KR20090037185A - Composition comprising (-)-decursin derivative showing treating and preventing atopic dermatitis disease - Google Patents

Abstract

A composition comprising a (-)-decursin derivative for treating and preventing atopic dermatitis diseases is provided to synthesize the (-)-decursin derivative by using a (-)-decursin as a precursor and to suppress MCP-1, IL-6 and IL-8 effectively. A composition for treating and preventing atopic dermatitis diseases comprises a (-)-decursin derivative and a pharmaceutically acceptable salts thereof. The (-)-decursin derivative compound is synthesized by using a (-)-decursin as a precursor and is represented by the formula (I). In the formula (I), R1 is at least one C1-C20 alkyl group, alkenyl group, alkynyl group or substituent of the formula (A); R' is a halogen atom, nitro group, amine group or C1-C4 low alkyl group. In the chemical formula (A), A is a substituent capable of being substituted at the position of o, m and p; A' is at least one substituent selected from the group consisting of hydrogen atom, -OH, nitro group, amine group, acetate, halogen atom, C1-C4 low alkyl group, lower alkoxy group, lower alkyl ester and lower alkyl carboxy group; and n is an integer of 0-4.

Description

Composition comprising (-)-decursin derivative showing treating and preventing atopic dermatitis disease}

The present invention provides a (-)-decursin derivative synthesized using a precursor of (-)-decursinol, which is a stereoisomer of (+)-decursinol, isolated from the Angelica gigas It relates to a composition containing 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 , pp 306-311, 1998; Kurashima K et al., Increase of chemokine levels in sputum precedes exacerbation of acute asthma attacks. J. Leukoc . Biol ., 59 , pp313-316, 1996

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

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

[13] 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.

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

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

Steroids are the most widely used and effective treatments for inflammatory diseases such as bronchial asthma. Recently, many mechanisms for steroids have been elucidated, but the mechanisms have not yet been fully understood, and some patients with bronchial asthma or rheumatoid arthritis show steroid resistance that does not respond to steroids. Although there are not many patients showing 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 monocyt e chemoattractant protein 1-deficient mice. J. Exp . Med ., 187 , pp601-608, 1998). This phenomenon was similar to the symptoms observed in animals with the CCR2 gene removed. In addition, MCP-1 has been reported to convert helper T progenitor cells (Th0 cells) into cells that secrete helper T cell cytokines (Karpus WJ et al., MIP-1 alpha and MCP-1) in vitro. differentially regulate acute and relapsing autoimmune encephalomy elitis asell as Th1 / Th2 lymphocyte differentiation. J. Leukoc. Biol., 62, pp681-687, 1997). Intravenous injection of MCP-1 decreased IL-12 production and increased IL-4 production. This indirectly means that IgE-dependent allergic inflammation can be exacerbated.

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

 (+)-Decursin (decursin) is a substance that has been attracting attention 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 confirmed the excellent atopic inhibitory effect and confirmed the possibility of use as a therapeutic agent for atopic dermatitis (10-2007-18057, treatment and prevention of atopic dermatitis disease including decursin derivatives). Composition).

Based on these results, the present inventors synthesized (-)-decursin derivatives, which are enantiomeric stereoisomers of (+)-decursin, and measured their anti-atopic effects. The present invention was completed by confirming.

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

(I)

(I)

In the above formula,

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

A substituent

Wherein A ′ is a substituent which may be optionally substituted at o, m, and p positions, and is a hydrogen atom, a hydroxyl group, an acetate group, a halogen atom, a C ₁ to C ₄ lower alkyl group, a lower alkoxy group and a lower alkyl ester and a lower alkyl At least one substituent selected from the group consisting of carboxy groups;

n is an integer of 0-4.

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

( 3R ) -3-Methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3 -Yl-ester, ( 3R ) -cis-2-methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2 -g] chromen-3-yl-ester, ( 3R ) -2-methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g] chromen-3-yl-ester, ( 3R ) -acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen- 3-yl-ester, ( 3R ) -3-phenyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3 -Yl-ester, ( 3R ) -3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g] chromen-3-yl-ester, ( 3R ) -3- (2-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -P Lano [3,2-g] chromen-3-yl-ester, ( 3R ) -3- (2-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro - 2H, 8H - Pyrano [3,2- g] chromene-3-yl-ester, (3 R) -3- (3- methoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- -2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -3- (3-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo- 3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -3- (3-acetoxy-phenyl) -acrylic acid 2,2- Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -3- (4-methoxy-phenyl) -Acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -3- (4 -Hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -3- (4-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl Ester, ( 3R ) -3- (3,4-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g] Chromene-3-yl-ester, (3 R) -3- (3,4,5- trimethoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H, 8H -Pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -3- (3,4,5-trihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo -3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester, ( 3R ) -3- (3,4-diacetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -3- (3,4 -Dihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, (3 R ) -benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester, ( 3R ) -3 , 4,5-trihydroxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester, ( 3R ) -3,4,5-Triacetoxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen- 3 days- Requesters.

(II)

In the above formula,

R ₂ is a C ₁ to C ₂₀ alkyl group, an alkenyl group, an alkynyl group, an A substituent or a B substituent which is unsubstituted or substituted with one or more R ′, wherein R ′ is a halogen atom, a nitro group, an amine group or C ₁ to C ₄ lower alkyl group;

A substituent

 ,

B substituent

Wherein A ′ or B ′ is a substituent which may be optionally substituted at o, m, and p positions, and is a hydrogen atom, a hydroxyl group, an acetate group, a halogen atom, a C ₁ to C ₄ lower alkyl group, a lower alkoxy group and a lower alkyl At least one substituent selected from the group consisting of esters and lower alkyl carboxy groups;

n is an integer of 0-4.

Preferred compound groups of the general formula (II) compound include R ₂ is a halogen atom, or a C ₁ to C ₁₀ alkyl group, an alkenyl group, an alkynyl group, an A substituent or B which is unsubstituted or substituted with a C ₁ to C ₄ lower alkyl group. Wherein A ′ or B ′ of the A substituent and B substituent is a hydrogen atom, a hydroxy group, an amine group, a halogen atom, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a nitro group, or a substituent substituted at o, m, or p positions One or more substituents selected from acetyl groups; 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 or B substituent; n is a group of compounds that is an integer of o or 1;

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

(7R) -7-methoxy-8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one, (7R) -8,8-dimethyl- 7- (3-Methyl-but-2-tenyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one, (7R) -8,8-dimethyl- 7- (2-methyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one, (7R) -8,8-dimethyl-7- (3 -Phenyl-propoxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one, (7R) -7- [3- (2-methoxy-phenyl)- Propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one, (7R) -7- [3- (3-methoxy- Phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one, (7R) -7- [3- (4- Methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one, (7R) -7- [3- (3,4-Dimethoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one, (7R)- 7- [3- (2,3-dimethoxy-phenyl) -propoxy] -8,8- dimethyl-7,8-dihydro-6H-pyrano [3,2- g] Romen-2-one, (7R) -8,8- dimethyl-7- [3- (3,4,5-trimethoxyphenyl) propoxy)] - 7,8-dihydro-6H-pyrano [3,2- g ] chromen-2-one, (7R) -8,8-dimethyl-7- (3-phenyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2 g ] chromen-2-one, (7R) -7- [3- (4-methoxy-phenyl) -allyloxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [ 3,2- g ] chromen-2-one.

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

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

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

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

Pharmaceutically acceptable salts of the compounds of formula (I) or (II) above 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 the general formula (I) or (II), which may be chemically synthesized by the method shown in the following schemes, but is not limited thereto.

Accordingly, the present invention is a mixture of (+)-decursinol (organic solvent), which preferably does not adversely affect the reaction of dichloromethane, chloroform, diethyl ether, tetrahydrofuran, preferably acetnitrile and carbon tetrachloride After dissolving in an organic solvent, sulfonylating agents such as triphenyl phosphine, para -toluenesulfonyl chloride, methanesulfonyl chloride, preferably triphenyl phosphine are reacted in a solvent such as pyridine or triethylamine, 8, A first step of obtaining 8-dimethyl- 8H -pyrano [3,2- g ] chromen-2-one; 8,8-dimethyl- 8H -pyrano [3,2- g ] chromen-2-one and (R, R)-(-), N, N`-bis (3,5) obtained in the first step -Di-tet butyl salicyridine) -1,2, -cyclohexanediamino manganese (III) chloride is dissolved in a solvent, and then in the presence of acid regulators and buffers such as sodium hyperchlorite solution and sodium phosphate dibasic solution. reaction of (6 R, 7 R) -6,7- dimethyl -8,8- epoxy -6 H - pyrano [3,2- g] a second step of preparing a chromen-2-one; 6 R , 7 R ) -6,7-epoxy-8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2-one obtained in the second step was converted to tetrahydrofuran and dichloromethane. , Dissolved in a solvent that does not adversely affect the reaction of chloroform, diethyl ether and the like, preferably tetrahydrofuran solvent, and then sodium cyanoborohydride and borane trifluoride diethyl etherate. It provides a manufacturing method for producing (-)-decursinol consisting of a manufacturing process comprising a third step of adding and reacting the reagent of the following, and the process will be described in more detail below.

  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 were synthesized according to procedures not included in the scope of Schemes 1-7, and detailed synthesis procedures for these compounds are described in their respective examples.

     Scheme (1) is used to prepare (-)-decursinol, the starting material used to synthesize (-)-decursinol derivatives from (+)-decursinol. The manufacturing process is shown.

In the first step, 85 g of (+)-decurinol ( 1 ) is dissolved in acrylonitrile and carbon tetrachloride 1: 1, and then triphenyl phosphine is added to carry out the reaction. The reaction temperature is not particularly limited, but may be generally performed at room temperature to 50-60 ° C., preferably at 50-60 ° C. The reaction time can be carried out for 3-5 hours, preferably by stirring for 3 hours 8,8-dimethyl- 8H -pyrano [3,2- g ] chromen-2-one (zanthyretin, 2 77.7g). In the second step, 1.3 g of 8,8-dimethyl- 8H -pyrano [3,2- g ] chromen-2-one (zanthyretin, 2 ) and (R, R)-(-), N, N` After dissolving -bis (3,5-di-tet butyl salicyridine) -1,2, -cyclohexanediamino manganese (III) chloride in dichloromethane, the sodium hyperchlorite solution and the sodium phosphate dibasic solution were Put and perform the reaction. In this case, the solvent used is ethanol, methanol, butanol, dichloromethane, chloroform and the like which do not adversely affect the reaction. The reaction temperature is not particularly limited, but may be generally performed at cold to room temperature, preferably at cold temperature. The reaction time can be carried out for 6 to 7 hours, preferably by stirring for 7 hours (6 R , 7 R ) -6,7-epoxy-8,8-dimethyl-6 H -pyrano [3, 784 mg of 2- g ] chromen-2-one ( 3 ) can be prepared. In the third step, 600 mg of (6 R , 7 R ) -6,7-epoxy-8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2-one is dissolved in tetrahydrofuran. After the reaction, sodium cyanoborohydride and borane trifluoride diethyl etherate were added to the reaction. The solvent used at this time is carried out using a solvent that does not adversely affect the reaction, dichloromethane, chloroform, diethyl ether, tetrahydrofuran and the like. The reaction temperature is not particularly limited, but may be generally performed at cold to room temperature, preferably at cold temperature. The reaction time can be carried out for 10 to 60 minutes, preferably stirred for 30 minutes to start the synthesis of the desired (-)-decursin derivatives (-)-decursinol (de-cursinol) , 4 ) can be prepared.

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

In the first step, 3,3-dimethylacrylic acid (5a) was dissolved in anhydrous dichloromethane, and 1,3-dicyclohexylcarbodiimide (DCC, 167.6 mg, 0.81 mmol) and 4-dimethylaminopyridine (DMAP, 19.9 mg) were dissolved. , 0.16 mmol) and stirred in (-)-decurinol (100 mg, 0.41 mmol). The solvent used at this time is carried out using a solvent that does not adversely affect the reaction, dichloromethane, chloroform, diethyl ether, tetrahydrofuran and the like. The reaction temperature is not particularly limited, but may be generally performed at cold to room temperature, and preferably at room temperature. The reaction time can be carried out for 6 to 24 hours, preferably stirred for 18 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column separation (3 R ) -3-methyl-but-2-tenophosphoric acid-2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 92.1 mg of 8H -pyrano [3,2- g ] chromen-3-yl-ester (6a) can be prepared.

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

In the first step, cinnamic acid is dissolved in anhydrous benzene, followed by reaction with thionyl chloride and N, N -dimethylformamide. The solvent used at this time is carried out using a solvent that does not adversely affect the reaction, dichloromethane, chloroform, diethyl ether, tetrahydrofuran and the like. The reaction temperature is not particularly limited, but may be generally performed at room temperature to 100 ° C, and preferably at 80 ° C. The reaction time may be performed for 3 to 18 hours, preferably stirred for 5 hours to prepare cinnamoyl chloride (8a), in the second step (-)-decursinol (200 mg, 0.81 mmol) was dissolved in pyridine and anhydrous dichloromethane, and cinnamoyl chloride (8a) was added dropwise, followed by stirring at room temperature for 18 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by ( 3R ) -3-phenyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3] by silica gel column separation. 164 mg of, 2- g ] chromen-3-yl-ester (9a) can be prepared.

Scheme (4) shows a two-step process for preparing a commercial compound or a compound synthesized by known methods.

In the first step, benzoic acid is dissolved in anhydrous benzene, and then thionyl chloride and N, N -dimethylformamide are added and reacted. The solvent used at this time is carried out using a solvent that does not adversely affect the reaction, dichloromethane, chloroform, diethyl ether, tetrahydrofuran and the like. The reaction temperature is not particularly limited, but may be generally performed at room temperature to 100 ° C, and preferably at 80 ° C. The reaction time may be performed for 3 to 18 hours, preferably stirred for 5 hours to prepare benzoyl chloride (11a), in the second step (-)-decursinol (200 mg) pyridine And it was dissolved in anhydrous dichloromethane, benzoyl chloride (11a) was added dropwise, and stirred at room temperature for 4 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by (3R) -benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g through silica gel column separation. ] 264.5 mg of chroman-3-yl-ester (12a) can be prepared.

Scheme (5) shows a one-step preparation process for preparing commercial compounds or compounds synthesized by known methods.

In the first step, (-)-decurinol (100 mg) is dissolved in anhydrous N, N -dimethylformamide , and then sodium hydride and methane iodide are added and reacted. 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 purified with silica gel column separation to obtain 57 mg of (7R) -7-methoxy-8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one. Can be manufactured.

Scheme (6) shows a three step preparation process for preparing a commercial compound or a compound synthesized by known methods.

In the first step, 2-methoxy cinnamic acid or 3- (2-methoxy) propionic acid is dissolved in anhydrous tetrahydrofuran, and then lithium aluminum hydride is added and reacted. In this case, the solvent used is the reaction using tetrahydrofuran, diethyl ether, dichloromethane, chloroform, and the like, which do not adversely affect the reaction, and preferably tetrahydrofuran is used. 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 6 hours. Distilled water (50 ml) was slowly added to the reaction solution, followed by stirring until no heat was generated. Add 3N HCl to pH 2 and extract with dichloromethane. The filtrate was dehydrated with anhydrous forget-me-not and concentrated under reduced pressure, and 200 mg of 3- (2-methoxyphenyl) propan-1-ol could be prepared by silica gel column separation. In the second step, 1- (3-bromo-propyl) -2-methoxybenzene or 1- (3-iodo-propyl) -2-methoxybenzene can be synthesized by two different methods and used in the next reaction. . The first method is to prepare 1- (3-bromo-propyl) -2-methoxybenzene. Dissolve 3-M2- (2-methoxyphenyl) propan-1-ol and 1M boron tribromide solution in 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 180 mg of 1- (3-bromo-propyl) -2-methoxybenzene 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 The reaction is performed by dissolving in toluene. The solvent used here is performed using toluene, benzene, and the like, which do not adversely affect the reaction. The reaction temperature can generally be carried out at 0 ℃ to room temperature, preferably at room temperature. 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 125 mg of 1- (3-iodo-propyl) -2-methoxybenzene through silica gel column separation. In this step, using the second method is economical and simpler and safer in the reaction operation, but in the case of a substance substituted with 2-methoxy group (17a), 3-methoxy group (17b) or 4-methoxy group (17c) It is more preferable to use the first method because triphenylphosphine, a reagent used in the reaction, is almost similar in polarity (R _f value), and is difficult to separate and purify. However, in the case of a substance in which 3,4-dimethoxy group 17d, 2,3-dimethoxy group 17e or 3,4,5-trimethoxy group 17f is substituted, it is preferable to use the second method. . In the third step, (-)-decurinol (100 mg) is dissolved in anhydrous N, N -dimethylformamide , and then reacted with sodium hydride and 1- (3-halo-propyl) -2-methoxybenzene. 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 (7R) -7- [3- (2-methoxyphenyl) propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- via silica gel column separation. g ] chromen-2-one 9 mg can be prepared.

Scheme (7) represents a four step preparation process for preparing a commercial compound or a compound synthesized by known methods.

In the first step, cinnamic acid is dissolved in methanol, 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 can be prepared 5.39g of 3-phenyl-acrylic acid methyl ester through silica gel column separation. In the second step, 3-phenyl-acrylic acid methyl ester was dissolved in anhydrous dichloromethane in a nitrogen-filled round flask and cooled to -78 ° C, followed by diisobutylaluminum hydride (DIBAL-H, 1M solution in hexane). Add dropwise over 30 minutes. The reaction solution was cooled to 0 ° C., stirred for 1 hour, and then methanol was added dropwise. The reaction solution was cooled to room temperature, stirred for 30 minutes, and saturated Rochelle's salt was added. The reaction solution was stirred vigorously for 2 hours, extracted with dichloromethane, dehydrated with anhydrous forget-me-not, and concentrated in dark and light. 4.0 g of 3-phenyl-pro-2-phen-1-ol may be prepared through silica gel column separation. In the third step, 3-phenyl-pro-2-phen-1-ol and boron tribromide (1M solution in dichloromethane) are dissolved in dichloromethane and reacted. 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 performed at -20 ° C to 50 ° C, and preferably at 0 ° C to room temperature. The reaction time may be carried out for 30 minutes to 24 hours and preferably stirred for 2 hours 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 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 933 mg of (3-bromo-propenyl) -benzene through silica gel column separation. In the fourth step, (-)-decurinol (100 mg) is dissolved in anhydrous N, N -dimethylformamide, followed by reaction with sodium hydride and (3-bromo-propenyl) -benzene. 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 (7R) -8,8-dimethyl-7- (3-phenyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen- via silica gel column separation. 52 mg of 2-one 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 method for the prevention of atopic dermatitis diseases containing (-)-decursin derivative compounds of the novel structures represented by the general formula (I) or (II) or pharmaceutically acceptable salts thereof as an active ingredient, and Provide pharmaceutical compositions for treatment.

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.

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.

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

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

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

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

The present invention relates to the prevention and treatment of atopic dermatitis diseases containing (-)-decursin derivative compounds of the novel structures represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof as an active ingredient. To provide health functional food for improvement.

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

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

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

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

In addition to the compounds of the present invention, the composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic and natural flavors, colorants and fillers (such as cheese, chocolate), pectic acid and salts thereof, alginic acid and Salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like. 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 derivative compounds of the present invention are MCP-1, IL-6 and IL- exhibiting atopic dermatitis response induced by ticks in THP-1 or EoL-1 cells. Effectively inhibiting the secretion amount of 8 can provide a pharmaceutical composition and health functional food for the prevention and treatment of atopic dermatitis disease.

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

As shown in the reaction scheme, (+)-decurinol (1) (85 g, 0.35 mol) and triphenylphosphine (226 g, 0.87 mol) were added to a round flask, acet nitrile (600 ml) and carbon tetrachloride (600 ml). Was dissolved in a 1: 1 ratio and then refluxed at 50-60 ° C. for 2 hours. After about half of the filtrate was concentrated under reduced pressure, 77.7 g of 8,8-dimethyl-8 H -pyrano [3,2- g ] chromen-2-one (2) having the following physical properties was obtained through silica gel column separation. It used as the sample of an experiment example.

Yield: 98.6%;

White solid phase (Solid);

m.p: 124 ° C;

R _f = 0.62 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.583 (d, J = 9.52, 1H), 7.049 (s, 1H), 6.711 (s, 1H), 6.340 (d, J = 10.0, 1H), 6.213 (d, J = 9.52, 1H), 5.691 (d, J = 9.76, 1H), 1.467 (s, 6H);

MS ( m / z ): 229 (M + H) ⁺

Example  2. (6 R , 7 R ) -6,7-epoxy-8,8-dimethyl-6 H - Pyrano [3,2- g ] Chrome Preparation of 2-one (3)

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

The first method is to put 15% sodium hyperchlorite solution (60ml) and 0.05M sodium phosphate dibasic solution (24ml) in a round flask and add 1N sodium hydroxide solution or 1N hydrochlorine to pH 11.3. Adjust to the ride solution. To this reaction solution was added 8,8-dimethyl- 8H -pyrano [3,2- g ] chromen-2-one (1.3 g, 5.7 mmol) (2) and (R, R)-(-), N, N`-bis (3,5-di-tet butyl salicyridine) -1,2, -cyclohexanediamino manganese (III) chloride (Joxensen auction) (69.9 mg, 0.11 mmol) in dichloromethane (15 ml ) Is dissolved. The reaction mixture was stirred at 0 ° C. for about 7 hours.

The reaction mixture was extracted with dichloromethane and washed with water to obtain a reddish brown organic layer. After the organic layer was removed with anhydrous forget-me-not, the filtrate was concentrated under reduced pressure. To obtain pure product (3), the concentrate was purified by silica gel column separation to obtain (6 R , 7 R ) -6,7-epoxy-8,8-dimethyl-6 H -pyrano [3,2- g having the following physical properties. ] 784 mg of chroman-2-one (3) was obtained and used as a sample of an experiment example.

The second method is 8,8-dimethyl- 8H -pyrano [3,2- g ] chromen-2-one (450 mg, 1.972 mmol) (2) and (R, R)-(-), in a round flask. N, N`-bis (3,5-di-tet butyl salicyridine) -1,2, -cyclohexanediamino manganese (III) chloride (Joxensen catalyst) (50 mg, 0.079 mmol) and tetrabutyl ammonium Um bisulfate (23.94mg, 0.071mmol) was dissolved in acetnitrile (15ml) and 50mM sodium tetraborate decahydrate solution (15ml) was added to 0.4mM ethylenediaminetetraacetic acid disodium salt dihydrate solution. do. The reaction mixture was cooled to 0 ° C., followed by addition of 1,1,1-trifluoroacetone (0.25 ml), followed by addition of oxone into 0.4 mM ethylenediamineteacetic acid disodium salt dihydrate solution. And sodium bicarbonate solution is slowly added to the reaction solution.

The reaction mixture is stirred for 1 hour 30 minutes. The reaction mixture was treated with water and extracted with diethyl ether. The organic layer thus extracted was treated with anhydrous forget-me-not to remove water, and the filtrate was concentrated under reduced pressure. To obtain pure product (3), the concentrate was purified by silica gel column separation to obtain (6 R , 7 R ) -6,7-epoxy-8,8-dimethyl-6 H -pyrano [3,2- g having the following physical properties. ] 157 mg of chroman-2-one (3) was obtained and used as a sample of an experiment example.

Yield: Method 1-56.3% / Method 2-32.5%;

White solid phase;

m.p: 145 ° C;

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

¹ H NMR (CDCl ₃ ): δ ppm 7.643 (d, J = 9.52, 1H), 7.470 (s, 1H), 6.754 (s, 1H), 1H), 6.265 (d, J = 9.52, 1H), 3.976 (d, J = 3.88, 1H), 3.551 (d, J = 3.88, 1H), 1.609 (s, 3H), 1.312 (s, 3H)

MS ( m / z ): 245 (M + H) ⁺ ;

+ 201.8(c=3, CHCl₃)

+ 201.8 (c = 3, CHCl ₃ )

3. (7 R ) -7- Hydroxy -8,8-dimethyl- 8H - Pyrano [3,2- g ] Chrome Preparation of 2-one (4)

A round flask, as shown in the reaction scheme ((6 R, 7 S) -6,7- dimethyl -8,8- epoxy -6 H - pyrano [3,2- g] chromen-2-one (3 (600 mg, 2.4566 mmol) was dissolved in tetrahydrofuran, and sodium cyanoborohydride and borane trifluoride diethyl etherate were added in. The reaction mixture was stirred at 0 ° C. for about 30 minutes. the filtrate was concentrated under reduced pressure, having the following physical data through a silica gel column separation (-) - Deco resorcinol [decursinol; (7 R) -7- hydroxy -8,8- dimethyl-8H-pyrano [3,2 495 mg of g ] chromen-2-one (4)] was used as a sample for the experimental example.

Yield: 98.6%;

White solid phase (Solid);

m.p: 135-136 deg.

R _f = 0.179 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.579 (d, J = 9.5, 1H), 7.180 (s, 1H), 6.780 (s, 1H), 6.219 (d, J = 9.52, 1H), 3.876 (d, J = 5.1, 1H), 3.112 (dd, J = 4.8, 16.7, 1H), 2.837 (dd, J = 5.6, 16.6, 1H), 1.397 (s, 3H), 1.367 (s, 3H)

MS ( m / z ): 247 (M + H) ⁺ ;

+ 18.4(c=4, CHCl₃)

+ 18.4 (c = 4, CHCl ₃ )

NO. matter Compound Molecular Weight Structure One 2 8,8-Dimethyl-8 H -pyrano [3,2- g ] chromen-2-one 228.24

2 3 (6 R , 7 R ) -6,7-epoxy-8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2-one 244.24

3 4 (7 R) -7-hydroxy- 8,8-dimethyl-6 H -pyrano [3,2- g] chromen-2-one 204.26

Example  4. (3 R ) -3- methyl Part-2- Tennophosphate  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (6a)

As shown in the reaction scheme, 3,3-dimethylacrylic acid (5a) (44.7 mg, 0.45 mmol), 1,3-dicyclohexylcarbodiimide (DCC, 167.6 mg, 0.81 mmol) and 4-dimethyl were placed in a round flask. Aminopyridine (DMAP, 19.9 mg, 0.16 mmol) was added and dissolved in anhydrous dichloromethane. (-)-Decursinol ( 4 , 100 mg, 0.41 mmol) was added to the reaction mixture, which was stirred for 18 hours at room temperature. The reaction mixture was washed with dichloromethane and filtered, and the filtrate was concentrated under reduced pressure. To obtain the pure product (6a), the concentrate was subjected to silica gel column separation to obtain ( 3R ) -3-methyl-but-2-tenophosphate 2,2-dimethyl-8-oxo-3,4-di having the following physical properties. 92.1 mg of hydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (6a) was obtained and used as a sample for the experimental example.

Yield: 69.1%;

Semi solid;

R _f = 0.70 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.586 (d, J = 9.5, 1H), 7.1580 (s, 1H), 6.788 (s, 1H), 6.219 (d, J = 9.5, 1H), 5.662 (t, J = 1.2, 1H), 5.086 (t, J = 4.9, 1H), 3.194 (dd, J = 4.52, 17.5 1H), 2.866 (dd, J = 4.88, 17.08, 1H), 2.144 (s, 3H), 1.878 (s, 3H), 1.383 (s, 3H), 1.364 (s, 3H)

MS ( m / z ): 329 (M + H) ⁺ ;

+ 105.3(c=1, CHCl₃)

+ 105.3 (c = 1, CHCl ₃ )

Example  5. (3 R )- Sheath -2- methyl Part-2- Tennophosphate  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (6b)

The reaction of Example 1, except that the round flask of Example 1 was replaced with cis -2-methyl-but - 2-tenoic acid (5b) instead of 3-methyl-but-2-tenophosphoric acid (5a). The same process as in (3 R ) -cis -2-methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -P 84.5 mg of rano [3,2- g ] chromen-3-yl-ester (6b) was obtained and used as a sample for the experimental example.

Yield: 63.4%;

Oil phase;

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

¹ H NMR (CDCl ₃ ): δ ppm 7.599 (d, J = 9.5 Hz, 1H), 7.170 (s, 1H), 6.809 (s, 1H), 6.224 (d, J = 9.5 Hz H), 5.091 (t , J = 4.8Hz, 1H), 3.215 (dd, J = 4.8, 17.0Hz, 1H), 2.889 (dd, J = 5.0, 16.9Hz, 1H), 1.802 (s, 3H), 1.769 (d, J = 6.8 Hz, 3H), 1.378 (s, 3H), 1.351 (s, 3H);

MS ( m / z ): 329 (M + H) ⁺ ;

+ 52.2(c=3, CHCl₃)

+ 52.2 (c = 3, CHCl ₃ )

Example  6. (3 R )-2- methyl -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (6c)

The same physical properties as in Example 1 were carried out except that the round flask of Example 1 was changed to 2-methyl-acrylic acid (5c) instead of 3-methyl-but-2-enonoic acid (5a). ( 3R ) -2-methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester 108 mg (6c) was obtained and used as a sample of an experiment example.

Yield: 84.6%;

Semi Solid;

R _f = 0.58 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.549 (d, J = 9.5 Hz, 1H), 7.124 (s, 1H), 6.752 (s, 1H), 6.185 (d, J = 9.5 Hz, 1H), 6.026 (s, 1H), 5.5361 (s, 1H), 5.048 (t, J = 5.0 Hz, 1H), 3.183 (dd, J = 4.9, 17.1 Hz, 1H), 2.857 (dd, J = 5.4, 17.1 Hz, 1H), 1.872 (s, 3H), 1.354 (s, 3H), 1.340 (s, 3H);

MS ( m / z ): 315 (M + H) ⁺ ;

+ 89.1(c=3, CHCl₃)

+ 89.1 (c = 3, CHCl ₃ )

Example 7. (3 R ) -Acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Production of Chromium-3-yl-ester (6d)

The same procedure as in Example 1 was carried out except that the round flask of Example 1 was replaced with acetic acid (5d) instead of 3-methyl-but-2-tenophosphoric acid (5a) to have the following physical properties (3 R ) -Acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (6d) to obtain 69.0 mg of experiment Used as an example sample.

Yield: 58.9%;

Solid phase;

m.p 125-126 ° C .;

R _f = 0.17 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.585 (d, J = 9.5 Hz, 1H), 7.159 (s, 1H), 6.795 (s, 1H), 6.232 (d, J = 9.5 Hz, 1H), 5.054 (t , J = 4.8 Hz, 1H), 3.185 (dd, J = 4.9, 17.1 Hz, 1H), 2.854 (dd, J = 4.9, 17.1 Hz, 1H), 2.071 (s, 3H), 1.379 (s, 3H) , 1.354 (s, 3 H);

MS ( m / z ): 289 (M + H) ⁺ ;

+ 73.3(c=3, CHCl₃)

+ 73.3 (c = 3, CHCl ₃ )

NO. matter Compound Molecular Weight Structure  4  6a (3 R ) -3-Phenyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3-yl-ester  328.36

 5  6b (3 R) - cis -2- Methyl-but-2-enoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl -ester  328.36

 6  6c ( 3R ) -2-Methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester  314.33

 7  6d ( 3R ) -Acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester  288.30

Example  8. (3 R ) -3- Phenyl -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (9a)

Step 1.

       Cinnamic acid (7a, 180 mg, in 100 ml round flask, completely dried

1.22 mmol) was dissolved in anhydrous benzene (15 mL). N, N -dimethylformamide (2 drops) and thionyl chloride (SOCl ₂ , 270 µl, 6.09 mmol) were added thereto, and the mixture was refluxed at 80 ° C. for 5 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to synthesize cinnamoyl chloride (8a), which was dissolved in anhydrous dichloromethane and applied to the next step.

Step 2.

(-)-Decursinol (4, 200 mg, 0.81 mmol) was added to a 100 mL round flask, dissolved in anhydrous dichloromethane (30 mL), pyridine (197 μL 2.44 mmol) and anhydrous dichloromethane (10 mL). Cinnamoyl chloride (8a) dissolved in) was added dropwise, followed by stirring at room temperature for 18 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column separation to obtain ( 3R ) -3-phenyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -blood having the following physical properties. 164 mg of rano [3,2- g ] chromen-3-yl-ester (9a) was obtained and used as a sample for the experimental example.

Yield: 53.7%;

Solid phase;

m.p 136-137 ° C .;

R _f = 0.53 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.679 (d, J = 15.9, 1H), 7.583 (d, J = 9.3, 1H), 7.511 (d, J = 2.0, 1H), 7.495 (d, J = 4.4 , 1H), 7.374 (dd, J = 3.4, 5.12, 3H), 7.174 (s, 4H), 6.835 (s, 1H), 6.420 (d, J = 16.1 Hz, 1H), 6.236 (d, J = 9.5 Hz, 1H), 5.200 (t, J = 4.8 Hz, 1H), 3.249 (dd, J = 4.4, 17.6 Hz, 1H), 2.942 (dd, J = 4.8, 17.4 Hz, 1H), 1.438 (s, 3H ), 1.395 (s, 3 H);

MS ( m / z ): 377 (M + H) ⁺ ;

+ 42.0(c=3, CHCl₃)

+ 42.0 (c = 3, CHCl ₃ )

Example  9. (3 R ) -3- (2- Methoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (9b)

The same properties as in Example 8 were carried out except that the 100 ml round flask completely dried in the first step of Example 8 was replaced with 2-methoxy cinnamic acid (7b) instead of cinnamic acid (7a). ( 3R ) -3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen 149.5 mg of -3-yl-ester (9b) was obtained and used as a sample for the experimental example.

Yield: 45.4%;

Solid phase;

m.p 68 ° C .;

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

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

MS ( m / z ): 407 (M + H) ⁺ ;

+ 55.8(c=3, CHCl₃)

+ 55.8 (c = 3, CHCl ₃ )

Example  10. (3 R ) -3- (2-hydroxy- Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (9c)

Step B.

3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen- in a 100 ml round flask Add 3-yl-ester (9b, 200mg, 0.492mmol), dissolve in anhydrous dichloromethane (20ml), add 1M boron tribromide solution (1M BBr ₃ in MC, 0.74µl, 0.74mmol) dropwise, and then room temperature Stirred for 2 h. The reaction mixture was poured into ice water (200 mL), stirred for 10 minutes, extracted with ethyl acetate, and dehydrated with anhydrous forget-me-not and concentrated under reduced pressure. The obtained residue was subjected to silica gel column separation to obtain ( 3R ) -3- (2-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H- having the following physical properties. 143 mg of pyrano [3,2- g ] chromen-3-yl-ester (9c) was obtained and used as a sample for the experimental example.

Yield: 74.1%;

Solid phase;

m.p 106 ° C .;

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

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

MS ( m / z ): 393 (M + H) ⁺ ;

+ 48.9(c=3, CHCl₃)

+ 48.9 (c = 3, CHCl ₃ )

Example  11. (3 R ) -3- (2- Acetoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (9d)

Step C.

In a 100 ml round flask, ( 3R ) -3- (2-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (9c, 58.2mg, 0.148mmol) was dissolved in anhydrous dichloromethane (20ml), pyridine (36µl, 0.445mmol) and acetyl chloride (0.15.8µl, 0.22 mmol) was added dropwise and stirred at room temperature for 2 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column separation to obtain ( 3R ) -3- (2-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-di having the following physical properties. 52.3 mg of hydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (9d) was obtained and used as a sample for the experimental example.

Yield: 81.2%;

White solid;

m.p 61 ° C .;

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

¹ H NMR (CDCl ₃ ): δ ppm 7.731 (d, J = 16.1 Hz, 1H), 7.598 (t, J = 8.6 Hz, 2H), 7.402 (t, J = 8.5 Hz, 1H), 7.238 (t, J = 7.7 Hz, 1H), 7.1824 (s, 1H), 7.105 (d, J = 8.1 Hz, 1H), 6.815 (s, 1H), 6.417 (d, J = 15.9 Hz, 1H), 6.228 (d, J = 9.3 Hz, 1H), 5.189 (t, J = 4.6 Hz, 1H), 3.247 (dd, J = 4.64, 17.2 Hz, 1H), 2.939 (dd, J = 4.6, 17.3 Hz, 1H), 2.296 (s , 3H), 1.431 (s, 3H), 1.392 (s, 3H);

MS ( m / z ) 435 (M + H) ⁺ ;

+ 46.1(c=3, CHCl₃)

+ 46.1 (c = 3, CHCl ₃ )

Example  12. (3 R ) -3- (3- Methoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H -blood Llan [3,2- g ] Preparation of Chromen-3-yl-ester (9e)

The same properties as in Example 8 were carried out except that the 100 ml round flask completely dried in the second step of Example 8 was replaced with 3-methoxy cinnamic acid (7c) instead of cinnamic acid (7a). ( 3R ) -3- (3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen 209.3 mg of -3-yl-ester (9e) was obtained and used as a sample for the experimental example.

Yield: 63.4%;

Solid phase;

m.p 72 ° C .;

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

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

MS ( m / z ) 407 (M + H) ⁺ ;

+ 35.1(c=3, CHCl₃)

+ 35.1 (c = 3, CHCl ₃ )

Example  13. (3 R ) -3- (3-hydroxy- Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (9f)

In a 100 mL round flask fully dried in Example 10, ( 3R ) -3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H ( 3R ) -3- (3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3 instead of pyrano [3,2- g ] chromen-3-yl-ester (9b) Except for changing to, 4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (9e), the same process as in Example 10 was carried out to give the following physical properties ( 3 R ) -3- (3-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3 125.7 mg of -yl-ester (9f) was obtained and used as a sample for the experimental example.

Yield: 65.1%;

Solid phase;

m.p 105 ° C .;

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

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

MS ( m / z ): 393 (M + H) ⁺ ;

+ 30.2(c=3, CHCl₃)

+ 30.2 (c = 3, CHCl ₃ )

Example  14. (3 R ) -3- (3- Acetoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (9 g)

Step C.

( 3R ) -3- (3-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-di having the following physical properties by performing the same process as in the fifth step of Example 11; 51.1 mg of hydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (9 g) was obtained and used as a sample for the experimental example.

Yield: 79.5%;

Solid phase;

m.p 181 ° C .;

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

¹ H NMR (CDCl ₃ ): δ ppm 7.635 (d, J = 16.0 Hz, 1H), 7.587 (d, J = 9.5 Hz, 1H), 7.367 (s, 2H), 7.239 (s, 1H), 7.175 ( s, 1H), 7.111 (dd, J = 2.0, 7.3 Hz, 1H), 6.832 (s, 1H), 6.405 (d, J = 16.1 Hz, 1H), 6.238 (d, J = 9.6 Hz, 1H), 5.193 (t, J = 4.6Hz, 1H), 3.244 (dd, J = 4.4, 17.3Hz, 1H), 2.934 (dd, J = 4.4, 17.3Hz, 1H), 2.299 (s, 3H), 1.429 (s , 3H), 1.390 (s, 3H);

MS ( m / z ): 435 (M + H) ⁺ ;

+ 35.0(c=3, CHCl₃)

+ 35.0 (c = 3, CHCl ₃ )

Example  15. (3 R ) -3- (4- Methoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (9h)

The same properties as in Example 8 were carried out except that the 100 ml round flask completely dried in the second step of Example 8 was replaced with 4-methoxy cinnamic acid (7d) instead of cinnamic acid (7a). ( 3R ) -3- (4-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen 175.5 mg of -3-yl-ester (9h) was obtained and used as a sample for the experimental example.

Yield: 53.3%;

Solid phase;

m.p 68 ° C .;

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

¹ H NMR (CDCl ₃ ): δ ppm 7.628 (d, J = 16.1 Hz, 1H), 7.576 (d, J = 9.5 Hz, 1H), 7.447 (d, J = 8.8 Hz, 1H), 7.165 (s, 1H ), 6.881 (d, J = 8.6 Hz, 2H), 6.826 (s, 1H), 6.279 (d, J = 15.8 Hz, 1H), 6.227 (d, J = 9.5 Hz, 1H), 5.187 (t, J = 4.8 Hz, 1H), 3.826 (s, 3H), 3.236 (dd, J = 4.8, 17.2 Hz, 1H), 2.930 (dd, J = 4.6, 17.3 Hz, 1H), 1.431 (s, 3H), 1.397 (s, 3H); MS ( m / z ): 407 (M + H) ⁺ ;

+ 18.0(c=3, CHCl₃)

+ 18.0 (c = 3, CHCl ₃ )

Example  16. (3 R ) -3- (4-hydroxy- Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (9i)

Step C.

( 3R ) -3- (4-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-di having the following physical properties by performing the same process as in the fifth step of Example 8; 165.1 mg of hydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (9i) was obtained and used as a sample for the experimental example.

Yield: 85.5%;

Solid phase;

m.p 181 ° C .;

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

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

MS ( m / z ): 393 (M + H) ⁺ ;

+ 20.9(c=3, CHCl₃)

+ 20.9 (c = 3, CHCl ₃ )

Example  17. (3 R ) -3- (4- Acetoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (9j)

Step C.

( 3R ) -3- (4-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-di having the following physical properties by carrying out the same process as in the fifth step of Example 11; 37.0 mg of hydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (9j) was obtained and used as a sample for the experimental example.

Yield: 57.5%;

Solid phase;

m.p 181 ° C .;

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

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

MS ( m / z ): 435 (M + H) ⁺ ;

+ 33.4(c=3, CHCl₃)

+ 33.4 (c = 3, CHCl ₃ )

Example  18. (3 R ) -3- (3,4- Dimethoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro in- 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (9k)

The same process as in Example 8 was carried out except that the 100 ml round flask completely dried in the second step of Example 8 was replaced with 3,4-dimethoxy cinnamic acid (7e) instead of cinnamic acid (7a). ( 3R ) -3- (3,4-Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- with physical properties g ] chromen-3-yl-ester (9k) was obtained as 151.3 mg and used as a sample for the experimental example.

Yield: 42.8%

Solid phase;

m.p 83 ° C .;

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

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

MS ( m / z ): 437 (M + H) ⁺ ;

+ 40.5(c=3, CHCl₃)

+ 40.5 (c = 3, CHCl ₃ )

Example  19. (3 R ) -3- (3,4,5- Trimethoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (9l)

The same process as in Example 13 was carried out except that the 100 ml round flask completely dried in the second step of Example 8 was replaced with 3,4,5-trimethoxy cinnamic acid (7f) instead of cinnamic acid (7a). ( 3R ) -3- (3,4,5-trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -P having the following physical properties 247 mg of rano [3,2- g ] chromen-3-yl-ester (9 l) was obtained and used as a sample for the experimental example.

Yield: 65.4%;

Solid phase;

m.p 87 ° C .;

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

¹ H NMR (CDCl ₃ ): δ ppm 7.610 (d, J = 4.1 Hz, 1H), 7.577 (s, 1H), 7.187 (s, 1H), 6.843 (s, 1H), 6.722 (s, 2H), 6.324 (d, J = 15.9 Hz, 1H), 6.242 (d, J = 9.3 Hz, 1H), 5.208 (t, J = 4.4 Hz, 1H), 3.871 (s, 9H), 3.255 (dd, J = 4.4, 17.3 Hz, 1H), 2.953 (dd, J = 4.2, 17.3 Hz, 1H), 1.454 (s, 3H), 1.395 (s, 3H);

MS ( m / z ): 467 (M + H) ⁺ ;

+ 26.4(c=2.4, CHCl₃)

+ 26.4 (c = 2.4, CHCl ₃ )

Example  20. (3 R ) -3- (3,4,5- Trihydroxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome -3-yl-ester (9m)

In Example 9 above, in a 100 ml round flask, 3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] 3- (3,4,5-trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H instead of chroman-3-yl-ester (9b) , The procedure of Example 9 was repeated except for changing to 8H -pyrano [3,2- g ] chromen-3-yl-ester (9l) to give 3- (3,4,5- having the following physical properties. Trihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (9 m) 38.0 mg was obtained and used as a sample of an experiment example.

Yield: 18.2%;

White solid;

m.p 144 ° C .;

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

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

MS ( m / z ): 425 (M + H) ⁺ ;

+ 24.4(c=3, CH₃OH)

+ 24.4 (c = 3, CH ₃ OH)

Example  21. (3 R ) -3- (3,4- Diacetoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (9n)

Step A.

       As shown in the reaction scheme, acetic anhydride (15.6 mL, 27.8 mmol) was added to a 100 mL round flask, and 3,4-dihydroxy cinnamic acid (7 h, 5 g, 27.8 mmol) and pyridine (7.8 mL, excess) were added thereto. . It was stirred at room temperature for one day and then concentrated under reduced pressure. The concentrate was subjected to silica gel column separation to obtain 3,4-diacetoxy cinnamic acid (7 g), a portion of which was applied to step 1.

Step 1.2

The same process as in Example 8 was performed except that the 100 ml round flask completely dried in the first step of Example 8 was replaced with 3,4-acetoxy cinnamic acid (7 g) instead of cinnamic acid (7a) ( 3 R ) -3- (3,4-diacetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chrome 310.6 mg of men-3-yl-ester (9n) was obtained and used as a sample for the experimental example.

Yield: 77.9%;

Solid phase;

m.p 92 ° C .;

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

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

MS ( m / z ): 493 (M + H) ⁺ ;

+ 24.8(c=3, CHCl₃)

+ 24.8 (c = 3, CHCl ₃ )

Example  22. (3 R ) -3- (3, 4-dihydroxy- Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (9o)

Step D.

( 3R ) -3- (3, 4-Diacetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] Chromen-3-yl-ester (9m, 81.6 mg) was dissolved in acetone (15 mL) and then 3N HCl (5 mL) was added dropwise. It was refluxed at 50-60 degrees for 12 hours, and then cooled to room temperature and concentrated under reduced pressure. The concentrated solution was dissolved in ethyl acetate and distilled water and separated. The ethyl acetate layers were collected, dehydrated with anhydrous forget-me-not and filtered and concentrated under reduced pressure. The concentrate was subjected to silica gel column separation to obtain ( 3R ) -3- (3,4-dihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, having the following physical properties: 46 mg of 8H -pyrano [3,2- g ] chromen-3-yl-ester (9o) was obtained and used as a sample for the experimental example.

Yield: 67.9%;

Solid phase;

m.p 115 ° C .;

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

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

MS ( m / z ): 409 (M + H) ⁺ ;

+ 19.3(c=3, CH₃OH)

+ 19.3 (c = 3, CH ₃ OH)

Example 23. (3 R ) -3- (3, 4-dihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Preparation of chromen-3-yl-ester (9p)

The same procedure as in Example 8 was carried out except that the 100 ml round flask completely dried in the first step of Example 8 was replaced with 4-nitro cinnamic acid (7i) instead of cinnamic acid (7a) to have the following physical properties. ( 3R ) -3- (4-Nitro-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3 -Il-ester (9p) was obtained and used as a sample of an experiment example.

Yield: 70.2%;

Light yellow solid;

m.p 193 ° C .;

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

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

MS ( m / z ) 422 (M + H) ⁺ .

+ 21.1(c=3, CHCl₃)

+ 21.1 (c = 3, CHCl ₃ )

Example  24. R ) -3- (3- Floro - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (9q)

The same properties as in Example 8 were carried out except that the 100 ml round flask completely dried in the first step of Example 8 was replaced with 3-flocin cinnamic acid (7j) instead of cinnamic acid (7a). ( 3R ) -3- (3-fluoro-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen 3-yl-ester (9q) was obtained and used as a sample for the experimental example.

Yield: 72.7%;

White solid;

m.p 149 ° C .;

R _f = 0.53 ( n- hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ ): δ ppm 7.629 (d, J = 15.6 Hz, 1H), 7.585 (d, J = 9.6 Hz, 1H), 7.372-7.209 (m, 3H), 7.175 (s, 1H), 0.079 (m, 1H), 6.835 (s, 1H), 6.412 (d, J = 16.0 Hz, 1H), 6.240 (d, J = 9.2 Hz, 1H), 5.200 (t, J = 4.8 Hz, 1H), 3.250 (dd, J = 4.8, 17.6 Hz, 1H), 2.941 (dd, J = 4.8, 17.6 Hz, 1H), 1.436 (s, 3H), 1.395 (s, 3H);

MS ( m / z ): 395 (M + H) ⁺ ;

+ 38.4(c=3, CHCl₃)

+ 38.4 (c = 3, CHCl ₃ )

Example 25. (3 R ) -3- (3-Bromo-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Chrome-3-yl-ester (9r) Preparation

The same properties as in Example 8 were carried out except that the 100 ml round flask completely dried in the first step of Example 8 was replaced with 3-bromo cinnamic acid (7k) instead of cinnamic acid (7a). ( 3R ) -3- (3-bromo-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen 3-yl-ester (9r) was obtained and used as a sample for the experimental example.

Yield: 68.2%;

White solid;

m.p 167 ° C .;

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

¹ H NMR (CDCl ₃ ): δ ppm 7.646 (s, 1H), 7.596 (m, 2H), 7.466 (d, J = 7.6 Hz, 1H), 7.412 (d, J = 7.6 Hz, 1H), 7.245 (t , J = 8.0 Hz, 1H), 7.173 (s, 1H), 6.831 (s, 1H), 6.413 (d, J = 16.0 Hz, 1H), 6.237 (d, J = 9.6 Hz, 1H), 5.197 (t , J = 4.4Hz, 1H), 3.249 (dd, J = 4.4, 17.6Hz, 1H), 2.936 (dd, J = 4.4, 17.6Hz, 1H), 1.432 (s, 3H), 1.392 (s, 3H) ;

MS ( m / z ): (M + H) ⁺ ;

+ 33.7(c=3, CHCl₃)

+ 33.7 (c = 3, CHCl ₃ )

Example 26. (3 R ) -3- (4-Bromo-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2- g ] Preparation of chromen-3-yl-ester (9s)

The same properties as in Example 8 were carried out except that the 100 ml round flask completely dried in the first step of Example 8 was replaced with 4-bromo cinnamic acid (7 l) instead of cinnamic acid (7a). ( 3R ) -3- (4-Bromo-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen 3-yl-ester (9s) was obtained and used as a sample for the experimental example.

Yield: 77.1%;

White solid;

m.p 120 ° C .;

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

¹ H NMR (CDCl ₃ ): δ ppm 7.605 (d, J = 16.4 Hz, 1H), 7.584 (d, J = 9.2, 1H), 7.503 (d, J = 8.4 Hz, 1H), 7.359 (d, J = 8.4 Hz, 1H), 7.174 (d, 1H), 6.829 (s, 1H), 6.407 (d, J = 16.4 Hz, 1H), 6.238 (d, J = 9.2 Hz, 1H), 5.197 (t, J = 4.4 Hz, 1H), 3.248 (dd, J = 4.4, 17.2 Hz, 1H), 2.937 (dd, J = 4.4, 17.2 Hz, 1H), 1.434 (s, 3H), 1.392 (s, 3H); MS ( m / z ):

456 (M + H) ⁺ ;

+ 22.9(c=3, CHCl₃)

+ 22.9 (c = 3, CHCl ₃ )

No . matter Compound Molecular Weight structure 8 9a (3 R ) -3-Phenyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3-yl-ester 376.40

9 9b ( 3R ) -3- (2-Methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3 -yl-ester 406.43

10 9c ( 3R ) -3- (2-Hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3 -yl-ester 392.40

11 9d ( 3R ) -3- (2-Acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3 -yl-ester 434.44

12 9e ( 3R ) -3- (3-Methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3 -yl-ester 406.43

13 9f ( 3R ) -3- (3-Hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3 -yl-ester 392.40

14 9g ( 3R ) -3- (3-Acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3 -yl-ester 434.44

15 9h ( 3R ) -3- (4-Methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3 -yl-ester 406.43

16 9i ( 3R ) -3- (4-Hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3 -yl-ester 392.40

17 9j ( 3R ) -3- (4-Acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3 -yl-ester 434.44

18 9k ( 3R ) -3- (3,4-Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen -3-yl-ester 436.45

19 9l ( 3R ) -3- (3,4,5-Trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3-yl-ester 466.48

20 9m ( 3R ) -3- (3,4,5-Trihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3-yl-ester 424.40

21 9n ( 3R ) -3- (3,4-Diacetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen -3-yl-ester 492.13

22 9o ( 3R ) -3- (3,4-Dihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen -3-yl-ester 408.40

23 9p ( 3R ) -3- (4-Nitro-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3 -yl-ester 421.40

24 9q (3 R )-(3- (3-Fluoro-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen- 3-yl-ester 394.39

25 9r ( 3R ) -3- (3-Bromo-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3 -yl-ester 455.30

26 9s ( 3R ) -3- (4-Bromo-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3 -yl-ester 455.30

Example  27. (3R)- Benzoic acid  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester 12a

Step 1.2

The same procedure as in Example 8 was carried out except that the 100 mL round flask completely dried in the first step of Example 8 was changed to benzoic acid (10a) instead of cinnamic acid (7a). 264.5 mg of, 2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (12a) was obtained and used as a sample for the experimental example. .

Yield 93.2%;

Semi solid;

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

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

MS ( m / z ): 351 (M + H) ⁺ ;

+ 74.8(c=3, CHCl₃)

+ 74.8 (c = 3, CHCl ₃ )

Example  28. (3R) -3,4,5- Triacetoxy - Benzoic acid  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester 12b

Step A.

       As shown in the reaction scheme of Example 22, acetic anhydride (11.5 ml, 25.6 mmol) and 3,4,5-trihydroxy benzoic acid (12b, 3 g, 17.6 mmol) were added and dissolved in a 100 ml round flask. -3 drops of concentrated sulfuric acid were added dropwise. The reaction mixture was refluxed at 80 degrees for 10 minutes and then cooled to room temperature. It was stirred while pouring 30 times (volume ratio) of ice water in the reaction mixture, and the crystals were filtered after standing at room temperature for 2 hours. The white crystals on the filter paper were washed with distilled water, which was dried at 40 ° C. for 12 hours to obtain 5.1 g of 3,4,5-triacetoxy benzoic acid (10c), a portion of which was applied to Step 1.

Step 1, 2.

The same process as in Example 13 except that the 100 mL round flask completely dried in Step A of Example 13 was replaced with 3,4,5-triacetoxy-benzoic acid (10c) instead of cinnamic acid (8a). To ( 3R ) -3,4,5-triacetoxy-benzophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] 122.3 mg of chromen-3-yl-ester (12b) was obtained and used as a sample for the experimental example.

Yield: 28.8%;

Solid phase;

m.p 97 ° C .;

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

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

MS ( m / z ): 525 (M + H) ⁺ ;

+ 59.0(c=3, CHCl₃)

+ 59.0 (c = 3, CHCl ₃ )

Example  29. (3R) -3,4,5- Trihydroxy - Benzoic acid  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2- g ] Chrome Preparation of 3-yl-ester (12c)

Step B.

In step B of Example 20, ( 3R ) -3- (3,4-diacetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H- ( 3R ) -3,4,5-triacetoxy-benzoic acid 2,2-dimethyl-8-oxo-3, instead of pyrano [3,2- g ] chromen-3-yl-ester (9m), Same process as step D of Example 20, except for changing to 4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (12b, 1.8 g, 3.43 mmol) ( 3R ) -3,4,5-trihydroxy-benzophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,] having the following physical properties 193.4 mg of 2- g ] chromen-3-yl-ester (12c) was obtained and used as a sample for the experimental example.

Yield: 98.7%;

Solid phase;

m.p 138 ° C .;

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

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

MS ( m / z ): 399 (M + H) ⁺ ;

+ 64.9(c=3, CHCl₃)

+ 64.9 (c = 3, CHCl ₃ )

No . matter Compound Molecular Weight structure 27 12a ( 3R ) -Benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester 350.36

28 12b (3 R ) -3,4,5-Triacetoxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3-yl -ester 524.13

29 12c (3 R ) -3,4,5-Trihydroxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2 H , 8 H -pyrano [3,2- g ] chromen-3-yl -ester 398.36

Example  30. (7R) -7- Methoxy -8,8-dimethyl-7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one 14a

As shown in the reaction scheme, (-)-decursinol ((-)-decursinol, 4 , 100 mg, 0.41 mmol) was dissolved in anhydrous N, N -dimethylformamide (3 ml) in a round flask at -20 ° C. Cooled. Methane iodide (13a) (37.91mg, 0.609mmol) was added to the reaction mixture, and stirred at -20 ° C for 24 hours. The reaction mixture was concentrated by filtration over a silica gel column, and the concentrated flask was then heated in 90-100 ° C. to remove N, N -dimethylformamide in vacuo. The concentrate was subjected to silica gel column separation to obtain pure product (14a). 57 mg of (7R) -7-methoxy-8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (14a) having the following physical properties Obtained and used as a sample of an experiment example.

Yield: 53.9%;

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  31. (7R) -8,8-Dimethyl-7- (3- methyl Part-2- Tenyloxy ) -7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one 14b

The same procedure as in Example 30 was carried out except that the round flask of Example 30 was changed to 3,3-dimethyl aryl bromide (13b) instead of methane iodide (13a) to have the following physical properties (7R) -8 31.0 mg of 8-dimethyl-7- (3-methyl-but-2-tenyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (14b) Obtained and used as a sample of an experiment example.

Yield: 24.2%;

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  32. (7R) -8,8-Dimethyl-7- (2- methyl - Allyloxy ) -7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one 14c

The same procedure as in Example 30 was carried out except that the round flask of Example 30 was changed to 3-bromo-2-methylpropene (13c) instead of methane iodide (13a) to obtain the following physical properties (7R 63 mg of 8,8-dimethyl-7- (2-methyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (14c) was obtained. It used as the sample of an experiment example.

Yield: 51.7%;

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  33. (7R) -8,8-Dimethyl-7- (3- Phenyl - Propoxy ) -7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (14d)

The same procedure as in Example 30 was carried out except that the round flask of Example 30 was replaced with 1-bromo-3-phenylpropane (13d) instead of methane iodide (13a) (7R). Experiment was obtained by obtaining 20 mg of -8,8-dimethyl-7- (3-phenyl-propoxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (14d). Used as an example sample.

Yield: 13.6%;

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 30 14a (7R) -7-Methoxy-8,8-dimethyl-7,8-dihydro- 6H- pyrano [3,2- g ] chromen-2-one 200.26

31 14b (7R) -8,8-Dimethyl-7- (3-methyl-but-2-enyloxy) -7,8-dihydro- 6H- pyrano [3,2-chromen-2-onene 314.38

32 14c (7R) -8,8-Dimethyl-7- (2-methyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one 300.14

33 14d 7R) -8,8-Dimethyl-7- (3-phenyl-propoxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one 364.43

Example 34. (7R) -7- [3- (2-Methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -Pyrano [3,2- g ] Production of chromen-2-one (18a)

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 subjected to silica gel column separation to obtain 200 mg of pure product 3- (2-methoxy) -propan-1-ol (16a), 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 (16a), which was applied to the next step.

Step 2.

      As shown in the reaction scheme, 3- (2-methoxyphenyl) -propan-1-ol (461 mg, 2.77 mmol) was added to a round flask and dissolved in anhydrous dichloromethane. 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 (17a) was obtained through silica gel column separation, which was applied to the next step.

Step 3.

The same procedure as in Example 30 was carried out except that the round flask of Example 30 was changed to 1- (3-bromo-propyl) -2-methoxy-benzene (17a) instead of methane iodide (13a). (7R) -7- [3- (2-methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g with the following physical properties ] 9 mg of chromen-2-one (18a) was obtained and used as a sample of an experiment example.

Yield: 5.5%;

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  35. (7R) -7- [3- (3- Methoxy - Phenyl )- Propoxy ] -8,8-dimethyl-7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (18b)

In the first step of Example 34, 3-methoxycinnamic acid instead of 2-methoxycinnamic acid in the round flask of the first method, and 3- (3) instead of 3- (2-methoxy) propionic acid in the round flask of the second method. (7R) -7- [3- (3-methoxy-phenyl) -propoxy] -8 having the following physical properties by the same process as the reaction of Example 34 except for changing to -methoxy) propionic acid; 3.5 mg of 8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (18b) was obtained and used as a sample for the experimental example.

Yield: 2.2%;

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  36. (7R) -7- [3- (4- Methoxy - Phenyl )- Propoxy ] -8,8-dimethyl-7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (18c)

In the first step of Example 34, 4-methoxycinnamic acid instead of 2-methoxycinnamic acid in the round flask of the first method, and 3- (4) instead of 3- (2-methoxy) propionic acid in the round flask of the second method. (7R) -7- [3- (4-methoxy-phenyl) -propoxy] -8 having the following physical properties by the same process as the reaction of Example 34 except for changing to -methoxy) propionic acid; 3.5 mg of 8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (18c) was obtained and used as a sample for the experimental example.

Yield: 5.2%;

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  37. (7R) -7- [3- (3,4- Dimethoxy - Phenyl )- Propoxy ] -8,8-dimethyl-7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (18d)

Step 1.

      In the first step of Example 34, 3,4-dimethoxycinnamic acid instead of 2-methoxycinnamic acid in the round flask of the first method, 3 instead of 3- (2-methoxy) propionic acid in the round flask of the second method The pure product 3- (3,4-dimethoxy) -propan-1-ol (16d) was subjected to the same process as the first step reaction of Example 34 except that it was changed to-(3,4-dimethoxy) propionic acid. ) 236 mg was applied 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 (16d) (180mg, 0.92mmol) was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and then 234 mg of pure product 1- (3-iodo-propyl) -3,4-dimethoxy-benzene (17d) was obtained through silica gel column separation, which was applied to the next step.

Step 3.

The same procedure as in Example 30, except that the round flask of Example 30 was changed to 1- (3-iodo-propyl) -3,4-dimethoxy-benzene (17d) instead of methane iodide (13a). (7R) -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 (18d) was obtained as a sample of the experimental example.

Yield: 14.6%;

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  38. (7R) -7- [3- (2,3- Dimethoxy - Phenyl )- Propoxy ] -8,8-dimethyl-7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (18e)

In the first step of Example 37, 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 37 was carried out to give (7R) -7- [ 3- (2,3-dimethoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (18e) 9.0 mg was obtained and used as a sample of an experiment example.

Yield: 3.1%;

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  39. (7R) -8,8-Dimethyl-7- [3- (3,4,5- Trimethoxy - Phenyl )- Propoxy ] -7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (18f)

In the first step of Example 37, 3,4,5-trimethoxycinnamic acid instead of 3,4-dimethoxycinnamic acid in the round flask of the first method, 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 37 was carried out to obtain (7R) ) -8,8-dimethyl-7- [3- (3,4,5-trimethoxy-phenyl) -propoxy] -7,8-dihydro- 6H -pyrano [3,2- g ] chrome 14.2 mg of men-2-ones (18f) were obtained and used as a sample of an experiment example.

Yield: 7.6%;

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 34 18a (7R) -7- [3- (2-Methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H- pyrano [3,2- g ] chromen-2-one 394.46

35 18b (7R) -7- [3- (3-Methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H- pyrano [3,2- g ] chromen-2-one 394.46

36 18c (7R) -7- [3- (4-Methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H- pyrano [3,2- g ] chromen-2-one 394.46

37 18d (7R) -7- [3- (3,4-Dimethoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H- pyrano [3,2- g ] chromen-2-one 424.19

38 18e (7R) -7- [3- (2,3-Dimethoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H- pyrano [3,2- g ] chromen-2-one 424.19

39 18f (7R) -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  40. (7R) -8,8-Dimethyl-7- (3- Phenyl - Allyloxy ) -7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (23a)

Step 1.

      As shown in the reaction scheme, cinnamic acid (19a) (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 (20a), which was applied to the next step.

Step 2.

      As shown in the reaction scheme, 3-phenyl-acrylic acid methyl ester (20a) (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 (21a), which was applied to the next step.

Step 3.

      As shown in the reaction scheme, 3-phenyl-pro-2-phen-1-ol (21a) (1 g, 7.45 mmol) was added to a round flask and dissolved in anhydrous dichloromethane, and boron tribromide (1M) was used for water vaporization. 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 (22a), which was applied to the next step.

Step 4.

The same procedure as in Example 30 was carried out except that the round flask of Example 30 was changed to (3-bromo-propenyl) -benzene (22a) instead of methane iodide (13a) to have the following physical properties ( 52 mg of 7R) -8,8-dimethyl-7- (3-phenyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (23a) Obtained and used as a sample of an experiment example.

Yield: 35.4%;

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  41. (7R) -7- [3- (4- Methoxy - Phenyl )- Allyloxy ] -8,8-dimethyl-7,8- Dehydro - 6H - Pyrano [3,2- g ] Chrome Preparation of 2-one (23b)

The same process as in the first, second, third, and fourth steps of Example 40 was repeated except that the first round flask was replaced with 4-methoxycinnamic acid (19b) instead of cinnamic acid (19a). (7R) -7- [3- (4-methoxy-phenyl) -allyloxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- having the following physical properties g ] chromen-2-one (23b) 5 mg was obtained and used as the sample of an experiment example.

Yield: 34.2%;

Oil phase;

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

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 40 23a (7R) -8,8-Dimethyl-7- (3-phenyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one 362-42

41 23b (7R) -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  Affectionate Decursin  Influence of Derivatives

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

THP-1 cells cultured in Reference Example 1 were dispensed in a 24 well plate at 2.0 × 10 ⁶ / m in RPMI containing 0.5% FBS and incubated in an incubator (37 ° C., 5% CO ₂ ) for 16 hours. After incubation, treatment with decursin derivatives (10 μg / ml) for 1 hour followed by HDE (1 μg / ml) for 24 hours, followed by monocyte chemoattractant protein-1 (monocyte) in supernatant using ELISA. The amount of chemoattractant protein-1, MCP-1), IL-6, IL8 was measured, and the experimental results are shown in Table 9 below.

matter MCP Amount of -1 ( pg Of ml ) IL - 6 of  Sheep ( pg Of ml ) IL - 8 of  amount( pg Of ml ) 2 39.2 96.3 2528 4 ND ND ND 6a ND ND ND 6b ND ND ND 6c ND ND ND 6d 90 470 2771 9a 78 128 2610 9b 77.4 265 2454 9c 129 635 2580 9d 110 313 2571 9e 91 435 2489 9f 91 348 2437 9g 82.1 259 2584 9h 63.3 218 2493 9i 35.6 33.3 1337 9j 292 657 2441 9k 128 511 2589 9l 73.3 156 2706 9m ND ND ND 9n 40.9 147 2715 9o 36.8 76.3 2663 9p ND ND ND 9q ND ND ND 9r ND ND ND 9s ND ND ND 12a ND ND ND 12b ND ND ND 12c ND ND ND 14a 97.4 258.2 2558.4 14b 44.5 115.2 2545.4 14c ND ND ND 14d 42.7 330.1 2619.3 18a ND ND ND 18b ND ND ND 18c ND ND ND 18d ND ND ND 18e ND ND ND 18f ND ND ND 23a ND 209.1 2339.9 23b ND ND ND Normal 33.3 23.3 40.9 Tick treatment group 93.9 525 2697 Dexamethasone treatment group 36.2 25.3 67

Experimental results show that the amounts of MCP-1, IL-6 and IL-8 in the normal group of THP-1 cells are 33.3, 23.3 and 40.9 pg / ml. The amount of 8 was found to increase to 93.9, 525 and 2697 pg / ml (Table 8). Treatment of dexamethasone, a positive control in the increased condition by ticks, reduced the amount of MCP-1, IL-6 and IL-8 to 36.2, 25.3 and 67 pg / ml, almost equivalent to that of the normal group. .

      Meanwhile, 9i and 9o of the synthesized (-) decursin derivatives reduced the amount of MCP-1 and IL-6 increased by the tick to the level almost equivalent to the dexamethasone treatment group. In addition, the 2, 9a, 9b, 9h, 9l and 9n materials also significantly reduced the amounts of MCP-1 and IL-6. Synthetic (-) decursin derivatives did not significantly affect the amount of IL-8 in general, but 9i substance reduced the amount of IL-8 by 50%.

       Taken together, (-)-decurin derivatives synthesized on THP-1 cells generally reduced the amount of MCP-1, IL-6 and IL-8 increased by ticks, especially 9i and 9o substances. They reduced the amount of MCP-1 and IL-6 increased by ticks to nearly the same level as dexamethasone, a drug used in existing atopic diseases.

Experimental Example 2 Measurement of the Effect of Decursin Derivatives on the MCP-induced MCP-1 / IL-6 / IL-8 Secretion in EoL-1

      Experiments were carried out as follows to measure the ELISA of decursin derivatives synthesized in 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, treatment with decursin derivatives (10 μg / ml) for 1 hour followed by HDE (1 μg / ml) for 24 hours, followed by monocyte chemoattractant protein-1 (monocyte) in supernatant using ELISA. The amount of chemoattractant protein-1, MCP-1), IL-6, IL8 was measured, and the experimental results are shown in Table 10 below.

matter MCP Amount of -1 ( pg Of ml ) IL - 6 of  Sheep ( pg Of ml ) IL Volume of -8 ( pg Of ml ) 2 59.2 117 474 4 ND ND ND 6a ND ND ND 6b ND ND ND 6c ND ND ND 6d 164 121 729 9a 105 107 1409 9b 121 264 1104 9c 36.8 43.1 374 9d 39.9 54.1 329 9e 151 222 1219 9f 43.8 52 354 9g 45.3 54.6 624 9h 87.6 229 914 9i 39.2 32 199 9j 40.7 70.4 309 9k 154 221 1154 9l 70.7 79.9 1284 9m ND ND ND 9n 44.5 93.1 1129 9o 33 34.1 674 9p ND ND ND 9q ND ND ND 9r ND ND ND 9s ND ND ND 12a ND ND ND 12b ND ND ND 12c ND ND ND 14a 194.7 121.6 834.1 14b 43.0 58.4 844.0 14c ND ND ND 14d 45.4 72.6 879.0 18a ND ND ND 18b ND ND ND 18c ND ND ND 18d ND ND ND 18e ND ND ND 18f ND ND ND 23a ND 136.5 703.2 23b ND ND ND Normal 43.8 26.2 184 Tick treatment group 237 219 819 Dexamethasone Treatment group 43.8 18.8 159

Experimental results show that the amount of MCP-1, IL-6 and IL-8 in the normal group of EoL-1 cells is 43.8, 26.2 and 184 pg / ml, whereas MCP-1, IL-6 and It was confirmed that the amount of IL-8 was increased to 237, 219 and 819 pg / ml (Table 9). Treatment of dexamethasone, a positive control in the increased state by ticks, showed that the amounts of MCP-1, IL-6 and IL-8 were reduced to 43.8, 18.8 and 159 pg / ml, almost equivalent to those of the normal group. .

       Meanwhile, the 9c, 9d, 9f, 9g, 9i, 9j, 9n, and 9o substances in the synthesized decursin derivatives reduced the amount of MCP-1 increased by ticks to almost the same level as the dexamethasone treated group. In addition, substances 9c, 9d, 9f, 9g, 9i, 9j, 9l, 9n, and 9o reduced the amount of IL-6 increased by about 80% or more ticks, almost the same level as the dexamethasone treatment group. The amount of phase IL-6 increased by ticks was reduced by at least 50%. In addition, substance 9i reduced the amount of IL-8 increased by ticks to approximately the same level as the dexamethasone treated group.

        Taken together, (-)-decursin derivatives synthesized on EoL-1 cells generally reduced the amount of MCP-1, IL-6 and IL-8 increased by ticks, especially 9c, 9d, 9f, 9i and 9o substances reduced the amount of MCP-1 and IL-6 increased by ticks to approximately 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 1 Preparation of Powder

(-)- Decursin Derivative ( 9o ) 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 Derivative ( 9o ) 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 Derivative ( 9o ) 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 Derivative ( 9o ) 10 mg

Mannitol 180 mg

Sterile distilled water for injection 2974 mg

Na ₂ HPO ₄ 12H ₂ O 26 mg

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

Formulation Example 5 Preparation of Liquid

(-)- Decursin Derivative ( 9o ) 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 Derivative ( 9o ) 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 Preparation of Healthy Drink

(-)- Decursin Derivative ( 9o ) 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 (15)

      (-)-Decursin derivative compounds of the novel structure represented by the following general formula (I) synthesized with (-)-decursinol as precursors and pharmaceutically acceptable salts thereof:

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

Here, A 'is a substituent which can be substituted at least one at o, m, p position, hydrogen atom, hydroxy group, nitro group, amine group, acetate group, halogen atom, C ₁ to C ₄ lower alkyl group, lower alkoxy group And at least one substituent selected from the group consisting of lower alkyl esters and lower alkyl carboxy groups; n is an integer of 0-4. A compound according to claim 1, wherein the compound of general formula (I) is R ₁ is a halogen atom, or a C ₁ to C ₁₀ alkyl group, an alkenyl group, an alkynyl group, or an A substitution unsubstituted or substituted with a C ₁ to C ₄ lower alkyl group, Wherein A 'of the A substituent is one or more substituents selected from hydrogen, hydroxy, amine, halogen, methyl, ethyl, methoxy, ethoxy, nitro or acetyl groups substituted at the o, m and p positions; n is an integer of 0 or 1 and a salt thereof. The compound of claim 2, wherein the general formula (I) compound is R ₁ Is an A substituent unsubstituted or 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 substituted in the o, m and p positions; n is an integer of 0 or 1 and a salt thereof. The method of claim 3 wherein the general formula (I) compound is (3 R) -3- methyl-2-part rim elderly acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H, 8H- Pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -cis-2-methyl-but-2-tenophosphate 2,2-dimethyl-8-oxo-3,4- Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -2-methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-di Hydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -3-phenyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H- Pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-di Hydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -3- (2-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo -3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -3- (2-acetoxy-phenyl) -acrylic acid 2, 2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester, ( 3R ) -3- (3-methoxy- Phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -3- (3-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, ( 3 R ) -3- (3-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3 -Yl-ester, ( 3R ) -3- (4-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g] chromen-3-yl-ester, ( 3R ) -3- (4-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -P Lano [3,2-g] chromen-3-yl-ester, ( 3R ) -3- (4-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester, ( 3R ) -3- (3,4-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8- Oxo -3,4-Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -3- (3,4,5-trimethoxy-phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -3- ( 3,4,5-Trihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl Ester, ( 3R ) -3- (3,4-diacetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2 -g] chromen-3-yl-ester, ( 3R ) -3- (3,4-dihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H , 8H -Pyrano [3,2-g] chromen-3-yl-ester, ( 3R ) -benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pi Lano [3,2- g ] chromen-3-yl-ester, ( 3R ) -3,4,5-trihydroxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester, ( 3R ) -3,4,5-triacetoxy-benzoic acid 2,2-dimethyl-8-oxo- 3,4-dehi Dro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester compound and salts thereof. (-)-Decursin derivative compounds of the novel structure represented by the following general formula (II) synthesized with (-)-decursinol as precursors and pharmaceutically acceptable salts thereof:

(II) In the above formula, R ₂ is a C ₁ to C ₂₀ alkyl group, an alkenyl group, an alkynyl group, an A substituent or a B substituent which is unsubstituted or substituted with one or more R ′, wherein R ′ is a halogen atom, a nitro group, an amine group or C ₁ to C ₄ lower alkyl group; A substituent

 , B substituent

Wherein A ′ or B ′ is a substituent which may be optionally substituted at o, m, and p positions, and is a hydrogen atom, a hydroxy group, an acetate group, a halogen atom, a C ₁ to C ₄ lower alkyl group, a lower alkoxy group and a lower alkyl ester And at least one substituent selected from the group consisting of lower alkyl carboxy groups; n is an integer of 0-4. The compound of formula (II) according to claim 5, wherein R ₁ is a C ₁ to C ₁₀ alkyl group, an alkenyl group, an alkynyl group, or an A substitution which is unsubstituted or substituted with a halogen atom or a C ₁ to C ₄ lower alkyl group, Wherein A 'of the A substituent is one or more substituents selected from hydrogen, hydroxy, amine, halogen, methyl, ethyl, methoxy, ethoxy, nitro or acetyl groups substituted at the o, m and p positions; n is an integer of 0 or 1 and a salt thereof. The compound of formula (II) according to claim 6, wherein R ₂ is substituted with one or more substituents selected from a hydrogen atom, a hydroxy group, a methyl group, an ethyl group, a methoxy group, an ethoxy group or an acetyl group in which R ₂ is substituted at o, m, and p positions; Unsubstituted A substituent or B substituent; n is an integer of o or 1 and a salt thereof. 8. A compound according to claim 7, wherein the compound of formula (II) is (7R) -7-methoxy-8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2. -One, (7R) -8,8-dimethyl-7- (3-methyl-but-2-tenyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2 -One, (7R) -8,8-dimethyl-7- (2-methyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one, ( 7R) -8,8-dimethyl-7- (3-phenyl-propoxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one, (7R) -7 -[3- (2-methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one, (7R ) -7- [3- (3-methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one , (7R) -7- [3- (4-methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen- 2-one, (7R) -7- [3- (3,4-dimethoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g] chromen-2-one, (7R) -7- [3- ( 2,3- dimethoxy-phenyl) -propoxy] -8,8- Methyl-7,8-dihydro - 6H - pyrano [3,2- g] chromen-2-one, (7R) -8,8- dimethyl-7- [3- (3,4,5-tree Methoxyphenyl) -propoxy)]-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one, (7R) -8,8-dimethyl-7- (3- Phenyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one, (7R) -7- [3- (4-methoxy-phenyl) -allyl Roxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one compound and salt thereof. After dissolving (+)-decursinol in an organic solvent, a sulfonylating agent, preferably triphenyl phosphine, is reacted in a solvent to give 8,8-dimethyl- 8H -pyrano [3,2- g ] First step of obtaining chromen-2-one; 8,8-dimethyl- 8H -pyrano [3,2- g ] chromen-2-one and (R, R)-(-), N, N`-bis (3,5) obtained in the first step -Di-tet butyl salicyridine) -1,2, -cyclohexanediamino manganese (III) chloride is dissolved in a solvent, and then in the presence of acid regulators and buffers such as sodium hyperchlorite solution and sodium phosphate dibasic solution. reaction of (6 R, 7 R) -6,7- dimethyl -8,8- epoxy -6 H - pyrano [3,2- g] a second step of preparing a chromen-2-one; (6 R , 7 R ) -6,7-epoxy-8,8-dimethyl-6 H -pyrano [3,2- g ] chromen-2-one obtained in the second step was dissolved in a solvent. Preparing (-)-decursinol comprising a third step of adding and reacting a sodium cyanoborohydride and borane trifloride diethyl etherate reagent. Manufacturing method. 10. The process according to claim 9, wherein the sulfonylating agent of the first step uses triphenyl phosphine, para -toluenesulfonyl chloride or methanesulfonyl chloride.      10. The process according to claim 9, wherein the sulfonylating agent of the first step is reacted in a pyridine or triethylamine solvent.      10. The process according to claim 9, wherein the acid modifier and buffer of the second step use sodium hyperchlorite solution and sodium phosphate dibasic solution.        Atopic dermatitis disease comprising as an active ingredient (-)-decurin derivative compound of the novel structure represented by the general formula (I) or (II) of claim 1 or 5 or a pharmaceutically acceptable salt thereof Pharmaceutical composition for prevention and treatment.  Atopic dermatitis disease comprising as an active ingredient (-)-decurin derivative compound of the novel structure represented by the general formula (I) or (II) of claim 1 or 5 or a pharmaceutically acceptable salt thereof Functional foods for prevention and improvement.         15. The dietary supplement of claim 14 in the form of a powder, granule, tablet, capsule or beverage.