WO2008004817A1 - Novel decursin derivatives and the use thereof - Google Patents

Novel decursin derivatives and the use thereof Download PDF

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Publication number
WO2008004817A1
WO2008004817A1 PCT/KR2007/003257 KR2007003257W WO2008004817A1 WO 2008004817 A1 WO2008004817 A1 WO 2008004817A1 KR 2007003257 W KR2007003257 W KR 2007003257W WO 2008004817 A1 WO2008004817 A1 WO 2008004817A1
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WIPO (PCT)
Prior art keywords
oxo
ester
dimethyl
dihydro
chromen
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Application number
PCT/KR2007/003257
Other languages
French (fr)
Inventor
Yong Jin Park
Gyu Yong Song
Jee Hyun Lee
Yong Seok Choi
Mi Young Yun
Gui Nam Shen
Eui Keom Kim
Sung Hoon Kim
Original Assignee
Yong Jin Park
Gyu Yong Song
Jee Hyun Lee
Yong Seok Choi
Mi Young Yun
Gui Nam Shen
Eui Keom Kim
Sung Hoon Kim
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Application filed by Yong Jin Park, Gyu Yong Song, Jee Hyun Lee, Yong Seok Choi, Mi Young Yun, Gui Nam Shen, Eui Keom Kim, Sung Hoon Kim filed Critical Yong Jin Park
Publication of WO2008004817A1 publication Critical patent/WO2008004817A1/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
    • A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention

Definitions

  • the present invention relates to novel decursin derivatives and the preparation thereof.
  • Cancer disease has been regarded as serious clinical problem and exerts an important social and economical effect on the human health care system.
  • As a carcinogenic substance to cause cancer disease smoking, ultraviolet ray, chemical substance, food and other environmental factors have been reported till now however the etiology of cancer is diverse, which results in difficulty in development of therapeutics as well as unequal potency of therapeutics according to the occurring region of cancer. Since presently used cancer drugs show considerable adverse effect and could not treat cancer selectively, there have been still needed to develop potent anticancer drug with little toxicity to treat and prevent cancer disease till now.
  • Chemoprevention can be classified into three stages, i.e., the 1 nd prevention stage to inhibit healthy human from cancer occurrence, the 2 prevention stage to reverse the cancer occurrence for the patients suffering rd with benign tumor and the 3 prevention stage to prevent cancer recurrence for the patient suffered from cancer disease.
  • the active components showing such pharmacological activities in the plant are (+)-decursin and (+)-decursinol angelate, a dihydropyranocoumarin, the esterified substance there with (+)- decursino1(7-hydroxy-8,8-dimethy1-7,8-dihydro-6H-pyrano(3,2-g)chromen-2-one) (Biol. Pharm. Bull., 21, pp990, 1998).
  • the present invention relates to novel decursin derivatives and the use thereof.
  • the present invention provides novel decursin derivatives and the pharmacologically acceptable salt thereof.
  • the present invention also provides a use of novel decursin derivatives and the pharmacologically acceptable salt thereof for the preparation of pharmaceutical composition to treat and prevent cancer diseases.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising novel decursin derivatives and the pharmacologically acceptable salt thereof as an active ingredient in an effective amount to treat and prevent cancer diseases.
  • the present invention also provides a method of treating or preventing inflammatory disease in a mammal comprising administering to said mammal an effective amount of novel decursin derivatives and the pharmacologically acceptable salt thereof, together with a pharmaceutically acceptable carrier thereof .
  • the present invention also provide a health care food composition comprising decursin derivatives as an active ingredient in an effective amount to prevent and alleviate cancer diseases.
  • the present invention provides a novel compound represented by the following general formula (I), and the pharmaceutically acceptable salt thereof '• ⁇ i6> [Chemical Formula I]
  • R 1 is C 1 -C 20 alkyl group, C 1 -C 20 alkenyl group, Ci-C 20 alkynyl group substituted or unsubstituted with R', or following A group
  • R' is halogen atom, nitro group, amine group, or C 1 -C 4 lower alkyl group and A' group is at least one attachable at o-, m- and p- position of phenyl group selected from group consisting of a hydrogen atom, hydroxyl group, nitro group, acetate group, halogen group, C 1 -C 4 lower alkyl group, C 1 -
  • n is integer of 0 to 4.
  • n is integer of 0 to 4.
  • R 1 is a CrCi 0 alkyl group, CrCi 0 alkenyl group, Cr
  • inventive compounds represented by general formula (I) can be transformed into their pharmaceutically acceptable salt and solvates by the conventional method well known in the art.
  • acid-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 acid 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.
  • organic acid or inorganic acid can be used.
  • organic acid such as methansulfonic acid, p- toluensulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonylic acid, vanillic acid, hydroiodic acid and the like, and inorganic acid such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid 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 hydroxide 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) comprise all the acidic 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 acid salt, phosphate salt, hydrogen phosphate salt, dihydrophosphate salt, acetate salt, succinate 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 present invention comprise all the optically active isomers, R or S stereoisomers and the mixtures thereof.
  • Present invention also comprises all the uses of racemic mixture, more than one optically active isomer or the mixtures thereof as well as all the preparation or isolation method of the diastereomer well known in the art.
  • the compounds of the invent ion of formula (I ) may be chemical ly 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.
  • 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 24 hrs, more preferably, 24 hrs with stirring to synthesize decursin derivatives having various alkyl substituents (lb-12b).
  • the reaction mixture of acetic acid anhydride and 3-or 4-(0H)n-cinnamic acid are dissolved in pyridine. 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.
  • an acid such as hydrochloric acid is added to the ( ⁇ )-decursin derivatives having 3- or 4-(0Ac)n-cinnamoyl substitutents prepared in step 3 dissolved in acetone dropwisely and the reaction mixture is performed to distillation, colling at room temperature and concentration under reduced pressure.
  • the solvent which does not cause to adverse effect for example, dimethylformamide, alcohol such as methanol, ethanol etc or acetone, preferably, acetone may be used in the reaction.
  • step 4 4- or 5-(0Ac)n-cinnamoyl substitutents prepared in step 4 are dissolved in dichloromethane and boron tribromide solution (BBr3 in Methylene chloride) is dropwisely added thereto.
  • boron tribromide solution for example, dichloromethane, chloroform 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 cool temperature.
  • (+)-decursinol and pyridine are dissolved in anhydrous dichloromethane and benzoyl chloride is added thereto to (+)- decursin derivatives having various benzoyl substitutents.
  • the solvent which does not cause to adverse effect such as dichloromethane, chloroform 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. th
  • the decursin derivatives having 3-, 4- or 5-(0Ac)n-benzoyl substitutents prepared in step 3 are dissolved in acetone and hydrochloric acid is dropwisely added thereto.
  • the solvent which does not cause to adverse effect for example, dimethylformamide, alcohol such as methanol, ethanol etc or acetone may be used in the reaction.
  • novel decursin derivatives prepared by the above-described method represented by general formula (I) shows strong anticancer activity being confirmed by various experiments such as cytotoxicity test in A549 lung cancer cell line, HCT15 colon cancer cell line and ACHN rectal cancer cell line, therefore the compounds can be useful in treating or preventing cancer diseases, preferably, lung cancer, colon cancer or rectal cancer.
  • ⁇ iO5> 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 (I) or the pharmaceutically acceptable salt thereof as an active ingredient in amount effective to treat or prevent cancer 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 (I) or the pharmaceutically acceptable salt thereof as an active ingredient in amount effective to treat or prevent cancer disease, together with pharmaceutically acceptable carriers or diluents.
  • ⁇ ii3> there is also provided a method of treating or preventing inflammatory disease in a mammal comprising administering to said mammal an effective amount of novel (+)-decursin derivatives represented by general formula (I) and the pharmacologically acceptable salt thereof, together with a pharmaceutically acceptable carrier thereof into the mammals including human suffering from said disease.
  • cancer diseases comprise various cancer disease, for example, lung cancer, colon cancer or rectal cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer or cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (eg., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymph
  • the compound according to the present invention can be provided as a pharmaceutical composition containing pharmaceutically acceptable carriers, adjuvants or diluents.
  • the compound of the present invention can be dissolved in oils, propylene glycol or other solvents which are commonly used to produce an injection. Suitable examples of the carriers include physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc., but are not limited to them.
  • 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 such 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.
  • the compound should be present between 0.0001 to 10% by weight, preferably 0.0001 to 1% by weight based on the total weight of the composition.
  • 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, rectal Iy or by intravenous, intramuscular, subcutaneous, intrathecal, epidural or intracerebroventricular injection.
  • novel (+)-decursin derivatives represented by general formula (I) 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 functional health food defined herein the functional food having enhanced functionality such 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.
  • ⁇ i35> 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), or the pharmacologically acceptable salt thereof, together with a sitologically acceptable additive for the prevention and alleviation of cancer disease.
  • 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 indirect ly-in its becoming a component or otherwise affecting the characteristics of any food for example, thickening agent, maturing agent, bleaching agent, sequesterants, humectant, anticaking 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 cancer disease.
  • 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 glucose, fructose etc; disaccharide such as maltose, sucrose etc; conventional sugar such as dextrin, cyclodextrin; and sugar alcohol such as xylitol, and erythritol etc.
  • natural deodorant such as taumatin, stevia extract such as levaudioside A, glycyrrhizin et al., and synthetic deodorant such as saccharin, 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 of 100 mH of present beverage composition.
  • 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 acid and the salt thereof, organic acid, 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 juice, 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 (+)-decursin derivatives of the present invention showed potent inhibiting effect on the cancer cell being confirmed by various experiments such as cytotoxicity test in A549 lung cancer cell line, HCT15 colon cancer cell line and ACHN rectal cancer cell line, therefore the compounds can be useful in treating or preventing cancer diseases as an anti-cancer agent, health care food, or functional health food.
  • Step 2 ⁇ 259> 1 equivalent amount of (+)-decursinol and 3 equivalent amount of pyridine were dissolved in anhydrous dichloromethane in round flask. 1.5 equivalent amount of cinnamyl chloride obtained in step 1 dissolved in anhydrous dichloromethane was added thereto and stirred for 2 hours at room temperature.
  • step 3 4-dihydro-2H,8H-pyrano[3,2g]-chromen-3-yl-ester obtained in step 3 was dissolved in acetone and 4-8 equivalent amount of 3N-HC1 was added thereto.
  • the reaction solution was performed to refux for 12 hours at 50-60 " C and cooled at room temperature.
  • the concentrate was fractionated with distilled water and ethylacetate and the collected ethylacetate soluble layer was dehydrated with anhydrous KMnO4, filtered and the supernatant was concentrated in vaccuo.
  • Step 2 ⁇ 351> 1 equivalent amount of (+)-decursinol and 3 equivalent amount of pyridine were dissolved in 50 folds volume of anhydrous dichloromethane in round flask. 1.5 equivalent amount of 3-(4-methoxy-phenyl)-acryloyl chloride obtained in step 1 dissolved in anhydrous dichloromethane was added thereto and stirred for 2 hours at room temperature.
  • Step 2 ⁇ 473> 1 equivalent amount of (+)-decursinol and 3 equivalent amount of pyridine were dissolved in 50 fold volume of anhydrous di chl or ome thane in round flask.
  • the benzoyl chloride obtained in step 1 dissolved in anhydrous dichloromethane was added thereto and stirred for 2 hours at room temperature.
  • A549 lung caner cell line, HCT 15 colon cancer cell line and ACHN rectal cancer cell line used in the present invention were procured from ATCC (American Type Culture Collection, U.S.A) and they were cultivated in RPMI 1640 culture medium containing L-glutamine, 10% inactivated FBS (Fetal Bovine Serum ) heated in water bath at 50°C for 30 mins, 1% antibiotics (penicillin- G, 100,000 units/streptomycin 100 mg) and 2g of NaHCO 3 at 37°C in 5% CO 2
  • Each cell line was mixed with 2x10 cells and inoculated into 96 well pates by 100 ⁇ /ml/we11 and the plates were incubated for 48 hours. The medium was discarded and 10 ⁇ of MTT (5mg/ml, 3-(4,5-demethylthiazol)-2,5- diphenyltetrazolium bromide, Sigma Co., USA) was added thereto to incubate for 4 hours. The cultivated plates were washed with PBS and 100 ⁇ l of DMSO was added thereto. The plates were left alone for 20 mins at room temperature to determine the absorbance using by ELISA reader at 570 ran.
  • MTT 5-mg/ml, 3-(4,5-demethylthiazol)-2,5- diphenyltetrazolium bromide, Sigma Co., USA
  • (+)-decursin isolated from Angelica gigas showed potent anticancer activity confirmed by various experiments using by human erythroleukemic cell lines procured from ATCC, for example, K562 (ED 50 :
  • (+)-decursin A cytotoxic agent and protein kinase C activator from the root of angelica gigas, Planta Med. 62, pp.7-9, 1996.
  • (+)- decursin showed potent inhibiting activity (54%) of survival rate for K562 cell, a human erythroleukemic cell lines procured from ATCC (Kim, H. H.
  • the ( ⁇ )-decursin derivatives having cinnamoyl groups (13c-18c) showed strong cell cytotoxicity in cancer cell lines whereas the (+)-decursin derivatives having alkyl groups (2b-12b) showed little cell cytotoxicity in cancer cell lines.
  • the compound (14c) showed most strong cell cyto-toxicity in A549 cell line (survival rate: 33%), HCT 15 cell line (survival rate: 12%) and ACHN cell line (survival rate: 43%) while the (+)-decursin derivatives having benzoyl groups (26c-29c) showed a little cell cytotoxicity in cancer cell lines.
  • the crucial group in the (+)- decursin derivatives of the present invention showing potent anticancer activity is aromatic functional group such as cinnamoyl group or benzoyl group, rather than alkyl group.
  • Powder preparation was prepared by mixing above components and filling sealed package.
  • Tablet preparation was prepared by mixing above components and filling gelatin capsule by conventional gelatin preparation method.
  • 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 conventional 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, mixing, stirred at 85°C for 1 hour, filtered and then filling all the components in 1000ra-£ ample and sterilizing by conventional health beverage preparation method.
  • the (+)-decursin derivatives of the present invention showed potent inhibiting effect on the cancer cell being confirmed by various experiments such as cytotoxicity test in A549 lung cancer cell line, HCT15 colon cancer cell line and ACHN rectal cancer cell line, therefore the compounds can be useful in treating or preventing cancer diseases as an anti-cancer agent, health care food, or functional health food

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Abstract

The present invention relates to novel (+)-decursin derivatives having anti-cancer activity, the preparation thereof and a composition containing the same for treating cancer disease. The (+)-decursin derivatives of the present invention showed potent inhibiting effect on the cancer cell being confirmed by various experiments such as cytotoxicity test in A549 lung cancer cell line, HCT15 colon cancer cell line and ACHN rectal cancer cell line, therefore the compounds can be useful in treating or preventing cancer diseases as an anti-cancer agent, health care food, or functional health food.

Description

[DESCRIPTION] [Invention Title]
NOVEL DECURSIN DERIVATIVES AND THE USE THEREOF [Technical Field]
<i> The present invention relates to novel decursin derivatives and the preparation thereof.
<2>
[Background Art]
<3> Cancer disease has been regarded as serious clinical problem and exerts an important social and economical effect on the human health care system. As a carcinogenic substance to cause cancer disease, smoking, ultraviolet ray, chemical substance, food and other environmental factors have been reported till now however the etiology of cancer is diverse, which results in difficulty in development of therapeutics as well as unequal potency of therapeutics according to the occurring region of cancer. Since presently used cancer drugs show considerable adverse effect and could not treat cancer selectively, there have been still needed to develop potent anticancer drug with little toxicity to treat and prevent cancer disease till now.
<4> Although various therapeutic methods such as chemotherapeutics, radiotherapeutics, surgical therapy, gene therapy and the like have been used now, the chemotherapeutics among them has been mostly wisely used. However it gives rise to lots of adverse response and does not provide complete treatment therefore new approach has been needed to treat cancer disease. Those approach can be classified into two ways, i.e., one way is to synthesize and develop new chemotherapeutic derivatives based on known chemotherapeutics showing significantly decreased adverse response with similar potency to the known chemotherapeutics through diverse synthetic methods and another way is a cancer chemoprevention to prevent the progress to malignant tumor by way of inhibiting from cancer occurrence or postponing or reversing cancer development.
<5> Recently, there have been much interested in the development of chemo- preventive and chemo-therapeutic substance showing potent potency with low toxicity from natural resources such as vegetable, fruit, medicinal herb etc in Western countries (Kelloff et al . , Annals New York Academy of Sciences, 889, ppl-13, 1999).
<6> Chemoprevention can be classified into three stages, i.e., the 1 nd prevention stage to inhibit healthy human from cancer occurrence, the 2 prevention stage to reverse the cancer occurrence for the patients suffering rd with benign tumor and the 3 prevention stage to prevent cancer recurrence for the patient suffered from cancer disease.
<7> Decursin, a component isolated from plants belonged to Angelica species, has been isolated from Angelica decursiva Fr. Et Sav. in 1966 at first and the component has been reported to be isolated from Angelica gigas Nakai in 1967 and 1969 (J. Pharm. Soc. Korea, 11, pp22-26, 1967; bid, 13, pp47-50, 1969) and from Peucedanum terevinthaceum Fisher et Turcz (Yakhak hoieji, 30(2), pp73-78, 1986).
<8> There are various kinds of plants belong to umbelliferae family, for example, Angelica sinensis distributed in China, Angelica acutilobae in Japan, and Angelica gigas in Korea, which have been used as a edible food and herbal drug for treating pain, nephrotoxicity, diabetic hypertension (Kor. J. Pharmacogn. , 1, pρ25, 1970). The active components showing such pharmacological activities in the plant are (+)-decursin and (+)-decursinol angelate, a dihydropyranocoumarin, the esterified substance there with (+)- decursino1(7-hydroxy-8,8-dimethy1-7,8-dihydro-6H-pyrano(3,2-g)chromen-2-one) (Biol. Pharm. Bull., 21, pp990, 1998).
<9> Present inventors extensively investigated to find new anti-cancer drug through the synthesis of (+)-decursin compounds based on Structure-Activity Relationship and finally, found new decursin derivatives showing strong anticancer activity being confirmed by various experiments such as cytotoxicity test in A549 lung cancer cell line, HCT15 colon cancer cell line and ACHN rectal cancer cell line to complete present invention. <10>
[Disclosure] [Technical Problem]
<π> The present invention relates to novel decursin derivatives and the use thereof. [Technical Solution]
The present invention provides novel decursin derivatives and the pharmacologically acceptable salt thereof.
The present invention also provides a use of novel decursin derivatives and the pharmacologically acceptable salt thereof for the preparation of pharmaceutical composition to treat and prevent cancer diseases.
The present invention also provides a pharmaceutical composition comprising novel decursin derivatives and the pharmacologically acceptable salt thereof as an active ingredient in an effective amount to treat and prevent cancer diseases.
The present invention also provides a method of treating or preventing inflammatory disease in a mammal comprising administering to said mammal an effective amount of novel decursin derivatives and the pharmacologically acceptable salt thereof, together with a pharmaceutically acceptable carrier thereof .
The present invention also provide a health care food composition comprising decursin derivatives as an active ingredient in an effective amount to prevent and alleviate cancer diseases.
Thus, the present invention provides a novel compound represented by the following general formula (I), and the pharmaceutically acceptable salt thereof '• <i6> [Chemical Formula I]
Figure imgf000004_0001
<17> (I) <19> wherein <20> R1 is C1-C20 alkyl group, C1-C20 alkenyl group, Ci-C20 alkynyl group substituted or unsubstituted with R', or following A group
<21>
Figure imgf000005_0001
<24> of which R' is halogen atom, nitro group, amine group, or C1-C4 lower alkyl group and A' group is at least one attachable at o-, m- and p- position of phenyl group selected from group consisting of a hydrogen atom, hydroxyl group, nitro group, acetate group, halogen group, C1-C4 lower alkyl group, C1-
C4 lower alkoxy group, Ci-C4 lower alkyl ester group, and C1-C4 lower alkyl carboxy1 group;
<25> n is integer of 0 to 4. <26> As preferable compounds of general formulae (I), the compounds of the present invention wherein R1 is a CrCi0 alkyl group, CrCi0 alkenyl group, Cr
Cio alkynyl group substituted or unsubstituted with halogen atom or CrC4 lower alkyl group or A group of which A group is at least one attachable at o-, m- and p- position of phenyl group selected from group consisting of a hydrogen atom, hydroxyl group, methyl group, ethyl group, methoxy group, ethoxy group, nitro group and acetyl group," n is integer of 0 to 1, are more preferable.
<27> <28> The most preferred compound of general formula (I) is one selected from the group consisting of;
<29> 3-methyl-but-2-enoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2tf,δ7f- ρyrano[3,2-g]chromen-3-yl-ester, <30> Cis-2-methy1-but-2-enoic acid 2,2-dimethy1-8-oxo-3,4-dihydro-2H,8H- py r ano [ 3 , 2-g ] chr omen-3-y 1 -es t er , <3i> Trans-2-methyl-but-2-enoic acid 2, 2-di methyl -8-oxo-3,4-di hydro-2#, 8#- pyrano[3,2-g]chromen-3-yl-ester, <32> 2-Methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2tf,8tf-pyrano[3,2- g] chr omen-3-y 1 -ester , <33> Pen-2-tenoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2tf,8tf-pyrano[3,2- g]chromen-3-yl-ester , <34> But-3-enoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2ff,8#-pyrano[3,2- g] chr omen-3-y 1 -ester , <35> Pen-4-tenoic acid 2,2-dimethyl-8-oxo-3,4~dihydro-2tf,8tf-pyrano[3,2- g] chr omen-3-y 1 -ester , <36> Acetic acid 2)2-dimethyl-8-oxo-3,4-dihydro-2tf,8#-pyrano[3,2-g]chromen-3- yl-ester, <37> Chloroacetic acid 2, 2-di methyl -8-oxo-3,4-di hydro-2tf,8ff~pyr ano [3,2- g]chromen-3-yl-ester , <38> Trichloroacetic acid 2, 2-di methyl -8-oxo-3,4-dihydro-2tf,8tf-pyr ano [3,2- g]chromen-3-yl-ester , <39> Pentanoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2tf,8tf-ρyrano[3,2-g]chromen-
3-yl-ester, <40> Decanoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2#,8tf-pyrano[3,2-g]chromen-
3-yl-ester, <4i> 3-Phenyl acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2tf,8tf-pyrano[3,2- g]chromen-3-yl-ester , <42> 3-(3-Hydroxy-ρhenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2tf,8#- pyr ano[3, 2-g] chr omen-3-y 1-ester, <43> 3-(3-Acetoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2//,8//- pyr ano [3, 2-g] chr omen-3-y 1-ester, <44> 3-(3,4-Dihydroxy-phenyl) acrylic acid 2,2~dimethyl-8-oxo-3,4-dihydro-
2H, 8//-ρyr ano [3 , 2-g] chr omen-3-y 1 -es t er , <45> 3-(3,4-Diacetoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-
2H, 8//-ρyrano[3 , 2-g] chr omen-3-y 1-ester , <46> 3-(4-Hydroxy-3-methoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4- d i hydr o~2H, 8tf-pyr ano [3 , 2-g] chromen-3-y 1 -est er , <47> 3-(4-Acetoxy-3-methoxy-phenyl) acrylic acid 2, 2-dimethyl-8-oxo-3,4- dihydro-2//,8tf-pyr ano [3, 2-g] chromen-3-yl -ester, <48> 3-(4-Acetoxy-3,5-dimethoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4- di hydro-2tf , 8#-pyr ano [3 , 2-g] chromen-3-y 1 -est er , <49> 3-(4-Methoxy-ρhenyl ) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2#,8#- pyrano[3,2-g]chromen-3-yl-ester, <50> 3-(4-Hydroxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2tf,8tf- pyrano[3,2-g]chromen-3-yl-ester, <5i> 3-(3, 4-Dimethoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-
2H, 8ff-pyr ano [3 , 2-g] chromen-3-y 1 -est er , <52> 3-(3,4,5-Trimethoxy-phenyl) acrylic acid 2,2~dimethyl-8-oxo-3,4-dihydro-
2H, 8#-pyrano[3 , 2-g] chromen-3-y 1 -ester , <53> 3- (3, 4, 5-Tri hydroxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-
2H, 8#-pyrano[3 , 2-g] chromen-3-yl -ester , <54> 3-(2-Methoxy-phenyl ) acrylic acid 2, 2-dimethyl-8-oxo-3,4-dihydro-2J7,8tf- py r ano [ 3 , 2-g ] chr omen-3-y 1 -e s t e r , <55> 3-(2-Hydroxy-phenyl ) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2#,8#- pyrano[3,2-g]chromen-3-yl-ester, <56> 3-(3-Methoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2Jϊ,8//- pyrano[3 , 2-g] chromen-3-yl -ester , <57> 3-(2,3-Dimethoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-
2H, 8//-pyr ano [3, 2-g] chr omen-3-y 1-ester , <58> 3-(2, 4-Dimethoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-
2H, 8/f-pyr ano [3 , 2-g] chromen-3-y 1 -est er , <59> 3-(2,5-Dimethoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-
2H, 8#-pyr ano [3 , 2-g] chromen-3-yl -est er , <60> 3-(2,4,5-Trimethoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-
2i/,8£f-pyrano[3,2-g]chr omen-3-y 1-ester, <6i> 3-(4-Nitro-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2//,8//- pyrano[3,2-g]chromen-3-y1-ester,
<62> Benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2tf,8tf-pyrano[3,2-g]chromen-3- yl-ester,
<63> 3,4,5-Trihydroxy benzoic acid 2, 2-dimethyl-8-oxo-3,4-dihydro-2tf,8#- pyrano[3,2-g]chromen-3-yl-ester,
<64> 3,4,5-Triacetoxy benzoic acid 2,2~dimethyl-8-oxo-3,4-dihydro-2#,8tf- pyrano[3,2-g]chromen-3-y1-ester.
<65> The inventive compounds represented by general formula (I) can be transformed into their pharmaceutically acceptable salt and solvates by the conventional method well known in the art. For the salts, acid-addition salt thereof formed by a pharmaceutically acceptable free acid thereof is useful and can be prepared by the conventional method. For example, after dissolving the compound in the excess amount of acid solution, the salts are precipitated by the water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile to prepare acid 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.
<66>
<67> As a free acid of above-described method, organic acid or inorganic acid can be used. For example, organic acid such as methansulfonic acid, p- toluensulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonylic acid, vanillic acid, hydroiodic acid and the like, and inorganic acid such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used herein.
<68>
<69> 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 hydroxide 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.
<70>
<7i> The pharmaceutically acceptable salt of the compound represented by general formula (I) comprise all the acidic or basic salt which may be present at the compounds, if it does not indicated specifically herein. For 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 acid salt, phosphate salt, hydrogen phosphate salt, dihydrophosphate salt, acetate salt, succinate 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.
<72>
<73> There may exist in the form of optically different diastereomers since the compounds represented by general formula (I) have unsymmetrical centers, accordingly, the compounds of the present invention comprise all the optically active isomers, R or S stereoisomers and the mixtures thereof. Present invention also comprises all the uses of racemic mixture, more than one optically active isomer or the mixtures thereof as well as all the preparation or isolation method of the diastereomer well known in the art.
<74>
<75> The compounds of the invent ion of formula (I ) may be chemical ly 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.
<76>
<77>
GENERAL SYNTHETIC PROCEDURES
<79> Scheme 1
Figure imgf000011_0001
C(CH3)2 1 b. -CH=C(CHa)2
(+)-decursinol R= 1a . -CH=
2a . -CTS-C(CHS)=CHCH3 2b. -c/s-C(CH3)=CHCH3
3a -/rans-(CH3)=CHCH3 3b. -framHCH3)=CHCH3
4a . -C(CH3I=CH2 4b. -C(CH3)=CH2
5a . -CH=CHCH2CH3 5b. -CH=CHCH2CH3
6a . -CH2CH=CH2 6b. -CH2CH=CH2
7a . -CH2CH2CH=CH2 7b. -CH2CH2CH=CH2 θa . -CH3 8b. -CH3
9a . -CH2CI 9b. -CH2CI
Figure imgf000011_0002
(+)-decursinol R= I Oa. -CCI3 R= 10b. -CCI3
11a. -(CH2)3CH3 11 b ,-(CH2)3CH3 12a. -(CH2)SCH3 12b. -(CH2)βCH3
<80> <81> As depicted in the above Scheme 1, the scheme explains the process for preparing novel decursin derivatives (l-12b) by reacting (+)-decursinol with carboxylic acid having various substituents (l-9a) or alkanoyl chloride (10- 12a).
<82> At the 1 step in reaction (a), the reaction mixture of (+)-decursinol , carboxylic acid, DCC(dicyclohexylcarbodiimide) and DMAP (dimethylaminopyridine) are dissolved in anhydrous dichloromethane to react with each other. At the 1 step in reaction (b), the reaction mixture of (+)- decursinol, alkanoyl chloride and pyridine are dissolved in anhydrous dichloromethane to react with each other. 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 5 hrs to 24 hrs, more preferably, 24 hrs with stirring to synthesize decursin derivatives having various alkyl substituents (lb-12b).
<83> <84> Scheme 2
Figure imgf000012_0001
13a. -H R= 13b. -H R = 13c. -H
-3-OH i d 14a. -3-OH 15b. -3-CAc 15a. -3-OAc 17b. -3,4-(QAc)2 -3-OAc
. p 16a. -3,4-(OH)2 19b. -4-QAC-3-OCH3 -3,4-(CH)2
17a. -3,4-(QAc)2 21b. -4-CAc-3,5-(0CH)2 -3,4-(QAc)2 18a. -4-OH-3-OC , p 18c. -4-OH-3-OCH3
22b. -4-CCH3 19a. -4-CAC-3-OCH3 . -4-CAC-3-OCH3 23b. -3,4-(OCH3)2 lV L- 19c i r 20a. -4-OB-3,5-(OOb)2 -4-CAc-3,5-(OCH3)2 24b. -3,4,5-(OCH3)3 21c. U21a. -4-QAc-3,5-(OCH3)2 25b. -2-OCH3 v r- 22c. -4-OCH3
22a. -4-OCH3 26b. -3-OCH3 U22d. -4-OH 23a. -3,4-(OCH3)2 27b. -2,3-(OCHa)2 23c. -3,4-(OCH3)2 24a. -3,4,5-(0CH3)3 28b. -2,4-(OCH3)2 -3,4,5-(CCH3)3 25a. -2-OCH3 29b. -2,5-(OOH3)2 V L*24d. -3,4,5-(OH)3 26a. -3-OCH3 30b. -2,4,5-(OCH3)3 r- 25c. -2-OCH3 27a. -2,3-(OCH3)2 31b. -4-(N02) V L~ 25d. -2-OH 28a. -2,4-(OCH3)2 26c. -3-OCH3 29a. -2,5-(OCHk 27c. -2,3-(OCHs)2 30a. -2,4,&-(0CH3)3 28c. -2,4-(CCH3)2 31a. -4-(NQ2) 29c. -2,5-(0CH3)2
30c. -2,4,5-(OCHs)3
31c. -4-(NO2)
<85> <86> As depicted in the above Scheme 2, the scheme explains the process for preparing novel (+)-decursin derivatives (13c-31c) from (+)-decursinol and cinnamic acid having various substituents (13a-31a). st
<87> At the 1 step in the reaction, the reaction mixture of acetic acid anhydride and 3-or 4-(0H)n-cinnamic acid are dissolved in pyridine. 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. nd
<88> At the 2 step in the reaction, N,N-dimethylformamide and thionyl chloride are added to cinnamic acid dissolved in anhydrous benzene to obtain acid halides. <89> At the 3 step in the reaction, (+)-decursinol and pyridine are dissolved in anhydrous dichloromethane and cinnamoyl chloride is added thereto to (+)- decursin derivatives having various cinnamoyl substitutents. The solvent which does not cause to adverse effect such as dichloromethane, chloroform 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.
<90> At the 4 step in the reaction, an acid such as hydrochloric acid is added to the (÷)-decursin derivatives having 3- or 4-(0Ac)n-cinnamoyl substitutents prepared in step 3 dissolved in acetone dropwisely and the reaction mixture is performed to distillation, colling at room temperature and concentration under reduced pressure. The solvent which does not cause to adverse effect, for example, dimethylformamide, alcohol such as methanol, ethanol etc or acetone, preferably, acetone may be used in the reaction.
<9i> At the 5 step in the reaction, the (+)-decursin derivatives having 3-,
4- or 5-(0Ac)n-cinnamoyl substitutents prepared in step 4 are dissolved in dichloromethane and boron tribromide solution (BBr3 in Methylene chloride) is dropwisely added thereto. The solvent which does not cause to adverse effect, for example, dichloromethane, chloroform 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 cool temperature.
<92>
<93> Scheme 3
<94>
Figure imgf000014_0001
R= 32a. -H R= 32b. -H R= 32C-H i r 33a-3,4,5-<0H)3 34b -3,4,5-<(>c)3 lwr 33c. -3,4,MCH)3 IVL 34c. -3,4,MO^c)3 U34a. -3,4,5-(0^c)3
<95> <96>
<97> As depicted in the above Scheme 3, the scheme explains the process for preparing novel (+)-decursin derivatives having various benzoyl groups (32c- 34c) from (+)-decursinol and benzoic acid having various substituents (32a- 34a).
St
<98> At the l°l step in the reaction, strong acid such as c-sulfuric acid is added to the reaction mixture of acetic acid anhydride and 3-, 4- or 5-(0H)n- benzoic acid and the solution is performed to reflux and react together.
<99> At the 2 step in the reaction, N,N-dimethylformamide and thionyl chloride are added to benzoic acid dissolved in anhydrous benzene to obtain acid halides.
<100> At the 3 step in the reaction, (+)-decursinol and pyridine are dissolved in anhydrous dichloromethane and benzoyl chloride is added thereto to (+)- decursin derivatives having various benzoyl substitutents. The solvent which does not cause to adverse effect such as dichloromethane, chloroform 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. th
<101> At the 4 ' step in the reaction, the decursin derivatives having 3-, 4- or 5-(0Ac)n-benzoyl substitutents prepared in step 3 are dissolved in acetone and hydrochloric acid is dropwisely added thereto. The solvent which does not cause to adverse effect, for example, dimethylformamide, alcohol such as methanol, ethanol etc or acetone may be used in the reaction.
<102>
<1O3> The novel decursin derivatives prepared by the above-described method represented by general formula (I) shows strong anticancer activity being confirmed by various experiments such as cytotoxicity test in A549 lung cancer cell line, HCT15 colon cancer cell line and ACHN rectal cancer cell line, therefore the compounds can be useful in treating or preventing cancer diseases, preferably, lung cancer, colon cancer or rectal cancer.
<104>
<iO5> 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 (I) or the pharmaceutically acceptable salt thereof as an active ingredient in amount effective to treat or prevent cancer disease, together with pharmaceutically acceptable carriers or diluents.
<106>
<iO7> It is another object of the present invention to provide the pharmaceutical composition comprising an efficient amount of the compound represented by general formula (I) or the pharmaceutically acceptable salt thereof as an active ingredient in amount effective to treat or prevent cancer disease, together with pharmaceutically acceptable carriers or diluents.
<108>
<1O9> In accordance with the other aspect of the present invention, there is also provided a use of the compound represented by general formula (I) or the pharmaceutically acceptable salt thereof for manufacture of medicines employed for treating or preventing cancer disease in mammals including human as an active ingredient in amount effective to treat or prevent cancer disease.
<πo>
<iii> In accordance with the other aspect of the present invention, there is also provided a use of the compound represented by general formula (I) or the pharmaceutically acceptable salt thereof for manufacture of medicines employed for treating or preventing cancer disease in mammals including human as an active ingredient in amount effective to treat or prevent cancer disease.
<112>
<ii3> In accordance with the other aspect of the present invention, there is also provided a method of treating or preventing inflammatory disease in a mammal comprising administering to said mammal an effective amount of novel (+)-decursin derivatives represented by general formula (I) and the pharmacologically acceptable salt thereof, together with a pharmaceutically acceptable carrier thereof into the mammals including human suffering from said disease.
<114>
<ii5> The term "cancer diseases" disclosed herein comprise various cancer disease, for example, lung cancer, colon cancer or rectal cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer or cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (eg., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphonas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), or neoplasms of the central nervous system (e.g., primary CNS lymphoma, spinal axis tumors, brain stem gliomas or pituitary adenomas), preferably solid cancer such as lung cancer or blood cancer, preferably, lung cancer, colon cancer or rectal cancer.
<116>
<ii7> The compound according to the present invention can be provided as a pharmaceutical composition containing pharmaceutically acceptable carriers, adjuvants or diluents. For example, the compound of the present invention can be dissolved in oils, propylene glycol or other solvents which are commonly used to produce an injection. Suitable examples of the carriers include physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc., but are not limited to them. For topical administration, the compound of the present invention can be formulated in the form of ointments and creams.
<118>
<ii9> Hereinafter, the following formulation methods and excipients are merely exemplary and in no way limit the invention.
<120>
<i2i> 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.
<122>
<i23> 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 such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
<124>
<125> 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 1% by weight based on the total weight of the composition.
<126>
<]27> The pharmaceutical 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, rectal Iy or by intravenous, intramuscular, subcutaneous, intrathecal, epidural or intracerebroventricular injection.
<128>
<i29> The novel (+)-decursin derivatives represented by general formula (I) 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.
<130>
<i3i> Accordingly, it is the other object of the present invention to provide a functional health food comprising novel (+)-decursin derivatives represented by general formula (I), or the pharmacologically acceptable salt thereof for aiding cancer chemotherapy.
<132>
<i33> The term "a functional health food" defined herein the functional food having enhanced functionality such 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. <134>
<i35> 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), or the pharmacologically acceptable salt thereof, together with a sitologically acceptable additive for the prevention and alleviation of cancer disease.
<136>
<137> 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.
<138>
<i39> The term "a sitologically acceptable additive" defined herein any substance the intended use which results or may reasonably be expected to result-directly or indirect ly-in its becoming a component or otherwise affecting the characteristics of any food for example, thickening agent, maturing agent, bleaching agent, sequesterants, humectant, anticaking 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.
<i40> 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.
<141>
<142> 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.
<143> <i44> Also, above described compounds can be added to food or beverage for prevention and improvement of cancer disease. 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.
<145>
<i46> 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 glucose, fructose etc; disaccharide such as maltose, sucrose etc; conventional sugar such 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 such as levaudioside A, glycyrrhizin et al., and synthetic deodorant such as saccharin, 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 mH of present beverage composition.
<147>
<148> 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 acid and the salt thereof, organic acid, 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 juice, 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.
<149> 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.
<150> <151>
[Advantageous Effects]
<153> As described in the present invention, the (+)-decursin derivatives of the present invention showed potent inhibiting effect on the cancer cell being confirmed by various experiments such as cytotoxicity test in A549 lung cancer cell line, HCT15 colon cancer cell line and ACHN rectal cancer cell line, therefore the compounds can be useful in treating or preventing cancer diseases as an anti-cancer agent, health care food, or functional health food.
<154>
[Best Mode] <155> 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. <156> 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. <i57> The following Reference Example, Examples and Experimental Examples are intended to further illustrate the present invention without limiting its scope.
<158>
[Mode for Invent ion] <i59> Example 1. l ,3-but-2-tenoic acid 2,2, -dimethyl-8-oxo-3,4-dihydro-2#,8#- ρyrano[3,2g]-chromen-3-yl-ester (Ib)
<160>
Figure imgf000023_0001
<163> As shown in the above-described reaction formulae, the mixture of 1 equivalent amount of 3-methyl-bu-2-tenoic acid, 1.1-2.0 equivalent amount of DCC (l.δ-dicyclohexylcarbodiimide) and 0.4 equivalent amount of 4- dimethylaminopyridine(DMAP) were added to (+)-decursinol in round flask and dissolved in anhydrous dichloromethane. The reaction solution was washed with dichloromethane, filtrated and concentrated in vaccuo. The concentrates were performed to Silica gel column chromatography with a mobile phase (n~ hexane:ethylacetate=10:l~l:l) to obtain semi-solid type of l,3-but-2-tenoic acid 2,2,-dimethyl-8-oxo-3,4-dihydro-2//,8tf-pyrano[3,2g]-chromen-3-yl-ester (Ib ; yield: 64.0%).
<164> Rf=O.35(n-hexane:ethylacetate=2-"I);
<165> H NMR(CDCl3, 400MHz) δ ppm 7.589(d, J=9.6Hz, IH), 7.160(s, IH),
6.788(s, IH), 6.222(d, /=9.6Hz, IH), 5.663(s, IH), 5.086(t, J=4.8Hz, IH), 3.197(dd, J=4.8, 17.2Hz, IH), 2.867(dd, /=4.8, 17.2Hz, IH), 2.146(d, J=LOHz, 3H), 1.880(d, J=LOHz, 3H), 1.384(s, 3H), 1.365(s, 3H);
<166> MS(fflA) 329 (M+H)+.
<167> <168> Example 2. cis-2-methyl-bu-2-tenoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2tf,8tf-pyrano[3,2-g]-chromen-3-yl-ester (2b)
<169>
<πo> Excepting that 1 equivalent amount of 3-methyl-bu-2-tenoic acid was substituted with 1 equivalent amount of cis-2-methyl-bu-2-tenoic acid, all the procedure was performed in a similar method to Example 1 to obtain oil type of Cis-2-methyl-bu-2-tenoic acid 2,2-dimethyl-8-oxo-3,4-dihydro--?//,5#- pyrano[3,2-g]-chromen-3-yl-ester (2b; yield: 56.3%).
<i7i> Rf=0.35(n-hexane: ethylacetate=2:l);
<172> 1H NMR(CDCl3, 400MHz): δ ppm 7.595(d, /=9.2Hz, IH), 7.167(s, IH),
6.819(qd, J=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, /=4.8, 17.2Hz, IH), 2.888(dd, /=5.4, 17.2Hz, IH), 1.803(d, J=I.2Hz, 3H), 1.767(d, J=6.8Hz, 3H), 1.398(s, 3H), 1.378(s, 3H);
<i73> MS(mA) 329 (M+H)+.
<174>
<i75> Example 3. trai2s-2-methyl-bu-2-tenoic acid 2 ,2-di methyl -8-oxo-3,4-di hydro- 2H, 8tf-pyrano[3 , 2-g]-chromen-3-yl -ester (3b)
<176>
<177> Excepting that 1 equivalent amount of 3-methyl-bu-2-tenoic acid was substituted with 1 equivalent amount of tra/2s-2-methyl-bu-2-tenoic acid, all the procedure was performed in a similar method to Example 1 to obtain oil type of trai2s-2-methyl-bu-2-tenoic acid 2, 2-di methyl -8-oxo-3,4-di hydro-2#,8ff- pyrano[3,2-g]-chromen-3-yl-ester (3b; yield: 43.9%).
<i78> Rf=O.48 (n-hexane: ethyl acet at e=2:l);
<179> 1H NMR(CDCl3, 400MHz): δ ppm 7.505(d, /=9.6Hz, IH), 7.074(s, IH), 6.743(m,
2H), 6.154(d, /=9.6Hz, IH), 5.009(t, /=4.8Hz, IH), 3.133(dd, /=4.8, 17.2Hz, IH), 2.806(dd, /=4.8, 17.2Hz, IH), 1.784(m, 6H), 1.352(s, 3H), 1.319(s, 3H); <i80> MS(/π/z) 329 (M+H)+'
<181>
<i82> Example 4. 2-methyl-acrylic acid 2, 2-dimethyl-8-oxo-3,4-dihydro-2//,3//- pyrano[3,2-g]-chromen-3-yl-ester (4b)
<183>
<184> Excepting that 1 equivalent amount of 3-methyl-bu-2-tenoic acid was substituted with 1 equivalent amount of 2-methyl-acrylic acid, all the procedure was performed in a similar method to Example 1 to obtain semi-solid type of 2-methyl-acrylic acid 2,2-dimethyl-8-oxo-3)4-dihydro-i?//',Sff- pyrano[3,2-g]-chromen-3-yl-ester (4b; yield: 93.3%).
<185> Rf=0.52(n-hexane: ethylacetate=l:l) ;
<i86> 1H NMR(CDCl3, 400MHz): δ ppm 7.565(d, J=9.6Hz, IH), 7.141(s, IH), 6.786(s,
IH), 6.216(d, /=9.6Hz, IH), 6.052(s, IH), 5.562(s, IH), 5.076(t, /=5.2Hz, IH), 3.209(dd, J=4.8, 16.8Hz, IH), 2.883(dd, J=5.6, 17.2Hz, IH), 1.903(s, 3H), 1.384(s, 3H), 1.370(s, 3H);
<i87> MS(m/z) 315 (M+H)+'
<188>
<i89> Example 5. pen-2-tenoic acid 2, 2-dimethyl-8-oxo-3,4-dihydro--2//,S#- ρyrano[3,2-g]-chromen-3-yl-ester (5b)
<190>
<i9i> Excepting that 1 equivalent amount of 3-methyl-bu-2-tenoic acid was substituted with 1 equivalent amount of pen-2-tenoic acid, all the procedure was performed in a similar method to Example 1 to obtain oil type of pen-2- tenoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2flr,Sff-pyrano[3,2-g]-chromen-3-yl- ester (5b; yield: 92.1%).
<192> Rf=0.400(n-hexane:ethylacetate=2:l);
<193> 1H NMR(CDCl3, 400MHz): δ ppm 7.58(d, J=9.6Hz, IH), 7.151(s, IH), 7.028(m, IH), 6.798(s, IH), 6.223(d, /=9.6Hz, IH), 5.803(d, J=15.6Hz, IH), 5.111(t, J=4.8Hz, IH), 3.204(dd, /=4.8, 17.2Hz, IH), 2.882 (dd, J=A.8, 17.2Hz, IH), 2.197(m, 2H), 1.390(s, 3H), 1.366(s, 3H), 1.049(t, /=7.6Hz, 3H);
<194> MS(fflA) 329 (M+H) +.
<195>
<196> Example 6. bu-3-tenoic acid 2, 2-dimethyl-8-oxo-3,4-dihydro-2/f,S//-pyrano[3,2- g]-chromen-3-yl -ester (6b)
<197>
<198> Excepting that 1 equivalent amount of 3~methyl-bu-2-tenoic acid was substituted with 1 equivalent amount of bu-3-tenoic acid, all the procedure was performed in a similar method to Example 1 to obtain semi-solid type of bu-3-tenoic acid 2,2-dimethyl-8-oxo-3,4-dihydro--?tf,#/^ρyrano[3,2-g]-chromen- 3-yl-ester (6b; yield: 90.2%).
<i99> Rf=0.65(n-hexane-"ethylacetate=l-'l);
<2oo> 1H NMR(CDCl3, 400MHz): δ ppm 7.584(d, J=9.6Hz, IH), 7.154(s, IH), 6.793(s,
IH), 6.232(d, /=9.6Hz, IH), 5.866(m, IH), 5.176(m, 2H), 5.063(t, J=4.8Hz, IH), 3.190(dd, /=4.8, 17.2Hz, IH), 3.096(m, 2H), 2.856(dd, /=5.2, 17.2Hz, IH), 1.373(s, 3H), 1.355(s, 3H);
<2oi> MS(m/z) 315 (M+H) +.
<202>
<203> Example 7. pen-4-tenoic acid 2, 2-dimethyl-8-oxo-3,4-dihydro-2//,8//- ρyrano[3,2-g]-chromen-3-yl-ester (7b)
<204>
<205> Excepting that 1 equivalent amount of 3-methyl-bu-2-tenoic acid was substituted with 1 equivalent amount of pen-4-tenoic acid, all the procedure was performed in a similar method to Example 1 to obtain oil type of pen-4- tenoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2/f,θi/-pyrano[3,2-g]-chromen-3-yl- ester (7b; yield: 81. ( <206> R1=O .51(n-hexane : ethy 1 acetate=2 : 1) ;
<207> 1H NMR(CDCl3, 400MHz): δ ppm 7.580 (d, /=9.6Hz, IH), 7.146(s, IH), 6.792(s,
IH), 6.231(d, J=9.6Hz, IH), 5.790(m, IH), 5.056-4.957 (m, 3H), 3.178(dd, /=4.8, 17.2Hz, IH), 2.837 (dd, /=5.2, 17.2Hz, IH), 2.433(m, 2H), 2.356(t, /=6.4Hz, 2H), 1.374(s, 3H), 1.352(s, 3H);
<208> MS(fflA) 329 (M+H)+.
<209>
<2io> Example 8. Acetic acid 2, 2-dimethyl-8-oxo-3,4-dihydro--2ff,5i¥-pyrano[3,2-g]- chromen-3-yl -ester (8b)
<211>
<2i2> Excepting that 1 equivalent amount of 3-methyl-bu-2-tenoic acid was substituted with 1 equivalent amount of acetic acid, all the procedure was performed in a similar method to Example 1 to obtain solid type of acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2ff,Sff-pyrano[3,2-g]-chromen-3-yl-ester (8b; yield: 89.8%).
<2i3> m.p 125- 126 °C;
<2i4> Rf=0.38(n-hexane: ethyl acetate=l:l);
<2i5> 1H NMR(CDCl3, 400MHz): δ ppm 7.579(d, /=9.6Hz, IH), 7.153(s, IH), 6.791(s,
IH), 6.229(d, /=9.6Hz, IH), 5.050(t, /=4.8Hz, IH), 3.184(dd, /=4.0, 17.2Hz, IH), 3.004(dd, /=4.8, 17.4Hz, IH), 2.041(s, 3H), 1.422(s, 3H), 1.378(s, 3H);
<2i6> MS(inA) 289 (M+H) +.
<217>
<2i8> Example 9. chloro Acetic acid 2, 2-dimethyl-8-oxo-3,4-dihydro-2tf,#/- pyrano[3,2-g]-chromen-3-yl-ester (9b)
<219>
<220> Excepting that 1 equivalent amount of 3-methyl-bu-2-tenoic acid was substituted with 1 equivalent amount of chloro acetic acid, all the procedure was performed in a similar method to Example 1 to obtain solid type of chloro acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2/ϊ,β/¥-pyrano[3f2-g]-chromen-3-yl- ester (9b; yield: 96.2%).
<221> m.p 147-148°C;
<222> Rf=0.46(n-hexane: ethylacetate=l:l);
<223> 1H NMR(CDCl3, 400MHz) : δ ppm 7.579(d, J=9.6Hz , IH) , 7.160(s , IH) , 6.794(s ,
IH) , 6.235(d, /=9.6Hz , IH) , 5.128(t , J=AMz , IH) , 4.088(d, J= 14.8Hz , IH) , 4.031(d, J=14.8Hz , IH) , 3.229(dd, J=A . S , 17.2Hz , IH) , 2.907(dd, /=4.8 , 17.2Hz , IH) , 1.400(s , 3H) , 1.375(s , 3H) ;
<224> US(m/z) 323 (M+H) +.
<225> <226> Example 10. trichloro Acetic acid 2, 2-dimethyl-8-oxo-3,4-dihyάτo-2H,8H- pyrano[3,2-g]-chromen-3-yl-ester (10b)
<227>
Figure imgf000028_0001
(+KfeθLrsinol R=IOa -OQ3 R=ICb. -OCb Ua -fOtøCHϊ 11bHOt)3Ot 12a. -(Qi)8CH 12b. -(Ot)8CH
<228> <229> As shown in the above-described reaction formula, the mixture of 2 equivalent amount of pyridine and 2 equivalent amount of trichloro acetyl chloride (10a) were added to (+)-decursinol dissolved in dichloromethane dropwisely and stirred for 2 hours at room temperature. The reaction solution was filtrated and the supernatant was concentrated in vaccuo. The concentrates were performed to Silica gel column chromatography with a mobile phase (n-hexane-'ethylacetate=10: 1-3:1) to obtain semi-solid type of trichloro acetic acid 2,2,-dimethyl-8-oxo-3,4-dihydro-2#,8#-pyrano[3,2g]-chromen-3-yl- ester (10b ; yield: 87.! <230> Rf=0.60(n-hexane: ethylacetate=l:l);
<23i> 1H NMR(CDCl3, 400MHz): δ ppm 7.578(d, /=9.6Hz, IH), 7.178(s, IH), 6.185(s,
IH), 6.245(d, J=9.6Hz, IH), 5.138(t, J=5.2Hz, IH), 3.292(dd, J=A.8, 16.8Hz, IH), 2.999 (dd, J=5.2, 17.2Hz, IH), 1.450(s, 3H), 1.435(s, 3H);
<232> MS(ffl/z) 392 (M+H) +.
<233>
<234> Example 11. pentanoic acid 2, 2-dimethyl-8-oxo-3,4-dihydro--?#,<8//-pyrano[3,2-- g]-chromen-3-yl-ester (lib)
<235>
<236> Excepting that 1 equivalent amount of trichloro acetyl chloride was substituted with 1 equivalent amount of pentanoyl chloride (valeroyl chloride), all the procedure was performed in a similar method to Example 1 to obtain oil type of pentanoic acid 2,2-dimethyl-8-oxo-3,4-dihydro--?#,<8/-L- pyrano[3,2-g]-chromen-3-yl-ester (lib; yield: 90.7%).
<237> Rf=0.39(n-hexane : ethyl acet at e=2 : 1 ) ;
<238> 1H NMR(CDCl3, 400MHz): δ ppm 7.576(d, 7=9.6Hz, IH), 7.145(s, IH), 6.788(s,
IH), 6.224(d, J=9.6Hz, IH), 5.044(tf J=5.2Hz, IH), 3.180(dd, /=4.8, 16.8Hz, IH), 2.837(dd, /=4.8, 16.8Hz, IH), 2.313(t, /=7.6Hz, 2H), 1.580(m, 2H), 1.372(s, 3H), 1.355(s, 3H), 1.377-1.256(m, 2H), 0.876(t, /=7.2Hz, 3H);
<239> MS(m/z) 331 (M+H) +.
<240>
<24i> Example 12. decanoic acid 2, 2-dimethyl-8-oxo-3,4-dihydro-2#,5//-pyrano[3,2- g]-chromen-3-yl-ester (12b)
<242>
<243> Excepting that 1 equivalent amount of trichloro acetyl chloride was substituted with 1 equivalent amount of decanoyl chloride, all the procedure was performed in a similar method to Example 1 to obtain oil type of decanoic acid 2 ,2-dimethy I-8-OXO-3, 4-dihydro--?^,8/7-ρyrano[3,2-g]-chromen-3-yl-ester (12b; yield: 93.0%).
<244> Rf=0.49(n-hexane: ethylacetate=2:l);
<245> 1H NMR(CDCl3, 400MHz): δ ppm 7.574(d, J=9.2Hz, IH), 7.143(s, IH), 6.788(s,
IH), 6.227(d, >9.2Hz, IH), 5.043(t, J=4.8Hz, IH), 3.178(dd, J=4.8, 16.8Hz, IH), 2.839(dd, /=4.8, 17.2Hz, IH), 2.323(t, /=8.0Hz, 2H), 1.615(tn, 2H), 1.406(s, 3H), 1.373(s, 3H), 1.336-1.256 (m, 12H), 0.888(t, J=7.2Hz, 3H);
<246> US(m/z) 401 (M+H) \
<247> <248> [Table 1]
Figure imgf000030_0001
Figure imgf000031_0001
[Table 3]
<251>
Figure imgf000031_0002
<252> Example 13. 3-phenyl-acrylic acid 2, 2-dimethyl-8-oxo-3,4-dihydro-2H,8H- pyrano[3,2-g]-chromen-3-yl-ester (13c)
Figure imgf000032_0001
R= 13a -H R= 13b. -H R= 13c. -H j r- 14a -3-CH 15b. -3-QAc tøf 14c. -3-CH u15a -3-OAc 17b. -3,4-(Qac)2 L 15c. -3-CΛc . r 16α -3,4-(0H)2 19b. -4-OkHMXH k-r16c. -3,4-(OH)2 ι u 17a -3,4-(QOc)2 21b. →4-Oβc-3,5-(OCI-b)2 U 17c. -3,4-(CAd2 i (-18a -^-O+-3-0CH3 iwr-18c.-4-α4-3-OCH3 I U19a -4-(>o-3-OCH3 1 L 19c . -^-Oac-3-OOb i r- 20a. -4-OH-3,5-(θα-b)2 21c. -4-Oac-3,MCX>fe)2 U21a ^-OΛc-3,5-((X>b)2
<253> <254> Step 1
<255> As shown in the above-described reaction formula, 30-40 equivalent amount of anhydrous benzene was added to 1.5 equivalent amount of 3-phenyl acrylic acid in round flask. Two drop of N,N-dimethyl formamide and 7.5 equivalent amount of thionyl chloride were added thereto and performed to refux for 5 hours at 70-80°C.
<256> The reaction solution was cooled to room temperature and concentrated in vaccuo to obtain cinnamoyl chloride.
<257> <258> Step 2 <259> 1 equivalent amount of (+)-decursinol and 3 equivalent amount of pyridine were dissolved in anhydrous dichloromethane in round flask. 1.5 equivalent amount of cinnamyl chloride obtained in step 1 dissolved in anhydrous dichloromethane was added thereto and stirred for 2 hours at room temperature. The reaction solution was concentrated in vaccuo and the concentrates were performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=10:i~l:l) to obtain solid type of 3-phenyl- acrylic acid 2,2,-dimethyl-8-oxo-3,4-dihydro-2^,8Λr-pyrano[3,2g]-chromen-3-yl- ester (13c ; yield: 49.3%). <260> m.p 136- 1370C;
<26i> Rf= 0.40(n-hexane:ethylacetate=l:l);
<262> 1H NMR(acetone-d6, 400MHz): δ ppm 7.882(d, 7=9.6Hz, IH), 7.707(m, 3H),
7.433(m, 4H), 6.754(s, IH), 6.568(d, 7=16. OHz, IH), 6.212(d, 7=9.2Hz, IH), 5.240U, 7=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);
<263> MS(m/z) 377 (M+H) +.
<264>
<265> Example 14. 3- (3-hydroxy-phenyl) -acrylic acid 2, 2-dimethyl-8-oxo-3,4- dihydro--?tf,5//-ρyrano[3,2-g]-chromen-3-yl-ester (14c)
<266> Step 1
<267> As shown in the above-described reaction formulae, 1 equivalent amount of 3-(3-hydroxy-phenyl)-acrylic acid and 10 equivalent amount of pyridine were added to 10 equivalent amount of acetic anhydride in round flask. The solution was stirred with magnetic bar for overnight and concentrated in vaccuo. The concentrate was performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=5: 1-1:1) to obtain purified product .
<268>
<269> Step 2
<270> 1.5 equivalent amount of 3-(3-acetoxy-phenyl)-acrylic acid were dissolved in 30-40 equivalent amount of anhydrous benzene in round flask. Two drop of N,N-dimethyl formamide and 7.5 equivalent amount of thionyl chloride were added thereto and performed to refux for 5 hours at 70-80°C .
<27i> The reaction solution was cooled to room temperature and concentrated in vaccuo to obtain 3-(3-acetoxy-phenyl)-acryloyl chloride.
<272>
<273> Step 3
<274> 1 equivalent amount of (+)-decursinol and 3 equivalent amount of pyridine were dissolved in 50 folds volume of anhydrous dichloromethane in round flask. 1.5 equivalent amount of 3-(3-acetoxy-phenyl)-acryloyl chloride obtained in step 2 dissolved in anhydrous dichloromethane was added thereto and stirred for 2 hours at room temperature. The reaction solution was concentrated in vaccuo and the concentrates were performed to Silica gel column chromatography with a mobile phase (n-hexane-ethylacetate=10-l~l;l) to obtain 3-(3-acetoxy-ρhenyl)-acrylic acid 2,2,-dimethyl-8-oxo-3,4-dihydro- 2tf,8/7-pyrano[3,2g]-chromen-3-y1-ester .
<275>
<276> Step 4
<277> 1 equivalent amount of 3- (3-acetoxy-phenyl) -acrylic acid 2, 2, -dimethyl -
8-0X0-3, 4-dihydro-2H,8H-pyrano[3,2g]-chromen-3-yl-ester obtained in step 3 was dissolved in acetone and 4-8 equivalent amount of 3N-HC1 was added thereto. The reaction solution was performed to refux for 12 hours at 50-60 "C and cooled at room temperature. The concentrate was fractionated with distilled water and ethylacetate and the collected ethylacetate soluble layer was dehydrated with anhydrous KMnO4, filtered and the supernatant was concentrated in vaccuo. The concentrates were performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=5: 1-2:1) to obtain solid type of 3- (3-hydroxy-phenyl) -acrylic acid 2,2,-dimethyl-8-oxo-3,4- dihydro-2iV,8iϊ-pyrano[3,2g]-chromen-3-yl-ester(14c; yield: 88.1%). .
<278> m.p 1050C;
<279> Rf= 0.21(n-hexane.'ethylacetate=l:l);
<280>
<28i> 1H NMR(acetone-d6, 400MHz): δ ppm 7.863(d, /=9.2Hz, IH), 7.622(d, /=15.6Hz,
IH), 7.442(s, IH), 7.252(t, /=7.8Hz, IH), 7.168(d, /=7.6Hz, IH), 7.111(s, IH), 6.915(d, J=SMz, IH), 6.751(s, IH), 6.489(d, /=16. OHz, IH), 6.213(d, /=9.6Hz, IH), 5.229(t, /=4.6Hz, IH), 3.337(dd, /=4.2, 17.2Hz, IH), 2.987(dd, J=AA, 17.6Hz, IH), 1.432(s, 3H), 1.422(s, 3H); <282> MS(fflA) 393 (M+H) \
<283>
<284> Example 15. 3~(3-acetoxy-phenyl)-acrylic acid 2, 2-dimethyl-8-oxo-3,4- dihydro-2tf,8tf-pyrano[3,2-g]-chromen-3-yl-ester (15c)
<285>
<286> Step 1
<287> As shown in the above-described reaction formula in Example 14, 1 equivalent amount of 3-(3-hydroxy-phenyl)-acrylic acid and 10 equivalent amount of pyridine were added to 10 equivalent amount of acetic anhydride in a round flask. The solution was stirred with magnetic bar for overnight and concentrated in vaccuo. The concentrate was performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=5:1-1:1) to obtain purified product.
<288>
<289> Step 2
<290> 1.5 equivalent amount of 3-(3-acetoxy-phenyl)-acrylic acid were dissolved in 30-40 equivalent amount of anhydrous benzene in a round flask.
Two drop of iV,/V-dimethyl formamide and 7.5 equivalent amount of thionyl chloride were added thereto and performed to refux for 5 hours at 70-800C. <29i> The reaction solution was cooled to room temperature and concentrated in vaccuo to obtain 3-(3-acetoxy-ρhenyl)-acryloyl chloride.
<292>
<293> Step 3
<294> 1 equivalent amount of (+)-decursinol and 3 equivalent amount of pyridine were dissolved in 50 folds volume of anhydrous dichloromethane in a round flask. 1.5 equivalent amount of 3-(3-acetoxy-phenyl)-acryloyl chloride obtained in step 2 dissolved in anhydrous dichloromethane was added thereto and stirred for 2 hours at room temperature. The reaction solution was concentrated in vaccuo and the concentrates were performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=10-"l~l."l) to obtain solid type of 3-(3-acetoxy-phenyl)-acrylic acid 2, 2, -dimethyl -8-oxo- 3,4-dihydro-2tf,8tf-pyrano[3,2g]-chromen-3-yl-ester (15c; yield: 87.0%). .
<295> m.p 1810C;
<296> Rf= 0.31(n-hexane: ethyl acetate=l:l);
<297> 1H NMR(acetone-d6) 400MHz): δ ppm 7.840(d, J=9.6Hz, IH), 7.684(d,
/=16. OHz, 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, J=15.6Hz, IH), 6.198(d, J=9.6Hz, IH), 5.232(t,
J=4.4Hz, IH), 3.336(dd, /=4.2, 17.6Hz, IH), 2.984(dd, /=4.8, 17.6Hz, IH), 2.258(s, 3H), 1.430(s, 3H), 1.422(s, 3H);
<298> MS(ΛJΛ) 435 (M+H) +.
<299>
<3oo> Example 16. 3- (3,4-di hydroxy-phenyl) -acrylic acid 2, 2-d i methyl -8-oxo-3, 4- dihydr o-2H, 8H-pyrano[3 , 2-g] -chromen-3-y 1 -est er ( 16c )
<301>
<302> Excepting that 1 equivalent amount of 3-(3-hydroxy-phenyl)-acrylic acid was substituted with 1 equivalent amount of 3- (3,4-di hydroxy-phenyl) -acrylic acid), all the procedure was performed in a similar method to Example 14 to obtain solid type of 3- (3,4-di hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8- oxo-3, 4-dihydro-2tf,S#-pyrano[3,2-g]-chromen-3-yl-ester (16c; yield: 93.2%).
<303> m.p 115°C;
<304> Rf= 0.36(n-hexane:ethylacetate=l:2);
<305>
<306> 1H NMR(CDCl3, 400MHz): δ ppm 7.618(d, /=8.8Hz, IH), 7.549(d, /=16. OHz,
IH), 7.181(s, IH), 7.068(s, IH), 6.948(dd, /=1.6, 8.4Hz, IH), 6.870(d, /=8.0Hz, IH), 6.821(s, IH), 6.223(m, 2H), 5.179(t, /=4.6Hz, IH), 3.231(dd, J=4.6, 17.6Hz, IH), 2.935(dd, /=4.6, 17.6Hz, IH), 1.428(s, 3H), 1.379(s, 3H); <307> MS(m/z) 409 (M+H) +.
<308>
<309> Example 17. 3-(3,4-diacetoxy-phenyl)-acrylic acid 2, 2-dimethyl-8-oxo-3,4- di hydr o~2H, Stf-pyr ano [3 , 2-g] -chr omen-3-y 1 -est er ( 17c )
<310>
<3ii> Excepting that 1 equivalent amount of 3~(3-hydroxy-phenyl) -aery lie acid was substituted with 1 equivalent amount of 3-(3,4-dihydroxy-phenyl)-acrylic acid), all the procedure was performed in a similar method to Example 14 to obtain solid type of 3-(3,4-diacetoxy-phenyl)-acrylic acid 2,2-dimethyl-8- oxo-3>4-dihydro-2//,8//-pyrano[3,2-g]-chromen-3-yl-ester (17c; yield: 84.5%).
<3i2> m.p 92 °C;
<3i3> Rf= 0.27(n-hexane:ethylacetate=l:l);
<3i4> 1H NMR(CDCl3, 400MHz): δ ppm 7.613(d, /=8.4Hz, IH), 7.58Kd, /=2.0Hz, IH),
7.389-7.339(m, 2H), 7.256-7.179 (m, 2H), 6.823(s, IH), 6.358(d, /=16.0, IH),
6.232(d, /=9.2Hz. IH), 5.190(t, J=4.6Hz, IH), 3.244(dd, /=4.6, 17.6Hz, IH),
2.932(dd, /=4.6, 17.6Hz, IH), 2.293(s, 3H), 2.290(s, 3H), 1.425(s, 3H), 1.389(s, 3H);
<3i5> MS(/π/z) 493 (M+H) +.
<316>
<317> Example 18. 3-(4-hydroxy-3-methoxy-phenyl)-acrylic acid 2, 2-dimethyl-8-oxo- 3 , 4-dihydro-.?#, Stf-pyrano[3 , 2-g] -chromen-3-yl -ester ( 18c)
<318>
<3t9> Excepting that 1 equivalent amount of 3-(3-hydroxy-phenyl)-acrylic acid was substituted with 1 equivalent amount of 3-(4-hydroxy-3-methoxy-phenyl)- acrylic acid, all the procedure was performed in a similar method to Example 14 to obtain solid type of 3-(4-hydroxy-3-methoxy-phenyl)-acrylic acid 2,2- dimethyl-8-oxo-3,4-dihydro-2//,,Si/-pyrano[3,2-g]-chromen-3-yl-ester (18c; yield: 91. i <320> m.p 1020C; <32i> Rf= 0.32(n-hexane:ethylacetate=l:l);
<322>
<323> 1H NMR(acetone-d6, 400MHz): δ ppm 7.843(d, /=9.6Hz, IH), 7.616(d, J= 16. OHz,
IH), 7.424(s, IH), 7.357(s, IH), 7.123(dd, /=2.0, 8.0Hz, IH), 6.851(d,
J=8.4Hz, IH), 6.740(s, IH), 6.387(d, J=15.6Hz, IH), 6.198(d, /=9.6Hz, IH),
5.22Kt, /=4.6Hz, IH), 3.895(s, 3H), 3.321(dd, J=A.6, 17.2Hz, IH)1 2.963(dd, J=AA, 17.6Hz, IH), 1.421(s, 3H), 1.413(s, 3H);
<324> MS(m/z) 423 (M+H) + .
<325>
<326> Example 19. 3-(4-acetoxy-3-methoxy-phenyl)-acrylic acid 2, 2-dimethyl-8-oxo- 3 , 4-dihydro-2ff, #tf-pyr ano [3 , 2-g] -chromen-3-y 1 -ester ( 19c )
<327>
<328> Excepting that 1 equivalent amount of 3-(3-hydroxy-phenyl)-acrylic acid was substituted with 1 equivalent amount of 3-(4-acetoxy-3-methoxy-phenyl)- acrylic acid, all the procedure was performed in a similar method to Example 14 to obtain solid type of 3-(4-acetoxy-3-methoxy-phenyl)-acrylic acid 2,2- dimethyl-8-oxo-3,4-dihydro-2F,θi/-ρyrano[3,2-g]-chromen-3-yl-ester (19c; yield: 42.4%).
<329>
<33o> m.p 98 °C ;
<33i> Rf= 0.40(n-hexane:ethylacetate=l:l);
<332> 1H NMR(acetone-d6, 400MHz): δ ppm 7.843(d, /=9.6Hz, IH), 7.679(d,
/=16. OHz, 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. OHz, 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); <333> MS(fflΛ) 465 (M+H)+.
<334>
<335> Example 20. 3-(4-acetoxy-3,5-dimethoxy-phenyl)-acrylic acid 2, 2-dimethyl-
8-0X0-3 ,4-dihydr o~2H, 8tf-pyrano[3 , 2-g]-chromen-3-yl-ester (21c)
<336>
<337> Excepting that 1 equivalent amount of 3-(3-hydroxy-phenyl)~acrylic acid was substituted with 1 equivalent amount of 3-(4-acetoxy-3,5-dimethoxy-phenyl)~ acrylic acid, all the procedure was performed in a similar method to Example 14 to obtain solid type of 3-(4-acetoxy-3,5-dimethoxy-ρhenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2//,8//-pyrano[3,2-g]-chromen-3-yl-ester (21c; yield: 10.8%).
<338> m.p 121 °C;
<339> Rf= 0.42(iHiexane: ethyl acetate=l:l);
<340> XH NMR(CDCl3): δ ppm 7.614(d, /=9.2Hz, IH), 7.582(d, /=2.4Hz, IH),
7.189(s, IH), 6.826(s, IH), 6.739(s, 2H), 6.362(d, /=16. OHz, IH), 6.227(d, /=9.2Hz, IH), 5.21Kt1 J=AMz, IH), 3.8OKs, 6H), 3.255(dd, J=A.8, 18.0Hz, IH), 2.935(dd, /=4.8, 18.0Hz, IH), 2.331(s, 3H), 1.451(s, 3H), 1.397(s, 3H);
<34i> MS(ffiA) 495 (M+H) +.
<342> <343>
<344> Example 21. 3-(4-methoxy-phenyl)-acrylic acid 2, 2-dimethyl-8-oxo-3,4- dihydro-2tf, 8#-ρyrano[3 ,2-g]-chromen~3-yl-ester (22c)
Figure imgf000040_0001
22a. -4-OCHa 22b. -4-OCH3 III r- 22c. -4-OCH3 23a. -3,4-(OCH3)2 23b. -3,4-(OCH3)2 1^ 22d. -4-OH 24a. -3,4,5-(OCH3)3 24b. -3,4,5-(OCH3)3 23c. -3,4-(OCH3)2 25a. -2-OCH3 25b. -2-OCH3 24c. -3,4,5-(OCH3)3 26a. -3-OCH3 26b. -3-OCH3 iii C ■ 24d. -3,4,&-(OH)3 27a. -2,3-(OCH3)2 27b. -2,3-(OCH3)2 28a. -2,4-(OCH3)2 28b. -2,4-(OCH3)2 iϋ EZfg -2-OCH3
-2-OH 29a. -2,5-(OCH3)2 29b. -2,5-(OCH3)2 26c. -3-OCH3 30a. -2,4,5-(OCH3)S 30b. -2,4,5-(OCH3)3 27c. -2,3-(OCH3)2 31a. -4-(NO2) 31b. -4-(NQ2) 28c. -2,4-(OCH3)2 29c. -2,5-(CCH3)2 30c. -2,4,5-(OCH3)3 31c. -4-(NO?)
<345> <346> Step 1
<347> As shown in the above-described reaction formula, 30-40 equivalent amount of anhydrous benzene was added to 1.5 equivalent amount of 3-(4- methoxy-phenyl) acrylic acid in round flask. Two drop of N,N~dimethyl formamide and 7.5 equivalent amount of thionyl chloride were added thereto and performed to refux for 5 hours at 70-80°C .
<348> The reaction solution was cooled to room temperature and concentrated in vaccuo to obtain cinnamoyl chloride.
<349> <350> Step 2 <351> 1 equivalent amount of (+)-decursinol and 3 equivalent amount of pyridine were dissolved in 50 folds volume of anhydrous dichloromethane in round flask. 1.5 equivalent amount of 3-(4-methoxy-phenyl)-acryloyl chloride obtained in step 1 dissolved in anhydrous dichloromethane was added thereto and stirred for 2 hours at room temperature. The reaction solution was concentrated in vaccuo and the concentrates were performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=10:l~l:l) to obtain solid type of 3-(4-methoxy-phenyl)-acrylic acid 2,2,-dimethyl-8-oxo- 3,4-dihydro-2//,8//-pyrano[3,2g]-chromen-3-yl-ester (22c ; yield: 91.2%).
<352>
<353> m.p 68 °C;
<354> Rf= 0.20(n-hexane:ethylacetate=2:l);
<355> 1H NMR(CDCl3, 400MHz): δ ppm 7.631(d, /=16. OHz, IH), 7.583(d, J=9.2Hz,
IH), 7.450(d, /=8.4Hz, IH), 7.170(s, IH), 6.882(d, /=8.8Hz, 2H), 6.829(s, IH), 6.282(d, J=16.0Hz, IH), 6.23Kd, /=9.2Hz, IH), 5.188(t, /=4.8Hz, IH), 3.828(s, 3H), 3.238(dd, /=4.4, 17.6Hz, IH), 2.934(dd, /=4.4, 17.6Hz, IH), 1.433(s, 3H), 1.39Ks, 3H);
<356> MS(mA) 407 (M+H) \
<357>
<358> Example 22. 3-(4-hydroxy-phenyl)-acrylic acid 2, 2-dimethyl-8-oxo-3,4- dihydro-ϋtf, Sff-pyrano[3,2-g]-chromen-3-yl -ester (22d)
<359>
<360> 1 equivalent amount of 3-(4-methoxy-phenyl)-acrylic acid 2, 2-dimethyl- 8-0X0-3,4-dihydro-.2//,6-ϊ-pyrano[3,2-g]-chromen-3-yl-ester (22c) was dissolved in anhydrous dichloromethane and 5 equivalent amount of IM boron tribromide solution (IM BBr3 in MC) was added thereto. The reaction solution was stirred for 2 hours at room temperature and poured into ice water to stir for 10 minutes. The solution was extracted with ethylacetate, dehydrated with anhydrous KMnO4, filtered and the supernatant was concentrated in vaccuo. The concentrates were performed to Silica gel column chromatography with a mobile phase (n-hexane.'ethylacetate=10:1-2:1) to obtain solid type of 3-(4-hydroxy- phenyl )-acryl ic acid 2,2,-dimethyl-8-oxo-3,4-dihydro-2tf,8tf-pyrano[3,2g]- chromen-3-yl-ester (22d; yield: 82.3%). .
<36i> m.p 104°C;
<362> Rf= 0.32(n-hexane:ethyl acetate=l:l);
<363> 1H NMR(CDCl3): δ ppm 7.608(m, 2H), 7.401(d, J=8.8Hz, 2H), 7.174(s, IH), 6.841(m, 2H), 6.252(m, 2H), 5.825(s, OH), 5.187(t, J=A.6Hz, IH), 3.237(dd, J=A.6, 17.6Hz, IH), 2.935(dd, /=4.6, 17.6Hz, IH), 1.432(s, 3H), 1.387(s, 3H);
<364> US(m/z) 393 (M+H) + .
<365>
<366> Example 23. 3-(3,4-dimethoxy-phenyl)-acrylic acid 2, 2-d i methyl -8-oxo~3, A- dihydro--?//,8iϊ-pyrano[3,2-g]-chromen-3-yl-ester (23c)
<367>
<368> Excepting that 1.5 equivalent amount of 3-(4-methoxy-phenyl)-acrylic acid was substituted with 1.5 equivalent amount of 3-(3,4-dimethoxy-phenyl)- acrylic acid, all the procedure was performed in a similar method to Example 21 to obtain solid type of 3-(3,4-dimethoxy-phenyl)-acrylic acid 2,2- dimethy1-8-0X0-3,4-dihydro-2//,8//-ρyrano[3,2-g]-chromen-3-yl-ester (23c; yield: 45.8%).
<369> m.p 83 °C;
<370> Rf= 0.35(/r-hexane: ethyl acetate=ll);
<37i> 1H NMR(CDCl3): δ ppm 7.608(m, 2H), 7.178(s, IH), 7.080(dd, /=8.4, 2.0Hz,
IH), 7.016(d, /=2.0Hz, IH), 6.848(m, 2H), 6.256(dd, /=14.4, 9.6Hz, 2H), 5.200(t, /=4.4Hz, IH), 3.916(s, 3H), 3.908(s, 3H), 3.230(dd, /=4.4, 16.8Hz, IH), 2.965(dd, /=4.4, 16.8Hz, IH), 1.446(s, 3H), 1.392(s, 3H);
<372> MS(fflA) 437 (M+H) \
<373>
<374> Example 24.3-(3,4,5-trimethoxy-phenyl)-acrylic acid 2, 2-dimethyl-8-oxo-3,4- dihyάro-2H, 5tf-ρyrano[3 , 2-g]-chromen-3-yl-ester (24c)
<375>
<376> Excepting that 1.5 equivalent amount of 3-(4-methoxy-phenyl)-acrylic acid was substituted with 1.5 equivalent amount of 3-(3,4,5-trimethoxy-phenyl)- acrylic acid, all the procedure was performed in a similar method to Example 21 to obtain solid type of 3-(3,4,5-trimethoxy-phenyl)-acrylic acid 2,2- dimethyl-8-0X0-3,4-dihydro-2iY,6W-pyrano[3,2-g]-chromen-3-yl-ester (24c; yield: 52.! <377> m.p 870C; <378> Rf= 0.23 (n-hexane: ethyl acetate=l:l);
<379> 1H NMR(CDCl3): δ ppm 7.607(d, /=5.6Hz, IH), 7.575(s, IH), 7.184(s, IH)1
6.840(s, IH), 6.722(s, 2H), 6.322(d, J=16.0Hz, IH), 6.240(d, J=9.2Hz, IH), 5.208(t, /=4.4Hz, IH), 3.904(s, 9H), 3.254(dd, /=4.4, 16.8Hz, IH), 2.951(dd, /=4.4, 16.8Hz, IH), 1.452(s, 3H), 1.395(s, 3H);
<38o> US(m/z) 467 (M+H) +.
<381>
<382> Example 25.3- (3, 4, 5-tri hydroxy-phenyl) -acrylic acid 2, 2-d i methyl -8-oxo~3, 4- dihydro-2//, Stf-pyrano[3 , 2-g]-chromen-3-yl-ester (24d)
<383>
<384> Excepting that 1 equivalent amount of 3-(4-methoxy-phenyl)-acrylic acid 2,
2-dimethyl-8-oxo-3,4-dihydro--?//,<^-pyrano[3,2-g]-chromen-3-yl-ester (22c) was substituted with 1 equivalent amount of 3-(3,4,5-trimethoxy-phenyl)-acrylic acid, 2, 2-dimethy 1-8-0X0-3, 4-dihydro-2/7,θ^-pyrano[3,2-g]-chromen-3-yl-ester (24c). all the procedure was performed in a similar method to Example 22 to obtain solid type of 3-(3,4,5-trihydroxy-ρhenyl)-acrylic acid 2,2-dimethyl-8- oxo-3,4-dihydro-^^/-ρyrano[3,2-g]-chromen-3-yl-ester (24d; yield: 18.2%).
<385> m.p 144 °C ;
<386> 0.44(chloroform:methanol=5:l);
<387> 1H NMR(acetone-d6) : δ ppm 7.849(d, /=9.6Hz, IH), 7.453(m, 2H), 6.737(s, IH),
6.720(s, 2H), 6.204(m, 2H), 5.195(t, /=4.8Hz, IH), 3.310(dd, /=16.8, 4.8Hz, IH), 2.937(dd, /=16.8, 4.8Hz, IH), 1.417(s, 6H);
<388>
<389> MS(fflA) 425 (M+H) \
<390>
<39i> Example 26. 3-(2-methoxy-phenyl)-acrylic acid 2, 2-dimethyl-8-oxo-3,4- dihydro-2^,S/r-pyrano[3,2-g]-chromen-3-yl-ester (25c)
<392>
<393> Excepting that 1.5 equivalent amount of 3-(4-methoxy-phenyl)-acrylic acid was substituted with 1.5 equivalent amount of 3-(2-methoxy-phenyl)-acrylic acid, all the procedure was performed in a similar method to Example 21 to obtain solid type of 3-(2-methoxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo- 3,4-dihydro--?i/,8i/-pyrano[3,2-g]-chromen-3-yl-ester (25c; yield: 81.8%).
<394> m.p 72°C;
<395> Rf= 0.48(n-hexane:ethyl acetate=l:l);
<396> 1H NMR(CDCl3): δ ppm 7.996(d, J=16.4Hz, IH), 7.589(d, J=9.6Hz, IH),
7.472(d, /=6.4Hz, IH), 7.352(t, /=7.8Hz, IH), 7.173(s, IH), 6.960~6.895(m, 2H), 6.804(s, IH), 6.508(d, J=16.0Hz, IH), 6.235(d, J=9.6Hz, IH), 5.194U, J=5.0Hz, IH), 3.87Ks, 3H), 3.242(dd, J=5.0, 17.2Hz, IH), 2.942(dd, /=5.0, 17.2Hz, IH), 1.437(s, 3H), 1.396(s, 3H);
<397> MS(mΛ) 407 (M+H) +.
<398>
<399> Example 27. 3-(2-hydroxy-phenyl)-acrylic acid 2, 2-dimethyl-8-oxo-3,4- dihydro--?F,8/f-pyrano[3,2-g]-chromen-3-yl-ester (25d)
<400>
<40i> Excepting that 1 equivalent amount of 3-(4-methoxy-phenyl)-acrylic acid 2, 2-dimethyl-8-oxo-3,4-dihydro-.?^S//-pyrano[3,2-g]-chromen-3-yl-ester (22c) was substituted with 1 equivalent amount of 3-(2-methoxy-phenyl)-acrylic acid, 2, 2-dimethyl-8-oxo-3,4-dihydro-2//,S//-pyrano[3,2-g]-chromen-3-yl-ester (25c). all the procedure was performed in a similar method to Example 22 to obtain white solid type of 3-(2-hydroxy-ρhenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4- dihydro-_?//,#tf-ρyrano[3,2-g]-chromen-3-yl-ester (25d; yield: 58.5%).
<402> m.p 106°C;
<403> Rf= 0.39(^-hexane:ethyl acetate=l:l);
<404> H NMR(acetone-d6): δ ppm 8.001(d, J=16.4Hz, IH), 7.851(d, 7=9.2Hz, IH), 7.613(d, J=TMz, IH), 7.434(s, IH), 7.253(t, /=6.8Hz, IH), 6.954(d, /=8.4Hz, IH), 6.883(t, J=7.4Hz, IH), 6.741(s, IH), 6.614(d, /=16. OHz, IH), 6.203(d, /=9.6Hz, IH), 5.233(t, /=4.4Hz, IH), 3.332(dd, J=4.4, 17.6Hz, IH), 2.984(dd, J=4.4, 17.6Hz, IH), 2.913(d, /=12. OHz, OH), 1.432(s, 3H), 1.421(s, 3H);
Figure imgf000045_0001
<406>
<407> Example 28. 3-(3-methoxy-ρhenyl)-acrylic acid 2, 2-dimethyl-8-oxo-3,4- dihydro-2ff,5tf-pyrano[3,2-g]-chrornen-3-yl~ester (26c)
<408>
<409> Excepting that 1.5 equivalent amount of 3-(4-methoxy-phenyl)-acrylic acid was substituted with 1.5 equivalent amount of 3- (3-methoxy-phenyl) -acrylic acid, all the procedure was performed in a similar method to Example 21 to obtain solid type of 3-(3-methoxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo- 3,4-dihydro-2//,8i/-pyrano[3,2-g]-chromen-3-yl-ester (26c; yield: 90.9 %).
<4io> m.p 720C;
<4iι> Rf= 0.51(/Hiexane: ethyl acetate=l:l);
<4i2> 1H NMR(CDCl3): δ ppm 7.644(d, J= 16. OHz, IH), 7.584(d, J=9.6Hz, IH),
7.282(t, J=8.4Hz, IH), 7.175(s, IH), 7.088(d, J=8.0Hz, IH), 6.932(dd, /=4.0, 8.4Hz, IH), 6.835(s, IH), 6.403(d, /=15.6Hz, IH), 6.236(d, /=9.6Hz, IH), 5.199(t, /=4.8Hz, IH), 3.813(s, 3H), 3.248(dd, J=4.8, 17.2Hz, IH), 2.943(dd, J=4.8, 17.2Hz, IH), 1.440(s, 3H), 1.394(s, 3H);
<4i3> MS(fflA) 407 (M+H) +.
<414>
<4i5> Example 29. 3-(2,3-dimethoxy-phenyl)-acrylic acid 2, 2-dimethyl-8-oxo-3,4- dihydro-2fif,8//-pyrano[3,2-g]-chromen-3-yl-ester (27c)
<416>
<4i7> Excepting that 1.5 equivalent amount of 3-(4-methoxy-phenyl)-acrylic acid was substituted with 1.5 equivalent amount of 3-(2,3-dimethoxy-ρhenyl)- acrylic acid, all the procedure was performed in a similar method to Example 21 to obtain white solid type of 3-(2,3-dimethoxy-phenyl)-acrylic acid 2,2- dimethy1-8-0X0-3,4-dihydro--2ff,5/f-pyrano[3,2-g]-chromen-3-yl-ester (27c; yield: 25.0%)
<418> m.p 149°C;
<4i9> Rf= 0.43 (n-hexane- ethyl acetate=l.'l);
<420> 1H NMR(CDCl3): δ ppm 8.021(d, J=16.0Hz, IH), 7.585(d, 7=9.6Hz, IH), 7.174(s,
IH), 7.121(d, 7=6.8Hz, IH), 7.032(t, J=8.0Hz, IH), 6.939(d, J=8.8Hz, IH), 6.829(s, IH), 6.449(d, J=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, /=4.8, 17.2Hz, IH), 1.435(s, 3H), 1.400(s, 3H);
<42i> MS(-πΛ) 437 (M+H) +.
<422>
<423> Example 30. 3-(2,4-dimethoxy-phenyl)-acrylic acid 2, 2-di methyl -8-oxo-3, 4- άihydro-2H, ##-ρyrano[3 , 2-g]-chromen-3-yl-ester (28c)
<424>
<425> Excepting that 1.5 equivalent amount of 3~(4-methoxy-phenyl)-acrylic acid was substituted with 1.5 equivalent amount of 3-(2,4-dimethoxy-phenyl)- acrylic acid, all the procedure was performed in a similar method to Example 21 to obtain white solid type of 3-(2,4-dimethoxy-phenyl)-acrylic acid 2,2- dimethyl-8-oxo-3,4-dihydro--?//',δ//-pyrano[3,2-g]-chromen-3-yl-ester (28c; yield: 25.0%)
<426> m.p 1490C;
<427> 0.43(fl-hexane: ethyl acetate=l:l);
<428> 1H NMR(CDCl3): δ ppm 8.021(d, 7=16. OHz, IH), 7.585(d, 7=9.6Hz,lH), 7.174(s,
IH), 7.121(d, 7=6.8Hz, IH), 7.032(t, 7=8. OHz, IH), 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, J=4.8, 17.2Hz, IH), 1.435(s, 3H), 1.400(s, 3H); <429> MS(ιnΛ) 437 (M+H) +.
<430>
<43i> Example 31. 3-(2,5-dimethoxy-phenyl)-acrylic acid 2, 2-d i methyl -8-oxo-3, 4- dihydro-2/f,8i/-pyrano[3,2-g]-chromen-3-yl-ester (29c)
<432>
<433> Excepting that 1.5 equivalent amount of 3-(4-methoxy-phenyl)-acrylic acid was substituted with 1.5 equivalent amount of 3-(2,5-dimethoxy-phenyl)- acryl ic acid, all the procedure was performed in a similar method to Example 21 to obtain pale yellow solid type of 3-(2,5-dimethoxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro--?i/,8tf-ρyrano[3,2-g]-chromen-3-yl-ester (29c; yield: 38.7%)
<434> m.p 77 °C;
<435> Rf= 0.46(/7-hexane: ethyl acetate=l:l);
<436> 1H NMR(CDCl3): δ ppm 7.983(d, /=16. OHz, IH), 7.592(d, J=IO.4Hz, IH),
7.178(s, IH), 7.00Kd, J=2.8Hz, IH), 6.912(dd, 7=2.8, 8.8Hz, IH),
6.849~6.827(m, 2H), 6.471(d, 7=16.4Hz, IH), 6.237(d, 7=9.2Hz, IH), 5.196(t,
7=4.8Hz, IH), 3.824(s, 3H), 3.768(s, 3H), 3.245(dd, 7=4.8, 17.2Hz, IH), 2.945(dd, 7=4.8, 17.2Hz, IH), 1.441(s, 3H), 1.396(s, 3H);
<437> MS(/π/z) 437 (M+H) \
<438>
<439> Example 32. 3-(2,4,5-trimethoxy-phenyl)-acrylic acid 2, 2-dimethyl-8-oxo- 3 , 4-di hydro~2H, Stf-pyrano [3 , 2-g] -chromen-3-y 1 -est er (30c )
<440>
<44i> Excepting that 1.5 equivalent amount of 3-(4-methoxy-phenyl)-acrylic acid was substituted with 1.5 equivalent amount of 3-(2,4,5-trimethoxy-phenyl)- acrylic acid, all the procedure was performed in a similar method to Example 21 to obtain yellow solid type of 3-(2,4,5-trimethoxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-^/,^-pyrano[3,2-g]-chromen-3-yI-ester (30c; yield: 33.5%) <442> m.p 93 °C;
<443> R{= 0.29 (n-hexane: ethyl acetate=i:l);
<444> 1H NMR(CDCl3): δ ppm 7.986(d, /=13.6Hz, IH), 7.586(d, J=9.6Hz, IH),
7.173(s, IH), 6.966(s, IH), 6.833(s, IH), 6.478(s, IH), 6.325(d, /=16. OHz, IH), 6.232(d, /=9.2Hz, IH), 5.19β(t, /=4.8Hz, IH), 3.922(s, 3H), 3.855(s, 3H), 3.840(s, 3H), 3.238(dd, J=A.8, 17.2Hz, IH), 2.940(dd, J=4.8, 17.2Hz, IH), 1.443(s, 3H), 1.393(s, 3H);
<445> MSC/ff/z) 483 (M+H) +.
<446>
<447> Example 33.3-(4-nitro-phenyl)-acrylic acid 2, 2-d i methyl -8-oxo-3,4-di hydr o- -2ff,fiff-pyrano[3,2-g]-chromen-3-yl-ester (31c)
<448>
<449> Excepting that 1.5 equivalent amount of 3-(4-methoxy-phenyl)-acrylic acid was substituted with 1.5 equivalent amount of 3-(4-nitro-phenyl)-acrylic acid, all the procedure was performed in a similar method to Example 21 to obtain pale yellow solid type of 3-(4-nitro-phenyl)-acrylic acid 2,2- dimethy 1-8-0X0-3, 4-dihydro--?/f/Sff-pyrano[3,2-g]-chromen-3-yl -ester (31c; yield: 65.7%)
<450> m.p 193 °C ;
<45i> Rf= 0.42 (fl-hexane: ethyl acetate=l:l);
<452> 1H NMR(CDCl3): δ ppm 8.237(d, /=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, J=Il.2Hz, IH), 6.248(d, /=9.6Hz, IH), 5.225(t, J=A. SRz, IH), 3.272(dd, 7=4.8, 17.2Hz, IH), 2.958(dd, J=4.8, 17.2Hz, IH), 1.449(s, 3H), 1.403(s, 3H);
<453> MS(mA) 422 (M+H) \
<454>
<455> [Table 4]
Figure imgf000049_0001
<457> [Table 5] <458>
Figure imgf000049_0002
<459> [Table 6] <460> No. name Compound M. W structure
20 21c 3-(4-Acetoxy-3 , 5-dimethoxy- 494.49 phenyD-acrylic acid 2,2- d i me thy 1-8-0X0-3, 4-dihydro- 2H, 8//-pyr ano [3 , 2-g] chromen-3- yl-ester
21 22c 3-(4-Methoxy-ρhenyl )-acryl ic 406.4; acid 2 ,2-di methyl -8-0X0-3, 4- dihydro-2/f, 8#-ρyrano[3 , 2- glchromen-3-yl -ester
22 22d 3-(4-Hydroxy-phenyl )-acryl ic 392.40 acid 2,2-dimethyl-8-oxo-3,4- dihydro-2F, 8//-pyrano[3 , 2- glchromen-3-yl -ester
23 23c 3- ( 3 , 4-D i me t hoxy-pheny 1 ) - 436.45 acrylic acid 2,2-dimethyl~8- oxo-3 , 4-di hydro-2//, SH- py r ano [ 3 , 2-g] chr omen-3-y 1 -
Figure imgf000050_0001
ester
[Table 7]
Figure imgf000051_0001
<462> [Table 8]
Figure imgf000051_0002
<464> [Table 9] <465> No . name Compound M. W structure
32 30c 3- ( 2 , 4 , 5-Tr i met hoxy-pheny 1 ) - 482.52 acryl ic acid 2 , 2-dimethyl-8- oxo-3 ,4-dihydro-2//, 8tf- py r ano [ 3 , 2-g] chr omen-3-y 1 -
Figure imgf000052_0001
ester
33 31c 3-(4-Ni tro-phenyl )-acryl ic 421.40 acid 2 , 2-di methyl -8-0X0-3 , 4- dihydro-2//, 8tf-pyrano[3 , 2- eλ chr omen-3-yl -ester
Figure imgf000052_0002
<466> Example 34. benzoic acid 2 , 2-dimethyl-8-oxo-3,4-dihydro-2tf, 8tf-pyrano[3 ,2-g]- chromen-3-yl-ester (32c)
Figure imgf000052_0003
R = 32C -H
R = 32a>. -H R= 32b. -H . ι- 33c. -3,4,5-(OH)3 i r 33a -3,4.5-(OH)3 34b -3,4,5-(OAc)3 IV L- 34c. -3,4,5-(OAc)3
34a. -3,4,5-(OAc)3
<467> <468> Step 1
<469> As shown in the above-described reaction formula, 30-40 equivalent amount of anhydrous benzene was added to 1.5 equivalent amount of benzoic acid in round flask. Two drop of jV,/f-dimethyl formamide and 7.5 equivalent amount of thionyl chloride were added thereto and performed to refux for 5 hours at 70-80°C .
<470> The reaction solution was cooled to room temperature and concentrated in vaccuo to obtain benzoyl chloride.
<471> <472> Step 2 <473> 1 equivalent amount of (+)-decursinol and 3 equivalent amount of pyridine were dissolved in 50 fold volume of anhydrous di chl or ome thane in round flask. The benzoyl chloride obtained in step 1 dissolved in anhydrous dichloromethane was added thereto and stirred for 2 hours at room temperature. The reaction solution was concentrated in vaccuo and the concentrates were performed to Silica gel column chromatography with a mobile phase (n-hexane-"ethylacetate=10:l~l:l) to obtain semi solid type of benzoic acid 2,2, -dimethyl-8-oxo-3 ,4-dihydro-2tf, 8ff-pyrano[3 , 2g]-chromen-3-yl-ester (32c ; yield: 93.2%). <474> Rf=O .52(n-hexane '• ethy 1 acet ate=l "• 1) ;
<475> 1H NMR(CDCl3, 400MHz): δppm 7.972(d, /=9.6Hz, 2H), 7.557(m, 2H), 7.417(t,
/=7.8Hz, 2H), 7.166(s, IH), 6.845(s, IH), 6.227(d, /=9.6Hz, IH), 5.296(t, /=4.8Hz, IH), 3.300(dd, /=4.4, 17.6Hz, IH), 3.004(dd, /=4.8, 17.6Hz, IH), 1.474(s, 3H), 1.428(s, 3H);
<476> MS(wΛ) 351 (M+H)+.
<477> <478>
<479> Example 35. 3, 4, 5-tri hydroxy-benzoic acid 2, 2-dimethyl-8-oxo-3,4-dihydro- 2tf,8#-ρyrano[3,2-g]-chromen-3-yl-ester (33c)
<480>
<48i> Step 1
<482> As shown in the above-described reaction formula in Example 34, 1 equivalent amount of 3,4,5-trihydroxy benzoic acid and 10 equivalent amount of pyridine were added to 10 equivalent amount of acetic anhydride in round flask. The solution was stirred with magnetic bar for overnight and concentrated in vaccuo. The concentrate was performed to Silica gel column chromatography with a mobile phase (n-hexane-1ethylacetate=5."l~l."I) to obtain purified product.
<483>
<484> Step 2 & 3
<485> Excepting that 1.5 equivalent amount of benzoic acid was substituted with 3,4,5-triacetoxy benzoic acid in step 2, all the procedure were performed by the similar method to the step 2 and step 3 in Example 34 to obtain pure 3,4,5-triacetoxy benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H-pyrano[3,2-g]-chromen-3-y1-ester .
<486>
<487> Step 4
<488> 3-4 equivalent amount of 3N HCl was added to 1 equivalent amount of 3,4,5-triacetoxy benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2tf,<S//- pyrano[3,2-g]-chromen-3-yl-ester dissolved in acetone obtained in step 2 and 3 dropwisely. The reaction solution was performed to refux for 12 hours at 50-600C and cooled at room temperature. The concentrate was fractionated with distilled water and ethylacetate and the collected ethylacetate soluble layer was dehydrated with anhydrous KMnθ4, filtered and the supernatant was concentrated in vaccuo. The concentrates were performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=5-'1-2:1) to obtain solid type of 3,4,5-trihydroxy benzoic acid 2,2,-dimethyl-8-oxo-3,4-dihydro- -2ff,Sff-pyrano[3,2g]-chromen-3-yl-ester(33c; yield: 98.7%).
<489> m.p 1380C ;
<490> Rf= 0.22(n-hexane:ethylacetate=l:2);
<49i> 1H NMR(CDCl3, 400MHz): δ ppm 7.674(d, J=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), 2.981(dd, J=4.6, 17.6Hz, IH), 1.443(s, 3H), 1.413(s, 3H)3H) 1.292(s, 3H), 1.287(s, 3H);
<492> MSim/z) 399 (M+H)+.
<493>
<494> Example 36. 3 ,4, 5-triacetoxy-benzoic acid 2 , 2-dimethyl-8-oxo-3,4-dihydro- 2#,#tf-pyrano[3,2-g]-chromen-3--yl-ester (34c)
<495>
<496> Step 1
<497> As shown in the above-described reaction formula in Example 34, 1 equivalent amount of 3,4,5-trihydroxy benzoic acid and 10 equivalent amount of pyridine were added to 10 equivalent amount of acetic anhydride in round flask. The solution was stirred with magnetic bar for overnight and concentrated in vaccuo. The concentrate was performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=5: 1-1:l) to obtain purified product.
<498>
<499> Step 2 & 3
<5oo> Excepting that 1.5 equivalent amount of benzoic acid was substituted with 3,4,5-triacetoxy benzoic acid in step 2, all the procedure were performed by the similar method to the step 2 and step 3 in Example 34 to obtain solid type of 3,4,5-triacetoxy benzoic acid 2,2-dimethyl-8-oxo-3,4~ dihydro--aff,5i¥-pyrano[3,2-g]-chromen-3-yl-ester. (34c; yield: 28.8%).
<501>
<502> m.p 97 °C;
<503> Rf= 0.44(n-hexane:ethylacetate=l:2);
<504> 1H NMR(acetone-d6, 400MHz) δ ppm 7.848(d, J=9.6Hz, IH), 7.740(s, 2H),
7.435(s, IH), 6.765(s, IH), 6.209(d, J=QMz, IH), 5.359(t, /=4.4, 17.6Hz, IH), 3.403(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);
<505> MS(mA) 525 (M+H)+.
<506>
<507> [Table 10] <508>
Figure imgf000056_0001
<509> <510> Experimental Example 1. cell cyto-toxicity test <51I> To determine the effect of (+)-decursin derivatives of the present invention on cell cytotoxicity in vitro test model, following experiment was performed.
<5J2> <513> A549 lung caner cell line, HCT 15 colon cancer cell line and ACHN rectal cancer cell line used in the present invention were procured from ATCC (American Type Culture Collection, U.S.A) and they were cultivated in RPMI 1640 culture medium containing L-glutamine, 10% inactivated FBS (Fetal Bovine Serum) heated in water bath at 50°C for 30 mins, 1% antibiotics (penicillin- G, 100,000 units/streptomycin 100 mg) and 2g of NaHCO3 at 37°C in 5% CO2
condition. Each cell line was mixed with 2x10 cells and inoculated into 96 well pates by 100 ^/ml/we11 and the plates were incubated for 48 hours. The medium was discarded and 10^ of MTT (5mg/ml, 3-(4,5-demethylthiazol)-2,5- diphenyltetrazolium bromide, Sigma Co., USA) was added thereto to incubate for 4 hours. The cultivated plates were washed with PBS and 100 μl of DMSO was added thereto. The plates were left alone for 20 mins at room temperature to determine the absorbance using by ELISA reader at 570 ran.
<514> <515> <5i6> Experimental Example 2. anticancer activity test
<5i7> There have been reported that (+)-decursin isolated from Angelica gigas showed potent anticancer activity confirmed by various experiments using by human erythroleukemic cell lines procured from ATCC, for example, K562 (ED50:
48/aπ), HL-60 (ED50: 42μm) and A549 lung cancer cell line (ED50: 39/an), (Ann KS et al., (+)-decursin: A cytotoxic agent and protein kinase C activator from the root of angelica gigas, Planta Med. 62, pp.7-9, 1996). Especially, (+)- decursin showed potent inhibiting activity (54%) of survival rate for K562 cell, a human erythroleukemic cell lines procured from ATCC (Kim, H. H. et al., Involvement of PKC and ROS in the cytotoxic mechanism of anti-leukemic (+)-decursin and its derivatives and their structure-activity relationship in human K562 erythroleukemia and U937 myeloleukemia cells. Cancer Lett. 223. pp. 191, 2005).
<5i8> The anticancer activity of (+)-decursin derivatives prepared in Examples showed in following Tables 11-13.
<5i9> As shown in Tables 11-13, the (÷)-decursin derivatives having cinnamoyl groups (13c-18c) showed strong cell cytotoxicity in cancer cell lines whereas the (+)-decursin derivatives having alkyl groups (2b-12b) showed little cell cytotoxicity in cancer cell lines. Especially, the compound (14c) showed most strong cell cyto-toxicity in A549 cell line (survival rate: 33%), HCT 15 cell line (survival rate: 12%) and ACHN cell line (survival rate: 43%) while the (+)-decursin derivatives having benzoyl groups (26c-29c) showed a little cell cytotoxicity in cancer cell lines.
<520> Accordingly, it has been confirmed that the crucial group in the (+)- decursin derivatives of the present invention showing potent anticancer activity is aromatic functional group such as cinnamoyl group or benzoyl group, rather than alkyl group.
<521>
<522> [Table 11] <523>
Figure imgf000058_0001
[Table 12]
<524>
Figure imgf000058_0002
<525> [Table 13]
<526>
<527>
Figure imgf000059_0001
<528> Hereinafter, the formulating methods and kinds of excipients will be discirbed, but the present invention is not limitied to them, the representative prearation examples were described as follows.
<529> Preparation of powder <530> Compound (14c) 20mg <531> Lactose lOOmg
<532> Talc lOmg <533> Powder preparation was prepared by mixing above components and filling sealed package.
<534> <535> Preparation of tablet <536> Compound (14c) lOmg <537> Corn Starch lOOmg <538> Lactose lOOmg <539> Magnesium Stearate 2mg <540> Tablet preparation was prepared by mixing above components and entabletting.
<541>
<542> Preparation of capsule
<543> Compound (14c) lOmg
<544> Corn starch lOOmg
<545> Lactose lOOmg
<546> Magnesium Stearate 2mg
<547> Tablet preparation was prepared by mixing above components and filling gelatin capsule by conventional gelatin preparation method.
<548>
<549> Preparation of injection
<550> Compound (14c) lOmg
<55i> Distilled water for injection optimum amount
<552> PH controller optimum amount
<553> 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 conventional injection preparation method.
<554>
<555> Preparat ion of l iquid
<556> Compound (14c) 20mg
<557> Sugar 5~10g
<558> Ci tri c acid 0.05-0.3%
<559> Caramel 0.005-0.02%
<560> Vi tamin C 0.1-1%
<561> Di st i l led water 79-94%
Figure imgf000060_0001
<563> Liquid preparation was prepared by dissolving active component, filling all the components and sterilizing by conventional liquid preparation method.
<564>
<565>
<566> Preparation of health care food
<567> Compound (14c) lOOOmg
<568> Vitamin mixture optimum amount
<569> Vitamin A acetate 70mg
<570> Vitamin E l.Omg
<571> Vitamin B1 0.13mg
<572> Vitamin B2 O.lδmg
<573> Vitamin B6 0.5mg
<574> Vitamin B12 0.2mg
<575> Vitamin C lOmg
<576> Biotin lOmg
<577> Amide nicotinic acid 1.7mg
<578> Folic acid 50mg
<579> Calcium pantothenic acid 0.5mg
<580> Mineral mixture optimum amount
<581> Ferrous sulfate 1.75mg
<582> Zinc oxide 0.82mg
<583> Magnesium carbonate 25.3mg
<584> Monopotassium phosphate 15mg
<585> Di calcium phosphate 55mg
<586> Potassium citrate 90mg
<587> Calcium carbonate lOOmg
<588> Magnesium chloride 24.8mg
<589> 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.
<590>
<59i> Preparation of health beverage
<592> Compound (14c) lOOOmg
<593> Citric acid lOOOmg
<594> Oligosaccharide lOOg
<595> Apricot concentration 2g
<596> Taurine Ig
<597> Distilled water 900m£
<598>
<599> Health beverage preparation was prepared by dissolving active component, mixing, stirred at 85°C for 1 hour, filtered and then filling all the components in 1000ra-£ ample and sterilizing by conventional health beverage preparation method.
<600>
<6oi> 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.
<602>
[Industrial Applicability]
<603> As described in the present invention, the (+)-decursin derivatives of the present invention showed potent inhibiting effect on the cancer cell being confirmed by various experiments such as cytotoxicity test in A549 lung cancer cell line, HCT15 colon cancer cell line and ACHN rectal cancer cell line, therefore the compounds can be useful in treating or preventing cancer diseases as an anti-cancer agent, health care food, or functional health food
<604>

Claims

[CLAIMS] [Claim 1]
<606> A novel compound represented by the following general formula (I), the pharmaceutically acceptable salt and the isomer thereof:
Figure imgf000063_0001
<607> ( I ) <608> wherein
<609> R1 i s Ci-C20 alkyl group, CrC20 alkenyl group, Ci-C20 alkynyl group subst i tuted or unsubst i tuted with R' or fol lowing A group
Figure imgf000063_0002
<612> of which R1 is halogen atom, nitro group, amine group, or Ci-C4 lower alkyl group and A' group is at least one attachable at o-, m- and p- position of phenyl group selected from group consisting of a hydrogen atom, hydroxyl group, nitro group, halogen group, CrC4 lower alkyl group, CrC4 lower alkoxy group, CrC4 lower alkyl ester group, and CrC4 lower alkyl carboxyl group;
<613> n is integer of 0 to 4. <614>
[Claim 2]
<615> The compound according to claim 1, wherein said Ri is a CrC1O alkyl group, CrC10 alkenyl group, CrC1O alkynyl group substituted or unsubstituted with halogen atom or CrC4 lower alkyl group or A group of which A' group is at least one attachable at o~, m- and p- position of phenyl group selected from group consisting of a hydrogen atom, hydroxyl group, methyl group, ethyl group, methoxy group, ethoxy group, nitro group and acetyl group; n is integer of 0 to 1.
<616>
[Claim 3] <6i7> The compound according to claim 1, wherein said compound is selected from the group consisting of: <6i8> 3-methyl-but-2-enoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2#,8tf- pyrano[3,2-g]chromen-3-yl-ester, <6i9> Cis-2-methyl-but-2-enoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2tf,8#- pyrano[3,2-g]chromen-3-yl-ester, <62o> Trans-2-methyl-but-2-enoic acid 2, 2-di methyl -8-oxo-3,4-di hydro-2tf, 8H- pyrano[3,2-g]chromen-3-yl-ester, <62i> 2-Methyl -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2tf,8tf-pyrano[3,2- g]chromen-3-yl -ester , <622> Pen-2-tenoic acid 2, 2-di methyl -8-oxo-3,4-di hydro~2//,8fl-pyr ano[ 3,2- g]chromen-3-yl-ester, <623> But-3-enoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2tf,8//-pyrano[3,2- g]chromen-3-yl-ester , <624> Pen-4-tenoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2J7,8/f-pyrano[3,2- g]chromen-3-yl~ester , <625> Acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2/f,8//-pyrano[3,2-g]chromen-3- yl-ester, <626> Chloroacetic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2//,8tf-ρyrano[3,2- g]chromen-3-yl -ester, <627> Trichloroacetic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2//,8tf-pyrano[3,2- g]chromen-3-yl -ester , <628> Pentanoic acid 2)2-dimethyl-8-oxo-3,4-dihydro-2tf,8#-pyrano[3,2-g]chromen-
3-yl-ester, <629> Decanoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2//,8tf-pyrano[3,2-g]chromen-
3-yl-ester, <630> 3-Phenyl acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2#,8tf-ρyrano[3,2- g]chromen-3-yl-ester , <63i> 3-(3-Hydroxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2//,8tf- ρyrano[3,2-g]chromen-3-yl-ester, <632> 3-(3-Acetoxy-ρhenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2//,8tf- pyrano[3,2-g]chromen-3-yl-ester , <633> 3- (3 ,4-Di hydroxy-phenyl) acrylic acid 2,2-dimethyl~8-oxo-3,4-dihydro-
2H, 8#-pyrano[3 , 2-g]chromen-3-yl -ester , <634> 3-(3,4-Diacetoxy-ρhenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-
2H, 8#-ρyrano[3 , 2-g] chroraen-3-yl -ester , <635> 3-(4-Hydroxy-3-methoxy-phenyl ) acrylic acid 2,2-dimethyl~8-oxo-3,4- dihydr 0-2/7, 8i/-ρyrano[3,2-g]chromen-3-yl-ester, <636> 3-(4-Acetoxy-3-methoxy-ρhenyl) acrylic acid 2, 2-dimethyl-8-oxo-3,4- dihydro-2i/, 8ff-pyrano[3 , 2-g] chromen-3-yl -ester , <637> 3-(4-Acetoxy-3,5-dimethoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4- dihydro-2#,8tf-ρyrano[3 , 2-g] chromen-3-yl -ester , <638> 3-(4-Methoxy-ρhenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2tf,8tf- pyrano [3, 2-g] chromen-3-yl -ester, <639> 3-(4-Hydroxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2//,8tf- pyrano[3,2-g]chromen-3-yl-ester, <640> 3-(3, 4-Dimethoxy-ρhenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-
2H, 8//-ρyrano[3 , 2-g] chromen-3-y l-ester , <64i> 3-(3,4,5-Trimethoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-
2H, 8//-pyr ano [ 3 , 2-g] chr omen-3-y 1 -es t er , <642> 3- ( 3, 4 ,5-Tr i hydroxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-
2H, 8ff-pyrano[3, 2-g] chr omen-3-y l-ester, <643> 3-(2-Methoxy-phenyl) acrylic acid 2, 2-dimethyl-8-oxo-3,4-dihydro-2tf,8tf- pyr ano [3, 2-g] chr omen-3-y l-ester, <644> 3-(2-Hydroxy-ρhenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2i/,8if- pyrano[3, 2-g] chr omen-3-y l-ester <645> 3-(3-Methoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2tf,8tf- pyrano[3,2-g]chromen-3-yl-ester <646> 3-(2,3-Dimethoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-
2H, 8/7-pyrano[3 , 2-g] chromen-3-y 1 -ester , <647> 3-(2,4-Dimethoxy-phenyl) acrylic acid 2, 2-di methyl -8-oxo-3,4-di hydro-
2H, 8tf-pyr ano [3 , 2-g] chromen-3-y 1 -ester , <648> 3-(2,5-Dimethoxy-phenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-
2/7, 8tf-pyrano[3 , 2-g] chromen-3-y 1 -ester , <649> 3-(2,4,5-Trimethoxy-ρhenyl) acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-
2H, 8tf-pyr ano [3 , 2-g] chromen-3-y 1 -ester , <650> 3-(4-Nitro-phenyl) acrylic acid 2 , 2-di methyl -8-oxo-3,4-di hydro-2//, 8H- pyrano[3,2-g]chromen-3-yl-ester, <65i> Benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2//,8tf-pyrano[3,2-g]chromen-3- yl-ester, <652> 3,4,5-Trihydroxy benzoic acid 2, 2-dimethyl-8-oxo-3,4-dihydro-2fl,8/f- pyrano[3,2-g]chromen-3-yl-ester, <653> 3,4,5-Triacetoxy benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2#,8//- pyr ano [ 3 , 2-g ] chr omen-3-y 1 -es t er .
<654>
[Claim 4]
<655> A pharmaceutical composition comprising an efficient amount of the compound represented by general formula (I) of claim 1 or the pharmaceutically acceptable salt thereof as an active ingredient in amount effective to treat or prevent cancer disease, together with pharmaceutically acceptable carriers or diluents.
[Claim 5]
<656> The pharmaceutical composition according to claim 4, wherein said cancer diseases is selected from lung cancer, colon cancer or rectal cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer or cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (eg., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphonas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), or neoplasms of the central nervous system (e.g., primary CNS lymphoma, spinal axis tumors or brain stem gliomas or pituitary adenomas).
<657>
[Claim 6]
<658> A method of treating or preventing inflammatory disease in a mammal comprising administering to said mammal an effective amount of novel (+)- decursin derivatives represented by general formula (I) of claim 1 and the pharmacologically acceptable salt thereof, together with a pharmaceutically acceptable carrier thereof into the mammals including human suffering from said disease.
<659>
[Claim 7]
<660> A use of the compound represented by general formula (I) of claim 1 or the pharmaceutically acceptable salt thereof for manufacture of medicines employed for treating or preventing cancer disease in mammals including human as an active ingredient in amount effective to treat or prevent cancer disease.
<661>
[Claim 8]
<662> A health care food comprising decursin derivatives represented by general formula (I) of claim 1, or the pharmacologically acceptable salt thereof, together with a sitologically acceptable additive for the prevention and alleviation of cancer disease. <663>
[Claim 9]
<664> The health care food according to claim 8, the health care food is a form of powder, granule, tablet, capsule or beverage.
<665> <666>
PCT/KR2007/003257 2006-07-05 2007-07-04 Novel decursin derivatives and the use thereof WO2008004817A1 (en)

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CN112480141A (en) * 2020-12-10 2021-03-12 吉林大学珠海学院 Pyranocoumarin derivative and preparation method and application thereof

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