WO2008102994A1 - Composition comprising decursin derivative for treating and preventing atopic dermatitis - Google Patents

Composition comprising decursin derivative for treating and preventing atopic dermatitis Download PDF

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Publication number
WO2008102994A1
WO2008102994A1 PCT/KR2008/001017 KR2008001017W WO2008102994A1 WO 2008102994 A1 WO2008102994 A1 WO 2008102994A1 KR 2008001017 W KR2008001017 W KR 2008001017W WO 2008102994 A1 WO2008102994 A1 WO 2008102994A1
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WIPO (PCT)
Prior art keywords
pyrano
dimethyl
chromen
group
ester
Prior art date
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PCT/KR2008/001017
Other languages
French (fr)
Inventor
Yong Jin Park
Joo Hwan Kim
Gyu Yong Song
Jin Suk Woo
Jin Sook Kim
Dong Hee Kim
Jee Hyun Lee
Chi-Young Yun
In Sik Kim
Ji Sook Lee
Young Kook Kim
Mun Chual Rho
Yong Seok Choi
Original Assignee
Yong Jin Park
Joo Hwan Kim
Gyu Yong Song
Jin Suk Woo
Jin Sook Kim
Dong Hee Kim
Jee Hyun Lee
Chi-Young Yun
In Sik Kim
Ji Sook Lee
Young Kook Kim
Mun Chual Rho
Yong Seok Choi
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Application filed by Yong Jin Park, Joo Hwan Kim, Gyu Yong Song, Jin Suk Woo, Jin Sook Kim, Dong Hee Kim, Jee Hyun Lee, Chi-Young Yun, In Sik Kim, Ji Sook Lee, Young Kook Kim, Mun Chual Rho, Yong Seok Choi filed Critical Yong Jin Park
Publication of WO2008102994A1 publication Critical patent/WO2008102994A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/232—Angelica
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/318—Foods, ingredients or supplements having a functional effect on health having an effect on skin health and hair or coat

Definitions

  • the present invention relates to a composition comprising decursin derivative for treating and preventing atopic dermatitis.
  • Atopic dermatitis is a chronic inflammatory disease having chronic recurrent tendency, which is characterized by itching, psoriasis, eczema, and keratin etc (Hanifin J.M. et al., Guidelines of care for atopic dermatitis. /. Am. Acd. Dermatol., 5Q pp391-404, 2004) and has been reported that it is caused by the hypersensitive immunologic response against environmental allergen such as the feces of mites, resulting in skin chronic inflammation (Oh J. W. et al., Nationalwide study for epidemiological change of atopic dermatitis in school aged children between 1995-2000 and kindergarten aged children in 2003 in Korea; Pediatr.
  • cytokines sirh as EL-4. IL-3 etc and TGF- involved in fibrosis, are released during chronic inflammation progress and the released cytokines increase fibroblast activating IL-6, which causes to the differentiation and proliferation of fibroblast to reproduce too abundant extra cellular matrix resulting in the modification and fibrosis of cells and tissues.
  • MCP-I Monocyte Chemoattraotant Protein-1
  • CCR2 chemokine receptor
  • MIP-I alpha and MCP-I differentially regulate acute and reapsing autoimmune encephalomyelitis as well as TH1/Th2 lymphocyte differentiation; J. Leukoc. Biol., 62, pp681-687, 1997).
  • Intraveneous injection of MCP-I redices the reproduction of IL-12 and increases the reproduction of IL-4, which indicates that it may become worsen IgE-dependent allergic inflammations indirectly.
  • IL-8 an important inflammatory chemokine released from bronchial epithelial cells, plays important roles in initial stage of inflammatory response (Harada A et al., Essential involvement of interleukin-8 in acute inflammation; J. Leukoc. Biol., pp559-564, 1994), which causes to bronchial hyperresponsiveness resulting in allergic rhinitis or bronchial asthma (Fujimura M et al., Role of leukotriene B4 in bronchial hy ⁇ perresponsiveness induced by interleukin 8; Eur. Respir.
  • the present inventors have endeavored to synthesize the effective decursin derivatives for treating and preventing atopic dermatitis and to study the pharmacological effect of the compounds and finally, the present inventors have found that the compounds based on decursin are effective in treating and preventing atopic dermatis as a medicine or health care food.
  • the present invention provides new decursin derivatives or the pharmaceutical acceptable salt thereof showing potent treating and preventing activity of atopic dermatitis.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising new decursin derivatives as an active ingredient in an amount effective to prevent and treat atopic dermatitis, together with a pharmaceutically acceptable carrier by inhibiting the release of MCP-I, IL-6 and IL-8 induced by mites.
  • the present invention also provides a method for treating atopic dermatitis by inhibiting the release of MCP-I, IL-6 and IL-8 indiced by mites in a mammal comprising administering to said mammal an effective amount of above-mentioned compounds, together with a pharmaceutically acceptable carrier thereof.
  • the present invention also provides a use of above described compounds for the preparation of for manufacture of medicament employed for preventing or treating atopic dermatitis in human or mammal.
  • the present invention also provides a health functional food comprising above compounds for the prevention or improvement of treating atopic dermatitis by inhibiting the release of MCP-I, IL-6 and IL-8 indited by mites as an xtive ingredient in an amount effective to preventing and improving atopic dermatitis.
  • the present invention provides a novel compound represented by the following general formula (I), or the pharmaceutically acceptable salt thereof:
  • A is hydrogen atom, C -C lower alkyl group, dialkyl acryloyl group or cinnamoyl
  • R' is optionally substituted at o-, m- and p- position with at least one selected from the group consisting of a hydrogen atom, hydroxyl group, acetate group, halogen atom, C - C lower alkyl group, lower alkoxy group, lower alkyl ester, and lower alkyl carboxy group.
  • the present invention provides a novel compound represented by the following general formula (II), and the pharmaceutically acceptable salt thereof:
  • [27] B is selected from the group consisting of hydrogen atom, hydroxyl group, C -C
  • the most preferred compound of general formula (II) is selected from the group consisting of; [30] methane sulfonr acid 2,2 ⁇ limethyl-8-oxo-3,4-dihydro-2 H,8H-pyrano[3,2-g] chromen-3-yl-ester, and benzene sulfonic arid 2,2-dimethyl-8ox>3,4-dihydro-2 H,8H
  • inventive compounds represented by general formula (I) and (II) can be transformed into their pharmaceutically acceptable salt and solvates by the con- ventional method well known in the art.
  • aid-addition salt thereof formed by a pharmaceutically acceptable free acid thereof is useful and can be prepared by the conventional method.
  • the salts are precipitated by the water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile to prepare aid addition salt thereof and further the mixture of equivalent amount of compound and diluted acid with water or alcohol such as glycol monomethylether, can be heated and subsequently dried by evaporation or filtrated under reduced pressure to obtain dried salt form thereof.
  • the water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile
  • organic acid or inorganic acid can be used as a free acid of above-described method.
  • organic acid such as methansulfonic add, p-toluensulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic aid, suxinic acid, oxalic acid, benzoic acid, lactic acid, glycolt acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic aid, ascorbic acid, carbonylic acid, vanillic acid, hydroiodic aid and the like, and inorganic acid such as hydrochloric add, phosphoric arid, sulfuric acid, nitric aid, tartaric aid and the like can be used herein.
  • the pharmaceutically acceptable metal salt form of inventive compounds may be prepared by using base.
  • the alkali metal or alkali-earth metal salt thereof can be prepared by the conventional method, for example, after dissolving the compound in the excess amount of alkali metal hydrosde or alkali-earth metal hydroxide solution, the insoluble salts are filtered and remaining filtrate is subjected to evaporation and drying to obtain the metal salt thereof.
  • sodium, potassium or calcium salt are pharmaceutically suitable and the corresponding silver salt can be prepared by reacting alkali metal salt or alkali-earth metal salt with suitable silver salt such as silver nitrate.
  • the pharmaceutically acceptable salt of the compound represented by general formula (I) and (H) comprise all the aidic or basic salt which may be present at the compounds, if it does not indicated specifically herein.
  • the pharmaceutically acceptable salt of the present invention comprise the salt of hydroxyl group such as the sodium, calcium and potassium salt thereof; the salt of amino group such as the hydrogen bromide salt, sulfuric acid salt, hydrogen sulfuric arid salt, phosphate salt, hydrogen phosphate salt, dihydrophosphate salt, acetate salt, sirxinate salt, citrate salt, tartarate salt, lactate salt, mandelate salt, methanesulfonate(mesylate) salt and p - toluenesulfonate (tosylate) salt etc, which can be prepared by the conventional method well known in the art.
  • the compounds of the invention may be chemically synthesized by the methods which will be explained by following reaction schemes hereinafter, which are merely exemplary and in no way limit the invention.
  • the reaction schemes show the steps for preparing the representative compounds of the present invention, and the other compounds also may be produced by following the steps with appropriate modifications of reagents and starting materials, which are envisaged by those skilled in the art.
  • (+)-decursinol dissolved in anhydrous dichloromethane is react with pyridium chloromate and molecular sieve.
  • the solvent which does not cause to adverse effect such as dichloromethane, chloroform, diethylether, tetrahydrofuran etc may be used in the reaction.
  • the reaction temperature in the reaction can be performed at cool temperature to room temperature, preferably, at room temperature however it is not limited thereto.
  • the reaction time .in the reaction can be performed in the range from 30 min to 1 hr, more preferably, 1 hr with stirring to synthesize 8,8-dimethyl-6H-pyrano(3,2-g] chromen-2,7-dione ( 17).
  • the reaction mixture of 8,8-dimethyl-6H-pyrano[3,2-g]chromen-2,7-dione (17) dissolved in anhydrous ethanol is react with hydroxyl ammoniurrchloride and pyridine.
  • the solvent which does not cause to adverse effect such as dichloromethane, chloroform, diethylether, tetrahydrofuran etc may be used in the reaction.
  • the reaction temperature in the reaction can be performed at the temperature ranging from room temperature to 100°C, preferably, 8O°C, however it is not limited thereto. It is preferable that the reaction time in the reaction can be performed in the range from 30 min to 1 hr, more preferably, 1 hr with stirring to synthesize 8,8-dimethyl-6 tf - pyrano[3,2-g]chromen-2,7-dione 7o»me ( 18).
  • reaction temperature in the reaction can be performed at the temperature ranging from cool temperature to room temperature, preferably, at room temperature, however it is not limited thereto.
  • the reaction time in the reaction can be performed in the range from 3 his to 18 hrs, more preferably, 5 hrs with stirring to synthesize 3,3-dimethyl acryloyl chloride ( 19a).
  • (+)-decursinol is dissolved in anhydrous dichloromethane and 3,3-dimethyl acryloyl chloride ( 19a) and pyridine are added thereto at the temperature ranging from cool temperature to room temperature, preferably, at room temperature, however it is not limited thereto.
  • the reaction time in the reaction can be performed in the range from 1 hr to 18 hrs, more preferably, 2 hrs ranging from room temperature.
  • the concentrated residue is performed to Silicagel oolumn chromatography to synthesize 8,8-dimethyl-6 /J-pyrano[3,2-g]chromen-2,7-dione 7-[0 ⁇ 3 > 3-dimethyl acryloyl)-oxime] ( 20a).
  • reaction temperature in the reaction can be performed at the temperature ranging from room temperature to 100°C, preferably, at 80°C,however it is not limited thereto.
  • the reaction time in the reaction can be performed in the range from 3 hrs to 18 hrs, more preferably, 5 hrs with stirring to synthesize cinnamoyl chloride (7a).
  • the reaction mixture of 8,8 ⁇ limethyl-6H-pyrano[3,2-g]chromen-2,7-dione 7-oxme ( 18) is dissolved in anhydrous dichloromethane to react with cinnamoyl chloride ( 7a).
  • the concentrated residue is performed to Silkagel column chromatography to synthesize 8,8-dimethyl-6 H-pyrano[3,2-g]chromen-2,7-dione 7-(0-cinnamoyl-o»me) ( 21a).
  • (+)-ttectfsinol R 15a. -CH 3 16a. -Ob 15b. -Ph 16b. -Ph
  • reaction temperature in the reaction can be performed at cool temperature to room temperature, preferably, at room temperature, however it is not limited thereto.
  • reaction time in the reaction can be performed in the range from 5 hrs to 20 hrs, more preferably, 15 hrs with stirring to synthesize methan sulfonic aixi 2,2-dimethyl-8ox>3,4-dihydro- 2H, ⁇ SH-pyrano[3,2-g]chromen-3-yl-ester ( 16a).
  • composition comprising novel decursin derivatives represented by the general formula (I) to (II) or the pharmaceutically acceptable salt thereof is proved to have potent treating and preventing effect on atopic dermatitis being confirmed by the various in vitro and in vivo experiments sich as the inhibition test on the release of MCP-I, IL-6, and IL-8 indiced by mites. Aooordingly, the composition can be useful as a pharmaceutical composition and health functional food for the prevention and treatment of atopic dermatitis.
  • the present invention provides to a pharmaceutical composition
  • a pharmaceutical composition comprising decursin derivative represented by general formula (I) and (II) as an active ingredient in an amount effective to prevent and treat atopic dermatitis, together with a pharmaceutically acceptable carrier by inhibiting the release of MCP-I, IL-6 and IL-8 indiced by mites.
  • the present invention also provides a method for treating atopic dermatitis by inhibiting the release of MCP-I, IL-6 and IL-8 indited by mites in a mammal comprising administering to said mammal an effective amount of decursin derivative represented by general formula (I) and (II), together with a pharmaceutically acceptable carrier thereof.
  • the present invention also provides a use of decursin derivative represented by general formula (I) and (II) for the preparation of for manufacture of medicament employed for preventing or treating atopic dermatitis in human or mammal.
  • the present invention also provides a health functional food comprising decursin derivative represented by general formula (I) and (II) for the prevention or improvement of treating atopic dermatitis by inhibiting the release of MCP-I, IL-6 and IL-8 induced by mites as an active ingredient in an amount effective to preventing and improving atopic dermatitis.
  • the present invention provides to a pharmaceutical composition
  • a pharmaceutical composition comprising decursin derivative represented by the following general formula (III) as an active ingredient in an amount effective to prevent and treat atopic dermatitis, together with a pharmaceutically acceptable carrier by inhibiting the release of MCP-I, IL-6 and IL-8 induced by mites:
  • R is C -C alkyl group, C -C alkenyl group, C -C alkynyl group unsubstituted
  • R 1 is halogen atom, nitro group, amine group or C -C lower alkyl group
  • a group is [64]
  • A is at least one optionally at o-, m- or p- position, selected from the group consisting of a hydrogen atom, hydroxyl group, acetate group, halogen atom, C -C lower alkyl group, C -C lower alkoxy group and C -C lower alkyl ester group;
  • n is an integer of 0 to 4.
  • R is halogen atom or C -C alkyl group, C -C alkenyl group, C -C
  • A is at least one optionally at ⁇ ?-, m- o ⁇ p- position, selected from group consisting of a hydrogen atom, hydroxyl group, methyl group, ethyl group, methoxy group, ethoxy group and acetyl group; n is an integer of 0 to 1.
  • the most preferred compound of general formula (III) is one selected from the group consisting of; [70] 3-Methyl-but-2-enoic aid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-py ⁇ wo[3,2-g] chromen-3-yl-ester, Cw-2-Methyl-but-2-enoic acid 2,2-dimethyl-8-o?D-3,4-dihydro- 2H,8H- pyrano[3 ,2-g]chromen-3-yl-ester, 7r ⁇ ns-2-Methyl-but-2-enoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 2-methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2tf,8tf-pyrano[3,2-g] chromen- 3-yl
  • the present invention provides to a pharmaceutical composition
  • a pharmaceutical composition comprising decursin derivative represented by the following general formula (IV) as an active ingredient in an amount effective to prevent and treat atopic dermatitis, together with a pharmaceutically axeptable carrier by inhibiting the release of MCP-I, IL-6 and IL- 8 induced by mites:
  • C is a hydrogen atom, C -C lower alkyl group or ketone group.
  • composition comprising an efficient amount of the compound represented by general formula (III) to (IV) or the pharmxeutically acceptable salt thereof as an active ingredient in amount effective to treat or prevent atopic dermatitis disease, together with pharmaceutically acceptable carriers or diluents.
  • It is another object of the present invention to provide the pharmaceutical composition comprising an efficient amount of the compound represented by general formula (III) to (IV) or the pharmaceutically acceptable salt thereof as an active ingredient in amount effective to treat or prevent atopic dermatitis disease, together with pharmaceutically acceptable carriers or diluents.
  • the present invention also provides a method for treating atopic dermatitis by inhibiting the release of MCP-I , IL-6 and IL-8 indiced by mites in a mammal comprising administering to said mammal an effective amount of decursin derivative represented by general formula (III) and (IV), together with a pharmaceutically acceptable carrier thereof.
  • the compound according to the present invention can be provided as a pharmaceutical composition containing pharmxeutically acceptable carriers, adjuvants or diluents, ⁇ br example, the compound of the present invention can be dissolved in oils, propylene glycol or other solvents which are commonly used to prodice an injection. Suitable examples of the carriers include physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc, but are not limited to them. R)r topical administration, the compound of the present invention can be formulated in the form of ointments and creams.
  • the compound of the present invention in pharmaceutical dosage forms may be used in the form of their pharmaceutically acceptable salts, and also may be used alone or in appropriate association, as well as in combination with other pharmaceutically active compounds.
  • the compound of the present invention may be formulated into preparations for injections by dissolving, suspending, or emulsifying them in aqueous solvents such as normal saline, 5% Dextrose, or non-aqueous solvent such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol.
  • aqueous solvents such as normal saline, 5% Dextrose, or non-aqueous solvent such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol.
  • the formulation may include conventional additives sich as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • the desirable dose of the inventive compound varies depending on the condition and the weight of the subject, severity, drug form, route and period of administration, and may be chosen by those skilled in the art. However, in order to obtain desirable effects, it is generally recommended to administer at the amount ranging 0.0001 - 100 mg/kg, preferably 0.001-10 mg/kg by weight/day of the inventive compound of the present invention. The dose may be administered in single or divided into several times per day. In terms of composition, the compound should be present between 0.0001 to 10% by weight, preferably 0.0001 to Y 3 Ic by weight based on the total weight of the composition.
  • the pharmaceutic composition of present invention can be administered to a subject animal such as mammals (rat, mouse, domestic animals or human) via various routes. All modes of administration are contemplated, for example, administration can be made by inhaled, orally, rectally or by intravenous, intramuscular, subcutaneous, intrathecal, epidural or intracerebroventricular injection.
  • novel (+)-decursin derivatives represented by general formula (I) to (IV) of the present invention also can be used as a main component or additive and aiding agent in the preparation of various functional health food and health care food.
  • a health functional food comprising decursin derivative represented by general formula (I), (II), (III) or (IV) for the prevention or improvement of treating atopic dermatitis by inhibiting the release of MCP-I, EL-6 and IL-8 indited by mites as an active ingredient in an amount effective to preventing and improving atopic dermatitis.
  • a functional health food defined herein the functional food having enhanced functionality sirh as physical functionality or physiological functionality by adding the compound of the present invention to conventional food to prevent or improve cancer disease in human or mammal.
  • a health care food defined herein the food containing the compound of the present invention showing no specific intended effect but general intended effect in a small amount of quantity as a form of additive or in a whole amount of quantity as a form of capsule, pill, tablet etc
  • a sitologically acceptable additive defined herein any substance the intended use which results or may reasonably be expected to result-directly or indirectly-in its becoming a component or otherwise affecting the characteristics of any food for example, thickening agent, maturing agent, bleaching agent, se- questerants, humectant, antkaking agent, clarifying agents, curing agent, emulsifier, stabilizer, thickner, bases and acid, foaming agents, nutrients, coloring agent, flavoring agent, sweetner, preservative agent, antioxidant, etc, which shall be explained in detail as follows.
  • a substance is added to a food for a specific purpose in that food, it is referred to as a direct additive and indirect food additives are those that become part of the food in trace amounts due to its packaging, storage or other handling.
  • Above described health foods can be contained in food, health beverage, dietary therapy etc, and may be used as a form of powder, granule, tablet, chewing tablet, capsule, beverage etc for preventing or improving cancer disease.
  • above described compounds can be added to food or beverage for prevention and improvement of atopic dermatitis.
  • the amount of above described compound in food or beverage as a functional health food or health care food may generally range from about 0.01 to 100 w/w % of total weight of food for functional health food composition.
  • the preferable amount of the compound of the present invention in the functional health food, health care food or special nutrient food may be varied in accordance to the intended purpose of each food, it is preferably used in general to use as a additive in the amount of the compound of the present invention ranging from about 0.01 to 5% in food such as noodles and the like, from 40 to 100% in health care food on the ratio of 100% of the food composition.
  • the health beverage composition of present invention contains above described compound as an essential component in the indicated ratio
  • the other component can be various deodorant or natural carbohydrate etc such as conventional beverage.
  • natural carbohydrate are monosaccharide such as glicose, fructose etc; disaxharide sich as maltose, sirrose etc; conventional sugar siEh as dextrin, cyclodextrin; and sugar alcohol such as xylitol, and erythritol etc
  • natural deodorant such as taumatin, stevia extract sich as levaudioside A, glycyrrhizin et al., and synthetic deodorant sich as saxharin, aspartam et al.
  • the amount of above described natural carbohydrate is generally ranges from about 1 to 20 g, preferably 5 to 12 g in the ratio
  • the other components than aforementioned composition are various nutrients, a vitamin, a mineral or an electrolyte, synthetic flavoring agent, a coloring agent and improving agent in case of cheese, chocolate et al., pectic acid and the salt thereof, alginic arid and the salt thereof, organic add, protective colloidal adhesive, pH controlling agent, stabilizer, a preservative, glycerin, alcohol, carbonizing agent used in carbonate beverage et al.
  • the other component than aforementioned ones may be fruit juice for preparing natural fruit juce, fruit juice beverage and vegetable beverage, wherein the component can be used independently or in combination.
  • the ratio of the components is not so important but is generally range from about 0 to 20 w/w % per 100 w/w % present composition.
  • Examples of addable food comprising aforementioned extract therein are various food, beverage, gum, vitamin complex, health improving food and the like.
  • the novel decursin derivatives of the present invention showed potent inhibiting activity of the release of MCP-I, BL-6 and IL-8 indiced by dermite in THP-I or EoL-I cell, therefore the compounds can be useful in treating or preventing atopic dermatitis.
  • THP-I Culture (111] THP-I cell (2.0 x 10 /m; human acute monocyte leukemia cell; American Type Culture Collection (Manassas, VA, USA), a human monocyte, was cultured in RPMI 1640 medium containing 10 U/ml of penicillin, 10 rag/ml of streptomicin, 25 ⁇ g/ml of ampoteri ⁇ n and 10% FBS at 37°C in CO incubator for 3 days.
  • EoL-I Culture (114) EoL-I cell (2.0 x loVm; eosinophilic leukemia cell; the RIKEN Bio Resource center (Tsukuba, Japan), a human eosinophil, was cultured in RPMI 1640 medium containing 10* U/ml of penicillin, 10 mg/ml of streptomicin, 25 ⁇ g/ml of amphotericin B and 10% FBS at 37°C in CO incubator for 3 days
  • (+)-decursinol (20mg, 0.081 mmol) in 100 ml round flask was dissolved in 20ml of anhydrous di ⁇ lorome thane. Pyridine (13.1 ⁇ t£, 0.162mmol) and trrhloro acetyl chloride (4a) were added thereto and stirred 2 hrs at room temperature. The reaction solution was filtrated and concentrated in vaocuo.
  • reaction solution was cooled to room temperature and concentrated in vaxuo to obtain ⁇ nnamoyl chloride (7a).
  • the reaction solution was dissolved in anhydrous dichloromethane.
  • Step 2 (+)-decursinol (2g, 8.12mmol) was dissolved in anhydrous dichloromethane in 100ml of round flask. Cinnamoyl chloride (7a) dissolved in mixture solvent of pyridine (1.97 ml, 24.4 mM) and anhydrous dichloromethane (30 ml) was added thereto and stirred for 2 hours at room temperature.
  • reaction solution was concentrated in vaocuo and the concentrates were performed to Silica gel column chromatography to obtain solid form of 3-phenyl-acrylic add 2,2-dimethy l-8-oxo-3 ,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (8a).
  • Example 15 2,2-d ⁇ methyl-8-oxo-3,4- ⁇ lihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (8b) of Example 15 was substituted with 3-(2-methoxy-phenyl)-acryl acid 2,2-dimethyl-8-oxo-3,4-dehydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (8g), all the procedure was performed in a similar method to Example 15 to obtain white solid form of 3-(2-hydroxy-phenyl)-acrylic acid 2 1 2-dimethyl-8-oxo-3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester (8h).
  • Example 13 Excepting that rinnamic arid (6a) used in the 1 st step of Example 13 was substituted with 2,5-dimethoxy rinnamic arid (61), all the procedure was performed in a similar method to Example 13 to obtain pale yellow solid form of 3-(2,5-dimethoxy-phenyl)-acrylic arid 2,2-dimethyl-8-oJo-3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester (81).
  • Step 2.3 Excepting that ⁇ nnamic acid (6a) used in the 1 st step of Example 13 was substituted with benzoic add (12a), all the procedure was performed in a similar method to Example 13 to obtain semi-solid form of benzoic add 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (14a).
  • Step 1 As shown in the above-described reaction formulae, 3,3-dimethylacrylic acid (2a, lOOmg, 0.999mmole) was dissolved in 3ml of anhydrous dbhloromethane and stirred in cold ice under nitrogen atmosphere, oxalyl chloride(356.8 ⁇ £, 3.996mmol) was added thereto dropwisely and stirred at 0? for 5 hours. The reaction solution was cooled to room temperature and concentrated to obtain 3,3-dimethylacryloyl chloride (19a) to dissolve in anhydrous dichloromethane. [477]
  • the THP-I cell line prepared in Reference Example was distributed to 24 well plates containing RPMI medium including 0.5% FBS in a concentration of 2.Ox 10 /ml and incubated in 5% CO incubator at 37 °C for 16 hours. After the incubation,
  • 14c, 16a, and 23 was also decreased to the almost equivalent level to that in positive control group and the level of IL-6 after the treatment of test samples prepared in Examples, i.e., compounds 3d, lla, lie, 14c, 16a, and 23 was also decreased to the almost equivalent levels to that in positive control group.
  • the level of IL-8 after the treatment of test samples prepared in Examples, especially, compounds 3d and 1 Ic was also decreased to the almost equivalent level to that in positive control group.
  • the test treatment group treated with compounds 3d, lie, Hd, 18 and 23, decreased the levels of MCP-I, DL-6 and IL-8.
  • the EoL-I cell line prepared in Reference Example was distributed to 24 well plates containing RPMI medium including 0.5% FBS in a concentration of 2.Ox 10 6 /ml and incubated in 5% CO incubator at 37 °C for 16 hours. After the incubation, 10 microgram/rnl of the decursin derivatives prepared in Examples was treated therewith for 1 hour and 1 microgram/ml of HDE was treated therewith for 24 hours.
  • the level of MCP-I, IL-6 and IL-8 in the supernatant was determined by ELISA method and the result was shown in following Tables 16 and 17.
  • the level of MCP-I after the treatment of test samples prepared in Examples, i.e., compounds 3d, lla-e, 14b-c, 18 and 23 was also decreased to the almost equivalent level to that in positive control group and the level of IL-6 after the treatment of test samples prepared m Examples, i.e., compounds 3d and l ie was also decreased to the almost equivalent levels to that in positive control group.
  • the level of IL-8 after the treatment of test samples prepared in Examples, especially, compounds 3d, l ie and 28 was also decreased to the almost equivalent level to that in positive control group.
  • the test treatment group treated with compounds 3d, l ie, and 23, decreased the levels of MCP-I, IL-6 and IL-8.
  • Tablet preparation was prepared by mbdng above components and entabletting.
  • Injection preparation was prepared by dissolving active component, controlling pH to about 7.5 and then filling all the components in 2 m£ ample and sterilizing by con ⁇ ventional injection preparation method.
  • liquid preparation was prepared by dissolving active component, filling all the components and sterilizing by conventional liquid preparation method.
  • Health beverage preparation was prepared by dissolving active component, mb ⁇ ng, stirred at 85°C for 1 hour, filtered and then filling all the components in 1000m£ ample and sterilizing by conventional health beverage preparation method.
  • the novel decursin derivatives of the present invention showed potent inhibiting activity of the release of MCP-I , IL-6 and IL-8 induced by dermite in THP-I or EoL-I cell, therefore the compounds can be useful in treating or preventing atopic dermatitis.

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Abstract

The present invention relates to the novel decursin derivatives, the preparation thereof and the composition comprising the same. The novel decursin derivatives of the present invention showedpotent inhibiting activity of the release of MCP-1, IL-6 and IL-8 induced by dermite in THP-1 or EoL-1 cell, therefore the compounds can be useful in treating or preventing atopic dermatitis.

Description

Description
COMPOSITION COMPRISING DECURSIN DERIVATIVE FOR TREATING AND PREVENTING ATOPIC
DERMATTΠS
Technical Field
[1] The present invention relates to a composition comprising decursin derivative for treating and preventing atopic dermatitis.
[2]
Background Art
[3] Atopic dermatitis is a chronic inflammatory disease having chronic recurrent tendency, which is characterized by itching, psoriasis, eczema, and keratin etc (Hanifin J.M. et al., Guidelines of care for atopic dermatitis. /. Am. Acd. Dermatol., 5Q pp391-404, 2004) and has been reported that it is caused by the hypersensitive immunologic response against environmental allergen such as the feces of mites, resulting in skin chronic inflammation (Oh J. W. et al., Nationwide study for epidemiological change of atopic dermatitis in school aged children between 1995-2000 and kindergarten aged children in 2003 in Korea; Pediatr. Allergy Respir. Dis,, 13, pp227-237, 2003). Recently, the occurrence of atopic dermatitis has been sharply increased in the world. However the fundamental treatment of the disease oould not be found yet and only the symptomatic treatment for the disease has been performed till now. (Williams H. C, Clinical practice, Atopic dermatitis. New England J. Med., 352. pp2314-24, 2005).
[4] Various kinds of cytokines, sirh as EL-4. IL-3 etc and TGF- involved in fibrosis, are released during chronic inflammation progress and the released cytokines increase fibroblast activating IL-6, which causes to the differentiation and proliferation of fibroblast to reproduce too abundant extra cellular matrix resulting in the modification and fibrosis of cells and tissues. It has been reported that MCP-I (Monocyte Chemoattraotant Protein-1) is bound to chemokine receptor (CCR2) and the MCP- 1 -deficient mice lose its chemotaxtic activity resulting in the debilitation of resistance against specific bacterial infection <I_u B et al., Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1 -deficient mice; J. Exp. Med., Ml, pp601-608, 1998), similarly in the experiment performed by CCR2-deficient mice. MCP-I ha been reported to converse ThO cells into Th2 cytokines-releasing cells (Karpus W. J. et al., MIP-I alpha and MCP-I differentially regulate acute and reapsing autoimmune encephalomyelitis as well as TH1/Th2 lymphocyte differentiation; J. Leukoc. Biol., 62, pp681-687, 1997). Intraveneous injection of MCP-I redices the reproduction of IL-12 and increases the reproduction of IL-4, which indicates that it may become worsen IgE-dependent allergic inflammations indirectly.
[5] IL-8, an important inflammatory chemokine released from bronchial epithelial cells, plays important roles in initial stage of inflammatory response (Harada A et al., Essential involvement of interleukin-8 in acute inflammation; J. Leukoc. Biol., pp559-564, 1994), which causes to bronchial hyperresponsiveness resulting in allergic rhinitis or bronchial asthma (Fujimura M et al., Role of leukotriene B4 in bronchial hy¬ perresponsiveness induced by interleukin 8; Eur. Respir. /., ϋ, pp306-311, 1998; kurashima K et al; Increase of chemokine levels in sputum precedes exacerbation of acute asthma attacks. /. Leukoc. Biol, £2, pp 313-316, 1996).
[6] Angelica gigas belonged to Umbelliferae has been reported to comprise
(+)-decursin, a dihydropyranocoumarin, and (+)-decursinols (7-hydroxy-8,8-dimethyl-7,8-dihydro-6 //-pyrano(3,2-g)chromen-2-one) as main components (Bae E. A. et al., Anti-helicobacter pylori activity of herbal medicines; Biol. Pharm. Bull. 21, pp990, 1998).
[7] However, there has been not reported or disclosed about therapeutic effect of various decursin derivatives synthesized from decursin on atopic dermatitis in any of above cited literatures, the disclosures of which are incorporated herein by reference.
[8] Therefore, the present inventors have endeavored to synthesize the effective decursin derivatives for treating and preventing atopic dermatitis and to study the pharmacological effect of the compounds and finally, the present inventors have found that the compounds based on decursin are effective in treating and preventing atopic dermatis as a medicine or health care food.
[9]
Disclosure of Invention Technical Problem
[10] According to one aspect, the present invention provides new decursin derivatives or the pharmaceutical acceptable salt thereof showing potent treating and preventing activity of atopic dermatitis.
[11] The present invention also provides a pharmaceutical composition comprising new decursin derivatives as an active ingredient in an amount effective to prevent and treat atopic dermatitis, together with a pharmaceutically acceptable carrier by inhibiting the release of MCP-I, IL-6 and IL-8 induced by mites.
[12] The present invention also provides a method for treating atopic dermatitis by inhibiting the release of MCP-I, IL-6 and IL-8 indiced by mites in a mammal comprising administering to said mammal an effective amount of above-mentioned compounds, together with a pharmaceutically acceptable carrier thereof.
[13] The present invention also provides a use of above described compounds for the preparation of for manufacture of medicament employed for preventing or treating atopic dermatitis in human or mammal.
[14] The present invention also provides a health functional food comprising above compounds for the prevention or improvement of treating atopic dermatitis by inhibiting the release of MCP-I, IL-6 and IL-8 indited by mites as an xtive ingredient in an amount effective to preventing and improving atopic dermatitis.
[15]
Technical Solution
[16] Accordingly, the present invention provides a novel compound represented by the following general formula (I), or the pharmaceutically acceptable salt thereof:
[17] ChemistryRgure 1
A
[18] (I)
[19] wherein
[20] A is hydrogen atom, C -C lower alkyl group, dialkyl acryloyl group or cinnamoyl
. group of which phenyl group is unsubstituted or substituted with R'; wherein R' is optionally substituted at o-, m- and p- position with at least one selected from the group consisting of a hydrogen atom, hydroxyl group, acetate group, halogen atom, C - C lower alkyl group, lower alkoxy group, lower alkyl ester, and lower alkyl carboxy group.
[21] As preferable compounds of general formulae (I), the compounds of the present invention wherein A is hydrogen atom, methyl group, dimethyl acryloyl group or cinnamoyl group of which phenyl group is unsubstituted or substituted with R'; wherein R' is optionally substituted with at least one selected from the group consisting of a hydrogen atom, methyl group, methoxy group and acetate group.
[22] The most preferred oompounds of general formula (I) are selected from the group consisting of;
[23] 8,8-dimetøyl-6H-pyrano[3,2-g]criromen-2,7-dione 7orime, 8,8-dimethyl-ό H - pyrano[3,2-g]chromen-2,7-dione 7-[0-(3,3-dimethyl∑cryloyl)-o»me], 8,8-dimethyl-6 H -pyrano[3,2-g]chromen-2,7-dione 7-(OJcinnamoylo»me), 8,8-dimethyl-6 H - pyrano[3,2-g]chromen-2,7-dione 7-[ 0-(4-methoxycinnarnoyl)-osme], 8,8-dimethyl-6 H-pyrano[3,2-g]chromen-2,7-dione 7-[0-(3,4-dimethoxydnnamoyl)-o}ime], 8,8-dimethyl-6Η-pyrano[3,2-g]chromen-2,7-dione 7-[O - (3,4,5-rrimethoxycinnamoyl)-oxime], 8,8-dimethyl-6 /f-pyrano[3,2-g] chromen- 2,7-dione 7-[0-(3-acetoxyάnnamoyl)-θ5άme], and 8,8-dimethyl-6 H-pyrano[3,2-g] chromen-2,7-dione 7-[ 0-(3,4-diacetoxycinnamoyl)-ojάme].
[24] Also, the present invention provides a novel compound represented by the following general formula (II), and the pharmaceutically acceptable salt thereof:
[25] ChemistryHgure 2
Figure imgf000005_0001
[26] Wherein,
[27] B is selected from the group consisting of hydrogen atom, hydroxyl group, C -C
1 4 lower alkyl group, C -C lower alkoxy group, halogen atom, and 5- or 6- membered
\ 6 heterocyclic ring unsubstituted or substituted with C -C lower alkyl group or C -C lower alkoxy group. [28] As preferable compounds of general formulae (II), the compounds of the present invention wherein B is selected from the group consisting of methyl group, halogen atom, C -C lower alkyl group, C -C lower alkoxy group and phenyl group. [29] The most preferred compound of general formula (II) is selected from the group consisting of; [30] methane sulfonr acid 2,2<limethyl-8-oxo-3,4-dihydro-2 H,8H-pyrano[3,2-g] chromen-3-yl-ester, and benzene sulfonic arid 2,2-dimethyl-8ox>3,4-dihydro-2 H,8H
-pyrano[3,2-g]chromen-3-yl-ester. [31] The inventive compounds represented by general formula (I) and (II) can be transformed into their pharmaceutically acceptable salt and solvates by the con- ventional method well known in the art. for the salts, aid-addition salt thereof formed by a pharmaceutically acceptable free acid thereof is useful and can be prepared by the conventional method. Ebr example, after dissolving the compound in the excess amount of aid solution, the salts are precipitated by the water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile to prepare aid addition salt thereof and further the mixture of equivalent amount of compound and diluted acid with water or alcohol such as glycol monomethylether, can be heated and subsequently dried by evaporation or filtrated under reduced pressure to obtain dried salt form thereof.
[32] As a free acid of above-described method, organic acid or inorganic acid can be used. Ibr example, organic acid such as methansulfonic add, p-toluensulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic aid, suxinic acid, oxalic acid, benzoic acid, lactic acid, glycolt acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic aid, ascorbic acid, carbonylic acid, vanillic acid, hydroiodic aid and the like, and inorganic acid such as hydrochloric add, phosphoric arid, sulfuric acid, nitric aid, tartaric aid and the like can be used herein.
[33] Further, the pharmaceutically acceptable metal salt form of inventive compounds may be prepared by using base. The alkali metal or alkali-earth metal salt thereof can be prepared by the conventional method, for example, after dissolving the compound in the excess amount of alkali metal hydrosde or alkali-earth metal hydroxide solution, the insoluble salts are filtered and remaining filtrate is subjected to evaporation and drying to obtain the metal salt thereof. As a metal salt of the present invention, sodium, potassium or calcium salt are pharmaceutically suitable and the corresponding silver salt can be prepared by reacting alkali metal salt or alkali-earth metal salt with suitable silver salt such as silver nitrate.
[34] The pharmaceutically acceptable salt of the compound represented by general formula (I) and (H) comprise all the aidic or basic salt which may be present at the compounds, if it does not indicated specifically herein. Ibr example, the pharmaceutically acceptable salt of the present invention comprise the salt of hydroxyl group such as the sodium, calcium and potassium salt thereof; the salt of amino group such as the hydrogen bromide salt, sulfuric acid salt, hydrogen sulfuric arid salt, phosphate salt, hydrogen phosphate salt, dihydrophosphate salt, acetate salt, sirxinate salt, citrate salt, tartarate salt, lactate salt, mandelate salt, methanesulfonate(mesylate) salt and p - toluenesulfonate (tosylate) salt etc, which can be prepared by the conventional method well known in the art. [35] The compounds of the invention may be chemically synthesized by the methods which will be explained by following reaction schemes hereinafter, which are merely exemplary and in no way limit the invention. The reaction schemes show the steps for preparing the representative compounds of the present invention, and the other compounds also may be produced by following the steps with appropriate modifications of reagents and starting materials, which are envisaged by those skilled in the art.
[36]
[37] GENERAL SYNTHETIC PROCEDURES
[38] [Scheme 1]
[39]
V k°ΛγAVJN
Figure imgf000007_0001
Figure imgf000007_0002
1. (+)-decursinol 17 18
[40] At the 1st step in reaction, (+)-decursinol dissolved in anhydrous dichloromethane is react with pyridium chloromate and molecular sieve. The solvent which does not cause to adverse effect such as dichloromethane, chloroform, diethylether, tetrahydrofuran etc may be used in the reaction. It is preferable that the reaction temperature in the reaction can be performed at cool temperature to room temperature, preferably, at room temperature however it is not limited thereto. It is preferable that the reaction time .in the reaction can be performed in the range from 30 min to 1 hr, more preferably, 1 hr with stirring to synthesize 8,8-dimethyl-6H-pyrano(3,2-g] chromen-2,7-dione ( 17). At the 2° step in reaction, the reaction mixture of 8,8-dimethyl-6H-pyrano[3,2-g]chromen-2,7-dione (17) dissolved in anhydrous ethanol is react with hydroxyl ammoniurrchloride and pyridine. The solvent which does not cause to adverse effect such as dichloromethane, chloroform, diethylether, tetrahydrofuran etc may be used in the reaction. It is preferable that the reaction temperature in the reaction can be performed at the temperature ranging from room temperature to 100°C, preferably, 8O°C, however it is not limited thereto. It is preferable that the reaction time in the reaction can be performed in the range from 30 min to 1 hr, more preferably, 1 hr with stirring to synthesize 8,8-dimethyl-6 tf - pyrano[3,2-g]chromen-2,7-dione 7o»me ( 18).
[41] [42] [Scheme 2]
[43]
Figure imgf000008_0001
Z=CH3
[44] . At the 1st step in reaction, 3,3-dimethyl a:rylate ( 2a) is dissolved in anhydrous dichloromethane and oxalylchloride is added thereto dropwisely. The solvent which does not cause to adverse effect such as dichloromethane, chloroform, diethylether, tetrahydrofuran etc may be used in the reaction. It is preferable that the reaction temperature in the reaction can be performed at the temperature ranging from cool temperature to room temperature, preferably, at room temperature, however it is not limited thereto. It is preferable that the reaction time in the reaction can be performed in the range from 3 his to 18 hrs, more preferably, 5 hrs with stirring to synthesize 3,3-dimethyl acryloyl chloride ( 19a). At the 2° step in the reaction, (+)-decursinol is dissolved in anhydrous dichloromethane and 3,3-dimethyl acryloyl chloride ( 19a) and pyridine are added thereto at the temperature ranging from cool temperature to room temperature, preferably, at room temperature, however it is not limited thereto. It is preferable that the reaction time in the reaction can be performed in the range from 1 hr to 18 hrs, more preferably, 2 hrs ranging from room temperature. The concentrated residue is performed to Silicagel oolumn chromatography to synthesize 8,8-dimethyl-6 /J-pyrano[3,2-g]chromen-2,7-dione 7-[0<3>3-dimethyl acryloyl)-oxime] ( 20a).
[45]
[46] [Scheme 3]
Figure imgf000008_0002
[48] At the 1st step in reaction, άnnamic acid is dissolved in anhydrous benzene and the mixture of thionyl chloride and M N-dimethylforrnarnide is added thereto to react together. The solvent which does not cause to adverse effect such as dichloromethane, chloroform, diethylether, tetrahydrofuran etc may be used in the reaction. It is preferable that the reaction temperature in the reaction can be performed at the temperature ranging from room temperature to 100°C, preferably, at 80°C,however it is not limited thereto. It is preferable that the reaction time in the reaction can be performed in the range from 3 hrs to 18 hrs, more preferably, 5 hrs with stirring to synthesize cinnamoyl chloride (7a). At the 2" step in reaction, the reaction mixture of 8,8<limethyl-6H-pyrano[3,2-g]chromen-2,7-dione 7-oxme ( 18) is dissolved in anhydrous dichloromethane to react with cinnamoyl chloride ( 7a). The concentrated residue is performed to Silkagel column chromatography to synthesize 8,8-dimethyl-6 H-pyrano[3,2-g]chromen-2,7-dione 7-(0-cinnamoyl-o»me) ( 21a).
[49] [50] [Scheme 4] [51]
Figure imgf000009_0001
1. (+)-ttectfsinol R= 15a. -CH3 16a. -Ob 15b. -Ph 16b. -Ph
[52] At the Is step in reaction, decursinol and triethylamine are dissolved in anhydrous dichloromethane to react with sulfonyl chloride. The reaction solvent which does not cause to adverse effect stch as dichloromethane, chloroform, diethylether, tetrahydrofuran etc may be used in the reaction. It is preferable that the reaction temperature in the reaction can be performed at cool temperature to room temperature, preferably, at room temperature, however it is not limited thereto. It is preferable that the reaction time in the reaction can be performed in the range from 5 hrs to 20 hrs, more preferably, 15 hrs with stirring to synthesize methan sulfonic aixi 2,2-dimethyl-8ox>3,4-dihydro- 2H,<SH-pyrano[3,2-g]chromen-3-yl-ester ( 16a).
[53] The inventive composition comprising novel decursin derivatives represented by the general formula (I) to (II) or the pharmaceutically acceptable salt thereof is proved to have potent treating and preventing effect on atopic dermatitis being confirmed by the various in vitro and in vivo experiments sich as the inhibition test on the release of MCP-I, IL-6, and IL-8 indiced by mites. Aooordingly, the composition can be useful as a pharmaceutical composition and health functional food for the prevention and treatment of atopic dermatitis.
[54] The present invention provides to a pharmaceutical composition comprising decursin derivative represented by general formula (I) and (II) as an active ingredient in an amount effective to prevent and treat atopic dermatitis, together with a pharmaceutically acceptable carrier by inhibiting the release of MCP-I, IL-6 and IL-8 indiced by mites.
[55] The present invention also provides a method for treating atopic dermatitis by inhibiting the release of MCP-I, IL-6 and IL-8 indited by mites in a mammal comprising administering to said mammal an effective amount of decursin derivative represented by general formula (I) and (II), together with a pharmaceutically acceptable carrier thereof.
[56] The present invention also provides a use of decursin derivative represented by general formula (I) and (II) for the preparation of for manufacture of medicament employed for preventing or treating atopic dermatitis in human or mammal.
[57] The present invention also provides a health functional food comprising decursin derivative represented by general formula (I) and (II) for the prevention or improvement of treating atopic dermatitis by inhibiting the release of MCP-I, IL-6 and IL-8 induced by mites as an active ingredient in an amount effective to preventing and improving atopic dermatitis.
[58] Also, the present invention provides to a pharmaceutical composition comprising decursin derivative represented by the following general formula (III) as an active ingredient in an amount effective to prevent and treat atopic dermatitis, together with a pharmaceutically acceptable carrier by inhibiting the release of MCP-I, IL-6 and IL-8 induced by mites:
[59] ChemistryHgure 3
Figure imgf000010_0001
[60] (in)
[61] wherein
[62] R is C -C alkyl group, C -C alkenyl group, C -C alkynyl group unsubstituted
1 1 20 r 2 20 3 20 or substituted with at least one R' or A group; of which R1 is halogen atom, nitro group, amine group or C -C lower alkyl group; and
1 4 [63] A group is [64]
Figure imgf000011_0001
[65] wherein [66] A is at least one optionally at o-, m- or p- position, selected from the group consisting of a hydrogen atom, hydroxyl group, acetate group, halogen atom, C -C lower alkyl group, C -C lower alkoxy group and C -C lower alkyl ester group;
[67] n is an integer of 0 to 4. [68] As preferable compounds of general formulae (ITI), the compounds of the present invention wherein R is halogen atom or C -C alkyl group, C -C alkenyl group, C -C
I 1 10 2 10 5 alkynyl group unsubstituted or substituted with C -C lower alkyl group or A group;
10 1 4 of which A is at least one optionally at <?-, m- oτp- position, selected from group consisting of a hydrogen atom, hydroxyl group, methyl group, ethyl group, methoxy group, ethoxy group and acetyl group; n is an integer of 0 to 1.
[69] The most preferred compound of general formula (III) is one selected from the group consisting of; [70] 3-Methyl-but-2-enoic aid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyτwo[3,2-g] chromen-3-yl-ester, Cw-2-Methyl-but-2-enoic acid 2,2-dimethyl-8-o?D-3,4-dihydro- 2H,8H- pyrano[3 ,2-g]chromen-3-yl-ester, 7rαns-2-Methyl-but-2-enoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 2-methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2tf,8tf-pyrano[3,2-g] chromen- 3-yl-ester, Pent-2-enoic acid 2,2-dimethyl-8-ox>3,4-dihydro- 2/7,Stf-pyrano[3,2-,g] chromen-3-yl-ester, But-3-enoic add 2>2-dimethyl-8-oxo-3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester, Pent-4-enoic acid 2,2<hmethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, Acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, Chloro-acetic acid
2,2-dimethyl-8ox>3,4-dihydro- 2H8H-pyrano[3,2-g]chrornen-3-yl-ester, Trichloroacetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, Pentanoic acid 2,2-dimethyl-8θ)θ-3,4-dihyclro- 2ff,SF-pyrano[3,2-g] chromen- 3-yl-ester, Decanoic aid 2,2-dimethyl-8-oxo-3)4-dihydro- 2H,8H-pyτano['h,2-g] chromen-3-yl-ester, 3 -phenyl- aery lie acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H.8H - pyrano[3,2-g]chromen-3-yl-ester, 3-(4-methoxy-phenyl)-acrylic acid 2,2-dimethyl-8-oJO-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-(4-hydroxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2Η,8H-pyrano[3,2- g]chromen-3-yl-ester, 3-(3,4-dimethoxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro - 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-(3,4,5-trimethoxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester, 3-(3,4,5-trihydroxy-phenyl)-acrylic acid 2,2-dimethy 1-8-oxo-3 ,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-(2-methoxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3 ,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester, 3-(2-hydroxy-phenyl)-acrylic acid 2,2-dimethy 1-8-OJD-3 ,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-(3-methoxy-phenyl)-acrylic arid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester, 3-(2,3-dimethoxy-phenyl)-acrylic arid 2,2-dimethy 1-8-oxo-3 ,4-dihydro- 2H,8H-pyrano[3)2-g]chromen-3-yl-ester, 3-(2,4-dimethoxy-phenyl)-acrylic arid 2,2-dimethyl-8-oxo-3 ,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester, 3-(2,5-dimethoxy-phenyl)-a:rylic acid 2,2-dimethyl-8-o>o-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-(2,4,5-trimethoxy-phenyl)-acrylic arid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester, 3-(4-nitro-phenyl)-acrylic arid 2,2- dimethyl- 8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-(3-hydroxy-phenyl)-acrylic arid 2,2- dimethyl-8-oxo-3,4-dihydro- 2H.8H - pyrano[3,2-g)chromen-3-yl-ester, 3-(3-xetoxy-phenyl)-a;rylb arid 2,2-dimethyl-8-θ}o-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-(3,4-dihydroxy-phenyl)-acrylic arid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester, 3-(3,4-diacetoxy-phenyl)-acrylic arid 2,2-dimethyl-8-oxo-3 ,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-(4-hydroxy-3-methoxy-phenyl)-acrylic arid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester, 3-(4-acetoxy-3-methoxy-phenyl)-acrylic arid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-(4-acetoxy-3,4-dimethoxy-phenyl)-acrylic arid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, Benzoic arid 2,2-dimethyl-8-oxo-3 ,4-dihydro- 2H,8H-pyrano[3,2-g]chromeπ-3-yl-ester, 3,4,5-trihydroxy-benzob arid 2,2-dimethy 1-8-oxo-3 ,4-dihydro- 2Zϊ)8f-'-pyrano[3!2-g] chromen-3-yl-ester and 3,4,5-triacetoxy-benzoic arid 2,2-dimethyl-8-ox>3,4-dihydro- 2HSH-pyrano[3,2-g]chromen-3-yl-ester. [71] Also, the present invention provides to a pharmaceutical composition comprising decursin derivative represented by the following general formula (IV) as an active ingredient in an amount effective to prevent and treat atopic dermatitis, together with a pharmaceutically axeptable carrier by inhibiting the release of MCP-I, IL-6 and IL- 8 induced by mites:
[72] ChemistryHgure 4
Figure imgf000013_0001
(IV)
[73] Wherein,
[74] C is a hydrogen atom, C -C lower alkyl group or ketone group.
1 4
[75] As preferable compounds of general formulae (IV), the compounds of the present invention wherein C is at least one selected from the group consisting of a hydrogen atom or ketone group.
[76] The most preferred compound of general formula (IV) is one selected from the group consisting of;
[77] 8,8-dimethyl-67ϊr-pyrano[3,2-g]chromen-2,7-dione, 8,8-dimethyl- 6H-pyrano[3,2-g] chromen-2-one.
[78] Accordingly, it is another object of the present invention to provide the pharmaceutical composition comprising an efficient amount of the compound represented by general formula (III) to (IV) or the pharmxeutically acceptable salt thereof as an active ingredient in amount effective to treat or prevent atopic dermatitis disease, together with pharmaceutically acceptable carriers or diluents.
[79] It is another object of the present invention to provide the pharmaceutical composition comprising an efficient amount of the compound represented by general formula (III) to (IV) or the pharmaceutically acceptable salt thereof as an active ingredient in amount effective to treat or prevent atopic dermatitis disease, together with pharmaceutically acceptable carriers or diluents.
[80] The present invention also provides a method for treating atopic dermatitis by inhibiting the release of MCP-I , IL-6 and IL-8 indiced by mites in a mammal comprising administering to said mammal an effective amount of decursin derivative represented by general formula (III) and (IV), together with a pharmaceutically acceptable carrier thereof.
[81] In accordance with the other aspect of the present invention, there is also provided a use of the compound represented by general formula (III) to (FV) or the pharma- ceutkally acceptable salt thereof for manufacture of medicines employed for treating or preventing atopic dermatitis disease in mammals including human as an active ingredient in an amount effective to treat or prevent atopic dermatitis disease.
[82] In accordance with the other aspect of the present invention, there is also provided a use of the compound represented by general formula (III) to (IV) or the pharmaceutically acceptable salt thereof for manufacture of medicines employed for treating or preventing atopc dermatitis disease in mammals including human as an active ingredient in an amount effective to treat or prevent atopic dermatitis.
[83] The compound according to the present invention can be provided as a pharmaceutical composition containing pharmxeutically acceptable carriers, adjuvants or diluents, ϊbr example, the compound of the present invention can be dissolved in oils, propylene glycol or other solvents which are commonly used to prodice an injection. Suitable examples of the carriers include physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc, but are not limited to them. R)r topical administration, the compound of the present invention can be formulated in the form of ointments and creams.
[84] Hereinafter, the following formulation methods and excipients are merely exemplary and in no way limit the invention.
[85] The compound of the present invention in pharmaceutical dosage forms may be used in the form of their pharmaceutically acceptable salts, and also may be used alone or in appropriate association, as well as in combination with other pharmaceutically active compounds.
[86] The compound of the present invention may be formulated into preparations for injections by dissolving, suspending, or emulsifying them in aqueous solvents such as normal saline, 5% Dextrose, or non-aqueous solvent such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol. The formulation may include conventional additives sich as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
[87] The desirable dose of the inventive compound varies depending on the condition and the weight of the subject, severity, drug form, route and period of administration, and may be chosen by those skilled in the art. However, in order to obtain desirable effects, it is generally recommended to administer at the amount ranging 0.0001 - 100 mg/kg, preferably 0.001-10 mg/kg by weight/day of the inventive compound of the present invention. The dose may be administered in single or divided into several times per day. In terms of composition, the compound should be present between 0.0001 to 10% by weight, preferably 0.0001 to Y3Ic by weight based on the total weight of the composition.
[88] The pharmaceutic composition of present invention can be administered to a subject animal such as mammals (rat, mouse, domestic animals or human) via various routes. All modes of administration are contemplated, for example, administration can be made by inhaled, orally, rectally or by intravenous, intramuscular, subcutaneous, intrathecal, epidural or intracerebroventricular injection.
[89] The novel (+)-decursin derivatives represented by general formula (I) to (IV) of the present invention also can be used as a main component or additive and aiding agent in the preparation of various functional health food and health care food.
[90] Accordingly, it is the other object of the present invention to provides a health functional food comprising decursin derivative represented by general formula (I), (II), (III) or (IV) for the prevention or improvement of treating atopic dermatitis by inhibiting the release of MCP-I, EL-6 and IL-8 indited by mites as an active ingredient in an amount effective to preventing and improving atopic dermatitis.
[91] The term "a functional health food" defined herein the functional food having enhanced functionality sirh as physical functionality or physiological functionality by adding the compound of the present invention to conventional food to prevent or improve cancer disease in human or mammal.
[92] It is the other object of the present invention to provide a health care food comprising decursin derivatives represented by the following general formula (I)-(FV), or the pharmacologically acceptable salt thereof, together with a sitologkally acceptable additive for the prevention and alleviation of cancer disease.
[93] The term "a health care food" defined herein the food containing the compound of the present invention showing no specific intended effect but general intended effect in a small amount of quantity as a form of additive or in a whole amount of quantity as a form of capsule, pill, tablet etc
[94] The term "a sitologically acceptable additive" defined herein any substance the intended use which results or may reasonably be expected to result-directly or indirectly-in its becoming a component or otherwise affecting the characteristics of any food for example, thickening agent, maturing agent, bleaching agent, se- questerants, humectant, antkaking agent, clarifying agents, curing agent, emulsifier, stabilizer, thickner, bases and acid, foaming agents, nutrients, coloring agent, flavoring agent, sweetner, preservative agent, antioxidant, etc, which shall be explained in detail as follows.
[95] If a substance is added to a food for a specific purpose in that food, it is referred to as a direct additive and indirect food additives are those that become part of the food in trace amounts due to its packaging, storage or other handling.
[96] Above described health foods can be contained in food, health beverage, dietary therapy etc, and may be used as a form of powder, granule, tablet, chewing tablet, capsule, beverage etc for preventing or improving cancer disease.
[97] Also, above described compounds can be added to food or beverage for prevention and improvement of atopic dermatitis. The amount of above described compound in food or beverage as a functional health food or health care food may generally range from about 0.01 to 100 w/w % of total weight of food for functional health food composition. In particular, although the preferable amount of the compound of the present invention in the functional health food, health care food or special nutrient food may be varied in accordance to the intended purpose of each food, it is preferably used in general to use as a additive in the amount of the compound of the present invention ranging from about 0.01 to 5% in food such as noodles and the like, from 40 to 100% in health care food on the ratio of 100% of the food composition.
[98] Providing that the health beverage composition of present invention contains above described compound as an essential component in the indicated ratio, there is no particular limitation on the other liquid component, wherein the other component can be various deodorant or natural carbohydrate etc such as conventional beverage. Examples of aforementioned natural carbohydrate are monosaccharide such as glicose, fructose etc; disaxharide sich as maltose, sirrose etc; conventional sugar siEh as dextrin, cyclodextrin; and sugar alcohol such as xylitol, and erythritol etc As the other deodorant than aforementioned ones, natural deodorant such as taumatin, stevia extract sich as levaudioside A, glycyrrhizin et al., and synthetic deodorant sich as saxharin, aspartam et al., may be useful favorably. The amount of above described natural carbohydrate is generally ranges from about 1 to 20 g, preferably 5 to 12 g in the ratio of 100 mi of present beverage composition.
[99] The other components than aforementioned composition are various nutrients, a vitamin, a mineral or an electrolyte, synthetic flavoring agent, a coloring agent and improving agent in case of cheese, chocolate et al., pectic acid and the salt thereof, alginic arid and the salt thereof, organic add, protective colloidal adhesive, pH controlling agent, stabilizer, a preservative, glycerin, alcohol, carbonizing agent used in carbonate beverage et al. The other component than aforementioned ones may be fruit juice for preparing natural fruit juce, fruit juice beverage and vegetable beverage, wherein the component can be used independently or in combination. The ratio of the components is not so important but is generally range from about 0 to 20 w/w % per 100 w/w % present composition. Examples of addable food comprising aforementioned extract therein are various food, beverage, gum, vitamin complex, health improving food and the like.
[100] The present invention is more specifically explained by the following examples.
However, it should be understood that the present invention is not limited to these examples in any manner. Advantageous Effects
[101] As described in the present invention, the novel decursin derivatives of the present invention showed potent inhibiting activity of the release of MCP-I, BL-6 and IL-8 indiced by dermite in THP-I or EoL-I cell, therefore the compounds can be useful in treating or preventing atopic dermatitis.
[102]
Best Mode for Carrying Out the Invention
[103] It will be apparent to those skilled in the art that various modifications and variations can be made in the compositions, use and preparations of the present invention without departing from the spirit or scope of the invention.
[104] The present invention is more specifically explained by the following examples.
However, it should be understood that the present invention is not limited to these examples in any manner.
[105] The following Reference Example, Examples and Experimental Examples are intended to further illustrate the present invention without limiting its soope.
[106]
Mode for the Invention
[107] Reference Example 1. Reagent and Instrument
[108] 1H-NMR (400MHZ) spectrometer (JNM-AL 400, JEa Ltd. Japan), Melting pointer (Yamako, MD-S3, Japan) and MS spectrum (PE SCK API 2000 MS/MS, Canada) were used in the experiment. All the reagents used in the experiment were procured from Aldrich Chemical Co. and the 1 s grade solvent was used as the other solvent. R>r purification, silica gel column chromatography (Silica gel, Merck, 230-400 mesh) was used.
[109] [HO] Reference Example 2. THP-I Culture [111] THP-I cell (2.0 x 10 /m; human acute monocyte leukemia cell; American Type Culture Collection (Manassas, VA, USA), a human monocyte, was cultured in RPMI 1640 medium containing 10 U/ml of penicillin, 10 rag/ml of streptomicin, 25 μg/ml of ampoteriάn and 10% FBS at 37°C in CO incubator for 3 days.
[112] [113] Reference Example 3. EoL-I Culture [114] EoL-I cell (2.0 x loVm; eosinophilic leukemia cell; the RIKEN Bio Resource center (Tsukuba, Japan), a human eosinophil, was cultured in RPMI 1640 medium containing 10* U/ml of penicillin, 10 mg/ml of streptomicin, 25 μg/ml of amphotericin B and 10% FBS at 37°C in CO incubator for 3 days
[115] [116] Example 1. 3-Methyl-but-2-enoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,Λ//-pyrano[3,2-g]chromen-3-yl-ester (3a)
Figure imgf000018_0001
1. (+)-decursinol R=
Figure imgf000018_0002
[118] As shown in the above-described reaction formulae, the mixture of
3-methyl-but-2-enob acid (410mg, 4.06 mmol), l,3<ϋcyclohexylcarbodiimide (DCC, 1.68g, 8.12mmol) and 4-dimethylaminopyridine (DMAP, 198mg, 1.62 mmol) were dissolved in anhydrous dchloromethane. (+)-decursinol was added thereto to react together with stirring for 24 hours. The reaction solution was washed with dichloromethane, filtrated and concentrated in vaccuo. The concentrates were performed to Silica gel column chromatography to obtain semi-solid form of 3-Methyl-but-2-enoκ aid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g] chromen-3-yl-ester (3a).
[119] yield: 64.0% ; [120] R = O.35(n-hexane:ethyl ∞etate=2: 1); [121] 1H NMR(CDCl , 400MHz) : ppm 7.589(d, 7=9.6Hz, IH), 7.160(s, IH), 6.788(s, IH), 6.222(d, 7=9.6Hz, IH), 5.663(s, IH), 5.086(t, 7=4.8Hz, IH), 3.197(dd, 7=4.8, 17.2Hz, IH), 2.867(dd, 7=4.8, 17.2Hz, lH), 2.146(d, /=1.0Hz, 3H), 1.88O(d, T=LOHz, 3H), 1.384(8, 3HX lJoS(S1 SH);
[122] MS(m/z) 329 (M+H)+.
[123]
[124] Example 2. 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 (3b)
[125] Excepting that 3-methyl-but-2-enoic acid (2a) was substituted with cis -
2-methyl-but-2-enoic acid (2b), all the procedure was performed in a similar method to Example 1 to obtain oil type of Cw-2-methyl-but-2-enoic acid 2,2 dimethyl- 8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (3b).
[126] yield: 56 3% ;
[127] R =O.35(n-hexane:ethyl acetate=2: l);
[128] 1H NMR(CDCl ): ppm 7.595(d, 7=9.2Hz, IH), 7.167(s, IH), 6.819(qd, 7=6.8,
1.2Hz, IH), 6.790(s, H), 6.223(d, /=9.2Hz, IH), 5.092(t, 7=5.4Hz, IH), 3.214(dd, 7 =4.8, 17.2Hz, IH), 2.888(dd, 7=5.4, 17.2Hz, IH), 1.8O3(d, 7=1.2Hz, 3H), 1.767(d, J =6.8Hz, 3H), 1.398(s, 3H), 1.378(s, 3H);
[129] MS{m/z): 329 (M+H)+
[130]
[131] Example 3. Trans-2-methyl-but-2-enoic acid 2,2 dimethyl-
8-oxo-3,4-dihydro-2H,8H-pyrano[3,2-g]chrornen-3-yl-ester (3c)
[132] Excepting that 3-methyl-but-2-enoic acid (2a) was substituted with trans -
2-methyl-but-2-enoic acid (2c), all the procedure was performed in a similar method to Example 1 to obtain oil form of rra«j-2-methyl-but-2-enoic acid 2,2 dimethyl- 8-oxo-3,4-dihydro- 2H,<SH-pyrano[3,2-g]chromen-3-yl-ester (3c).
[133] yield: 43.9% ;
[134] R = 0.48(n-hexane:ethyl acetate=2: 1);
[135] 1H NMR(CDCl3): ppm 7.505(d, /=9.6Hz, IH), 7.074(s, IH), 6.743(m, 2H),
6.154(d, 7=9.6Hz, IH), 5.009(t, 7=4.8Hz, IH), 3.133(dd, 7=4.8, 17.2Hz, IH), 2.806(dd, 7=4.8, 17.2Hz, IH), 1.784(m, 6H), 1.352(s, 3H), 1.319(s, 3H);
[136] MS(M^) : 329 (M+H)+
[137]
[138] Example 4. 2-Methyl-acryl acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H,8H- pyrano[3,2-g]chromen-3-yl-ester (3d) [139] Excepting that 3-methyl-but-2-enoic add (2a) was substituted with
2-methyl-acryl arid (2d), all the procedure was performed in a similar method to Example 1 to obtain semi-solid form of 2-methyl-acryl acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (3d).
[140] yield: 93.3% ;
[141] R =O.52(n-hexane:ethyl acetate=l:l) ;
[142] 1H NMR(CDCl , 400MHz): ppm 7.565(d, /=9.6Hz, IH), 7.141(8, IH), 6.786(s,
IH), 6.216(d, /=9.6Hz, IH), 6.052(s, IH)1 5.562(s, IH), 5.076(t, /=5.2Hz, IH), 3.209(dd, /=4.8, 16.8Hz, IH), 2.883(dd, /=5.6, 17.2Hz, IH), 1.903(s, 3H), 1.384(s, 3H), 1.370(s, 3H);
[143] MS(m/z) : 315 (M+H)+
[144]
[145] Example 5. Pent-2-enoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H^H - pyrano[3,2-g]chromen-3-yl-ester (3e)
[146] Excepting that 3-methyl-but-2-enoc acid (2a) was substituted with Pent-2-enoic add (2e), all the procedure was performed in a similar method to Example 1 to obtain oil form of Pent-2-enoic aid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,#tf-pyrano[3,2-g] chromen-3-yl-ester (3e).
[147] yield: 92.1% ;
[148] R =0.40(n-hexane:ethyl a:etate=2:l) ;
[149] 1H NMR(CDCl ): ppm 7.58(d, /=9.6Hz, IH), 7.151(s, IH), 7.028(m, IH), 6.798(s,
IH), 6.223(d, /=9.6Hz, IH), 5.803(d, /=15.6Hz, IH), 5.111(t, /=4.8Hz, IH), 3.204(dd, /=4.8, 17.2Hz, IH), 2.882 (dd, /=4.8, 17.2Hz, lH), 2.197(m, 2H), 1.390(s, 3H), 1.366(s, 3H), 1.049(t, /=7.6Hz, 3H);
[150] MS(m/z) : 329 (M+H)*
[151]
[152] Example 6. But-2-enoic acid 2,2-dimethyl-8-oxo-3/l-dihydro-v2H)-?flr - pyrano[3,2-g]chromen-3-yl-ester (3f)
[153] Excepting that 3-methyl-but-2-enoic acid (2a) was substituted with but-3-enoic acid (2f), all the procedure was performed in a similar method to Example 1 to obtain oil form of but-2-enoic acid 2,2-dimetb.yl-8-oxo-3,4-dihydro- 2flr,8flr-pyrano[3,2-g] chromen-3-yl-ester (3f).
[154] yield: 90.2% ;
[155] R = O.65(rt-hexane:ethyl acetate=l:l);
[156] 1H NMR(CDCl ): ppm 7.584(d, /=9.6Hz, IH), 7.154(s, IH), 6.793(s, IH), 6.232(d, 7=9.6Hz, IH), 5.866(m, IH), 5.176(m, 2H), 5.063(t, 7=4.8Hz, IH), 3.190(dd, 7=4.8, 17.2Hz, IH), 3.096(m, 2H), 2.856(dd, 7=5.2, 17.2Hz, IH), 1.373(s, 3H), 1.355(s, 3H);
[157] MS(w/z) : 315 (M+H)+
[158]
[159] Example 7. Pent-4-enoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2/-r,£H - pyrano[3,2-£]chromen-3-yl-ester (3g)
[160] Excepting that 3-methyl-but-2-enoic add (2a) was substituted with Pent-4-enoic add (2g), all the procedure was performed in a similar method to Example 1 to obtain oil form of pent-4-enoic acid 2,2-dimethyl-8-ox>3,4-dihydro- 2H,8H-pyrano[3,2-g] chromen-3-yl-ester (3g).
[161] yield: 81.0% ;
[162] R= 0.51(n-hexane:ethyl εcetate=2:l);
[163] 1H NMR(CDCl ): ppm 7.580(d, 7=9.6Hz, IH), 7.146(s, IH), 6.792(s, IH), 6.231(d,
7=9.6Hz, IH), 5.790(m, IH), 5.056-4.957(m, 3H), 3.178(dd, 7=4.8, 17.2Hz, IH), 2.837 (dd, 7=5.2, 17.2Hz, IH), 2.433(m, 2H), 2.356(t, 7=6.4Hz, 2H), 1.374(s, 3H), 1.352(s, 3H);
[164] MS(m/z) : 329 (M+H)+
[165]
[166] Example 8. Acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H)«-ϊ - pyrano[3,2-g]chromen-3-yl-ester (3h)
[167] Excepting that 3-methyl-but-2-enoic add (2a) was substituted with acetic add
(2h), all the procedure was performed in a similar method to Example 1 to obtain solid form of acetic add 2,2-dimethyl-8«x)-3,4-dihydro- 2//,8H-pyrano[3,2-g] chromen- 3-yl-ester (3h).
[168] yield: 89.8% ;
[169] m.p 125-126 °C;
[170] R =O.38(n-hexane:ethyl acetate=l: l);
[171] 1H NMR(CDCl ): ppm 7.579(d, 7=9.6Hz, IH), 7.153(s, IH), 6.791(s, IH), 6.229(d,
7=9.6Hz, IH), 5,050(t, 7=4.8Hz, IH), 3.184(dd, 7=4.0, 17.2Hz, IH), 3.004(dd, 7=4.8, 17.4Hz, IH), 2.041(s, 3H), 1.422(s, 3H), 1.378(s, 3H);
[172] MS(m/z) : 289 (M+H)+
[173]
[174] Example 9. Chloro-acetic acid 2,2-diraethyl-8-oxo-3,4-dihydro-2if^fiT - pyrano[3,2-g]chiOmen-3-yl-ester (3i)
[175] Excepting that 3-methyl-but-2-enoic add (2a) was substituted with chloro acetic aid (2i), all the procedure was performed in a similar method to Example 1 to obtain solid form of chloro-acetb acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,5//-pyrano[3,2-g] chromen-3-yl-ester (3i) [176] yield: 96.2% ; [177] m.p 147-148 °C; [178] R =0.46 («-hexane:ethyl xetate=l :l); [179] 1H NMR(CDCl ): ppm 7.579(d, 7=9.6Hz, IH), 7.160(s, IH), 6.794(s, IH), 6.235(d,
7=9.6Hz, IH), 5.128(t, 7=4.8Hz, IH), 4.088(d, J= 14.8Hz, IH), 4031(d, 7=14.8Hz,
IH), 3.229(dd, 7=4.8, 17.2Hz, IH), 2.907(dd, 7=4.8, 17.2Hz, IH), 1.400(s, 3H),
1.375(s, 3H);
[180] MS(m/z) : 323 (M+H)+ [181] [182] Example 10. Trichloro-acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H^if
-pyranoP^-^chromen-S-yl-ester (5a)
Figure imgf000022_0001
1. (+)-dβαιrsinol R= 4a -CQ3 R= 5a -CQ3
4b. -(CΗ2)3CΗ3 5b .-(CH2)3CH3
4c. -(CH2)SCH3 5c. -(CH2)SCH3
[184] As shown in the above-described reaction formulae, (+)-decursinol (20mg, 0.081 mmol) in 100 ml round flask was dissolved in 20ml of anhydrous di±lorome thane. Pyridine (13.1 ^t£, 0.162mmol) and trrhloro acetyl chloride (4a) were added thereto and stirred 2 hrs at room temperature. The reaction solution was filtrated and concentrated in vaocuo. The concentrates were performed to Silica gel column chromatography to obtain semi-solid form of trichloro-acetic aάά 2,2-dimethyl-8--oxo-3,4<lihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (5a).
[185] yield: 87.5% ;
[186] R = 0.60(n-hexane:ethyl acetate=l: 1);
[187] Η NMR(CDCl ): ppm 7.578(d, 7=9.6Ηz, IH), 7.178(s, IH), 6.185(s, IH), 6.245(d,
7=9.6Hz, IH), 5.138(t, 7=5.2Hz, IH), 3.292(dd, 7=4.8, 16.8Hz, IH)1 2.999 (dd, 7=5.2, 17.2Hz, IH), 1.450(s, 3H), 1.435(s, 3H);
[188] MS(«ι/z) : 392(M+H)+
[189]
[190] Example 11. Pentanoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2if^H - pyrai.o[3,2-g]chromen-3-yl-ester (5b) [191] Excepting that trichloroacetyl chloride (4a) was substituted with pentanoyl chloride
(4b), all the procedure was performed in a similar method to Example 10 to obtain oil form of pentanoic aid 2,2-dimethyl-8-oxo-3)4-dihydro- 2H,8H-pyrano[3,2-g] chromen- 3-yl-ester (5b).
[192] yield: 90.7% ;
[193] R = 0.39(n-hexane:ethyl acetate=2:l);
[194] 1H NMR(CDCl ): ppm 7.576(d, /=9.6Hz, IH), 7.145(s, IH), 6.788(s, IH), 6.224(d,
7=9.6Hz, IH), 5.044(t, /=5.2Hz, IH), 3.18O(dd, /=4.8, 16.8Hz, IH), 2,837(dd, 7=4.8, 16.8Hz, IH)1 2.313(1, /=7.6Hz, 2H), 1.58O(m, 2H), 1.372(s, 3H), 1.355(s, 3H), 1.377-1.256(m, 2H), 0.876(t, 7=7.2Hz, 3H);
[195] MS(m/z) : 329 (M+H)+ [196] [197] Example 12. Decanoic acid 2,2-dimethyl-8-oxo-3,4-dihydro--?//^H - pyrano[3,2-£)chromen-3-yl-ester (5c)
[198] Excepting that trichloroacetyl chloride (4a) was substituted with decanoyl chloride
(4c), all the procedure was performed in a similar method to Example 10 to obtain oil form of decanoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,SΗ-pyrano[3,2-g] chromen-
3-yl-ester (5c). [199] yield: 93.0% ; [200] R = 0.49(n-hexane: ethyl a=etate=2: 1);
[201] Η NMR(CDCl ): ppm 7.574(d, /=9.2Ηz, IH), 7.143(s, IH), 6.788(s, IH), 6.227(d,
/=9.2Hz, IH), 5.043(t, 7=4.8Hz, IH), 3.178(dd, 7=4.8, 16.8Hz, IH), 2.839(dd, 7=4.8,
17.2Hz, IH), 2.323(t, 7=8.0Hz, 2H)1 1.615(m, 2H), 1.406(s, 3H), 1.373(s, 3H)1
1.336-1.256(m, 12H), 0.888(t, 7=7.2Hz, 3H); [202] MS(m/2) : 331 (M+H)+
[203] Table 1
Figure imgf000023_0001
Figure imgf000024_0001
[204] [205] Table 2
Figure imgf000025_0001
[206] Table 3
Figure imgf000025_0002
[207] Example 13. 3-Phenyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H,8H -pyrano[3,2-g]chromen-3-yl-ester (8a) [208]
Figure imgf000026_0001
[209] Step l
[210] As shown in the above-described reaction formula, cinnam acid (6a, 1.81g,
12.2mmol) in 100 mi round flask was dissolved in 20 ml of anhydrous benzene. Two drop of N,N-dimethyl formamide and thionyl chloride (4.44 mi, 60.9mmol) were added thereto to reflux for 5 hours at 70-80 °C.
[211] The reaction solution was cooled to room temperature and concentrated in vaxuo to obtain άnnamoyl chloride (7a). The reaction solution was dissolved in anhydrous dichloromethane.
[212] [213] Step 2 [214] (+)-decursinol (2g, 8.12mmol) was dissolved in anhydrous dichloromethane in 100ml of round flask. Cinnamoyl chloride (7a) dissolved in mixture solvent of pyridine (1.97 ml, 24.4 mM) and anhydrous dichloromethane (30 ml) was added thereto and stirred for 2 hours at room temperature. The reaction solution was concentrated in vaocuo and the concentrates were performed to Silica gel column chromatography to obtain solid form of 3-phenyl-acrylic add 2,2-dimethy l-8-oxo-3 ,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (8a).
[215] yield: 49.3% ;
[216] m.p 136-137 °C;
[217] R = 0.40(n-hexane;ethyl acetate=l:l);
[218] 1H ΝMR(acetone-d ): ppm 7.882(d, /=9.6Hz, IH), 7.707(m, 3H), 7.433(m, 4H),
6.754(s, IH), 6.568(d, /=16.0Hz, IH), 6.212(d, 7=9.2Hz, IH)1 5.240(t, /=4.6Hz, IH), 3.344(dd, 7=4.6, 17.6Hz, IH), 2.991(dd, 7=4.4, 17.6Hz, IH), 1.436(s, 3H), 1.424(s, 3H);
[219] MS(Wz) : 377 (M+H)+
[220] Example 14. 3-(4-Methoxy-phenyl>acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2fT^'H-pyrano[3,2-^]chroinen-3-yl-ester (8b)
[221] Excepting that άnnamic arid (6a) used in the 1 " step of Example 13 was substituted with 4-methoxy άnnamr: acid (6b), all the procedure was performed in a similar method to Example 13 to obtain solid form of 3-(4-methoxy-phenyl)-acrylic acid 2,2-dimethyl-8-o>D-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (8b).
[222] yield: 91.2% ;
[223] m.p 68 °C;
[224] R = 0.20(n-hexane: ethyl asetate=2: 1 ) ;
[225] 1H NMR(CDCl ): ppm 7.631(d, /=16.0Hz, IH), 7.583(d, 7=9.2Hz, IH), 7.450(d, 7
=8.4Hz, IH), 7.170(s, IH), 6.882(d, 7=8.8Hz, 2H), 6.829(s, IH), 6.282(d, /=16.0Hz, IH), 6.231(d, /=9.2Hz, IH), 5.188(t, /=4.8Hz, IH), 3.828(s, 3H), 3.238(dd, /=4.4, 17.6Hz, IH), 2.934(dd, 7=4.4, 17.6Hz, IH), 1.433(s, 3H), 1.391(s, 3H);MS(Wz) ;
[226] 407 (M+H)+
[227]
[228] Example 15. 3-(4-Hydroxy-phenyl)-acrylic acid
2,2-dimethyl-8-oxo-3,4-dihydro-2H,8H-pyrano[3,2-g]chromen-3-yI-ester (8c)
[229] 3-(4-methoxy-phenyl)-acrylic aid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H.8H - pyrano[3,2-g]chromen-3-yl-ester (lOOmg, 0.246 mmol) in 100 ml of round flask was dissolved in anhydrous dbhloromethane (20 m£). IM borone tribromide (2.46ml, 2.46mmol) was added thereto dropwisely and stirred for 2 hrs at room temperature. The reaction solution was oooled with an ice water (200 m£) and stirred for 10 min. The solution was extracted with ethyl acetate, dehydrated with anhydrous KMnO and concentrated in vaxuo. The concentrates were performed to Silica gel column chromatography to obtain solid form of 3-(4-hydroxy-phenyl)-acrylic add 2,2-dimethyl-8--oxo-3,4-dihydro- 2H,θH-pyrano[3,2-g]chromen-3-yl-ester (8c).
[230] yield: 82.3% ;
[231] m.p lO4 °C;
[232] R = O.32(n-hexane:ethyl acetate=l: l);
[233] 1H NMR(CDCl3): ppm 7.608(m, 2H), 7.401(d, /=8.8Hz, 2H), 7.174(s, IH),
6.841(m, 2H), 6.252(m, 2H), 5.825(s, OH), 5.187(t, 7=4.6Hz, IH), 3.237(dd, 7=4.6, 17.6Hz, IH), 2.935(dd, 7=4.6, 17.6Hz, IH), 1.432(s, 3H), 1.387(s, 3H);
[234] MS(m/z) : 393 (M+H)+
[235]
[236] Example 16. 3-(3,4-Dimethoxy.phenyl>acrylic acid
2,2-dimethyl-8-oxo-3,4-dihydro-2H,8H-pyrano[3,2-^]chromen-3-yl-ester (8d) [237] Excepting that cinnamic arid (6a) used in the 1 st step of Example 13 was substituted with 3,4-dimethoxy cinnamic acid (6d), all the procedure was performed in a similar method to Example 13 to obtain solid form of 3-(3,4-dimethoxy-phenyl)-a:rylic aid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester (8d).
[238] yield: 45.8% ;
[239] m.p 83 °C;
[240] R = 0.35 (n-hexane:ethyl a;etate=l 1);
[241] Η NMR(CDCl ): ppm 7.608(m, 2H), 7.178(s, IH), 7.080(dd, 7=8.4, 2.0Hz, IH),
7.016(d, 7=2.0Hz, IH), 6.848(m, 2H), 6.256(dd, 7=14.4, 9.6Hz, 2H), 5.200(t, 7=4.4Hz, IH), 3.916(s, 3H), 3.908(s, 3H), 3.230(dd, 7=4.4, 16.8Hz, IH), 2.965(dd, 7=4.4, 16.8Hz, IH), 1.446(s, 3H), 1.392(s, 3H);
[242] MS(m/z) : 437 (M+H)+
[243]
[244] Example 17. 3-(3,4,5-Trimethoxy-phcnyl)-acrylic acid
2,2-dimethyl-8-oxo-3,4-dihydro-2H,8H-pyrano[3,2-g]chromen-3-yl-ester (8e)
[245] Excepting that cinnarruc acid (6a) used in the 1 st step of Example 13 was substituted with 3,4,5-trimethoxy cinnamic arid (6e), all the procedure was performed in a similar method to Example 13 to obtain solid form of 3-(3,4,5-trimethoxy-phenyl)- acrylic add 2,2-dimethyl-8-ox>3,4-dihydro- 2H5H-pyrano[3,2-g]chromen-3-yl-ester (8e).
[246] yield: 52.9% ;
[247] m.p 87 °C;
[248] R = O.23(n-hexane:ethyl ∑cetate=l:l);
[249] 1H NMR(CDCl ): ppm 7.607(d, 7=5.6Hz, IH), 7.575(s, IH), 7.184(s, IH), 6.840(s,
IH), 6.722(s, 2H), 6.322(d, 7= 16.OHz, IH), 6.240(d, 7=9.2Hz, IH), 5.208(t, 7=4.4Hz, IH), 3.904(s, 9H), 3.254(dd, 7=4.4, 16.8Hz, IH), 2.95 l(dd, 7=4.4, 16.8Hz, IH), 1.452(s, 3H), 1.395(s, 3H);
[250] MS(Wz) : 467 (M+H)*
[251]
[252] Example 18. 3-(3,4,5-Trihydroxy-phenyl)-acryHc acid
2,2-dimethyl-8-oxo-3,4-dihydro-2fr^ff-pyrano[3,2-^]chromen-3-yl-ester (8f)
[253] Excepting that 3-(4-methoxy-phenyl)-acrylc acid
2,2-dimethyl-8-oxo-3,4-dihydro- 2H,δH-pyrano[3,2-g]chromen-3-yl-ester (8b) of Example 15 was substituted with 3-(3,4,5-trimethoxy-phenyl)-acryl arid 2,2-dimethyl-8-o>o-3,4-dehydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (8e), all the proceduj-e was performed in a similar method to Example 15 to obtain white solid form of 3-(3,4,5-trihydroxy-phenyl)- acrylic aid 2,2-dιmethyl-8-oxo-3,4-dihydro- 2H.8H - pyrano[3,2-g]chromen-3-yl-ester (8f).
[254] yield: 18.2% ;
[255] m.p 144 °C;
[256] R = 0.44 (chloroforni:methanol=5: 1);
[257] 1H NMR (∑cetone-d ): ppm 7.849(d, /=9.6Hz, IH), 7.453(m, 2H)1 6.737(s, IH), 6.720(s, 2H), 6.204(m, 2H), 5.195(t, J=4.8Hz, IH), 3.310(dd, J=16.8, 4.8Hz, IH), 2.937(dd, /=16.8, 4.8Hz, IH), 1.417(s, 6H);
[258] MS(m/z) : 425 (M+H)+
[259]
[260] Example 19. 3-(2-Methoxy-phenyl>acrylic acid
2,2-dimethyl-8.oxo-3,4-dihydro-2H,8H-pyrano[3,2-^]chromen-3-yl-ester (8g)
[261] Excepting that tinnamic acid (6a) used in the 1 " step of Example 13 was subst ituted with 2-methoxy cinnamic acid (6g), all the procedure was performed in a similar method to Example 13 to obtain white solid form of 3-(2-methoxy-phenyl)- acrylic acid 2,2-dimethyl-8--oxo-3,4-dihydro- 2H<5H-pyrano[3,2-g]chromen~3-yl-ester (8g).
[262] yield: 81.8% ;
[263] m.p 72 °C;
[264] R = 0.48 (n-hexane:ethyl acetate=l : 1 );
[265] 1H NMR(CDCl ): ppm 7.996(d, J= 16.4Hz, IH), 7.589(d, 7=9.6Hz, IH), 7.472(d, 7 =6.4Hz, IH), 7.352(t, 7=7.8Hz, IH), 7.l73(s, IH), 6.960~6.895(m, 2H)1 6.804(s, IH), 6.508(d, 7=16.0Hz, IH), 6.235(d, 7=9.6Hz, IH)1 5.194(t, 7=5.0Hz, IH), 3.871(s, 3H), 3.242(dd, 7=5.0, 17.2Hz, IH), 2.942(dd, 7=5.0, 17.2Hz, IH)1 1.437(s, 3H), 1.396(s, 3H).
[266]
[267] Example 20. 3-(2-Hydroxy-phenyl>acrylic acid
2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H- pyranol3>^]chromen-3-yl-ester (8h)
[268] Excepting that 3-(4-methoxy-phenyl)-acrylic add
2,2-dιmethyl-8-oxo-3,4-<lihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (8b) of Example 15 was substituted with 3-(2-methoxy-phenyl)-acryl acid 2,2-dimethyl-8-oxo-3,4-dehydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (8g), all the procedure was performed in a similar method to Example 15 to obtain white solid form of 3-(2-hydroxy-phenyl)-acrylic acid 212-dimethyl-8-oxo-3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester (8h).
[269] yield: 58.5% ;
[270] tn.p 106 °C;
[271] R = 0.39 (rc-hexane:ethyl acetate=l:l);
[272] 1H NMR(xetone-d ): ppm 8.001(d, 7=16.4Hz, IH), 7.851(d, 7=9.2Hz, IH),
7.613(d, /=7.6Hz, IH), 7.434(s, IH), 7.253(t, 7=6.8Hz, IH), 6.954(d, 7=8.4Hz, IH), 6.883(t, 7=7.4Hz, IH), 6.741(s, IH), 6.614(d, 7=16.0Hz, IH), 6.203(d, 7=9.6Hz, IH), 5.233(1, 7=4.4Hz, IH), 3.332(dd, 7=44, 17.6Hz, IH), 2.984(dd, 7=4.4, 17.6Hz, IH), 2.913(d, 7=12.0Hz, OH), 1.432(s, 3H), 1.421(s, 3H);
[273] MS(m/z) : 393 (M+H)+
[274]
[275] Example 21. 3-(3-Methoxy-phenyl>acrylic acid
2,2-dimethyl-8-oxo-3,4-dihydro-2H^ff-pyrano[3,2-^]chromen-3-yl-ester (8i)
[276] Excepting that cinnamic arid (6a) used in the 1 " step of Example 13 was substituted with 3-methoxy cinnamic arid (6i), all the procedure was performed in a similar method to Example 13 to obtain white solid form of 3-(3-methoxy-phenyl)- acrylic arid 2,2-dimethyl-8-o7D-3,4-dihydro- 2H,#H-pyrano[3,2-g]chromen-3-yl-ester (8i).
[277] yield: 90.9% ;
[278] m.p 72 °C;
[279] R = 0.51 (n-hexane: ethyl £cetate=l:l);
[280] 1H NMR(CDCl ): ppm 7.644(d, 7=16.0Ηz, IH), 7.584(d, 7=9.6Hz, IH), 7.282(t, J
=8.4Hz, IH), 7,175(s, IH), 7.088(d, 7=8.0Hz, IH), 6.932(dd, 7=4.0, 8.4Hz, IH), 6.835(s, IH), 6.403(d, 7=15.6Hz, IH), 6.236(d, 7=9.6Hz, IH), 5.199(t, 7=4.8Hz, IH), 3.813(s, 3H), 3.248(dd, 7=4.8, 17.2Hz, IH), 2.943(dd, 7=4.8, 17.2Hz, IH), 1.440(s, 3H), 1.394(s, 3H);
[281] MS(m/z) 407 (M+H)+.
[282]
[283] Example 22. 3-(2,3-Dimethoxy-phenyl>acrylic acid
2,2-dimethyl-8-oxo-3,4-dihydro-2H^flr-pyrano[3,2-^]chromen-3-yl-ester (8j)
[284] Excepting that rinnamic arid (6a) used in the 1 " step of Example 13 was substituted with 2,3-dimethoxy dnnamic arid (6j), all the procedure was performed in a similar method to Example 13 to obtain white solid form of 3-(2,3-dimethoxy-phenyl)- acrylic add 2,2-dimethyl-8-o70-3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester (8j). [285] yield: 25.0% ;
[286] m.p 149 °C;
[287] R = O.43(n-hexane:ethyl acetate=l: 1);
[288] 1H NMR(CDCl ): ppm 8.021(d, /=16.0Hz, IH), 7.585(d, /=9.6Hz,lH), 7.174(s,
IH), 7.121(d, /=6.8Hz, IH), 7.032(t, 7=8.0Hz, IH), 6.939(d, /=8.8Hz, IH), 6.829(s, IH), 6.449(d, 7=16.8Hz, IH), 6.232(d, /=9.6Hz, IH), 5.192(t, 7=4.8Hz, IH), 3.868(s, 3H), 3.832(s, 3H)1 3.249(dd, 7=4.8, 17.2Hz, IH), 2.945(dd, 7=4.8, 17.2Hz, IH), 1.435(S) 3H), 1.400(s, 3H);
[289] MS(m/z) 437 (M+H)+.
[290]
[291] Example 23. 3-(2,4-Dimethoxy-phenyl>acrylic acid
2,2-dimethyI-8-oxo-3,4-dihydro-2jH^iϊ.pyrano[3,2-g]chromen-3-yl-ester (8k)
[292] Excepting that cinnamc arid (6a) used in the 1 s' step of Example 13 was substituted with 2,4-dimethoxy rinnamc arid (6k), all the procedure was performed in a similar method to Example 13 to obtain white solid form of 3-(2,4-dimethoxy-phenyl)- acrylic arid 2,2-dimethyl-8-ox>3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester (8k).
[293] yield: 25.0% ;
[294] m.p 149 °C ;
[295] R = O.43(n-hexane:ethyl acetate=l :l);
[296] 1H NMR(CDCl ): ppm 8.021(d, 7=16.0Hz, IH), 7.585(d, 7=9.6Hz,lH), 7.174(s,
IH), 7.121(d, 7=6.8Hz, IH), 7.032(t, 7=8.0Hz, lH), 6.939(d, 7=8.8Hz, IH), 6.829(s, IH), 6.449(d, 7=16.8Hz, IH), 6.232(d, 7=9.6Hz, IH), 5.192(t, 7=4.8Hz, IH), 3.868(s, 3H), 3.832(s, 3H), 3.249(dd, 7=4.8, 17.2Hz, IH), 2.945(dd, 7=4.8, 17.2Hz, IH), 1.435(s, 3H), 1.400(s, 3H);
[297] MS(m/z) : 437 (M+H)+.
[298]
[299] Example 24. 3-(2,5-Dimethoxy-phenyl>acrylic acid ijl-dimethyl-S-oxo-S^-dihydro-Jff^H-pyranoP^-glchromen-S-yl-ester (81)
[300] Excepting that rinnamic arid (6a) used in the 1 st step of Example 13 was substituted with 2,5-dimethoxy rinnamic arid (61), all the procedure was performed in a similar method to Example 13 to obtain pale yellow solid form of 3-(2,5-dimethoxy-phenyl)-acrylic arid 2,2-dimethyl-8-oJo-3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester (81).
[301] yield: 38.7% ; [302] m.p 77 °C;
[303] R = 0.46 (n-hexane:ethyl acetate=l:l);
[304] 1H NMR(CDCl3): ppm 7.983(d, /=16.0Hz, IH), 7.592(d, /=10.4Hz, IH), 7.178(s,
IH), 7.001(d, /=2.8Hz, IH), 6.912(dd, /=2.8, 8.8Hz, IH), 6.849~6.827(m, 2H), 6.47 l(d, /=16.4Hz, IH), 6.237(d, /=9.2Hz, IH), 5.196(t, /=4.8Hz, IH), 3.824(s, 3H), 3.768(s, 3H), 3.245(dd, /=4.8, 17.2Hz, IH), 2.945(dd, 7=4.8, 17.2Hz, IH), l.441(s, 3H), 1.396(s, 3H);
[305] MS(Wz) : 437 (M+H)+.
[306]
[307] Example 25. 3-(2,4,5-Trimethoxy-phenyl)-acrylic acid
2,2-dimethyI-8-oxo-3,4-dihydro-2/T^H-pyrano[3,2-g]chromen-3-yI-ester (8m)
[308] Excepting that cinnamic add (6a) used in the 1 " step of Example 13 was substituted with 2,4,5-trimethoxy cinnamic acid (6m), all the procedure was performed in a similar method to Example 13 to obtain yellow solid form of 3-(2,4,5-trimethoxy-phenyl)-acrylic add 2,2-dimethyl-8-ojcι-3,4<iihydro- 2H.8H - pyrano[3,2-g]chromen-3-yl-ester (8m).
[309] yield: 33.5% ;
[310] m.p 93 °C;
[311] R = 0.29(n-hexane:ethyl aoetate=l :l);
[312] 1H NMR(CDCl ): ppm 7.986(d, /=13.6Hz, IH), 7.586(d, /=9.6Hz, IH), 7.173(s,
IH), 6.966(s, IH), 6.833(s, IH), 6.478(s, IH), 6.325(d, /=16.0Hz, IH), 6.232(d, J =9.2Hz, IH), 5.196(t, /=4.8Hz, IH), 3.922(s, 3H), 3.855(s, 3H), 3.840(s, 3H), 3.238(dd, /=4.8, 17.2Hz, IH), 2.940(dd, /=4.8, 17.2Hz, IH)1 1.443(s, 3H), 1.393(s, 3H);
[313] MS(m/z) : 483 (M+H)\
[314]
[315] Example 26. 3-(4-Nitro-phenyl}-acrylic acid
2,2-dimethyl-8-oxo-3,4-dihydro-2f-r^H-pyrano[3,2-5r]chromen-3-yl-ester (8n)
[316] Excepting that cinnamic add (6a) used in the 1 s step of Example 13 was substituted with 4-nitro άnnamic add (6n), all the procedure was performed in a similar method to Example 13 to obtain solid type of 3-(4-Nitro-phenyl)-acrylic add 2,2-dimethyl-8-ojo-3,4<lihydro- 2H,8H-pyrano[3,2-g]chrornen-3-yl-ester (8n).
[317] yield: 65.7% ;
[318] m.p l93 °C;
[319] R = 0.42(rc-hexane:ethyl a:etate=l:l); [320] 1H NMR(CDCl ): ppm 8.237(d, 7=8.8Hz, 2H), 7.727~7.623(m, 3H), 7.598(d, /
=9.2Hz, IH), 7.218(s, IH), 6.840(s, IH), 6.560(d, 7=11.2Hz, IH), 6.248(d, 7=9.6Hz, IH), 5.225(t, 7=4.8Hz, IH), 3.272(dd, 7=4.8, 17.2Hz, IH), 2.958(dd, 7=4.8, 17.2Hz, IH), 1.449(s, 3H), 1.403(s, 3H);
[321] MS(m/z) 422 (MH-H)+.
[322]
[323] Example 27. 3-(3-Hydroxy-phenyl>acrylic acid
2,2-dimethy[-8-oxo-3,4-dihydro-2H,8H-pyrano[3,2-^]chromen-3-yl-ester (11a)
[324]
Figure imgf000033_0001
[325] Step l
[326] As shown in the above-described reaction formula, acetic anhydride (11.5 ml, 25.6 mM) in 100ml of round flask was added to 3-hydroxy cinnamic acid (9a, 2g, 12.8 mmol) and excess pyridine (10ml). The reaction solution was stirred for 24 hrs at room temperature and concentrated with vaxuo. The concentrates were performed to Silica gel column chromatography to obtain 3-acetoxy cinnamic acid (9b) to use in following steps.
[327]
[328] Step 2.3
[329] Excepting that cinnamic acid (6a) used in the 1 st step of Example 13 was substituted with 3-acetoxy cinnamic arid (9b), all the procedure was performed in a similar method to Example 13 to obtain solid type of 3-(3-acetoxy-phenyl)-acrylic arid 2,2-dimethyl-8-θ3θ-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (1 Ib) to use in following steps.
[330]
[331] Step 4
[332] 1.8g of 3-(3-acetoxy-phenyl)-acrylic arid 2,2-dimethyl-8-oxo-3,4-dihydro- 2Η,8H - pyrano[3,2-g]chromen-3-yl-ester (lib) was dissolved in 60 ml of acetone and 3N HCl (20ml) was added thereto. The reaction solution was performed to reflux for 12 hrs at 50 °C to 60 °C and cooled to room temperature to concentrate in vaxuo. The concentrate was dissolved in ethyl acetate and distilled water to fractionate and the collected ethyl xetate layer was dehydrated with anhydrous KMnO . The solution was filtrated and concentrated with vaxuo. The concentrates were performed to Silica gel column chromatography to obtain solid form of 3-(3-hydroxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydπ> 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (1 Ia).
[333] yield: 88.1% ;
[334] m.p 105 °C;
[335] R = 0.21(rc-hexane:ethyl acetate=l: l);
[336] 1H NMR(acetone-d ): ppm 7.863(d, /=9.2Hz, IH), 7.622(d, 7=15.6Hz, IH)1
7.442(s, lH), 7,252(t, /=7.8Hz, lH), 7.168(d, /=7.6Hz, lH), 7.111(s, lH), 6.915(d, J =8.4Hz, IH)1 6.751(s, IH), 6.489(d, /=16.0Hz, IH), 6.213(d, /=9.6Hz, IH), 5.229(t, J =4.6Hz, IH), 3.337(dd, /=4.2, 17.2Hz, IH), 2.987(dd, /=4.4, 17.6Hz, IH), 1.432(s, 3H), 1.422(s, 3H);
[337] M$(m/z) : 393 (M+H/
[338]
[339] Example 28. 3-(3-Acetoxy-phenyl>acrylic acid
2,2-dimethyl-8-oxo-3,4-dihydro-2JJ^i/φyrano[3,2-g]chromen-3-yl-ester (lib)
[340] Steps 1.2.3
[341] All the procedure was performed in a similar method to Example 27 to obtain solid form of 3-(3-acetoxy-phenyl)-acrylb acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester (1 Ib).
[342] yield: 87.0% ;
[343] m.p 181 °C;
[344] R = 0.31 (n-hexane:ethyl acetate=l: l);
[345] 1H NMR(aoetone<l ); ppm 7.840(d, /=9.6Hz, IH), 7.684(d, 7=16.0Hz, IH),
7.558(d, 7=7.6Hz, IH), 7.451(m, 3H), 7.180(dd, /=2.4, 7.6Hz, IH), 6.737(s, IH), 6.574(d, /=15.6Hz, IH), 6.198(d, /=9.6Hz, IH), 5.232(t, /=4.4Hz, IH), 3.336(dd, / =4.2, 17.6Hz, IH), 2.984(dd, 7=4.8, 17.6Hz, IH), 2.258(s, 3H), 1.430(s, 3H), 1.422(s, 3H);
[346] MS(m/z) : 435 (M+H)+
[347]
[348] Example 29. 3-(3,4-Dihydroxy-phenyl>acrylic acid
2,2-dimethyl-8.oxo-3,4-d-hydro-^H^JFr-pyrano[3,2-^]chromen-3-yl-ester (lie)
[349] Excepting that 3-hydroxy cinnamic acid (9a) used in the I " step of Example 27 was substituted with 3,4-dihydroxy rinnamb acid (9c, 7g, 38.9mmol), all the procedure was performed in a similar method to Example 27 to obtain solid form of 3-(3,4-Dihydroxy-phenyl)-acrylic acid 2,2-<limethyl-8-oxo-3,4-dihydro- 2H1SH - pyrano[3,2-g]chromen-3-yl-ester (1 Ic).
[350] yield: 93.2% ;
[351] m.p l l5 °C;
[352] R = O.36(n-hexane:ethyl acetate=l :2);
[353] 1H NMR(CDCl ): ppm 7.618(d, 7=8.8Hz, IH), 7.549(d, 7=16.0Hz, IH), 7.181(s,
IH), 7.068(s, IH), 6.948(dd, 7=1.6, 8.4Hz, IH), 6.87O(d, J=8.0Hz, IH), 6.821(s, IH), 6.223(m, 2H), 5.179(t, /=4.6Hz, IH), 3.231(dd, 7=4.6, 17.6Hz, IH), 2.935(dd, 7=4.6, 17.6Hz, IH), 1.428(s, 3H), 1.379(s, 3H);
[354] MS(/n/z) : 409 (M+H)+
[355]
[356] Example 30. 3-(3,4-Diacetoxy-phenyl>acrylic acid
2,2-dimethyl-8-oxo-3,4-dihydro-2H^-r-pyrano[3,2-^]chromen-3-yl-ester (lid)
[357] Excepting that 3-hydroxy cinnamic add (9a) used in the 1 s step of Example 27 was substituted with 3,4-diacetoxy cinnamic acid (9c, 7g, 38.9mmol), all the procedure was performed in a similar method to Example 27 to obtain solid form of 3-(3,4-<ϋacetoxy-phenyl)-acrylfc acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H - ρyrano[3,2-g]chromen-3-yl-ester (l id).
[358] yield: 84.5% ;
[359] m.p 92 °C;
[360] R = 0.27(rt-hexane:ethyl acetate=l: l);
[361] 1H NMR(CDCl ): ppm 7.613(d, 7=8.4Hz, IH), 7.58 l(d, 7=2.0Hz, IH),
7.389-7.339(m, 2H), 7.256-7.179(m, 2H), 6.823(s, IH), 6.358(d, 7=16.0, IH), 6.232(d, 7=9.2Hz. IH), 5.19O(t, 7=4.6Hz, IH), 3.244(dd, 7=4.6, 17.6Hz, IH), 2.932(dd, 7=4.6, 17.6Hz, IH), 2.293(s, 3H), 2.290(s, 3H), 1.425(s, 3H), 1.389(s, 3H);
[362] MS(m/z) : 493 (M+H)+
[363]
[364] Example 31. 3-(4-Hydroxy-3-methoxy-phenyl)-acrylic acid
2,2-dimethyI-8-oxo-3,4-dihydro-2/ir^'jy-pyrano[3,2-^]chromen-3-yl-ester (lie)
[365] Excepting that 3-hydroxy cinnamic acid (9a) used in the 1 s' step of Example 27 was substituted with 4-hydroxy cinnamic acid (9e, 5g, 25.7mmol), all the procedure was performed in a similar method to Example 27 to obtain solid form of 3-(4-hydroxy-3-methoxy phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester (1 Ie).
[366] yield: 91.8% ;
[367] m.p 102 °C;
[368] R = 0.32 (n-hexane: ethyl acetate=l : 1);
[369] 1H NMRCcCetone-d ): ppm 7.843(d, /=9.6Hz, IH), 7.616(d, /=16.0Hz, IH), 7.424(s, IH), 7.357(s, IH), 7.123(dd, 7=2.0, 8.0Hz, IH), 6.851(d, /=8.4Hz, IH), 6.740(s, IH), 6.387(d, /=15.6Hz, lH), 6.198(d, 7=9.6Hz, IH), 5.221(t, /=4.6Hz, IH), 3.895(s, 3H), 3.321(dd, /=4.6, 17.2Hz, IH), 2.963(dd, /=4.4, 17.6Hz, IH), 1.421(s, 3H), 1.413(s, 3H);
[370] MS(Wz) : 423 (M+H)+
[371]
[372] Example 32. 3-(4-Acetoxy-3-methoxy-phenyl)-acrylic acid
2,2-dimethyl-8-oxo-3,4-dihydro-.?fir^r-pyrano[3,2-^]chromen-3-yl-ester (Hf)
[373] Step 1.2.3
[374] Excepting that 3-hydroxy dnnamic add (9a) used in the 1 " step of Example 27 was substituted with 4-hydroxy-3-methoxy-dnnamic acid (9e, 5g, 25.7mmol), all the procedure was performed in a similar method to Example 27 to obtain solid form of 3-(4-acetoxy-3-methoxy-phenyl)-acrylic acid 2,2«iimethyl-8-ox>3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester (Hf).
[375] yield: 42.4% ;
[376] m.p 98 °C;
[377] R = 0.40(n-hexane:ethyl ∑cetate=l : 1);
[378] 1H NMR(acetone-d ): ppm 7.843(d, /=9.6Ηz, IH), 7.679(d, /=16.0Hz, IH),
7.480(s, IH), 7.428(s, IH), 7.247(d, /=8.4Hz, IH), 7.095(d, /=8.4Hz, IH), 6.742(s, IH), 6.568(d, /=16.0Hz, IH), 6.200(d, /=9.6Hz, IH), 5.243(t, /=4.4Hz, IH), 3.872(s, 3H), 3.338(dd, /=4.4, 17.6Hz, IH), 2.982(dd, /=4.4, 17.6, IH), 2.242(s, 3H), 1.428(s, 3H), 1.418(s, 3H);
[379] MS(m/z) : 465 (M+H)+
[380]
[381] Example 33. 3-(4-Acetoxy-3,5-dimethoxy-phenyl)-acryHc acid
2,2-dimethyI-8-oxo-3,4-dihydro-2if^flr-pyrano[3^-^]chromen-3-yl-ester (llg)
[382] Steps 1.2.3
[383] Excepting that~3-hydroxy cinnamic arid (9a) used in the 1 5t step of Example 27 was substituted with 4-hydroxy-3,5-dimethoxy-cinnamk; arid (9e, 50Og, 2.23mmol), all the procedure was performed in a similar method to Example 27 to obtain solid form of 3-(4-acetoxy-3,5-dimethoxy-phenyl)-εcrylic arid 2,2-dimethyl-8θ}o-3,4-dihyciro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (1 Ig).
[384] yield: 10.8% ; [385] m.p 121 °C; [386] R = 0.42 («-hexane:ethyl acetate=l: l); [387] 1H NMR(CDCl ): ppm 7.614(d, J=9.2Hz, IH), 7.582(d, J=2.4Hz, IH)1 7.189(s, IH), 6.826(s, IH), 6.739(s, 2H), 6.362(d, J=16.0Hz, IH), 6.227(d, J=9.2Hz, IH), 5.21 l(t, J=4.8Hz, IH), 3.801(s, 6H), 3.255(dd, J=4.8, 18.0Hz, IH), 2.935(dd, J=4.8, 18.0Hz, IH), 2.331(8, 3H), 1.451(s, 3H), 1.397(s, 3H);
[388] MS(w/z) : 495 (M+H)+ [389] [390] Table 4
Figure imgf000037_0001
[391] [392] Table 5
Figure imgf000038_0001
[393] [394] Table 6
Figure imgf000038_0002
[395] [396] Table 7
Figure imgf000039_0001
[397] [398] Table 8
Figure imgf000039_0002
[399] [400] Table 9
Figure imgf000040_0002
[401] [402] Example 34. Benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H,8H - pyrano[3,2-g]chromen-3-yl-ester (14a)
Figure imgf000040_0001
[404] Step 2.3 [405] Excepting that άnnamic acid (6a) used in the 1 st step of Example 13 was substituted with benzoic add (12a), all the procedure was performed in a similar method to Example 13 to obtain semi-solid form of benzoic add 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (14a).
[406] yield: 93.2% ; [407] R =0.52 (n-hexane: ethyl acetate=l:l); [408] 1H NMR(CDCl ): ppm 7.972(d, /=9.6Hz, 2H), 7.557(m, 2H), 7.417(t, 7=7.8Hz, 2H), 7.166(s, IH), 6.845(s, IH), 6.227(d, /=9.6Hz, IH), 5.296(t, 7=4.8Hz, IH), 3.300(dd, i=4.4, 17.6Hz, IH), 3.004(dd, 7=4.8, 17.6Hz, IH), 1.474(s, 3H), 1.428(s, 3H);
[409] MS(w/z) : 351 (M+H)+ [410] [411] Example 35. 3,4,5-trihydroxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H,8H-pyrano[3,2-g]chromen-3-yl-ester (14b) [412] Step l
[413] As shown in the above-described reaction formula in Example 34, 3,4,5-trihydroxy benzoic acid (3g, 17.6mmol) is dissolved in acetic anhydride (11.5ml, 25.6mM) in 100ml of round flask and 2 to 3 drop of conosulfuric acid were added thereto. The reaction solution was refluxed at 80? for 10 mins and cooled to room temperature. 30 fold volume of iced water was poured thereto with stirring and left alone at room temperature for 2 hours to filtrate the precipitate. The precipitate was washed with distilled water and dried at 40? for 12 hours to obtain 3,4,5-trihydroxy benzoic add (12c).
[414]
[415] Step 2 .3
[416] Excepting that cinnamic acid (6a) used in the 1 " step of Example 13 was substituted with 3 ,4,5-triacetoxy benzoic acid (12c, 5g, 0.017 mM), all the procedure were performed by the similar method to the procedure disclosed in Example 13 to obtain 3,4,5-triacetoxy benzoic aid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g] - chromen-3-yl-ester (14c).
[417]
[418] Step 4
[419] Excepting that 3-(3-acetoxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (1 Ib) used in the 4 step of Example 27 was substituted with 3,4,5-triacetoxy benzoic acid 2,2-dimethyl-8-ojo-3,4<iihydro- 2H.8H - pyrano[3,2-g]chromen-3-yl-ester (14c, 1.8g. 3.43 mM), all the procedure were performed by the similar method to the step 4 of Example 27 to obtain 1.5g of solid 3,4,5-triacetoxy benzoic acid 2,2-dimethyl-8-oJO-3,4-dihydro- 2Η,<3Η-pyrano[3,2-g] - chromen-3-yl-ester (14b).
[420] yield: 98.7% ;
[421] m.p l38 °C;
[422] R = 0.22(«-hexane:ethyl acetate=l :2);
[423] 1H NMR(CDCl ): ppm 7.674(d, /=9.2Hz, IH), 7.242(s, IH), 7.132(s, 2H), 6.782(s,
IH), 6.228(d, /=9.2Hz, IH), 5.215(t, /=4.8Hz, IH), 3.284(dd, /=4.2, 17.6Hz, IH), 2.98 l(dd, 7=4.6, 17.6Hz, IH), 1.443(s, 3H), 1.413(s, 3H);
[424] MS(w/z) : 399(M+H)+
[425]
[426] Example 36. 3,4,5-Triacetoxy-benzoic acid
2,2-dimethyl-8-oxo-3,4-dihydro-2ϋr^H-pyrano[3,2-^]chromen-3-yl-ester (14c) [427] All the procedure was performed in the similar method to the steps 1,2,3 of Example 35 to obtain solid form of 3,4,5-triacetoxy-benzoic add 2,2-dimethyl-8--oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester (14c).
[428] yield: 28.8% ; [429] m.p 97 °C; [430] R = 0.44(n-hexane:ethyl acetate=l:2); [431] 1H NMR(a:etone-d ) ppm 7.848(d, /=9.6Hz, IH), 7.740(s, 2H), 7.435(s, IH), 6.765(s, IH), 6.209(d, 7=9.6Hz, IH), 5.359(t, /=4.4, 17.6Hz, IH), 3.4O3(dd, /=4.2, 17.6Hz, IH), 3.123(dd, /=4.4, 17.6Hz, IH), 2.317(s, 3H), 2.283(m, 6H), 1.479(s, 3H), 1.457(s, 3H);
[432] MS(m/z) : 525 (M+H)+ [433] [434]
Figure imgf000042_0002
[435] [436] Example 37. Methane sulfonic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H- pyrano[3,2-g]chromen-3-yl-ester (16a)
[437]
Figure imgf000042_0001
[438] As shown in the above-described reaction scheme, the mixture of decursinol (1, 20mg, 0.081mmol) and triethylamine (TEA, 34μl, 0.024mmol) was dissolved in 5ml of anhydrous dichloromethane. Methane sulfonyl chloride (il μJt, 0.406mmol) was added thereto in cold water dropwisely. The reaction solution was stirred for 15 hrs at room temperature and half volume of the solution was concentrated at room temperature. The concentrates were performed to Silica gel column chromatography to obtain solid form of methane sulfonic acid 2,2-dimethyl-8-o>o-3,4-dehydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester (16a).
[439] yield: 91.2% ;
[440] m.p 174 °C;
[441] R = 0.32(rt-hexane:ethyl acetate=l : 1);
[442] 1H NMR(CDCl ) ppm 7.591(d, J=9.6Hz, IH), 7.197(s, IH), 6.786(s, IH), 6.244(d, 7
=9.6Hz, IH), 4.884(t, 7=4.8Hz, IH), 3.293(dd, /=4.8, 17.6Hz, IH), 3.179(dd, 7=4.8, 17.6Hz, IH), 3.067(s, 3H), 1.456(s, 3H), 1.407(s, 3H);
[443] MS(wi/z) : 325 (M+H)+
[444]
[445] Example 38. Benzene sulfonic acid 2,2-dimethyl-8-oxo-3,4-dihydro-
2H^H-pyrano[3,2-g]chromtn-3-yl-ester (16b)
[446] Excepting that methane sulfonyl chloride (15a) used in Example 37 was substituted with benzene sulfonyl chloride (15b), all the procedure was performed in the similar method to the procedure disclosed in Example 37 to obtain solid form of benzene sulfonic acid 2,2-dimethyl-8-oxo-3,4-dehydro- 2H,S/."-pyrano[3,2-g]chromen-3-yl-ester (16b).
[447] yield: 36.2% ;
[448] m.p 64 °C;
[449] R = 0.21(n-hexane:ethyl acetate=2:l);
[450] 1H NMR(CDCl ) ppm 7.907(d, /=7.6Hz, 2H), 7.682(m, IH), 7.567(m, 3H),
7.085(s, IH), 6.744(s, IH), 6.236(d, /=9.2Hz, IH), 4.706(t, /=5.2Hz, IH), 3.173(dd, / =5.2, 18.0Hz, IH), 3.036(dd, /=5.2, 18.0Hz, IH), 1.283(s, 3H), 1.245(s, 3H);
[451] MS(W1Z) : 387 (M+H)+
[452]
[453] Table 11
Figure imgf000044_0003
[454]
[455] Example 39. 8,8-Dimethyl^H-pyrano[3,2-g]chromen-2,7-dione (17)
[456]
Stepi
Figure imgf000044_0001
Figure imgf000044_0002
1. (+)-decursinol 17
[457] As shown in the above-described reaction formulae, the mixture of pyridinium chlorochromate (PCC, 1.74g, 8.12mmol) and molecular sieve 4 A (2g, wt/wt=2/l) in 100ml of round flask were dissolved in anhydrous dichloromethane (150 ml). The reaction solution was stirred with for 5 mins in cold ice. Decursinol (Ig, 4.06mmol) was added thereto and stirred for 1 hrs at 0 °C. Half volume of the reaction solution was filtrated and concentrated with vaccuo at room temperature. The concentrates were performed to Silica gel column chromatography to obtain yellow solid form of 8,8-dimethyl- 6H-pyrano[3,2-g]chromen-2,7-dione (17).
[458] yield: 41.9% ; [459] m.p : 165 °C ; [460] R = 0.47(n-hexane:ethyl acetate=l :l) ; [461] 1H NMR(CDCl ): ppm 7.642(d, 7=9.6Hz, IH), 7.229(s, IH), 6.969(s, IH), 6.313(d. /=9.6Hz, IH), 3.660(s, 2H), 1.453(s, 6H) ;
[462] MS(m/z) : 245 (M+H)+ [463] [464] Example 40. 8,8-Dimethyl-tfH-pyrano[3,2-g]chromen-2,7-dione 7-oxime (18)
[465] Stepi
Figure imgf000045_0001
Figure imgf000045_0002
17 18
[466] As shown in the above-described reaction formulae, 8, 8 -dimethyl- 67/-pyrano[3,2-g ]chromen-2,7-dione (17, 788mg, 3.23mmol) in 100ml of round flask was dissolved in anhydrous ethanol (20 ml). Hydroxy ammonium chloride (NH OHCl, 336mg, 4.85mmol) and pyridine (391 μi, 4.85mmol) were added thereto. The reaction solution was stirred for 1 hrs at 8O°C with reflux and cooled to room temperature. The residue was concentrated, recrystallized with hexane and ethylacetate and filtrated with hexane with washing. The recrystallized substance was purified with Silica gel column chromatography to obtain pale yellow solid form of 8,8-dimethyl-67f-pyrano[3,2-g] chromen-2,7-dione 7-oxime (18).
[467] yield: 83.0% ; [468] m.p : 217 °C ; [469] R = 0.30 (n-hexane:ethyl acetate=2: l) ; [470] 1H NMR(CDCl ): ppm 7.614(d, /=9.6Hz, IH), 7.253(s, IH), 6.858(s, IH), 6.277(d, 7=9.6, IH), 3.851(s, 2H), 1.525(s, 6H) ;
[471] MS(m/z) : 260 (M+H)+ [472] [473] Example 41. 8,8-Dimethyl-tff-'-pyrano[3,2-g]chromen-2,7-dione 7-[O - (3,3-dimethylacryloyl)-oxime] (20)
[474]
Step2
Figure imgf000045_0003
Figure imgf000045_0004
2a. X=H, Y=CH3, Z=CH3 19a. X=H, Y=CH3, Z=CH3 20a. X=H, Y=CH3, Z=CH3
[475] Step 1 [476] As shown in the above-described reaction formulae, 3,3-dimethylacrylic acid (2a, lOOmg, 0.999mmole) was dissolved in 3ml of anhydrous dbhloromethane and stirred in cold ice under nitrogen atmosphere, oxalyl chloride(356.8μ£, 3.996mmol) was added thereto dropwisely and stirred at 0? for 5 hours. The reaction solution was cooled to room temperature and concentrated to obtain 3,3-dimethylacryloyl chloride (19a) to dissolve in anhydrous dichloromethane. [477]
[478] Step 2
[479] 8,8-dimethyl-6'H-pyrano[3,2-g]chrornen-2,7-dione 7-ωime (18, 103.5mg, 0.399 mmole) was dissolved in anhydrous dichloromethane (30ml). 3,3-dimethyl acryloyl chloride (19a) dissolved in pyridine (96.9 μZ, 1.197mmol) and 20ml of anhydrous dichloromethane was added thereto dropwisely and stirred at room temperature for 2 hours. The residue was concentrated and performed to Silica gel column chromatography to obtain yellow solid form of 8,8-dimethyl-6'H-pyrano[3,2-g] chromen- 2,7-dione 7-[0-(3,3-dimethyla:ryloyl)oxιme] (20).
[480] Yield: 66.8 % ;
[481] m.p : 147 °C ;
[482] R = 0.26 (n-hexane:ethyl acetate=2: 1) ;
[483] 1H NMR(CDCl ): ppm 7.612(d, /=9.4Hz, IH), 7.243(s, IH), 6.885(s, IH), 6.288(d,
/=9.4Hz, IH), 5.83O(s, IH), 3.914(s, 2H), 2.254(s, 3H), 1.991(s, 3H), 1.620(s, 6H),
[484] MS(m/z) : 342 (M+H)+
[485]
[486] Example 42. 8,8-Dimethyl-Λϊ-pyrano[3,2-^]chromen-2,7-dione 7-[0 - cinnamoyl-oxime] (21a)
Figure imgf000046_0001
R = 6a. -H R = 7a. -H R = 21a. -H βb. -4-OCH3 7b. -4-OCH3 21 b. -4-OCH3
6d. -3,4-(OCH3)2 7d. -3,4-(OCH3)2 21d. -3,4"(OCH3)2
6e. -3,4,5-(OCH3)3 7e. -3,4,5-(OCHj)3 21e. -3,4,5-(OCH3)3
[488] Step l
[489] As shown in the above-described reaction formulae, cinnamic acid (6a, 85.7mg,
0.579mmole) was dissolved in 6ml of anhydrous benzene. 2 drops of N,N- dimethylformamide and thionyl chloride (SOCl , 211μ£, 2.893mmol) were added thereto dropwisely and refluxed at 70-80? for 5 hours. The reaction solution was cooled to room temperature and concentrated to obtain άnnamoyl chloride (7a) to dissolve in anhydrous dichloromethane.
[490]
[491] Step 2
[492] 8,8-<liinethyl-6H-pyrano[3,2-^chromen-2(7-dione 7-oxime (18, lOOmg, 0.386 mmole) was dissolved in anhydrous dichloromethane (30ml). cinnamoyl chloride (7a) dissolved in pyridine (93.6μi, 1.158mmol) and 20ml of anhydrous dbhloromethane was added thereto dropwisely and stirred at room temperature for 2 hours. The residue was concentrated and performed to Silica gel column chromatography to obtain white solid form of δ.δ-dimethyl^H-pyranotS.Z-glchromen^J-dione T-[O - άnnamoyl-oxime] (21a).
[493] Yield: 60.7 % ;
[494] m.p : 175 °C ;
[495] R = 0.44 (n-hexane-.ethyl acetate=l:l) ;
[496] 1H NMR(CDCl ): ppm 7.867(d, /=16.0Hz, IH), 7.609(m, 3H), 7.436(m, 3H),
7.279(s, IH), 6.912(8, IH), 6.614(d, /=16.0Hz, lH), 6.304(d, /=9.4Hz, IH), 3.999(s, 2H), 1.654(s, 6H);
[497] MS(m/z) : 390 (M+H)+
[498]
[499] Example 43. 8,8-Dimethyl-tfff-pyrano[3,2-g]chromen-2,7-dione 1-[O - methoxycinnamoyl-oxime] (21b)
[500] Excepting that cinnamfc acid (6a) used in the 1 " step of Example 42 was substituted with 4-methoxy cinnamic acid (6b), all the procedure was performed in the similar method to the procedure disclosed in Example 42 to obtain white solid form of 8,8-dimethyl- <5H-pyrano[3,2-g]chromen-2,7-dione 7-[ 0-(4-methoxyrinnamoyl)o»me] (21b).
[501] Yield: 62.4 % ;
[502] m.p : 175 °C;
[503] R = 0.39 (n-hexane:ethyl acetate=l: l) ;
[504] 1H NMR(CDCl ): ppm 7.820(d, /=16.0Hz, IH), 7.625(d, /=9.6Hz, IH), 7.546(d, J
=8.8Hz, 2H), 7.278(s, IH), 6.942(d, 7=8.8Hz, 2H), 6.908(s, IH), 6.476(d, /=16.0Hz, IH), 6.302(d, 7=9.6Hz, IH), 3.994(s, 2H), 3.865(s, 3H), 1.650(s, 6H);
[505] MS(/n/z) : 420 (M+H)+
[506]
[507] Example 44. 8,8-Dimethyl-<{jff-pyrano[3,2-g]chromen.2,7-dione l-[0 - (3,4-dimethoxycinnamoyl>oxime] (2Id)
[508] Excepting that cinnamic acid (6a) used in the 1 " step of Example 42 was substituted with 3,4-dimethoxy cinnamic arid (6d), all the procedure was performed in the similar method to the procedure disclosed in Example 42 to obtain pale yellow solid form of 8,8-dimethyl-6H-pyrano[3,2-g]chrornen-2,7-dione 7-[0 - (3,4-dimethoxycinnamoyl)-oxime] (2Id). [509] Yield: 56.0 % ;
[510] m.p : 202 °C;
[511] R = 0.26 (n-hexane:ethyl acetate=l : 1) ;
[512] 1H NMR(CDCl ): ppm 7.801(d, 7=16.0Hz, IH), 7.615(d, /=9.4Hz, IH), 7.275(s,
IH), 7.184(d, 7=8.4, 2.0Hz, IH), 7.100(d, /=2.0Hz, IH), 6.904(m, 2H), 6.459(d, /
= 16.0Hz, IH), 6298(d, /=9.4Hz, IH), 3.999(s, 2H), 3.948(s, 2H), 3.940(s, 3H),
1.651(s, 6H);
[513] MS(m/z) : 450 (M+H)+
[514] [515] Example 45. S^-Dimethyl^H-pyranoβ^-glchromen-V-dione l-[0 -
(3,4,5-trimethoxycinnamoyl>oxime] (2Ie) [516] Excepting that άnnamic acid (6a) used in the 1 s' step of Example 42 was substituted with 3,4,5-trimethoxy dnnamic acid (6e), all the procedure was performed in the similar method to the procedure disclosed in Example 42 to obtain yellow solid form of 8,8-dimethyl-6H-pyrano[3,2-g]chromen-2,7-dione 7-[0 -
(3,4,5-trimethoxycinnamoyl)o»me] (2Ie). [517] Yield: 72.8 % ;
[518] m.p : 175°C ;
[519] R = 0.24(n-hexane:ethyl acetate=l:l) ;
[520] 1H NMR(CDCl ): d ppm 7.776(d, /=16.0Hz, IH)1 7.617(d, /=9.4Hz, IH), 7.277(s,
IH), 6.912(s, IH), 6.814(s, 2H), 6.487(d, 7=16.0Hz, IH), 6.303(d, /=9.4Hz, IH),
4.005(s, 2H), 3.923(s, 9H), 1.653(s, 6H) ; [521] MS(Wz) : 480 (M+H)+
[522] [523] Example 46. 8,8-Dimethyl-tf#-pyrano[3,2-g]chromen-2,7-dione l-[0 -
(3-acetoxy cinnamoyl)-oxime] (22a)
Figure imgf000048_0001
a 22a. -3-OAc n 22b. -3,4"(OAC)2
Figure imgf000048_0002
[525] Step l
[526] All the procedure was performed with the similar method to the 1 sl step of Example
27 to obtain 3-acetoxy cinnamic acid (9b). [527]
[528] Step 2
[529] Excepting that cinnamic acid (6a) used in the 1 " step of Example 42 was substituted with 3-acetoxy cinnamic acid (9b), all the procedure was performed in the similar method to the procedure disclosed in Example 42 to obtain yellow solid form of 8,8<limethyl-6H-pyrano[3,2-g]chroinen-2,7-dione 7-[O -
(3-acetoxycinnamoyl)-oήme] (22a). [530] Yield: 91.5 % ;
[531] m.p : 160°C ;
[532] R = 0.47(n-hexane:ethyl acetate=l : 1) ; [533] 1H NMR(CDCl ): d ppm 7.823(d, J=IOOHz, IH), 7.625(d, J=9.4Hz, IH), 7.443(d,
/=2.4Hz, 2H), 7.342(s, IH), 7.282(s, IH), 7.164(m, IH), 6.905(s, IH), 6.591(d, /
= 16Hz, IH), 6,301(d, /=9.4Hz, IH), 3.989(s, 2H), 2.325(s, 3H), 1.649(s, 6H) ; [534] MS(m/z) : 448 (M+H)+
[535] [536] Example 47. 8,8-Dimethy_^iJφyrano[3,2-g]chr<>men-2,7-cIi(>ne 1-[O -
(3,4-diacetoxy cinnamoyl)-oxime] (22b) [537] Step l
[538] Excepting that cinnamic acid (9a) used in the 1 " step of Example 27 was substituted with 3,4-diacetoxy cinnamic add (9c, 7g, 38.9mmole), all the procedure was performed in the similar method to the procedure disclosed in the 1 step of
Example 27 to obtain 3,4-diaoetoxy cinnamic acid(9d). [539]
[540] Step 2
[541] Excepting that cinnamic aid (6a) used in the 1 " step of Example 42 was substituted with 3,4-diacetoxy cinnamic acid (9d), all the procedure was performed in the similar method to the procedure disclosed in Example 42 to obtain yellow solid form of 8,8-dimethyl- 6H-pyrano[3,2-g]chromen-2,7-dione 7-[ 0-(3,4-dixetox yάnnamoyl)-oκme] (22b). [542] Yield: 77.1 % ;
[543] m.p : 192°C ;
[544] R = 0.23(n-hexane:ethyl acetate=l: 1) ;
[545] Η NMR(CDCl ): d ppm 7.794(d, /=16.4Ηz, IH), 7.625(d, /=9.4Hz, IH), 7.462(m,
2H), 7.268(m, 2H), 6.907(s, IH), 6.544(d, /=16.4Hz, IH), 6.303(d, J=9.4Hz, IH),
3.947(s, 2H), 2.308(s, 3H), 2.298(s, 3H), 1.647(s. 6H) ; [546] MS(w/z) : 506 (M+H)+
[547]
[548] Example 48. 8,8-Dimethyl-^H-pjτano[3,2-g]chromen-2-one (23)
[549]
Figure imgf000050_0001
1. (+Heαιrsnol 23
[550] decursinol (1, lOOmg, 0.406 mmole) and triphenylphospine (213mg, 0.821 mmole) in 100 ml of round flask were dissolved in anhydrous dichloromethane (4ml) and ace- tonitrile (4ml) and refluxed at 70-80? for 2 hours. Half of the rea:tion solution was concentrated and the concentrate was performed to Silica gel column chromatography to obtain white solid form of 8,8-dimethyl-6H-pyrano[3,2-g]chromen-2-one (23).
[551] Yield: 95.6 % ; [552] m.p : 124°C ; [553] R = 0.69(n-hexane:ethyl acetate=l:l) ; [554] 1H NMR(CDCl ): d ppm ;7.576(d, 7=9.2Hz, IH), 7.045(s, IH)1 6.724(s, IH), 6.339(d, 7=10.0Hz, IH), 6.219(d, 7=9.6Hz, IH), 5 688(d, 7=9.6Hz, IH), 1.468(s, 6H);
[555] MS(m/z) : 229 (M+H)+ [556] Table 12
Figure imgf000051_0001
[557] [558] Table 13
Figure imgf000052_0002
Figure imgf000052_0001
[559] [560] Experimental Example 1. The effect on the release of MCP- 1/IL-6/IL-8 induced by mite in THP-I cell
[561] To determine the inhibitory effect of the decursin derivatives prepared in Examples on the release of MCP-1/IL-6/IL-8 induced by mite in THP- 1 , following experiment using by human acute monocytic leukemia cell line (THP-I; American Type Culture Collection (Manassas, VA, USA)) was performed and the result was determined by ELISA method pursuant to the manufacture's manual (BD bioscience).
[562] The THP-I cell line prepared in Reference Example was distributed to 24 well plates containing RPMI medium including 0.5% FBS in a concentration of 2.Ox 10 /ml and incubated in 5% CO incubator at 37 °C for 16 hours. After the incubation,
2 lOmbrogram/ml of the decursin derivatives prepared in Examples was added thereto and 1 microgram/ml of HDE was treated therewith for 24 hours. The level of MCP- 1 , IL-6 and IL-8 in the supernatant was determined by ELISA method and the result was shown in following Tables 14 and 15.
[563] [564] Table 14
Figure imgf000053_0001
[565] [566] Table 15
Figure imgf000054_0001
67] At the result, the level of MCP-I, IL-6 and IL-8 in normal control group showed
31, 19 and 181 pg/ml respectively and those after the treatment of mite allergen were increased to 342, 148 and 2319 pg/ml respectively. However, those levels of MCP-I, IL-6 and IL-8 after the treatment of positive control (dexamethasone) were decreased to 29, 18 and 132 pg/ml respectively. The level of MCP-I after the treatment of test samples prepared in Examples, i.e., compounds 3d, 11a, llof. 14c, 16a, and 23 was also decreased to the almost equivalent level to that in positive control group and the level of IL-6 after the treatment of test samples prepared in Examples, i.e., compounds 3d, lla, lie, 14c, 16a, and 23 was also decreased to the almost equivalent levels to that in positive control group. The level of IL-8 after the treatment of test samples prepared in Examples, especially, compounds 3d and 1 Ic was also decreased to the almost equivalent level to that in positive control group. In summary, the test treatment group treated with compounds 3d, lie, Hd, 18 and 23, decreased the levels of MCP-I, DL-6 and IL-8.
[568]
[569] Experimental Example 2. The effect on the release of MCP- 1/IL-6/IL-8 induced by mite in EoL-I
[570] To determine the inhibitory effect of the decursin derivatives prepared in Examples on the release of MCP-1/IL-6/IL-8 induced by mite in EoL-I cell, following experim ent using by human eosinophil (eosinophilic leukemia cell; EoL-I; the RIKEN Bio Resource center (Tsukuba, Japan)) was performed and the result was determined by ELISA method pursuant to the manufacture's manual (BD biosάence).
[571] The EoL-I cell line prepared in Reference Example was distributed to 24 well plates containing RPMI medium including 0.5% FBS in a concentration of 2.Ox 106/ml and incubated in 5% CO incubator at 37 °C for 16 hours. After the incubation, 10 microgram/rnl of the decursin derivatives prepared in Examples was treated therewith for 1 hour and 1 microgram/ml of HDE was treated therewith for 24 hours. The level of MCP-I, IL-6 and IL-8 in the supernatant was determined by ELISA method and the result was shown in following Tables 16 and 17.
[572] Table 16
Figure imgf000055_0001
[573] [574] Table 17
Figure imgf000056_0001
[575] At the result, the level of MCP-I, IL-6 and IL-8 in normal control group showed 91, 73 and 403 pg/ml respectively and those after the treatment of mite allergen were increased to 247 , 281 and 812 pg/ml respectively. However, those levels of MCP- 1 , IL-6 and BL-8 after the treatment of positive control (dexamethasone) were decreased to 73, 69 and 361 pg/ml respectively. The level of MCP-I after the treatment of test samples prepared in Examples, i.e., compounds 3d, lla-e, 14b-c, 18 and 23 was also decreased to the almost equivalent level to that in positive control group and the level of IL-6 after the treatment of test samples prepared m Examples, i.e., compounds 3d and l ie was also decreased to the almost equivalent levels to that in positive control group. The level of IL-8 after the treatment of test samples prepared in Examples, especially, compounds 3d, l ie and 28 was also decreased to the almost equivalent level to that in positive control group. In summary, the test treatment group treated with compounds 3d, l ie, and 23, decreased the levels of MCP-I, IL-6 and IL-8.
[576] [577] [578] Hereinafter, the formulating methods and kinds of exαpients will be described, but the present invention is not limited to them. The representative preparation examples were described as follows. [579] [580] The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all sich modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims. [581] [582] Hereinafter, the formulating methods and kinds of excipients will be described, but the present invention is not limited to them. The representative preparation examples were described as follows. [583]
[584] Preparation of powder [585] Compound (l ie) 20mg [586] Lactose lOOmg [587] Talc lOmg [588] Powder preparation was prepared by mbdng above components and filling sealed package. [589]
[590] Preparation of tablet
[591] Compound (l ie) lOmg [592] Com Starch lOOmg [593] Lactose lOOmg [594] Magnesium Stearate 2mg
[595] Tablet preparation was prepared by mbdng above components and entabletting.
[596]
[597] Preparation of capsule
[598] Compound (l ie) lOmg [599] Corn starch lOOmg [600] Lactose lOOmg [601] Magnesium Stearate 2mg [602] Tablet preparation was prepared by miring above components and filling gelatin capsule by conventional gelatin preparation method. [603] [604] Preparation of iniection [605] Compound (1 Ic) lOmg
[606] Distilled water for injection optimum amount
[607] PH controller optimum amount
[608] Injection preparation was prepared by dissolving active component, controlling pH to about 7.5 and then filling all the components in 2 m£ ample and sterilizing by con¬ ventional injection preparation method.
[609]
[610] Preparation of liquid
[611] Compound (lie) 20mg
[612] Sugar 5~10g
[613] Citric acid 0.05-0.3%
[614] Caramel 0.005-0.02%
[615] Vitamin C 0.1-1%
[616] Distilled water 79-94%
[617] CO gas 0.5-0.82%
[618] liquid preparation was prepared by dissolving active component, filling all the components and sterilizing by conventional liquid preparation method.
[619]
[620]
[621] Preparation of health care food
[622] Compound (1 Ic) lOOOmg
[623] Vitamin mixture optimum amount
[624] Vitamin A acetate 70mg
[625] Vitamin E l.Omg
[626] Vitamin B 0.13mg
[627] Vitamin B 0.15mg
[628] Vitamin B6 0.5mg
[629] Vitamin B 120.2mg
[630] Vitamin C lOmg
[631] Biotin lOmg
[632] Amide nicotinic acid 1.7mg
[633] R)IK aid 50mg
[634] Calcium pantothenic add 0.5mg
[635] Mineral mixture optimum amount
[636] Ferrous sulfate 1.75mg [637] Zinc oxide 0.82mg
[638] Magnesium carbonate 25.3mg
[639] Monopotassium phosphate 15mg
[640] Dkalcium phosphate 55mg
[641] Potassium citrate 90mg
[642] Calcium carbonate lOOmg
[643] Magnesium chloride 24.8mg
[644] The above-mentioned vitamin and mineral mixture may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention.
[645]
[646] Preparation of health beverage
[647] Compound (1 Ic) lOOOmg
[648] Citric add lOOOmg
[649] Oligosaxharide lOOg
[650] Apricot concentration 2g
[651] Taurine Ig
[652] Distilled water 900m£
[653] Health beverage preparation was prepared by dissolving active component, mbάng, stirred at 85°C for 1 hour, filtered and then filling all the components in 1000m£ ample and sterilizing by conventional health beverage preparation method.
[654]
[655] The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.
[656]
Industrial Applicability
[657] As described in the present invention, the novel decursin derivatives of the present invention showed potent inhibiting activity of the release of MCP-I , IL-6 and IL-8 induced by dermite in THP-I or EoL-I cell, therefore the compounds can be useful in treating or preventing atopic dermatitis.

Claims

Claims
[1] A novel compound represented by the following general formula (I), or the pharmaceutically acceptable salt thereof:
Figure imgf000060_0001
(D wherein
A is hydrogen atom, C -C lower alkyl group, dialkyl acryloyl group or
1 4 cinnamoyl group of which phenyl group is unsubstituted or substituted with R'; wherein R' is optionally substituted at o-, m- and p- position with at least one selected from the group consisting of a hydrogen atom, hydroxyl group, acetate group, halogen atom, C -C lower alkyl group, lower alkoxy group, lower alkyl ester, and lower alkyl carboxy group.
[2] The compound according to claim 1, wherein A is hydrogen atom, methyl group, dimethyl acryloyl group or cinnamoyl group of which phenyl group is unsubstituted or substituted with R'; wherein R' is optionally substituted with at least one selected from the group consisting of a hydrogen atom, methyl group, methoxy group and acetate group.
[3] The compound according to claim 2, wherein said compound is selected from the group consisting of:
8,8-dimethyl-6H-pyrano[3,2-g]chτomen-2,7-dione 7-oxime, 8,8-dimethyl-6 H - pyrano[3,2-g]chromen-2,7-dione 7-[ 0-(3,3-dimethylacryloyl)«jime], 8 ,8 -dimethy 1-6 H-pyrano [3 ,2-g]chromen-2,7 -dione 7 - ( 0-cinnamoy 1-oxime) , 8,8<umethyl-6H-pyrano[3,2-g]chrornen-2,7-dione 7-[O - (4-methoxycinnamoyl)-o»me], 8,8-dimethyl-6 /f-pyrano[3,2-g] chromen- 2,7-dione 7-[0-(3,4-dimethoxycinnamoyl)-o»me], 8,8-dimethyl-6 H-pyrano[3,2- g]chromen-2,7-dione 7-[ 0-(3,4,5-tximethoxyrinnamoyl)-o»rne], 8,8-<limethyl-6 H-pyrano[3,2-g]chromen-2,7-dione 7-[0-(3-a:etoxycinnamoyl)o)dme], and δ.S^imethyl-δH-pyranoβ^-gfchromen^J-dione 1-[O - (3 ,4-diacetoxycinnamoyl)-oxime] .
[4] A pharmaceutical composition comprising decursin derivative represented by general formula (I) as set forth in claim 1 as an active ingredient in an amount effective to prevent and treat atopc dermatitis, together with a pharmaceutically acceptable carrier by inhibiting the release of MCP-I, IL-6 and IL-8 induced by mites.
[5] A novel compound represented by the following general formula (II), and the pharmaceutically acceptable salt thereof:
Figure imgf000061_0001
O ( H )
Wherein,
B is selected from the group consisting of hydrogen atom, hydroxyl group, C -C
1 4 lower alkyl group, C -C lower alkoxy group, halogen atom, and 5- or 6-
L 6 membered heterocyclic ring unsubstituted or substituted with C -C lower alkyl group or C -C lower alkoxy group.
[6] The compound according to claim 5, wherein B is selected from the group consisting of methyl group, halogen atom, C -C lower alkyl group, C -C lower alkoxy group and phenyl group.
[7] The compound according to claim 6, wherein said compound is selected from the group consisting of: methane sulfonic aid 2,2-dimethyl-8-o?D-3,4-dihydro-2 H,8H-pyrano[3,2-g] chromen-3-yl-ester, and benzene sulfonic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2
H,8H-pyrano[3,2-g]chromen-3-yl-ester.
[8] A pharmaceutical composition comprising decursin derivative represented by the following general formula (III) as an active ingredient in an amount effective to prevent and treat atopic dermatitis, together with a pharmaceutically acceptable carrier by inhibiting the release of MCP-I, IL-6 and DL-8 induced by mites:
Figure imgf000061_0002
(HI) wherein
R is C -C alkyl group, C -C alkenyl group, C -C alkynyl group un-
1 1 20 ° r 2 20 ' ° ) M substituted or substituted with at least one R'; or A group; of which R' is halogen atom, nitro group, amine group or C -C lower alkyl group; and A group is
Figure imgf000062_0001
wherein
A is at least one optionally at o-, m- or p- position, selected from the group consisting of a hydrogen atom, hydroxyl group, acetate group, halogen atom, C - C lower alkyl group, C -C lower alkoxy group and C -C lower alkyl ester
4 1 4 1 4 group; n is an integer of 0 to 4.
[9] The composition according to claim 8, wherein R is halogen atom or C -C
1 1 10 alkyl group, C -C alkenyl group, C -C alkynyl group unsubstituted or
2 10 1 10 substituted with C -C lower alkyl group or A group; of which A is at least one optionally at o-, m- orp- position, selected from group consisting of a hydrogen atom, hydroxyl group, methyl group, ethyl group, methoxy group, ethoxy group and acetyl group; n is an integer of 0 to 1.
[10] The composition according to claim 9, wherein said compound is one selected from the group consisting of;
3-Methyl-but-2-enoic aid 2,2-dimethyl-8-oxo-3,4-dihydro- 2tf,S-:/-pyrano[3,2-g] chromen-3-yl-ester, Cϊs-2-Methyl-but-2-enoic aαd
2,2-dimethyl-8--oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, Trans - 2-Methyl-but-2-enoic aid 2,2-dimethyl-8-oxo-3,4-dihydro- 2tf,SΗ-pyrano[3,2-g] chromen-3-yl-ester, 2-methyl-acrylic aid 2,2-dimethyl-8-o>D-3,4-dihydro- 2H,δH-pyrano[3,2-g]chromen-3-yl-ester, Pent-2-enoic acid 2,2-dimethyl-8«Jo-3,4-dihydro- 2H,8H-pyrano [3, 2-g] chromen-3-yl-ester, But- 3-enoic arid 2,2-dimethyl-8--oxo-3,4-dihydro- 2flr,8tf-pyrano[3,2-g] chromen- 3-yl-ester, Pent-4-enoic arid 2>2-dimethyl-8cx)-3,4-dihydro- 2H,SΗ-pyrano[3,2- g]chromen-3-yl-ester, Acetic arid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H - pyrano[3,2-g]chromen-3-yl-ester, Chloro-acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, Trichloro-acetk: add 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g] chromen-3-yl-ester, Pentanoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H.8H - pyrano[3,2-g]chromen-3-yl-ester, Decanoic arid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-phenyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g] chromen-3-yl-ester, 3-(4-methoxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g)chromen-3-yl-ester, 3-(4-hydroxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H - pyrano[3,2-g]chromen-3-yl-ester, 3-(3,4-dimethoxy-phenyl)-acrylic add 2,2-dimethyI-8-oxo-3,4-dehydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-(3,4,5-trimethoxy-phenyl)-acrylic add 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H- -pyrano[3,2-g]chromen-3-yl-ester, 3-(3,4,5-trihydroxy-phenyl)-acrylic add 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-(2-methoxy-phenyl)-acrylic add 2,2-ditnethyl-8-oxo-3,4-dihydro- 2H.8H - pyrano[3,2-g]chromen-3-yl-ester, 3-(2-hydroxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-(3-methoxy-phenyl)-acrylic add 2,2-dimethyl-8-oxo-3,4<iihydro- 2H.8H - pyrano[3,2-g]chromen-3-yl-ester, 3-(2,3-dimethoxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-(2,4-dimethoxy-phenyl)-acrylic add 2,2-dimethyl-8-oxo-3,4-dihydro- 22H,8H- pyrano[3,2-g]chromen-3-yl-ester, 3-(2,5-dimethoxy-phenyl)-acrylic add 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-(2,4,5-trimethoxy-phenyl)-acrylic add 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H- -pyrano[3,2-g]chiomen-3-yl-ester, 3-(4-nitro-phenyl)-acrylic add 2,2- dimethyl- 8-oxo-3 ,4-dihydro- 2H,8H-pyrano[3 ,2-g]chromcn-3-yl-ester, 3-(3-hydroxy-phenyl)-xrylic add 2,2- dimethyl-8-oxo-3,4-dihydro- 2H,8H- pyrano[3,2-g]chromen-3-yl-ester, 3-(3-acetoxy-phenyl)-acrylic add 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chroraen-3-yl-ester, 3-(3,4-dihydroxy-phenyl)-acrylic add 2,2-dimethyl-8-oxo-3 ,4-dihydro- 2H,8H- pyrano[3,2-glchromen-3-yl-ester, 3-(3,4-diacetoxy-phenyl)-acrylic add 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-glchroraen-3-yl-ester, 3-(4-hydroxy-3-methoxy-phenyl)-acrylic add 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]chromen-3-yl-ester, 3-(4-acetoxy-3-methoxy-phenyl)-acry lie acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,<5H-pyrano[3,2-g]chromen-3-yl-ester, 3-(4-acetoxy-3,4-dimethoxy-phenyl)-acrylic acid
2,2-dimethyl-8-oxo-3,4-dihydro- 2H,<5H-pyrano[3,2-g]chromen-3-yl-ester, Benzoic acid 2,2-dimethyl-8ox>3,4-dihydro- 2H,8H-pyrano[3,2-g] chromen- 3-yl-ester, 3,4,5-trihydroxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H.8H -pyrano[3,2-g]chromen-3-yl-ester and 3,4,5-triacetoxy-benzoic add 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,<SH-pyrano[3>2-£]chromen-3-yl-ester.
[11] A pharmaceutical composition comprising decursin derivative represented by the following general formula (IV) as an active ingredient in an amount effective to prevent and treat atopic dermatitis, together with a pharmaceutically acceptable carrier by inhibiting the release of MCP-I, IL-6 and IL-8 induced by mites:
Figure imgf000064_0001
(IV)
Wherein,
C is a hydrogen atom, C -C lower alkyl group or ketone group.
[12] The composition according to claim 11, wherein C is at least one selected from the group consisting of a hydrogen atom or ketone group.
[13] The composition according to claim 12, wherein said compound is one selected from the group consisting of;
8,8-dimethyl- όH-pyranoP^-gJchromen^J-dione, 8,8-dimethyl- 6H-pyrano[3,2- g]-chromen-2-one.
[14] A health functional food comprising decursin derivative represented by general formula (T), (TT), (III) or (FV) for the prevention or improvement of atopic dermatitis by inhibiting the release of MCP-I, IL-6 and EL-8 induced by mites as an active ingredient in an amount effective to preventing and improving atopic dermatitis.
[15] The health care food according to claim 14, the health care food is a form of powder, granule, tablet, capsule or beverage.
[16] A use of decursin derivative represented by general formula (T), (II), (III) or (TV) for the preparation of for manufacture of medicament employed for preventing or treating atopic dermatitis in human or mammal.
[17] A method for treating atopic dermatitis by inhibiting the release of MCP-I, IL-6 and CL-8 induced by mites in a mammal oomprising administering to said mammal an effective amount of decursin derivative represented by general formula (I), (II), (III) or (IV), together with a pharmaceutically acceptable carrier thereof.
PCT/KR2008/001017 2007-02-22 2008-02-21 Composition comprising decursin derivative for treating and preventing atopic dermatitis WO2008102994A1 (en)

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