KR20080004332A - Novel decursin derivative, the preparation thereof and a composition containing the same for treating and preventing cancer disease - Google Patents

Abstract

A (+)-decursin derivative is provided to secure potent inhibiting effect on the cancer cell such as A549 lung cancer cell line, HCT15 colon cancer cell line and ACHN rectal cancer cell line, thereby capable of being used for treating or preventing cancer diseases as an anti-cancer agent, health care food, or functional health food. A decursin derivative compound synthesized from (+)-decursinol isolated from Angelica gigas as a precursor is represented by the formula(1), wherein R1 is C1-20 alkyl, alkenyl, alkynyl substituted or unsubstituted with R'( R1 is halogen, nitro, amine, or C1-4 lower alkyl) or an A substituents represented from the formula(I-a)(wherein A' is at least one attachable at o-, m- and p- position of phenyl group selected from group consisting of H, hydroxyl, nitro, halogen, C1-4 lower alkyl, lower alkoxy, lower alkyl ester and lower alkyl carboxy; and n is an integer of 0 to 4). A pharmaceutical composition for treating and preventing cancer diseases comprises an efficient amount of the compound of the formula(1) or a pharmaceutically acceptable salt thereof as an effective ingredient. A health functional food for preventing and treating cancer diseases comprises the compound of the formula(1).

Description

Decursin derivatives, methods for preparing the same, and compositions for the treatment and prevention of cancer diseases including the same {Novel decursin derivative, the preparation conjugate and a composition containing the same for treating and preventing cancer disease}

    The present invention relates to a composition having an anticancer effect containing as an active ingredient a decursin derivative synthesized using (+)-decursinol isolated from a real Angelica as a precursor.

    Cancer is still a serious clinical problem and has a significant social and economic impact on human healthcare systems.

Despite the development of diagnosis, prevention and treatment in modern medicine, there are still millions of patients worldwide (Cheng YL et al., Anti-proliferative activity of Bupleurum) scrozonerifolium in A549 human lung cancer cells in vitro and in vivo. Cancer Letters , 222 (2 ), pp. 183-93, 2005). The carcinogens that cause these cancers include smoking, ultraviolet rays, chemicals, foods, and other environmental factors. However, due to various causes, the development of therapeutic agents is difficult, and the effects of the therapeutic agents vary depending on the site of occurrence. . Currently, the substances used as therapeutic agents are extremely toxic and cannot selectively remove only cancer cells. Therefore, there is an urgent need for the development of low-toxic and effective anti-cancer agents to prevent cancer after treatment. .

     Every year, there are 10 million new cancer cases worldwide and 6 million people die of cancer, accounting for 12% of all deaths. If this trend continues, it is estimated that by 2020, 15.7 million cancer patients will die every year and 10 million will die from cancer. Korea has also been increasing steadily since cancer was the first cause of death in Korea since 1983.

     Many methods, including chemotherapy, radiation therapy, surgical therapy, and gene therapy, are used to treat cancer, but chemotherapy using drugs is most commonly used. However, chemotherapy has many side effects and is not easily cured, requiring a new approach to cancer treatment. Two approaches are being attempted. The first is the synthesis and development of new derivatives that maintain the efficacy of the existing anticancer drugs through various synthetic methods and the side effects are significantly reduced. The second is the progression to malignant cancers by inhibiting cancer development itself or delaying or reversing the progression of cancer. It is chemical chemoprevention that inhibits cancer.

In recent years, much attention has been paid in developing countries to develop nontoxic and efficacious chemical cancer preventives and anticancer agents from natural resources such as vegetables, fruits and medicinal plants (Kelloff et al., Annals) . New York Academy of Sciences , 889 , pp. 1-13, 1999).

     Chemical cancer prevention is primarily intended to prevent cancer from appearing in healthy individuals and secondary prevention, malignancy, metastasis and complications to reverse the carcinogenic process in people with benign cancer. It can be applied step by step as a third prevention to prevent recurrence in people who have been treated. Therefore, it can be very useful as a therapeutic agent as well as cancer prevention.

Decursin is an ingredient extracted from Angelica vulgaris. decursiv a Fr. et Sav.), a natural substance isolated from decursin and Angelica, Angelica gigas Nakai) was found in 1967 and 1969 (J., Pharm . Soc . Korea , 11 , pp.22-26, 1967; 13 , pp.47-50, 1969), and other plants The furnace has also been isolated from the fruit of the oil sprouts (Peucedanum terevinthaceum Fisher et Turcz.) (Korean Journal of Pharmacy, 30 (2) , pp.73-78, 1986).

    Decursin has a strong lethal action on cancer cells, while it has a far lower lethal action on cancer cells than on cancer cells, and has potential for use as an anticancer agent. Conventional decursins have been reported to have been separated from the fruit extracts of the body herb after the first separation, and also from the fruits of Korean Angelica and oil herb. The development of derivatives for these has important significance.

Angelica Angelica gigas ) is a plant of the umbelliferae, and the Chinese Angelica ( Angelica) sinesis ), Japanese heron ( Angelica acutiloba e), Korean trellis ear ( Angelica gigas ). Since ancient times, Angelica has edible young shoots as herbs, and its roots have been used as a medicine for various diseases such as analgesic effect, renal toxicity alleviation, and treatment of diabetic hypertension (Chi, H. J and Kim HS: Studies on the components of Umbelliferae Plants in Korea. Kor. J. Pharmacogn., 1, pp.25, 1970). The main components exhibiting these various activities are (+)-decursinol, such as (+)-decursin and (+)-decursinol angelate, which are dihydropyranocoumarin-based substances. Secondary alcohol groups of 7-hydroxy-8,8-dimethyl-7,8-dihydro- 6H- pyrano (3,2-g) chromen-2-one] are esterified substances (Bae, EA et al., Anti -Helicobacter pylori activity of herbal medicines. Biol Pharm Bull . 21 , pp. 990, 1998).

Recently, there have been reports that coumarin-based substances isolated from Angelica gigas have anti-cancer effects as well as the aforementioned pharmacological effects (Kim, HH et al., Decursin and PDBu: Two PKC activators distinctively acting) in the megakaryocytic differentiation of K562 human erythroleukemia cells. Leuk Res ., 29 , pp. 1407, 2005). Therefore, we synthesized new derivatives of ester forms of various structures that do not exist in Dong-guk using (+)-decursinol as starting material, and showed the optimal anticancer activity by examining the relationship between their structure-activity. It was concluded that a study for deriving a substance was needed to complete the present invention.

An object of the present invention is a novel decursin derivative synthesized by using (+)-decursinol isolated from a real Angelica as a precursor and a pharmaceutical for the prevention and treatment of cancer diseases containing the same as an active ingredient It is to provide a composition and dietary supplement.

   In order to achieve the above object, the present invention is a decursin derivative of a novel structure represented by the following general formula (I) synthesized by using (+)-decursinol isolated from the real Angelica as a precursor Provided are compounds and pharmaceutically acceptable salts thereof:

                                              (I)

 In the above formula,

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

A substituent

Where A 'is a substituent which may be substituted at least one at positions o, m and p , and is a hydrogen atom, a hydroxy group, a nitro group, an acetate group, a halogen atom, a C ₁ to C ₄ lower alkyl group, a lower alkoxy group and a lower alkyl ester And at least one substituent selected from the group consisting of lower alkyl carboxy groups;

n is an integer of 0-4.

The formula (I) as a preferred compound group of compounds R ₁ is substituted with a halogen atom or a C ₁ to C ₄ lower alkyl group, unsubstituted C ₁ to C ₁₀ alkyl group, an alkenyl group, an alkynyl group or an A substituent, and where A 'in the A substituent is at least one substituent selected from hydrogen atom, hydroxy group, methyl group, ethyl group, methoxy group, ethoxy group, nitro group or acetyl group substituted in o, m, p position; n is a group of compounds that is an integer of 0 or 1.

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

3-Methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl - ester, Cis -2-methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl- Ester, trans -2-methyl-but-2-tenophosphate 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3 -Yl-ester, 2-methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, pen 2-Tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, but-3-te Senile acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, phen-4-tenophosphoric acid 2, 2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, acetic acid 2,2-dimethyl-8-oxo-3, 4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, chloro-acetic acid 2,2-dimethyl-8-oxo-3,4- Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, trichloroacetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H- Pyrano [3,2-g] chromen-3-yl-ester, pentanophosphate 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g ] Crommen-3-yl-ester, decanoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl- Ester, 3-phenyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (3 -Hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- ( 3-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (3,4-Dihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl- Ester, 3- (3,4-diacetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4 -Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4-hydroxy-3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8 -Oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4-acetoxy-3-methoxy-phenyl) -acrylic acid 2 , 2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4-acetoxy-3,5- Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4 -Methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- ( 4-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (3,4-Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester 3- (3,4,5-trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2-g] chromen-3-yl-ester, 3- (3,4,5-trihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4 -Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3, 4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3 , 4-Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo- 3,4-Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2,3-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8 -Oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2,4-dimethoxy-phenyl) -acrylic acid 2,2- Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2,5-dimethoxy-phenyl) -acrylic acid 2 , 2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2,4,5-t Rimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4 -Nitro-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, benzoic acid 2, 2-Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3,4,5-trihydroxy-benzophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester or 3,4,5-triacetoxy-benzo Phosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester.

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

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

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

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

Pharmaceutically acceptable salts of the above compounds of formula (I) include salts of acidic or basic groups which may be present in compounds of formula (I), unless otherwise indicated. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, which are known in the art. It can be prepared through.

      Another object of the present invention is to provide a method for preparing the compound of Formula (I), which may be chemically synthesized by the method shown in the following schemes, but is not limited thereto.

The following reaction schemes represent the preparation steps of the representative compounds of the present invention. The various compounds of the present invention may be prepared by small changes such as changing the reagents, solvents, and reaction sequences used in the synthesis of Schemes 1 to 3. Can be. Some compounds of the present invention have been synthesized according to processes not included in the scope of Schemes 1 through 3, and detailed synthesis procedures for these compounds are described in their respective examples.

    Scheme (1) is a deco having various alkyl group substituents by reacting (+)-decursinol with carboxylic acid (1-9a) or alkanoyl chloride (10-12a) having various substituents. A process for preparing a decursin derivative (1-12b) is shown.

   In the first step of Scheme (a), (+)-decursinol, carboxylic acid, dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) are dissolved with anhydrous dichloromethane. Let's do it. In addition, in the first step of Scheme (b), (+)-decursinol, alkanoyl chloride and pyridine are dissolved with anhydrous dichloromethine. The solvent used at this time is carried out using a solvent that does not adversely affect the reaction, dichloromethane, chloroform, diethyl ether, tetrahydrofuran and the like. The reaction temperature is not particularly limited, but may be generally performed at cold to room temperature, and preferably at room temperature. The reaction time can be carried out for 5 to 24 hours, preferably stirred for 24 hours to synthesize decursin derivatives (1b-12b) having various alkyl substituents.

    Scheme (2) is a process for preparing a decursin derivative having various cinnamoyl group substituents by reacting cinnamic acid with various substituents to (+)-decursinol. Indicates.

In the first step acetic anhydride, 3- or 4- (OH) _n -cinnamic acid and pyridine are added. The reaction temperature is not particularly limited, but can be generally performed at cold to room temperature, preferably at room temperature. In the second step, cinnamic acid is dissolved in anhydrous benzene, and N, N -dimethylformamide and thionyl chloride are added thereto to synthesize a compound to obtain an acid halide. In the third step, (+)- Decursinol and pyridine are dissolved in anhydrous dichloromethane and cinnamoyl chloride is added to prepare derivative compounds with cinnamoyl substituents. At this time, the solvent is used to perform the reaction using a solvent that does not adversely affect the reaction, dichloromethane, chloroform and the like. The reaction temperature is not particularly limited, but is generally carried out at cold to room temperature, preferably at room temperature. In the fourth step, a derivative having a 3- or 4- (OA _C ) _n -cinamoyl substituent is dissolved in acetone, 3N hydrochloric acid (3N HCl) is added dropwise to reflux, and cooled at room temperature to be concentrated under reduced pressure to carry out the reaction. do. At this time, the solvent used is carried out in the presence of a solvent that does not adversely affect the reaction, examples of the solvent that can be used for this purpose may be carried out using an alcohol solvent such as dimethylformamide, methanol, ethanol or acetone , Preferably using acetone. In the fifth step, a derivative having a 3-, 4 or 5- (OCH ₃ ) _n -cinamoyl substituent is dissolved in dichloromethane, and then a reaction is performed by dropwise adding a 1M boron tribromide solution (1M BBr ₃ in MC). . At this time, the solvent is used to perform the reaction using a solvent that does not adversely affect the reaction, dichloromethane, chloroform and the like. The reaction temperature is generally carried out at cold to room temperature, preferably at cold temperature.

   Scheme (3) represents a process of preparing decursin derivatives having various benzoyl group substituents by reacting decursinol with benzoic acid having various substituents.

In the first step, acetic anhydride and 3,4,5- (OH) ₃ -benzoic acid are dissolved, and concentrated sulfuric acid is added dropwise and refluxed to obtain a compound. In the second step, benzoic acid was dissolved in anhydrous benzene, and N, N -dimethylformamide and thionyl chloride were added to reflux. In the third step, an acid halide compound is prepared by dissolving (+)-decurinol and pyridine with anhydrous dichloromethane and adding benzoyl chloride. At this time, the solvent is used to perform the reaction using a solvent that does not adversely affect the reaction, dichloromethane, chloroform and the like. The reaction temperature is not particularly limited, but is generally carried out at cold to room temperature, preferably at room temperature. In the fourth step, a 3,4,5- (OA _C ) ₃ -benzoyl decursin derivative is dissolved in acetone, and then refluxed with 3N hydrochloric acid (3NHCl) dropwise to prepare a compound having a benzoyl substituent. In this case, the solvent used is an alcohol solvent such as dimethylformamide, methanol, ethanol, or acetone, which do not adversely affect the reaction.

     The general formula (I) compounds obtained by the above production method confirmed the cytotoxic effects on cancer cells such as lung cancer cells A549, colon cancer cells HCT15, and rectal cancer cells ACHN, and the decursin derivative compounds of the present invention are cancers. It can be usefully used as a pharmaceutical composition and health functional food for the prevention and treatment of diseases.

      Accordingly, the present invention provides a pharmaceutical composition for the prevention and treatment of cancer diseases containing a decursin derivative compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

 The cancer disease includes general cancer diseases, preferably gastric cancer, colon cancer, breast cancer, lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, melanoma in the skin or eye, uterine cancer, ovarian cancer, large intestine Cancer, small bowel cancer, rectal cancer, anal muscle cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, lymph gland cancer, bladder cancer, gallbladder cancer, endocrine cancer , Thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocyte lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS; central) nervous system) tumors, primary CNS lymphoma, spinal cord tumors, brainstem glioma or pituitary adenoma, more preferably lung cancer, colon cancer, rectal cancer.

     Compositions comprising a compound of the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods.

     Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The compositions comprising the compounds of the present invention are each formulated in the form of oral dosage forms, external preparations, suppositories, or sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., in accordance with conventional methods. Can be used.

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

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

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

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

The present invention provides a dietary supplement for the prevention and improvement of cancer diseases, comprising as an active ingredient a decursin derivative compound of the general formula (I), which shows the effect of preventing and treating cancer diseases.

Compounds of the present invention can be used in a variety of drugs, food and beverages for the prevention and improvement of cancer diseases. Examples of the food to which the compound of the present invention may be added include various foods, beverages, gums, teas, vitamin complexes, health supplements, and the like, and may be used in the form of powders, granules, tablets, capsules, or beverages. have.

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

The compounds of the present invention can be added to food or beverages for the purpose of preventing and treating cancer diseases. At this time, the amount of the compound in the food or beverage is generally added to the health food composition of the present invention to 0.01 to 15% by weight of the total food weight, the health beverage composition is 0.02 to 30 g based on 100 ml, preferably Can be added in a ratio of 0.3 to 10 g.

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

      In addition to the compounds of the present invention, the composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid And salts thereof, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. The compositions of the present invention may also contain pulp for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical but is generally selected from the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.

        Hereinafter, the present invention will be described in detail by Examples and Experimental Examples.

 However, the following Examples and Experimental Examples are only illustrative of the present invention, and the content of the present invention is not limited to the following Examples and Experimental Examples.

Example  1-3 methyl Part-2- Tennophosphate  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H -Pyrano [ 3,2-g] chromen Preparation of 3-yl-ester (1b)

As shown in the reaction scheme, 1 equivalent of 3-methyl-but-2-tenophosphoric acid, 1.1-2.0 equivalents of 1,3-dicyclohexylcarbodiimide in a round flask with (+)-decursinol (DCC) and 0.4 equivalent of 4-dimethylaminopyridine (DMAP) were added and dissolved in anhydrous dichloromethane. 1 equivalent of decursinol was added to the reaction mixture, which was stirred for 24 hours at room temperature. The reaction mixture was washed with dichloromethane and filtered, and the filtrate was concentrated under reduced pressure. To obtain the pure product (1b), the concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 1: 1) to give 3-methyl-but- 2-Tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (1b) was obtained.

Yield: 64.0%;

Semi solid;

R _f = 0.35 (n-hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.589 (d, J = 9.6 Hz, 1 H), 7.160 (s, 1 H), 6.788 (s, 1 H), 6.222 (d, J = 9.6 Hz, 1 H), 5.663 (s, 1H), 5.086 (t, J = 4.8 Hz, 1H), 3.197 (dd, J = 4.8, 17.2 Hz, 1H), 2.867 (dd, J = 4.8, 17.2 Hz, 1H), 2.146 (d , J = 1.0 Hz, 3H), 1.880 (d, J = 1.0 Hz, 3H), 1.384 (s, 3H), 1.365 (s, 3H);

MS ( m / z ) 329 (M + H) ⁺ .

Example 2. Sheath 2-Methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of Pyrano [3,2-g] chromen-3-yl-ester (2b)

The above example except that in a round flask with (+)-decursinol was replaced with cis -2-methyl-but - 2-tenophosphoric acid instead of one equivalent of 3-methyl-but-2-tenophosphoric acid. The same reaction process as in 1 was carried out to carry cis -2-methyl-but-2-tenophosphate 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano having the following physical properties. [3,2-g] chromen-3-yl-ester (2b) was obtained.

Yield: 56.3%;

Oil phase;

R _f = 0.35 (n-hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.595 (d, J = 9.2 Hz, 1H), 7.167 (s, 1H), 6.819 (qd, J = 6.8, 1.2 Hz, 1H), 6.790 (s, H ), 6.223 (d, J = 9.2Hz, 1H), 5.092 (t, J = 5.4Hz, 1H), 3.214 (dd, J = 4.8, 17.2Hz, 1H), 2.888 (dd, J = 5.4, 17.2Hz , 1H), 1.803 (d, J = 1.2 Hz, 3H), 1.767 (d, J = 6.8 Hz, 3H), 1.398 (s, 3H), 1.378 (s, 3H);

MS ( m / z ) 329 (M + H) ⁺ .

Example  3. Trans -2- methyl Part-2- Tennophosphate  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester (3b)

The above example except that transcuring with (+)-decursinol and trans -2-methyl-but-2-tenophosphoric acid instead of one equivalent of 3-methyl-but-2-tenophosphoric acid in a round flask The same reaction process as in the reaction of 1 was carried out to give trans -2-methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano having the following physical properties. [3,2-g] chromen-3-yl-ester (3b) was obtained.

Yield: 43.9%;

Oil phase;

R _f = 0.48 (n-hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.505 (d, J = 9.6 Hz, 1H), 7.074 (s, 1H), 6.743 (m, 2H), 6.154 (d, J = 9.6 Hz, 1H), 5.009 (t, J = 4.8 Hz, 1H), 3.133 (dd, J = 4.8, 17.2 Hz, 1H), 2.806 (dd, J = 4.8, 17.2 Hz, 1H), 1.784 (m, 6H), 1.352 (s, 3H), 1.319 (s, 3H);

MS ( m / z ) 329 (M + H) ⁺ .

Example 4. 2-Methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of pyrano [3,2-g] chromen-3-yl-ester (4b)

The same reaction process as in Example 1 was carried out except that (+)-decursinol was changed to 2-methyl-acrylic acid instead of 1 equivalent of 3-methyl-but-2-tenophosphoric acid in a round flask. 2-methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester having the following physical properties 4b).

Yield: 93.3%;

Semi Solid;

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

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.565 (d, J = 9.6 Hz, 1H), 7.141 (s, 1H), 6.786 (s, 1H), 6.216 (d, J = 9.6 Hz, 1H), 6.052 (s, 1H), 5.562 (s, 1H), 5.076 (t, J = 5.2 Hz, 1H), 3.209 (dd, J = 4.8, 16.8 Hz, 1H), 2.883 (dd, J = 5.6, 17.2 Hz, 1H), 1.903 (s, 3H), 1.384 (s, 3H), 1.370 (s, 3H);

MS ( m / z ) 315 (M + H) ⁺ .

Example 5. Phen-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of Pyrano [3,2-g] chromen-3-yl-ester (5b)

Same as the reaction of Example 1, except that (+)-decursinol was replaced with phen-2-tenophosphoric acid instead of 1 equivalent of 3-methyl-but-2-tenophosphoric acid in a round flask. Phen-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3 having the following physical properties -Yl-ester (5b) was obtained.

Yield: 92.1%;

Oil phase;

R _f = 0.400 (n-hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.58 (d, J = 9.6 Hz, 1H), 7.151 (s, 1H), 7.028 (m, 1H), 6.798 (s, 1H), 6.223 (d, J = 9.6 Hz, 1H), 5.803 (d, J = 15.6 Hz, 1H), 5.111 (t, J = 4.8 Hz, 1H), 3.204 (dd, J = 4.8, 17.2 Hz, 1H), 2.882 (dd, J = 4.8, 17.2 Hz, 1H), 2.197 (m, 2H), 1.390 (s, 3H), 1.366 (s, 3H), 1.049 (t, J = 7.6 Hz, 3H);

MS ( m / z ) 329 (M + H) ⁺ .

Example 6. But-3-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of Pyrano [3,2-g] chromen-3-yl-ester (6b)

Same reaction as in Example 1, except that (+)-decursinol was replaced with but-3-tenophosphoric acid instead of 1 equivalent of 3-methyl-but-2-tenophosphoric acid in a round flask Butanetenenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3- One-ester (6b) was obtained.

Yield: 90.2%;

Semi Solid;

R _f = 0.65 (n-hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.584 (d, J = 9.6 Hz, 1H), 7.154 (s, 1H), 6.793 (s, 1H), 6.232 (d, J = 9.6 Hz, 1H), 5.866 (m, 1H), 5.176 (m, 2H), 5.063 (t, J = 4.8 Hz, 1H), 3.190 (dd, J = 4.8, 17.2 Hz, 1H), 3.096 (m, 2H), 2.856 (dd, J = 5.2, 17.2 Hz, 1 H), 1.373 (s, 3 H), 1.355 (s, 3 H);

MS ( m / z ) 315 (M + H) ⁺ .

Example 7. Phen-4-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of pyrano [3,2-g] chromen-3-yl-ester (7b)

The same reaction as in Example 1, except that (+)-decursinol was changed to phen-4-tenophosphoric acid instead of 1 equivalent of 3-methyl-but-2-tenophosphoric acid in a round flask. Phen-4-tenoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3 having the following physical properties by carrying out the process -Work-ester (7b) was obtained.

Yield: 81.0%;

Oil phase;

R _f = 0.51 (n-hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.580 (d, J = 9.6 Hz, 1 H), 7.146 (s, 1 H), 6.792 (s, 1 H), 6.231 (d, J = 9.6 Hz, 1 H), 5.790 (m, 1H), 5.056-4.957 (m, 3H), 3.178 (dd, J = 4.8, 17.2 Hz, 1H), 2.837 (dd, J = 5.2, 17.2 Hz, 1H), 2.433 (m, 2H), 2.356 (t, J = 6.4 Hz, 2H), 1.374 (s, 3H), 1.352 (s, 3H);

MS ( m / z ) 329 (M + H) ⁺ .

Example 8 Acetic Acid 2,2-Dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of Pyrano [3,2-g] chromen-3-yl-ester (8b)

The following physical properties were carried out in the same manner as in the reaction of Example 1, except that (+)-decursinol was changed to acetic acid instead of 1 equivalent of 3-methyl-but-2-tenophosphoric acid in a round flask. An acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (8b) was obtained.

Yield: 89.8%;

Solid phase;

m.p 125-126 ° C .;

R _f = 0.38 (n-hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.579 (d, J = 9.6 Hz, 1H), 7.153 (s, 1H), 6.791 (s, 1H), 6.229 (d, J = 9.6 Hz, 1H), 5.050 (t, J = 4.8 Hz, 1H), 3.184 (dd, J = 4.0, 17.2 Hz, 1H), 3.004 (dd, J = 4.8, 17.4 Hz, 1H), 2.041 (s, 3H), 1.422 (s, 3H), 1.378 (s, 3H);

MS ( m / z ) 289 (M + H) ⁺ .

Example 9.Chloro-acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of Pyrano [3,2-g] chromen-3-yl-ester (9b)

The reaction process was carried out in the same manner as in Example 1, except that (+)-decursinol was replaced with chloro-acetic acid instead of 1 equivalent of 3-methyl-but-2-tenophosphoric acid in a round flask. Chloro-acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (9b) having the following physical properties was obtained. .

Yield: 96.2%;

Solid phase;

m.p 147-148 ° C .;

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

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.579 (d, J = 9.6 Hz, 1H), 7.160 (s, 1H), 6.794 (s, 1H), 6.235 (d, J = 9.6 Hz, 1H), 5.128 (t, J = 4.8 Hz, 1H), 4.088 (d, J = 14.8 Hz, 1H), 4.031 (d, J = 14.8 Hz, 1H), 3.229 (dd, J = 4.8, 17.2 Hz, 1H), 2.907 (dd, J = 4.8, 17.2 Hz, 1 H), 1.400 (s, 3 H), 1.375 (s, 3 H);

MS ( m / z ) 323 (M + H) ⁺ .

Example  10. Trichloro Acetic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester (10b)

As shown in the reaction scheme, (+)-decursinol was dissolved in anhydrous dichloromethane, and 2 equivalents of pyridine and 2 equivalents of trichloro acetyl chloride (10a) were added dropwise, followed by room temperature. Stirred for 2 h. The filtrate was concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 3: 1) to obtain a pure product (10b). Trichloro-acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (10b) was obtained.

Yield: 87.5%;

Semi Solid;

R _f = 0.60 (n-hexane: ethyl acetate = 1: 1);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.578 (d, J = 9.6 Hz, 1H), 7.178 (s, 1H), 6.185 (s, 1H), 6.245 (d, J = 9.6 Hz, 1H), 5.138 (t, J = 5.2 Hz, 1H), 3.292 (dd, J = 4.8, 16.8 Hz, 1H), 2.999 (dd, J = 5.2, 17.2 Hz, 1H), 1.450 (s, 3H), 1.435 (s, 3H);

MS ( m / z ) 392 (M + H) ⁺ .

Example  11. Pentanophosphate  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester (11b)

The reaction process was carried out in the same manner as in Example 10, except that (+)-decursinol was changed to pentanoyl chloride or valeroyl chloride instead of 1 equivalent of trichloro acetyl chloride in a round flask. Pentanophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (11b) having the following physical properties was obtained. .

Yield: 90.7%;

Oil phase;

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

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.576 (d, J = 9.6 Hz, 1H), 7.145 (s, 1H), 6.788 (s, 1H), 6.224 (d, J = 9.6 Hz, 1H), 5.044 (t, J = 5.2 Hz, 1H), 3.180 (dd, J = 4.8, 16.8 Hz, 1H), 2.837 (dd, J = 4.8, 16.8 Hz, 1H), 2.313 (t, J = 7.6 Hz, 2H) , 1.580 (m, 2H), 1.372 (s, 3H), 1.355 (s, 3H), 1.377-1.256 (m, 2H), 0.876 (t, J = 7.2 Hz, 3H);

MS ( m / z ) 331 (M + H) ⁺ .

Example  12. Decanoic acid  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester 12b

The following physical properties were carried out in the same manner as in the reaction of Example 10, except that the decursinol and decursinol were changed to decanoyl chloride instead of 1 equivalent of trichloro acetyl chloride in a round flask. Decanoate 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (12b) having was obtained.

Yield: 93.0%;

Oil phase;

R _f = 0.49 (n-hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.574 (d, J = 9.2 Hz, 1H), 7.143 (s, 1H), 6.788 (s, 1H), 6.227 (d, J = 9.2 Hz, 1H), 5.043 (t, J = 4.8 Hz, 1H), 3.178 (dd, J = 4.8, 16.8 Hz, 1H), 2.839 (dd, J = 4.8, 17.2 Hz, 1H), 2.323 (t, J = 8.0 Hz, 2H) , 1.615 (m, 2H), 1.406 (s, 3H), 1.373 (s, 3H), 1.336-1.256 (m, 12H), 0.888 (t, J = 7.2 Hz, 3H);

MS ( m / z ) 401 (M + H) ⁺ .

Example  13. 3- Phenyl -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester (13c)

Step 2.

As shown in the reaction scheme, 1.5 equivalent of 3-phenyl-acrylic acid was added to a 1-neck round flask and dissolved in 30-40 equivalents of anhydrous benzene. Two drops of N, N -dimethylformamide and 7.5 equivalents of thionyl chloride were added thereto, and the mixture was refluxed at 70-80 ° C. for 5 hours. It was cooled to room temperature and concentrated under reduced pressure.

Step 3.

One equivalent of a round flask was charged with 1 equivalent of (+)-deculcinol and 3 equivalents of pyridine and dissolved in 50 times (volume ratio) of anhydrous dichloromethane. Herein, 1.5 equivalents of cinnamoyl chloride reacted in the first step was dissolved in anhydrous dichloromethane, and stirred at room temperature for 2 hours. After concentration under reduced pressure, the concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 1: 1), and 3-phenyl-acrylic acid 2,2- having the following physical properties. Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (13c) was obtained.

Yield: 49.3%;

Solid phase;

m.p 136-137 ° C .;

R _f = 0.40 (n-hexane: ethyl acetate = 1: 1);

¹ H NMR (acetone-d ₆ , 400 MHz): δ ppm 7.882 (d, J = 9.6 Hz, 1H), 7.707 (m, 3H), 7.433 (m, 4H), 6.754 (s, 1H), 6.568 (d , J = 16.0 Hz, 1H), 6.212 (d, J = 9.2 Hz, 1H), 5.240 (t, J = 4.6 Hz, 1H), 3.344 (dd, J = 4.6, 17.6 Hz, 1H), 2.991 (dd , J = 4.4, 17.6 Hz, 1H), 1.436 (s, 3H), 1.424 (s, 3H);

MS ( m / z ) 377 (M + H) ⁺ .

Example 14. 3- (3-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of Pyrano [3,2-g] chromen-3-yl-ester (14c)

Step 1.

   As shown in the reaction scheme of Example 13, 10 equivalents of acetic anhydride was added to a 1-neck round flask, and 1 equivalent of 3- (3-hydroxy-phenyl) -acrylic acid and 10 equivalents of pyridine were added. After stirring for one day in a magnetic stirrer, it was concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 5: 1 ~ 1: 1) to obtain a pure product.

Step 2

1.5 equivalent of 3- (3-acetoxy-phenyl) -acrylic acid was added to a 1-neck round flask and dissolved in 30-40 equivalents of anhydrous benzene. Two drops of N, N -dimethylformamide and 7.5 equivalents of thionyl chloride were added thereto, and the mixture was refluxed at 70-80 degrees for 5 hours. It was cooled to room temperature and concentrated under reduced pressure.

Step 3.

One equivalent of a round flask was charged with 1 equivalent of (+)-deculcinol and 3 equivalents of pyridine and dissolved in 50 times (volume ratio) of anhydrous dichloromethane. 1.5 equivalent of 3- (3-acetoxy-phenyl) -acryloyl chloride reacted in the second step was dissolved in anhydrous dichloromethane and stirred at room temperature for 2 hours. After concentration under reduced pressure, the concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 1: 1), and the pure product 3- (3-acetoxy-phenyl). 2,2-Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester was obtained.

Step 4.

3- (3-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] black synthesized in the third step One equivalent of Men-3-yl-ester was dissolved in acetone, and then 4-8 equivalents of 3N HCl was added dropwise. It was refluxed at 50-60 degrees for 12 hours, and then cooled to room temperature and concentrated under reduced pressure. The concentrated solution was dissolved in ethyl acetate and distilled water and separated. The ethyl acetate layers were collected, dehydrated with anhydrous forget-me-not, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 5: 1 to 2: 1) to have 3- (3-hydroxy-phenyl) -acrylic acid 2, having the following physical properties. 2-Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (14c) was obtained.

Yield: 88.1%;

Solid phase;

m.p 105 ° C .;

R _f = 0.21 (n-hexane: ethyl acetate = 1: 1);

¹ H NMR (acetone-d ₆ , 400 MHz): δ ppm 7.863 (d, J = 9.2 Hz, 1H), 7.622 (d, J = 15.6 Hz, 1H), 7.442 (s, 1H), 7.252 (t, J = 7.8 Hz, 1H), 7.168 (d, J = 7.6 Hz, 1H), 7.111 (s, 1H), 6.915 (d, J = 8.4 Hz, 1H), 6.751 (s, 1H), 6.489 (d, J = 16.0 Hz, 1H), 6.213 (d, J = 9.6 Hz, 1H), 5.229 (t, J = 4.6 Hz, 1H), 3.337 (dd, J = 4.2, 17.2 Hz, 1H), 2.987 (dd, J = 4.4, 17.6 Hz, 1 H), 1.432 (s, 3 H), 1.422 (s, 3 H);

MS ( m / z ) 393 (M + H) ⁺ .

Example  15. 3- (3- Acetoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester (15c)

Step 1.

    As shown in the reaction scheme of Example 13, 10 equivalents of acetic anhydride was added to a 1-neck round flask, and 1 equivalent of 3- (3-hydroxy-phenyl) -acrylic acid and 10 equivalents of pyridine were added. After stirring for one day in a magnetic stirrer, it was concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 5: 1 ~ 1: 1) to obtain a pure product.

Step 2.

1.5 equivalent of 3- (3-acetoxy-phenyl) -acrylic acid was added to a 1-neck round flask and dissolved in 30-40 equivalents of anhydrous benzene. Two drops of N, N -dimethylformamide and 7.5 equivalents of thionyl chloride were added thereto, and the mixture was refluxed at 70-80 ° C. for 5 hours. It was cooled to room temperature and concentrated under reduced pressure.

Step 3.

One equivalent of a round flask was charged with 1 equivalent of (+)-deculcinol and 3 equivalents of pyridine and dissolved in 50 times (volume ratio) of anhydrous dichloromethane. 1.5 equivalent of 3- (3-acetoxy-phenyl) -acryloyl chloride reacted in the second step was dissolved in anhydrous dichloromethane and stirred at room temperature for 2 hours. After concentration under reduced pressure, the concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 1: 1), and 3- (3-acetoxy- having the following physical properties. Phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (15c) was obtained.

Yield: 87.0%;

Solid phase;

m.p 181 ° C .;

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

¹ H NMR (acetone-d ₆ , 400 MHz): δ ppm 7.840 (d, J = 9.6 Hz, 1H), 7.684 (d, J = 16.0 Hz, 1H), 7.558 (d, J = 7.6 Hz, 1H), 7.451 (m, 3H), 7.180 (dd, J = 2.4, 7.6 Hz, 1H), 6.737 (s, 1H), 6.574 (d, J = 15.6 Hz, 1H), 6.198 (d, J = 9.6 Hz, 1H ), 5.232 (t, J = 4.4 Hz, 1H), 3.336 (dd, J = 4.2, 17.6 Hz, 1H), 2.984 (dd, J = 4.8, 17.6 Hz, 1H), 2.258 (s, 3H), 1.430 (s, 3H), 1. 422 (s, 3H);

MS ( m / z ) 435 (M + H) ⁺ .

Example  16. 3- (3,4-dihydroxy- Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester 16c

In the first step of Example 14, 10 equivalents of acetic anhydride was added to a 1-neck round flask and 3- (3,4-dihydroxy-phenyl) instead of 1 equivalent of 3- (3-hydroxy-phenyl) -acrylic acid. Except for changing to acrylic acid, the same process as in Example 14 was carried out to give 3- (3,4-dihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-di having the following physical properties; Hydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (16c) was obtained.

Yield 93.2%;

Solid phase;

m.p 115 ° C .;

R _f = 0.36 (n-hexane: ethyl acetate = 1: 2);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.618 (d, J = 8.8 Hz, 1H), 7.549 (d, J = 16.0 Hz, 1H), 7.181 (s, 1H), 7.068 (s, 1H), 6.948 (dd, J = 1.6, 8.4 Hz, 1H), 6.870 (d, J = 8.0 Hz, 1H), 6.821 (s, 1H), 6.223 (m, 2H), 5.179 (t, J = 4.6 Hz, 1H) , 3.231 (dd, J = 4.6, 17.6 Hz, 1H), 2.935 (dd, J = 4.6, 17.6 Hz, 1H), 1.428 (s, 3H), 1.379 (s, 3H);

MS ( m / z ) 409 (M + H) ⁺ .

Example  17. 3- (3,4- Diacetoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester (17c)

Except for changing the equivalent of 3- (3,4-dihydroxy-phenyl) -acrylic acid instead of one equivalent of 3- (3-hydroxy-phenyl) -acrylic acid in the first round flask of Example 15. 3- (3,4-Diacetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -P having the same physical properties as in Example 15 was carried out. Llano [3,2-g] chromen-3-yl-ester (17c) was obtained.

Yield: 84.5%;

Solid phase;

m.p 92 ° C .;

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

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.613 (d, J = 8.4 Hz, 1H), 7.581 (d, J = 2.0 Hz, 1H), 7.389-7.339 (m, 2H), 7.256-7.179 (m , 2H), 6.823 (s, 1H), 6.358 (d, J = 16.0, 1H), 6.232 (d, J = 9.2 Hz. 1H), 5.190 (t, J = 4.6 Hz, 1H), 3.244 (dd, J = 4.6, 17.6 Hz, 1H), 2.932 (dd, J = 4.6, 17.6 Hz, 1H), 2.293 (s, 3H), 2.290 (s, 3H), 1.425 (s, 3H), 1.389 (s, 3H );

MS ( m / z ) 493 (M + H) ⁺ .

Example 18. 3- (4-Hydroxy-3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of pyrano [3,2-g] chromen-3-yl-ester (18c)

In the first step of Example 14, 10 equivalents of acetic anhydride was added to a 1-neck round flask and 3- (4-hydroxy-3-methoxy- instead of 1 equivalent of 3- (3-hydroxy-phenyl) -acrylic acid. Except for changing to phenyl) -acrylic acid, the same process as in Example 14 was carried out to provide 3- (4-hydroxy-3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3 having the following physical properties. , 4-Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (18c) was obtained.

Yield: 91.8%;

Solid phase;

m.p 102 ° C .;

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

¹ H NMR (acetone-d ₆ , 400 MHz): δ ppm 7.843 (d, J = 9.6 Hz, 1H), 7.616 (d, J = 16.0 Hz, 1H), 7.424 (s, 1H), 7.357 (s, 1H ), 7.123 (dd, J = 2.0, 8.0 Hz, 1H), 6.851 (d, J = 8.4 Hz, 1H), 6.740 (s, 1H), 6.387 (d, J = 15.6 Hz, 1H), 6.198 (d , J = 9.6 Hz, 1H), 5.221 (t, J = 4.6 Hz, 1H), 3.895 (s, 3H), 3.321 (dd, J = 4.6, 17.2 Hz, 1H), 2.963 (dd, J = 4.4, 17.6 Hz, 1H), 1.421 (s, 3H), 1.413 (s, 3H);

MS ( m / z ) 423 (M + H) ⁺ .

Example  19. 3- (4- Acetoxy -3- Methoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester (19c)

In the first step of Example 15, only one equivalent of 3- (3-hydroxy-3-methoxy-phenyl) -acrylic acid was replaced with one equivalent of 3- (3-hydroxy-3-phenyl) -acrylic acid in a one-neck round flask. The procedure of Example 15 was repeated except that 3- (4-acetoxy-3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H having the following physical properties , 8H -pyrano [3,2-g] chromen-3-yl-ester (19c) was obtained.

Yield: 42.4%;

Solid;

m.p 98 ° C .;

R _f = 0.40 (n-hexane: ethyl acetate = 1: 1);

¹ H NMR (acetone-d ₆ , 400 MHz): δ ppm 7.843 (d, J = 9.6 Hz, 1H), 7.679 (d, J = 16.0 Hz, 1H), 7.480 (s, 1H), 7.428 (s, 1H) , 7.247 (d, J = 8.4 Hz, 1H), 7.095 (d, J = 8.4 Hz, 1H), 6.742 (s, 1H), 6.568 (d, J = 16.0 Hz, 1H), 6.200 (d, J = 9.6 Hz, 1H), 5.243 (t, J = 4.4 Hz, 1H), 3.872 (s, 3H), 3.338 (dd, J = 4.4, 17.6 Hz, 1H), 2.982 (dd, J = 4.4, 17.6, 1H ), 2.242 (s, 3H), 1.428 (s, 3H), 1.418 (s, 3H);

MS ( m / z ) 465 (M + H) ⁺ .

Example 20. 3- (4-Acetoxy-3,5-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of pyrano [3,2-g] chromen-3-yl-ester (21c)

In the first step of Example 15, a 1-neck round flask was replaced with 3- (4-hydroxy-3,5-dimethoxy-phenyl) -acrylic acid instead of 1 equivalent of 3- (3-hydroxy-phenyl) -acrylic acid. A 3- (4-acetoxy-3,5-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4- having the following physical properties was carried out in the same manner as in Example 15 except for the change. Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (21c) was obtained.

Yield: 10.8%;

Solid;

m.p 121 ° C .;

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

₁ H NMR (CDCl ₃ ): δ ppm 7.614 (d, J = 9.2 Hz, 1H), 7.582 (d, J = 2.4 Hz, 1H), 7.189 (s, 1H), 6.826 (s, 1H), 6.739 (s , 2H), 6.362 (d, J = 16.0 Hz, 1H), 6.227 (d, J = 9.2 Hz, 1H), 5.211 (t, J = 4.8 Hz, 1H), 3.801 (s, 6H), 3.255 (dd , J = 4.8, 18.0 Hz, 1H), 2.935 (dd, J = 4.8, 18.0 Hz, 1H), 2.331 (s, 3H), 1.451 (s, 3H), 1.397 (s, 3H);

MS ( m / z ) 495 (M + H) ⁺ .

Example  21. 3- (4- Methoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H -blood Lanolin [3,2-g] Chromen-3-yl-ester (22c)

Step 1.

As shown in the reaction scheme, 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid was added to a 1-neck round flask and dissolved in 30-40 equivalents of anhydrous benzene. Two drops of N, N -dimethylformamide and 7.5 equivalents of thionyl chloride were added thereto, and the mixture was refluxed at 70-80 ° C. for 5 hours. It was cooled to room temperature and concentrated under reduced pressure.

Step 2.

One equivalent of a round flask was charged with 1 equivalent of (+)-deculcinol and 3 equivalents of pyridine and dissolved in 50 times (volume ratio) of anhydrous dichloromethane. 1.5 equivalent of 3- (4-methoxy-phenyl) -acryloyl chloride reacted in the first step was dissolved in anhydrous dichloromethane and stirred at room temperature for 2 hours. After concentration under reduced pressure, the concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 1: 1), and 3- (4-methoxy-) having the following physical properties. Phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (22c) was obtained.

Yield: 91.2%;

Solid phase;

m.p 68 ° C .;

R _f = 0.20 (n-hexane: ethyl acetate = 2: 1);

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.631 (d, J = 16.0 Hz, 1H), 7.583 (d, J = 9.2 Hz, 1H), 7.450 (d, J = 8.4 Hz, 1H), 7.170 (s , 1H), 6.882 (d, J = 8.8 Hz, 2H), 6.829 (s, 1H), 6.282 (d, J = 16.0 Hz, 1H), 6.231 (d, J = 9.2 Hz, 1H), 5.188 (t , J = 4.8 Hz, 1H), 3.828 (s, 3H), 3.238 (dd, J = 4.4, 17.6 Hz, 1H), 2.934 (dd, J = 4.4, 17.6 Hz, 1H), 1.433 (s, 3H) , 1.391 (s, 3 H);

MS ( m / z ) 407 (M + H) ⁺ _.

Example  22. 3- (4-hydroxy- Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H -blood Lanolin [3,2-g] Preparation of Chromen-3-yl-ester (22d)

One equivalent of a round flask with 1 equivalent of 3- (4-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] Chromium-3-yl-ester (22c) was added thereto, dissolved in anhydrous dichloromethane, and 5 equivalents of 1M boron tribromide solution (1M BBr ₃ in MC) was added dropwise, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into iced water, stirred for 10 minutes and extracted with ethyl acetate, which was dehydrated with anhydrous forget-me-not and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 1: 1), and 3- (4-hydroxy-phenyl) -acrylic acid 2 having the following physical properties. , 2-Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (22d) was obtained.

Yield: 82.3%;

Solid phase;

m.p 104 ° C .;

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

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

MS ( m / z ) 393 (M + H) ⁺ .

Example  23. 3- (3,4- Dimethoxy - Phenyl )- Acrylic acid 2 , 2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H -blood Lanolin [3,2-g] Preparation of Chromen-3-yl-ester (23c)

In the first step of Example 21, except that the 1-neck round flask was replaced with 3- (3,4-dimethoxy-phenyl) -acrylic acid instead of 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid. The process of Example 21 was carried out to give 3- (3,4-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [ 3,2-g] chromen-3-yl-ester (23c) was obtained.

Yield: 45.8%

Solid phase;

m.p 83 ° C .;

R _f = 0.35 ( n- hexane: ethyl acetate = 11);

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

MS ( m / z ) 437 (M + H) ⁺ .

Example  24. 3- (3,4,5- Trimethoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester 24c

In the first step of Example 21, only one point of the round flask was replaced with 3- (3,4,5-trimethoxy-phenyl) -acrylic acid instead of 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid. The procedure of Example 21 was repeated except that 3- (3,4,5-trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H having the following physical properties , 8H -pyrano [3,2-g] chromen-3-yl-ester (24c) was obtained.

Yield: 52.9%;

Solid phase;

m.p 87 ° C .;

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

₁ H NMR (CDCl ₃ ): δ ppm 7.607 (d, J = 5.6 Hz, 1H), 7.575 (s, 1H), 7.184 (s, 1H), 6.840 (s, 1H), 6.722 (s, 2H), 6.322 (d, J = 16.0 Hz, 1H), 6.240 (d, J = 9.2 Hz, 1H), 5.208 (t, J = 4.4 Hz, 1H), 3.904 (s, 9H), 3.254 (dd, J = 4.4, 16.8 Hz, 1H), 2.951 (dd, J = 4.4, 16.8 Hz, 1H), 1.452 (s, 3H), 1.395 (s, 3H);

MS ( m / z ) 467 (M + H) ⁺ .

Example 25. 3- (3,4,5-Trihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of Pyrano [3,2-g] chromen-3-yl-ester (24d)

In Example 22, one equivalent of a round-necked flask, 1 equivalent of 3- (4-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3 3- (3,4,5-trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro instead of, 2- g ] chromen-3-yl-ester (22c) The procedure of Example 22 was repeated except that the result was changed to 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (24c), to give 3- (3,4, 5-Trihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (24d )

Yield: 18.2%;

Solid phase;

m.p 144 ° C .;

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

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

MS ( m / z ) 425 (M + H) ⁺ .

Example 26. 3- (2-Methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of Pyrano [3,2-g] chromen-3-yl-ester (25c)

Example 21 except that in the first step of Example 21, 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid was replaced with 3- (2-methoxy-phenyl) -acrylic acid in a one-neck round flask. 3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- having the following physical properties g] chromen-3-yl-ester (25c) was obtained.

Yield: 81.8%;

White solid;

m.p 72 ° C .;

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

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

MS ( m / z ) 407 (M + H) ⁺ .

Example 27. 3- (2-Hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of Pyrano [3,2-g] chromen-3-yl-ester (25d)

In Example 22, one equivalent of a round-necked flask, 1 equivalent of 3- (4-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3 3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H instead of, 2- g ] chromen-3-yl-ester (22c) The procedure of Example 22 was repeated except for changing to pyrano [3,2- g ] chromen-3-yl-ester (25c) to give 3- (2-hydroxy-phenyl) -acrylic acid having the following physical properties. 2,2-Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (25d) was obtained.

Yield: 58.5%;

White solid;

m.p 106 ° C .;

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

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

MS ( m / z ) 393 (M + H) ⁺ .

Example 28. 3- (3-Methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of Pyrano [3,2-g] chromen-3-yl-ester (26c)

Example 21 except that in the first step of Example 21, 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid was replaced with 3- (3-methoxy-phenyl) -acrylic acid in a one-neck round flask. 3- (3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- having the following physical properties g] chromen-3-yl-ester (26c) was obtained.

Yield: 90.9%;

White solid;

m.p 72 ° C .;

R _f = 0.51 ( n- hexane: ethyl acetate = 1: 1);

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

MS ( m / z ) 407 (M + H) ⁺ .

Example 29. 3- (2,3-Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of pyrano [3,2-g] chromen-3-yl-ester (27c)

In the first step of Example 21, except that the 1-neck round flask was replaced with 3- (2,3-dimethoxy-phenyl) -acrylic acid instead of 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid. The same process as in Example 21 was carried out to give 3- (2,3-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [ 3,2-g] chromen-3-yl-ester (27c) was obtained.

Yield: 25.0%;

White solid;

m.p 149 ° C .;

R _f = 0.43 ( n- hexane: ethyl acetate = 1: 1);

₁ H NMR (CDCl ₃ ): δ ppm 8.021 (d, J = 16.0 Hz, 1H), 7.585 (d, J = 9.6 Hz, 1H), 7.174 (s, 1H), 7.121 (d, J = 6.8 Hz, 1H ), 7.032 (t, J = 8.0 Hz, 1H), 6.939 (d, J = 8.8 Hz, 1H), 6.829 (s, 1H), 6.449 (d, J = 16.8 Hz, 1H), 6.232 (d, J = 9.6 Hz, 1H), 5.192 (t, J = 4.8 Hz, 1H), 3.868 (s, 3H), 3.832 (s, 3H), 3.249 (dd, J = 4.8, 17.2 Hz, 1H), 2.945 (dd , J = 4.8, 17.2 Hz, 1H), 1.435 (s, 3H), 1.400 (s, 3H);

MS ( m / z ) 437 (M + H) ⁺ .

Example 30. 3- (2,4-Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H Preparation of Pyrano [3,2-g] chromen-3-yl-ester (28c)

In the first step of Example 21, except that the 1-neck round flask was replaced with 3- (2,4-dimethoxy-phenyl) -acrylic acid instead of 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid. The process of Example 21 was carried out to give 3- (2,4-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [ 3,2-g] chromen-3-yl-ester (28c) was obtained.

Yield: 25.0%;

White solid;

m.p 149 ° C .;

R _f = 0.43 ( n- hexane: ethyl acetate = 1: 1);

₁ H NMR (CDCl ₃ ): δ ppm 8.021 (d, J = 16.0 Hz, 1H), 7.585 (d, J = 9.6 Hz, 1H), 7.174 (s, 1H), 7.121 (d, J = 6.8 Hz, 1H ), 7.032 (t, J = 8.0 Hz, 1H), 6.939 (d, J = 8.8 Hz, 1H), 6.829 (s, 1H), 6.449 (d, J = 16.8 Hz, 1H), 6.232 (d, J = 9.6 Hz, 1H), 5.192 (t, J = 4.8 Hz, 1H), 3.868 (s, 3H), 3.832 (s, 3H), 3.249 (dd, J = 4.8, 17.2 Hz, 1H), 2.945 (dd , J = 4.8, 17.2 Hz, 1H), 1.435 (s, 3H), 1.400 (s, 3H);

MS ( m / z ) 437 (M + H) ⁺ .

Example  31. 3- (2,5- Dimethoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester (29c)

Except for changing to 1.5 equivalent 3- (4-methoxy-phenyl) -acrylic acid instead of 3- (2,5-dimethoxy-phenyl) -acrylic acid in the first round flask in Example 21. The process of Example 21 was carried out to give 3- (2,5-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [ 3,2-g] chromen-3-yl-ester (29c) was obtained.

Yield: 38.7%;

Light yellow solid;

m.p 77 ° C .;

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

₁ H NMR (CDCl ₃ ): δ ppm 7.983 (d, J = 16.0 Hz, 1H), 7.592 (d, J = 10.4 Hz, 1H), 7.178 (s, 1H), 7.001 (d, J = 2.8 Hz, 1H ), 6.912 (dd, J = 2.8, 8.8 Hz, 1H), 6.849-6.827 (m, 2H), 6.471 (d, J = 16.4 Hz, 1H), 6.237 (d, J = 9.2 Hz, 1H), 5.196 (t, J = 4.8 Hz, 1H), 3.824 (s, 3H), 3.768 (s, 3H), 3.245 (dd, J = 4.8, 17.2 Hz, 1H), 2.945 (dd, J = 4.8, 17.2 Hz, 1H), 1.441 (s, 3H), 1.396 (s, 3H);

MS ( m / z ) 437 (M + H) ⁺ .

Example  32. 3- (2,4,5- Trimethoxy - Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester 30c

In the first step of Example 21, in the one-neck round flask, only 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid was replaced with 3- (2,4,5-trimethoxy-phenyl) -acrylic acid. The procedure of Example 21 was repeated except that 3- (2,4,5-trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H having the following physical properties , 8H -pyrano [3,2-g] chromen-3-yl-ester (30c) was obtained.

Yield: 33.5%;

Yellow solid;

m.p 93 ° C .;

R _f = 0.29 ( n- hexane: ethyl acetate = 1: 1);

₁ H NMR (CDCl ₃ ): δ ppm 7.986 (d, J = 13.6 Hz, 1H), 7.586 (d, J = 9.6 Hz, 1H), 7.173 (s, 1H), 6.966 (s, 1H), 6.833 (s , 1H), 6.478 (s, 1H), 6.325 (d, J = 16.0 Hz, 1H), 6.232 (d, J = 9.2 Hz, 1H), 5.196 (t, J = 4.8 Hz, 1H), 3.922 (s , 3H), 3.855 (s, 3H), 3.840 (s, 3H), 3.238 (dd, J = 4.8, 17.2 Hz, 1H), 2.940 (dd, J = 4.8, 17.2 Hz, 1H), 1.443 (s, 3H), 1.393 (s, 3H);

MS ( m / z ) 483 (M + H) ⁺ .

Example  33. 3- (4-nitro- Phenyl ) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester 31c

Example 21 and 1 except that in the first step of Example 21 was replaced with 3- (4-nitro-phenyl) -acrylic acid instead of 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid in a one-neck round flask 3- (4-nitro-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] having the following physical properties by carrying out the same process Chromen-3-yl-ester (31c) was obtained.

Yield: 65.7%;

Light yellow solid;

m.p 193 ° C .;

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

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

MS ( m / z ) 422 (M + H) ⁺ .

Example  34. Benzoic acid  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester 32c

Step 2.

As in the reaction scheme, 1.5 equivalents of benzoic acid was added to a 1-neck round flask and dissolved in 30-40 equivalents of anhydrous benzene. Two drops of N, N -dimethylformamide and 7.5 equivalents of thionyl chloride were added thereto, and the mixture was refluxed at 70-80 degrees for 5 hours. It was cooled to room temperature and concentrated under reduced pressure.

Step 3.

One equivalent of a round flask was charged with 1 equivalent of (+)-decurinol and 3 equivalents of pyridine and dissolved in 50 times (volume ratio) of anhydrous dichloromethane. The benzoyl chloride synthesized in the second step was dissolved in anhydrous dichloromethane and added thereto, followed by stirring at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 1: 1) to obtain pure product benzoic acid 2,2-dimethyl-8-. Oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (32c) was obtained.

Yield 93.2%;

Semi solid;

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

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.972 (d, J = 9.6 Hz, 2H), 7.557 (m, 2H), 7.417 (t, J = 7.8 Hz, 2H), 7.166 (s, 1H), 6.845 (s, 1H), 6.227 (d, J = 9.6 Hz, 1H), 5.296 (t, J = 4.8 Hz, 1H), 3.300 (dd, J = 4.4, 17.6 Hz, 1H), 3.004 (dd, J = 4.8, 17.6 Hz, 1H), 1.474 (s, 3H), 1.428 (s, 3H);

MS ( m / z ) 351 (M + H) ⁺ .

Example  35. 3,4,5- Trihydroxy - Benzoic acid  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester (33c)

Step 1.

    As shown in the reaction scheme of Example 34, 10 equivalents of acetic anhydride was added to a 1-neck round flask, and 1 equivalent of 3,4,5-trihydroxy benzoic acid and 10 equivalents of pyridine were added thereto. After stirring for one day in a magnetic stirrer, it was concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 5: 1 ~ 1: 1) to obtain a pure product.

Step 2 and Step 3

The same process as the second step and the third step of Example 34, except that the first round flask in Example 34 was replaced with 3,4,5-triacetoxy benzoic acid instead of 1.5 equivalents of benzoic acid. Pure product 3,4,5-triacetoxy benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen- 3-yl-ester was obtained.

Step 4.

3,4,5-triacetoxy benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] synthesized in steps 2 and 3 above One equivalent of chromen-3-yl-ester was dissolved in acetone, and then 4-8 equivalents of 3N HCl was added dropwise. It was refluxed at 50-60 degrees for 12 hours, and then cooled to room temperature and concentrated under reduced pressure. The concentrated solution was dissolved in ethyl acetate and distilled water and separated. The ethyl acetate layers were collected, dehydrated with anhydrous forget-me-not, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 5: 1 to 2: 1) to give 3,4,5-trihydroxy benzoic acid 2,2 having the following physical properties. -Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (33c) was obtained.

Yield: 98.7%;

Solid phase;

m.p 138 ° C .;

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

¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 7.674 (d, J = 9.2 Hz, 1H), 7.242 (s, 1H), 7.132 (s, 2H), 6.782 (s, 1H), 6.228 (d, J = 9.2 Hz, 1H), 5.215 (t, J = 4.8 Hz, 1H), 3.284 (dd, J = 4.2, 17.6 Hz, 1H), 2.981 (dd, J = 4.6, 17.6 Hz, 1H), 1.443 (s, 3H), 1.413 (s, 3H) 3 H) 1.292 (s, 3H), 1.287 (s, 3H);

MS ( m / z ) 399 (M + H) ⁺ .

Example  36. 3,4,5- Triacetoxy - Benzoic acid  2,2-dimethyl-8-oxo-3,4- Dehydro - 2H, 8H - Pyrano [3,2-g] chromen Preparation of 3-yl-ester 34c

Step 1.

    As shown in the reaction scheme of Example 34, 10 equivalents of acetic anhydride was added to a 1-neck round flask, and 1 equivalent of 3,4,5-trihydroxy benzoic acid and 10 equivalents of pyridine were added thereto. After stirring for one day in a magnetic stirrer, it was concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 5: 1 ~ 1: 1) to obtain a pure product.

Step 2 and Step 3

The same process as in the second and third steps of Example 34 was carried out except that the first round flask was changed to 3,4,5-triacetoxy benzoic acid instead of 1.5 equivalents of benzoic acid in the second step of Example 34. 3,4,5-triacetoxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen having the following physical properties 3-yl-ester (34c) was obtained.

Yield: 28.8%;

Solid phase;

m.p 97 ° C .;

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

¹ H NMR (acetone-d ₆ , 400 MHz): δ 7.848 (d, J = 9.6 Hz, 1H), 7.740 (s, 2H), 7.435 (s, 1H), 6.765 (s, 1H), 6.209 (d, J = 9.6 Hz, 1H), 5.359 (t, J = 4.4, 17.6 Hz, 1H), 3.403 (dd, J = 4.2, 17.6 Hz, 1H), 3.123 (dd, J = 4.4, 17.6 Hz, 1H), 2.317 (s, 3H), 2.283 (m, 6H), 1.479 (s, 3H), 1.457 (s, 3H);

MS ( m / z ) 525 (M + H) ⁺ .

Experimental Example 1. Measurement of cytotoxicity

A549 lung cancer cells, HCT15 colon cancer cells, and ACHN rectal cancer cells were used for in vitro cytotoxicity measurement, and all of their cultures were incubated in a RPMI 1640 medium containing L-glutamine (glutamine) for 30 minutes in a 56 ° C water bath and inactivated. It was prepared by adding 10% serum (FBS) and adding 1% antibiotic (penicillin-G 100,000 units / streptomycin 100 mg) and 2 g of sodium bicarbonate (NaHCO ₃ ).

RPMI 1640 to which 10% FBS was added was used while culturing the cells at 5% CO ₂ , 37 ° C. Each cancer cell was mixed with 2 × 10 ⁴ cells with a constant concentration of sample and dispensed into a 96 well plate at 100 μl per well. After 48 hours of incubation, the culture medium was discarded and 10 μl of MTT (5 mg / ml) was added to B16-BL6 and A549 cells, followed by 4 hours of incubation. After the culture plate was washed with PBS, 100 μl of DMSO was added thereto, and the plate was left at room temperature for 20 minutes, and the absorbance was measured at 570 nm with an ELISA reader.

Experimental Example 2. Evaluation of anticancer activity of decursin derivatives

Decursins isolated from Angelica gigas were human erythroleukemic (KCC), K562 (ED ₅₀ 48uM), HL-60 (ED ₅₀ 42uM), and lung cancer cells A549 (ED ₅₀ 39uM) purchased from American Type Culture Collection (ATCC). (Ahn 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). In addition, decursin showed 54% survival inhibition against human erythroleukemic K562 purchased from ATCC (American Type Culture Collection) at a concentration of 50 uM (Kim, HH 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).

    The anticancer effects of three types of decancin derivatives synthesized in this study were lung cancer cells (A549), colon cancer cells (HCT15) and rectal cancer cells (ACHN) (purchased from the American Type Culture Collection). Table 4 shows. As a result, the test groups treated with 10 uM decursin (1b) and derivatives having alkyl group structure (2b-12b) for 48 hours showed no cytotoxic effect on all three cancer cells. In contrast, the cinnamoyl derivative (13c-18c) treatment group showed a strong cytotoxic effect. In particular, the compound (14c) material showed the strongest cytotoxic effect on the A549, HCT15 and ACHN cancer cells 33%, 12% and 43% respectively. In addition, the benzoyl derivatives (26c-29c) showed a weak cytotoxic effect. As a result, the structure of the decursin derivative for showing anticancer activity was confirmed to have a structure having aromatic functional groups such as cinnamoyl group and benzoyl group rather than alkyl group (see Table 10).

      Examples of the formulation of the composition are described below, but are not intended to limit the present invention but to explain in detail only.

Formulation Example 1 Preparation of Powder

Decursinol derivative (14C) 20 mg

Lactose 100 mg

Talc 10 mg

     The above ingredients are mixed and filled in an airtight cloth to prepare a powder.

Formulation Example 2 Preparation of Tablet

Decursinol derivative (14C) 10 mg

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

     After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.

Formulation Example 3 Preparation of Capsule

Decursinol derivative (14C) 10 mg

3 mg of crystalline cellulose

Lactose 14.8 mg

Magnesium Stearate 0.2 mg

    According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.

Formulation Example 4 Preparation of Injection

Decursinol derivative (14C) 10 mg

Mannitol 180 mg

Sterile distilled water for injection 2974 mg

Na ₂ HPO ₄ 12H ₂ O 26 mg

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

Formulation Example 5 Preparation of Liquid

Decursinol derivative (14C) 20 mg

10 g of isomerized sugar

5 g of mannitol

Purified water

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

Formulation Example 6 Preparation of Healthy Food

Decursinol derivative (14C) 1000 mg

Vitamin mixture proper amount

70 μg of Vitamin A Acetate

Vitamin E 1.0 mg

Vitamin B1 0.13 mg

Vitamin B2 0.15 mg

Vitamin B6 0.5 mg

0.2 μg of vitamin B12

Vitamin C 10 mg

10 μg biotin

Nicotinic Acid 1.7 mg

Folate 50 ㎍

Calcium Pantothenate 0.5mg

Mineral mixture

Ferrous Sulfate 1.75 mg

Zinc Oxide 0.82 mg

Magnesium carbonate 25.3 mg

Potassium monophosphate 15 mg

Dibasic calcium phosphate 55 mg

Potassium Citrate 90 mg

Calcium Carbonate 100 mg

Magnesium chloride 24.8 mg

     Although the composition ratio of the above-mentioned vitamin and mineral mixtures is mixed with a component suitable for a health food in a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health food manufacturing method. The granules may be prepared and used for preparing a health food composition according to a conventional method.

Formulation Example 7 Preparation of Healthy Drink

Decursinol derivative (14C) 1000 mg

Citric acid 1000 mg

100 g oligosaccharides

Plum concentrate 2 g

1 g of taurine

Add 900 ml of purified water

     After mixing the above components according to a conventional healthy beverage manufacturing method, and then stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 L container, sealed and sterilized and then refrigerated and stored in the present invention For the preparation of healthy beverage compositions.

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

As described above, the decursin derivative compounds of the present invention confirm the cytotoxic effects on cancer cells such as lung cancer cells A549, colon cancer cells HCT15 and rectal cancer cells ACHN for the prevention and treatment of cancer diseases. Pharmaceutical compositions and nutraceuticals can be provided.

Claims (7)

     A decursin derivative compound having a novel structure represented by the following general formula (I) synthesized by using (+)-decursinol isolated from Chalcobendum as a precursor and a pharmaceutically acceptable salt thereof:

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

Where A 'is a substituent which may be substituted at least one at positions o, m, and p , and hydrogen atom, hydroxy group, nitro group, acetate group, halogen atom, C ₁ to C ₄ lower alkyl group, lower alkoxy group and lower alkyl At least one substituent selected from the group consisting of esters and lower alkyl carboxy groups; n is an integer of 0-4. The compound of formula (I) according to claim 1, wherein R ₁ is a C ₁ to C ₁₀ alkyl group, an alkenyl group, an alkynyl group or an A substituent which is unsubstituted or substituted with a halogen atom or a C ₁ to C ₄ lower alkyl group. , Wherein A ′ of the A substituent is at least one substituent selected from hydrogen atom, hydroxy group, methyl group, ethyl group, methoxy group, ethoxy group, nitro group or acetyl group substituted at o, m, p positions; n is an integer of 0 or 1 and a salt thereof. The compound of claim 1, wherein the general formula (I) compound is 3-methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3]. , 2-g] chromen-3-yl - ester, cis-2-methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, trans-2-methyl-but-2-tenophosphate 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H- Pyrano [3,2-g] chromen-3-yl-ester, 2-methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2 -g] chromen-3-yl-ester, phen-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chrome Men-3-yl-ester, but-3-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3 -Yl-ester, phen-4-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester , Acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-S Chloro-acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, trichloro-acetic acid 2, 2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, pentanoic acid 2,2-dimethyl-8-oxo- 3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, decanoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H , 8H -pyrano [3,2-g] chromen-3-yl-ester, 3-phenyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [ 3,2-g] chromen-3-yl-ester, 3- (3-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (3-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -P Lano [3,2-g] chromen-3-yl-ester, 3- (3,4-dihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H , 8H-pyrano [3,2-g] chromen-3-yl-ester, 3- (3,4-dia -Phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H, 8H-pyrano [3,2-g] chromen-3-yl-ester, 3- (4- Hydroxy-3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester , 3- (4-acetoxy-3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen 3-yl-ester, 3- (4-acetoxy-3,5-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [ 3,2-g] chromen-3-yl-ester, 3- (4-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H- Pyrano [3,2-g] chromen-3-yl-ester, 3- (3,4-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H , 8H-pyrano [3,2-g] chromen-3-yl-ester, 3- (3,4,5-trimethoxy-phenyl) - ah Rilsan 2,2-dimethyl-8-oxo-3,4-dihydro-2H, 8H-pyrano [3,2-g] chromen-3-yl-ester, 3- (3,4,5-tree Hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2 -Methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- ( 2-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3 -(2,3-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl- Ester, 3- (2,4-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3 -Yl-ester, 3- (2,5-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H- Pyrano [3,2-g] chromen-3-yl-ester, 3- (2,4,5-trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-di Hydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4-nitro-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-di Hydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [ 3,2-g] chromen-3-yl-ester, 3,4,5-trihydroxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester or 3,4,5-triacetoxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -P Lano [3,2-g] chromen-3-yl-ester compounds and salts thereof. A pharmaceutical composition for the treatment and prophylaxis of cancer diseases, comprising as an active ingredient a decursin derivative compound or a pharmaceutically acceptable salt thereof having a novel structure represented by the general formula (I) of claim 1. The method of claim 4, wherein the cancer disease is gastric cancer, colon cancer, breast cancer, lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or eye melanoma, uterine cancer, ovarian cancer, colon cancer, small intestine cancer , Rectal cancer, anal muscle cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, lymph gland cancer, bladder cancer, gallbladder cancer, endocrine cancer, thyroid cancer Thyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocyte lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor , Primary CNS lymphoma, spinal cord tumor, brain stem glioma or pituitary adenoma.       A health functional food for the prevention and improvement of cancer diseases containing the decursin derivative compound represented by the general formula (I) of claim 1 as an active ingredient. The dietary supplement according to claim 6 in the form of a powder, granule, tablet, capsule or beverage.