1.339 (s, 3H);

MS ( m / z ): 425 (M + H) ⁺ ;

+131.2(c=2, CHCl₃)

+131.2 (c = 2, CHCl ₃ )

Example  9. (7S) -7- [3- (2,3- Dimethoxy - Phenyl )- Propoxy ] -8,8-dimethyl-7,8- Dehydro - 6H -blood Llan [3,2- g ] Cro Preparation of Men-2-one (7e)

In the first step of Example 8, 2,3-dimethoxycinnamic acid instead of 3,4-dimethoxycinnamic acid in the round flask of the first method, 3- (3,4-dimethic acid in the round flask of the second method Except for changing to 3- (2,3-dimethoxy) propionic acid instead of oxy) propionic acid, the same process as in the first, second and third steps of Example 8 was carried out to give (7S) -7- [ 3- (2,3-dimethoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (7e) 9.5 mg was obtained and used as a sample of an experiment example.

Yield: 3.4%;

Oil phase;

R _f = 0.50 ( n- hexane: ethyl acetate = 1: 1);

₁ H NMR (CDCl ₃ ): δ ppm 7.571 (d, J = 9.6 Hz, 1H), 7.143 (s, 1H), 6.962 (t, J = 7.6 Hz, 1H), 6.785-6.725 (m, 3H), 6.207 (d, J = 9.6 Hz, 1H), 3.856 (s, 3H), 3.801 (s, 3H), 3.670 (m, 1H), 3.463 (m, 2H), 3.043 (dd, J = 4.8, 16.4 Hz , 1H), 2.796 (dd, J = 7.2, 16.0 Hz, 1H), 2.690 (t, J = 7.2 Hz, 2H), 1.873 (q, J = 6.9 Hz, 2H), 1.412 (s, 3H), 1.331 (s, 3H);

MS ( m / z ): 425 (M + H) ⁺ ;

+34.6(c=0.5, CHCl₃)

+34.6 (c = 0.5, CHCl ₃ )

Example  10. (7S) -8,8-Dimethyl-7- [3- (3,4,5- Trimethoxy - Phenyl )- Propoxy ] -7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (7f)

3,4,5-trimethoxycinnamic acid instead of 3,4-dimethoxycinnamic acid in the round flask of the first method in the first step of Example 8, 3- (3,4 in the round flask of the second method Except for changing to 3- (3,4,5-trimethoxy) propionic acid instead of dimethoxy) propionic acid, the same process as in the first, second and third steps of Example 8 was carried out to obtain (7S) ) -8,8-dimethyl-7- [3- (3,4,5-trimethoxy-phenyl) -propoxy] -7,8-dihydro- 6H -pyrano [3,2- g ] chrome 13.6 mg of men-2-one (7f) was obtained and used as a sample in an experimental example.

Yield: 6.9%;

Oil phase;

R _f = 0.33 ( n- hexane: ethyl acetate = 1: 1);

₁ H NMR (CDCl ₃ ): δ ppm 7.568 (d, J = 9.6 Hz, 1H), 7.141 (s, 1H), 6.764 (s, 1H), 6.383 (s, 2H), 6.211 (d, J = 9.6 Hz, 1H), 3.836 (s, 6H), 3.823 (s, 3H), 3.682 (m, 1H), 3.458 (m, 2H), 3.505 (dd, J = 5.2, 16.4 Hz, 1H), 2.794 (dd , J = 7.6, 16.8 Hz, 1H), 2.628 (td, J = 3.2, 7.2 Hz, 2H), 1.899 (q, J = 6.9 Hz, 2H), 1.417 (s, 3H), 1.343 (s, 3H) ;

MS ( m / z ): 455 (M + H) ⁺ ;

+165.2(c=3, CHCl₃)

+165.2 (c = 3, CHCl ₃ )

No . matter Compound Molecular Weight structure 5 7a (7S) -7- [3- (2-Methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H- pyrano [3,2- g ] chromen-2-one 394.46

6 7b (7S) -7- [3- (3-Methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H- pyrano [3,2- g ] chromen-2-one 394.46

7 7c (7S) -7- [3- (4-Methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H- pyrano [3,2- g ] chromen-2-one 394.46

8 7d (7S) -7- [3- (3,4-Dimethoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H- pyrano [3,2- g ] chromen-2-one 424.19

9 7e (7S) -7- [3- (2,3-Dimethoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H- pyrano [3,2- g ] chromen-2-one 424.19

10 7f (7S) -8,8-Dimethyl-7- [3- (3,4,5-trimethoxy-phenyl) -propoxy] -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2- one 454.20

Example  11. (7S) -8,8-Dimethyl-7- (3- Phenyl - Allyloxy ) -7,8- Dehydro - 6H - Pyrano [3,2- g ] in Preparation of Men-2-one 12a

Step 1.

      As shown in the reaction scheme, cinnamic acid (8a) (5 g, 33.7 mmol) was dissolved in methanol (50 ml) in a round flask, and 5 drops of concentrated sulfuric acid was added thereto and refluxed at 80 ° C. for 24 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The concentrate was purified by silica gel column separation to obtain 5.39 g of pure product 3-phenyl-acrylic acid methyl ester (9a), which was then applied to the next step.

Step 2.

      As shown in the reaction scheme, 3-phenyl-acrylic acid methyl ester (9a) (4 g, 24.7 mmol) was added to a round flask filled with nitrogen gas, and then dissolved in anhydrous dichloromethane, and cooled to -78 ° C. Diisobutylaluminum hydride (DIBAL-H, 1M solution in hexane) (74 ml, 74.0 mmol) was added dropwise to the reaction solution over 30 minutes, and the reaction solution was cooled to 0 ° C., stirred for 1 hour, and then methanol ( 22 ml) was added dropwise. The reaction solution was cooled to room temperature, stirred for 30 minutes, and saturated Rochelle's salt (88 ml) was added. The reaction mixture was stirred vigorously at room temperature for 2 hours, extracted with dichloromethane, dehydrated with anhydrous forget-me-not, and concentrated in gamyeo. The concentrate was subjected to silica gel column separation to obtain 4.0 g of pure product 3-phenyl-pro-2-phen-1-ol (10a), which was applied to the next step.

Step 3.

      As shown in the above reaction scheme, 3-phenyl-pro-2-phen-1-ol (10a) (1 g, 7.45 mmol) was added to a round flask and dissolved in anhydrous dichloromethane, and boron tribromide (1M) was used for water deposition. Solution in dichloromethane), (253.6 μl, 2.61 mmol) was added and stirred for 1 hour. The reaction solution was poured into a Erlenmeyer flask containing distilled water (50 ml) and stirred for 10 minutes. The reaction mixture was separated with saturated sodium hydrogen carbonate and diethyl ether, and the diethyl ether layer was dehydrated with anhydrous manganese and concentrated under reduced pressure. Silicagel column separation gave 933 mg of pure product (3-bromo-propenyl) -benzene (11a), which was applied to the next step.

Step 4.

The same procedure as in Example 1 was carried out except that the round flask of Example 1 was changed to (3-bromo-propenyl) -benzene (11a) instead of methane iodide (2a) to have the following physical properties ( 48 mg of 7S) -8,8-dimethyl-7- (3-phenyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (12a) Obtained and used as a sample of an experiment example.

Yield: 32.7%;

Solid;

m.p 143 ° C .;

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

₁ H NMR (CDCl ₃ ): δ ppm 7.564 (d, J = 9.6 Hz, 1H), 7.382-7.231 (m, 5H), 7.157 (s, 1H), 6.763 (s, 1H), 6.590 (d, J = 16.0 Hz, 1H), 6.308-6.237 (m, 1H), 6.202 (d, J = 9.6 Hz, 1H), 4.341 (dd, J = 6.0, 12.8 Hz, 1H), 4.215 (dd, J = 6.0, 12.4 Hz, 1H), 3.590 (dd, J = 5.2, 7.6 Hz, 1H), 3.076 (dd, J = 4.8, 16.0 Hz, 1H), 2.857 (dd, J = 7.2, 16.4 Hz, 1H), 1.417 ( s 3H), 1.360 (s, 3H);

MS ( m / z ): 363 (M + H) ⁺ ;

+117.6(c=1, CHCl₃)

+117.6 (c = 1, CHCl ₃ )

Example  12. (7S) -7- [3- (4- Methoxy - Phenyl )- Allyloxy ] -8,8-dimethyl-7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (12b)

The same process as in the first, second, third, and fourth steps of Example 11 was repeated except that the round flask was changed to 4-methoxy cinnamic acid (8b) instead of cinnamic acid (8a) in the first step of Example 11. (7S) -7- [3- (4-methoxy-phenyl) -allyloxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- having the following physical properties g ] 4 mg of chroman-2-one (12b) was obtained and used as a sample of an experiment example.

Yield: 30.2%;

Oil phase;

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

₁ H NMR (CDCl ₃ ): δ ppm 7.568 (d, J = 9.6 Hz, 1H), 7.312 (d, J = 8.8 Hz, 2H), 7.155 (s, 1H), 6.857 (d, J = 8.8 Hz, 2H), 6.767 (s, 1H), 6.530 (d, J = 16.4 Hz, 1H), 6.211 (d, J = 9.6 Hz, 1H), 6.153 (m, 1H), 4.315 (dd, J = 6.4, 12.8 Hz, 1H), 4.196 (dd, J = 6.4, 12.8 Hz, 1H), 3.812 (s, 3H), 3.583 (dd, J = 4.8, 7.2 Hz, 1H), 3.074 (dd, J = 4.8, 7.2 Hz , 1H), 2.846 (dd, J = 7.6, 16.8 Hz, 1H), 1.415 (s, 3H), 1.349 (s, 3H);

MS ( m / z ): 393 (M + H) ⁺ ;

+7.9(c=0.1, CHCl₃)

+7.9 (c = 0.1, CHCl ₃ )

No. matter Compound Molecular Weight structure 11 12a (7S) -8,8-Dimethyl-7- (3-phenyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one 362.42

12 12b (7S) -7- [3- (4-Methoxy-phenyl) -allyloxy] -8,8-dimethyl-7,8-dihydro- 6H- pyrano [3,2- g ] chromen-2-one 392.44

Experimental Example  One. THP From -1 mite Induced by MCP -One/ IL -6 / IL - At eight minutes  Mick (+)- Decursin Measuring the effect of ether derivatives

In order to measure the ELISA of the decursine-ether derivatives synthesized in the above example using human acute monocytic leukemia cell line (hereinafter referred to as THP-1) purchased from the American Cell Line Bank, experiments were performed as follows. Was performed.

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 derivative (10 ㎍ / mL) for 1 hour followed by HDE (1 ㎍ / mL) for 24 hours, respectively, followed by monocyte chemoattractant protein-1 (monocyte) in supernatant using ELISA. The amount of chemoattractant protein-1, MCP-1), IL-6, IL-8 was measured, and the experimental results are shown in Table 1 below.

matter MCP Amount of -1 ( pg Of ml ) IL - 6 of  Sheep ( pg Of ml ) IL - 8 of  Sheep ( pg Of ml ) 3a 87.4 313.3 2732.17 3b 39.1 172.3 2458.26 3c 56.8 235.3 2684.34 3d 45.0 147.3 2362.60 7a 45.0 116.3 2571.30 7b 36.8 138.3 2780.00 7c 87.4 289.3 2888.69 7d 36.8 169.3 2419.1 7e 52.1 118.3 2649.5 7f 39.1 182.3 2553.9 12a ND 198.0 2193.0 12b 87.4 289.3 2888.6 Normal 33.2 23.3 40.8 Control 93.8 525.3 2697.0 Dexamethasone 36.2 25.3 66.9

The results showed that the levels of MCP-1, IL-6 and IL-8 in the normal group of THP-1 cells were 33.2, 23.3 and 40.8 pg / ml. The amount of -8 was found to increase to 93.8, 525.3 and 2697.0 pg / ml (Table 1). Treatment of dexamethasone, a positive control, in the increased state by ticks, reduced the amount of MCP-1, IL-6 and IL-8 to 36.2, 25.3 and 66.9 pg / ml, almost equivalent to that of the normal group. .

Meanwhile, substances 3b, 7b, 7d and 7f of the synthesized (+)-decurin-ether derivatives reduced the amount of MCP-1 increased by ticks to almost the same level as the dexamethasone treated group. In addition, substances 7a, 7b and 7e significantly reduced the amount of IL-6. The synthesized (+)-decurin-ether derivatives were found to have no significant effect on the amount of IL-8 as a whole.

Taken together, the (+)-decurin-ether derivatives synthesized against THP-1 cells generally reduced the amount of MCP-1 and IL-6 increased by ticks, in particular 3b, 7b, 7d and 7f substances reduced the amount of MCP-1 increased by ticks to nearly the same level as dexamethasone, a drug used in existing atopic diseases.

Experimental Example  2. EoL From -1 mite Induced by MCP -One/ IL -6 / IL - At eight minutes  Mick (+)- Decursin Measuring the effect of ether derivatives

Experiments were carried out as follows to measure the ELISA of the decursin-ether derivatives synthesized in the above example using human eosinophil EoL-1 (eosinophilic leukemia cell) cells purchased from Bank of Japan.

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, the (+)-decurin-ether derivative (10 μg / ml) was treated for 1 hour, and HDE (1 μg / ml) was treated for 24 hours, respectively, and then monocyte chemoattractant was induced in the supernatant using ELISA. The amount of substance protein-1 (monocyte chemoattractant protein-1, MCP-1), IL-6, IL-8 was measured, and the experimental results are shown in Table 2 below.

matter MCP Amount of -1 ( pg Of ml ) IL Volume of -6 ( pg Of ml ) IL - 8 of  Sheep ( pg Of ml ) 3a 213.0 109.8 1143.5 3b 54.5 23.5 273.5 3c 43.0 73.5 863.5 3d 45.3 72.5 878.5 7a 68.3 66.7 1273.5 7b 62.3 74.6 1048.5 7c 65.3 87.2 943.5 7d 49.9 139.9 603.5 7e 83.7 113.0 1128.5 7f 43.7 112.5 628.5 12a ND 184.0 937.2 12b 133.7 102.5 1113.5 Normal 43.7 26.2 183.5 Control 236.8 218.8 818.5 Dexamethasone 43.7 18.84 158.5

Experimental results showed that the amount of MCP-1, IL-6 and IL-8 in the normal group of EoL-1 cells was 43.7, 26.2 and 183.5 pg / ml, whereas MCP-1, IL-6 and It was confirmed that the amount of IL-8 was increased to 236.8, 218.8 and 818.5 pg / ml (Table 2). Treatment of dexamethasone, a positive control, in the increased state by ticks, reduced the amount of MCP-1, IL-6, and IL-8 to 43.7, 18.8, and 158.5 pg / ml, almost equivalent to those of the normal group. .

Meanwhile, 3b, 3c, 3d, 7d and 7f substances in the synthesized (+)-decursin-ether derivatives reduced the amount of MCP-1 increased by ticks to almost the same level as the dexamethasone treated group. In addition, substance 3b reduced the amount of IL-6 and IL-8 increased by ticks to approximately the same level as the dexamethasone treated group.

Taken together, (+)-decurin-ether derivatives synthesized against EoL-1 cells generally reduced the amount of MCP-1, IL-6 and IL-8 increased by ticks, especially 3b, The 3c, 3d, 7d and 7f substances reduced the amount of MCP-1 or IL-6 increased by ticks to nearly the same level as dexamethasone, a drug used in existing atopic diseases.

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  One. Powder  Produce

(+)-Decursin-ether derivative (3b) 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 Tablets

(+)-Decurin-ether derivative (3c) 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. Manufacture of capsule

(+)-Decursin-ether derivative (7a) 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

(+)-Decursin-ether derivatives (7b) 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. Liquid  Produce

(+)-Decurin-ether derivative (12a) 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. Manufacture of healthy food

(+)-Decursin-ether derivative (12b) 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 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. Manufacture of health drinks

(+)-Decurin-ether derivative (3a) 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.

Claims (7)

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

(I) In the above formula, R ₁ is a C ₁ to C ₂₀ alkyl group unsubstituted or substituted with one or more R ′, C ₂ to C ₂₀ Alkenyl groups, C ₂ to C ₂₀ At least one substituent selected from the group consisting of an alkynyl group and an A substituent, 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

Where R '' is one or more substituents optionally substituted at o, m, p positions, hydrogen atom, hydroxy group, acetate group, halogen atom, C ₁ to C ₄ lower alkyl group, C ₁ to C ₄ lower alkoxy One or more substituents selected from the group consisting of C ₁ to C ₄ lower alkyl esters and 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 halogen atom or a C ₁ to C ₁₀ alkyl group unsubstituted or substituted with a C ₁ to C ₄ lower alkyl group, C ₂ to C ₁₀ Alkenyl groups, C ₂ to C ₁₀ Alkynyl is a substituent selected from the group and the group A consisting of the substituents, where the A substituent of R '' is o, m, p of the hydrogen atoms substituted at the position, a hydroxy group, an amine group, a halogen atom, a methyl group, an ethyl group, a methoxy group, At least one substituent selected from an ethoxy group, a nitro 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 substituted with one or more substituents selected from hydrogen, hydroxy, methyl, ethyl, methoxy, ethoxy or acetyl groups 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. The compound of formula (I) according to claim 3, wherein the compound of formula (I) is (7S) -7-methoxy-8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen- 2-one (3a), (7S) -8,8-dimethyl-7- (3-methyl-but-2-tenyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] Chromen-2-one (3b), (7S) -8,8-dimethyl-7- (2-methyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chrome Men-2-one (3c), (7S) -8,8-dimethyl-7- (3-phenyl-propoxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen 2-one (3d), (7S) -7- [3- (2-methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3, 2- g ] chromen-2-one (7a), (7S) -7- [3- (3-methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -Pyrano [3,2- g ] chromen-2-one (7b), (7S) -7- [3- (4-methoxy-phenyl) -propoxy] -8,8-dimethyl-7, 8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (7c), (7S) -7- [3- (3,4-dimethoxy-phenyl) -propoxy]- 8,8- dimethyl-7,8-dihydro - 6H - pyrano [3,2- g] chromen-2-one (7d), (7S) -7- [3- (2,3- di -Phenyl) -propoxy] -8,8- dimethyl-7,8-dihydro-6H-pyrano [3,2- g] chromen-2-one (7e), (7S) -8,8 -Dimethyl-7- [3- (3,4,5-trimethoxyphenyl) -propoxy)]-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (7f), (7S) -8,8-dimethyl-7- (3-phenyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one ( 12a) or (7S) -7- [3- (4-methoxy-phenyl) -allyloxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chrome Men-2-one (12b) or a pharmaceutically acceptable salt thereof. Pharmaceutical for the prevention and treatment of atopic dermatitis disease containing (+)-decursin-ether derivative compound of the novel structure represented by the general formula (I) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient Composition. Health for the prevention and improvement of atopic dermatitis disease containing (+)-decursin-ether derivative compound or a pharmaceutically acceptable salt thereof having a novel structure represented by the general formula (I) of claim 1 as an active ingredient Nutraceutical. The dietary supplement according to claim 6 in the form of a powder, granule, tablet, capsule or beverage.