KR101674145B1 - Decursinol-carbamate derivatives, and pharmaceutical composition containing the same for preventing or treating cancer - Google Patents

Abstract

The present invention relates to a decursinol carbamate derivative represented by chemical formula 1, and to a composition for preventing or treating cancer containing the same. The decursinol carbamate derivative shows excellent activity of inhibiting a wnt/-catenin pathway, and thus can be useful for pharmaceutical compositions for preventing or treating cancer or functional health foods.

Description

The present invention relates to a decursinol carbamate derivative, a decursinol-carbamate derivative, and a pharmaceutical composition for preventing or treating cancer,

The present invention relates to a decursinol carbamate derivative and a pharmaceutical composition for preventing or treating cancer comprising the same.

Cancer, also called neoplasia, is commonly characterized as "uncontrolled cell growth." Abnormal cell growth of cancer cells forms a mass of cells called tumors that penetrate into surrounding tissues and, in severe cases, to other organs of the body. Cancer is an intractable chronic disease that, even if treated with surgery, radiation, and chemotherapy, in many cases can not be cured, causes pain to the patient, and ultimately leads to death.

There are many causes of cancer, but internal factors include genetic factors, immunological factors, and external factors include chemicals, radiation, and viruses. Although the exact mechanism by which the normal cells are transformed into cancer cells has not been clearly elucidated, the balance between the genes involved in the development of cancer, namely, oncogenes and tumor suppresor genes Cancer occurs when collapsed due to the internal or external factors.

Cancer is largely classified into blood cancer and solid cancer and includes lung cancer, gastric cancer, breast cancer, oral cancer, liver cancer, cervical cancer, endometrial cancer, prostate cancer, ovarian cancer, thyroid cancer, esophageal cancer, colorectal cancer, rectal cancer, pancreatic cancer, It occurs in almost all parts of the body. Among these, prostate cancer is a disease limited to men, but the increase is remarkable, and research on drug development to treat it is actively increasing.

Prostate cancer can be classified into three types: prostate cancer, metastasis of cancer, difference between normal prostate tissue and tumor, patient's age and health status, atmospheric observation, curative surgery, radiotherapy, hormone therapy or chemotherapy (Oncolink patient guide: prostate cancer, James M. Metz, MH 2010, pp. 49-136).

Prostate cancer patients continue to go on hormone therapy (hormone alone can not be controlled by the state of the cancer does not respond to the state) to progress to hormone-resistant prostate cancer, about 30% of all prostate cancer patients, hormone resistance (Walsh & Worthington, 2005, pp. 473). It has been reported to progress to prostate cancer (Dr. Patrick Walsh's guide to surviving prostate cancer). The prognosis of these hormone-resistant prostate cancers is very poor and the survival period is only 1-2 years. Currently, chemotherapy such as docetaxel and estramustine is being performed, but the response rate is 12% Since it does not have anticancer effect, it is aimed to treat the improvement of the quality of life by alleviating the pain along with the administration of the anticancer drug and the like. From now on, it is urgently required to develop anticancer drug for hormone-resistant prostate cancer .

Among the cellular signal transduction systems targeted for the development of anticancer drugs, the Wnt / β-catenin signal transduction system is highly related to human prostate cancer, and the β-catenin gene (CTNNB1) Stabilization has been reported to occur in about 5% of prostate cancer patients (Cancer Res. 1998, 58 (12), 2520-2523 .; Genes Chromosomes Cancer. 2002, 34 (1) 16.).

In addition, the Wnt signaling mouse model of prostate tumor formation showed the importance of activated β-catenin in early prostate cancer and progressive prostate cancer, and both groups showed stabilized β-catenin increase in prostate tissue, In particular, abnormal β-catenin levels have been reported to be observed more frequently in advanced prostate cancer than in early prostate cancer (Curr. Drug Targets 2008, 9 (7), 571-580).

Wnt / β-catenin signal transduction system plays an important role in various processes such as development, differentiation and cell proliferation by acting as a ligand to various receptors by stimulating an intracellular signal transduction pathway. When Wnt does not act as a ligand, GSK3β , CK1a, Anexin, and APC form a complex to phosphorylate β-catenin and phosphorylated β-catenin is ubiquitinated by the E3 ligase and degraded by the 26S proteosome, When combined with the Frizzled receptor and the co-receptor Lipoprotein receptor-related protein 5 (LRP5) or LRP6, the signal is activated and the signal transduction begins to occur sequentially, leading to the release of β-catenin After entering the nucleus, β-catenin binds to the Lymphoid Enhancer-Binding Factor (LEF) and TCF (T cell factor) proteins to activate the expression of the target gene It is to adjust. At this time, the target genes whose expression is activated are c-myc, cyclin Beta] -catenin-responsive genes such as Dl and metalloproteinase-7 (Science, 1998, 281 (5382), 1509-1512 .; Nature, 1999, 398 ), 422-426 .; Oncogene, 2002, 21 (38), 5861-5867.).

In addition, it is known that the increase of abnormal? -Catenin induces the hormone resistance of prostate cancer. If it effectively blocks the activity of? -Catenin, it is known that the growth of hormone-resistant prostate cancer is effectively inhibited. It can be a very effective target for the development of anticancer drugs against hormone-resistant prostate cancer.

Thus, the present inventors have reported for the first time that (+) - decursin isolated from Angelica gigas Nakai promotes the decomposition of? -Catenin to inhibit the differentiation of prostate cancer cell line regardless of androgen (Mol. Pharmacol. 2007, 72 (6), 1599-1606.). That is, increased intracellular β-catenin enters the nucleus and binds to TCF-4 to induce the expression of the cancer gene. The (+) - decurine inhibits the expression of these target genes Cyclin D1, c- myc .

(+) - CGK-062 (IC ₅₀ = 12.3 μM) was obtained from (+) - CGK-062, which has excellent anticancer activity against hormone-resistant prostate cancer. Β-catenin signaling pathway-inhibiting activity 10 times more potent than decursin (IC ₅₀ = 175.9 μM) (Plos one. 2012, e46697.).

Leading substances such as (+) - CGK-062 are not only low in solubility in water, they are administered into the body as a result of animal experimentation with chemical and metabolic instability, and rapidly (+) - decursinol +) - decursinol. The inventors of the present invention have made intensive studies on an anticancer composition containing a chemically and metabolically stable decursinol carbamate derivative, and as a result, the present invention has been completed.

On the other hand, it has been reported that decursinol phenylthiocarbamate (DPTC) can be used for the treatment of prostate cancer (Invest Nes Drugs. 2012, 30 (5), 1820-1829) The use of decursinol carbamate derivatives or their chemotherapeutic treatments as in the invention has not been disclosed.

Korean Patent No. 812093 discloses a decursin derivative, a method for producing the same, and a composition for treating and preventing cancers including the same. Korean Patent No. 1215379 discloses a composition for treating inflammation, cancer, And Korean Patent No. 1320486 discloses a pharmaceutical composition for therapeutic use such as dexacin and / or dexacinol angelate or dexacin and / or dexacinol angelate as an active ingredient. Have been disclosed, but the use of decursinol carbamate derivatives or their chemotherapeutic treatments as in the present invention has not been disclosed.

Korea Patent No. 812093 (Decrucine derivatives, a method for producing the same, and a composition for the treatment and prevention of cancer diseases containing the same, 2008.03.04.) Korean Patent No. 1215379 (a pharmaceutical composition containing a decacyinol derivative, registered on Dec. 18, 2012) Korean Registered Patent No. 1320486 (Chemotherapeutic Adjuvant Composition Composition Containing Angelica gigantosa Extract, Decalkin and / or Decoxynol Angelate, or Decoxin and / or Decoxynol Angelate as Active Ingredients, Registered Oct. 15, 2013.)

Oncolink patient guide: prostate cancer, James M. Metz, M. H. 2010, pp. 49-136. Dr. Patrick Walsh's guide to surviving prostate cancer, Walsh & Worthington, 2005, PP. 473. Voeller, H. J., et al. Beta-catenin mutations in human prostate cancer. Cancer Res. 1998, 58 (12), 2520-2523. Gerstein, A. V., et al. APC / CTNNB1 (beta-catenin) pathway alterations in human prostate cancers. Genes Chromosomes Cancer. 2002, 34 (1), 9-16. Robinson, D. R., et al. Wnt signaling and prostate cancer. Curr. Drug Targets. 2008, 9 (7). 571-580. He, T. C., et al. Identification of c-MYC as a target of the APC pathway. Science. 1998, 281 (5382), 1509-1512.  Tetsu, O., et al. Beta-catenin regulates expression of Cyclin D1 in colon carcinoma cells. Nature. 1999, 398 (6726), 422-426. Takahashi, M., et al. Identification of membrane-type matrix metalloproteinase-1 as a target of the beta-catenin / Tcf4 complex in human colorectal cancers. Oncogene, 2002, 21 (38). 5861-5867. Song, G. Y., et al. Decursin suppresses human androgen-independent PC3 prostate cancer cell proliferation by promoting the degradation of beta-catenin. Mol. Pharmacol. 2007, 72 (6), 1599-1606. Gwak, J. S., et al. Small molecule-based promotion of PKCα-mediated β-catenin degradation suppresses the proliferation of CRT-positive cancer cells. Plos one. 2012, e46697. Zhang, Y., et al. A synthetic decursin analogs with increased in vivo stability suppresses androgen receptor signaling in vitro and in vivo. Invest Nes Drugs. 2012, 30 (5), 1820-1829. Dignam JD, et al. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983, 11 (5), 14751489 Park, S., et al. Hexachlorophene inhibits Wnt / b-catenin pathway by promoting Siah-Mediated β-catenin degradation. Mol. Pharmacol. 2006, 70, 960-966.

It is an object of the present invention to provide a decursinol carbamate derivative or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a pharmaceutical composition for prevention or treatment of cancer comprising a decursinol carbamate derivative of the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, or a health functional food have.

The present invention relates to a decursinol-carbamate derivative of formula (I) or a pharmaceutically acceptable salt thereof.

(I)

In the formula (I)

n is from 0 to 4, m is 0 or 1;

when m is 0, n is from 0 to 4, and R is a phenyl group, a furanyl group, a cyclopentyl group, or a cyclohexyl group substituted or unsubstituted with at least one substituent R ₁ , wherein the substituent R ₁ is a halogen atom, A nitro group, a hydroxy group, an acetyl group, a C1 to C4 lower alkyl group, a C1 to C4 lower alkoxy group, or a naphthyl group;

when m is 1, n is from 0 to 2 and R is a phenyl or furanyl group substituted or unsubstituted with at least one substituent R ₁ wherein the substituent R ₁ is selected from the group consisting of a halogen atom, a nitro group, a hydroxy group, an acetyl group, a C1 To C4 lower alkyl groups, C1 to C4 lower alkoxy groups, or naphthyl groups.

The compound of formula (I) is preferably selected from the group consisting of (7S) - (+) - 3-nitrophenylcarbamic acid 8,8-dimethyl-2-oxo-6,7-dihydro- 2H, 8H- , 2- g] chromene-7-yl ester, (7S) - (+) - 2- nitro-phenylcarbamoyl acid 8,8- dimethyl-2-oxo-6,7-dihydro-2H, 8H-blood (7S) - (+) - 4-nitrophenylcarbamic acid 8,8-dimethyl-2-oxo-6,7-dihydro- 2H -pyrrolo [3,2- g ] chromen- 8H -pyrano [3,2- g ] chromen-7-yl-ester, (7S) - (+) - 4-chlorophenylcarbamic acid 8,8- - 2H, 8H -pyrano [3,2- g ] chromen-7-yl ester, (7S) - (+) - cyclohexylcarbamic acid 8,8-dimethyl- dihydro-2H, 8H-pyrano [3,2- g] chromene-7-yl ester, (7S) - (+) - 4- ethyl-phenylcarbamoyl acid 8,8- dimethyl-2-oxo-6, Dihydro- 2H, 8H -pyrano [3,2- g ] chromen-7-yl ester, (7S) - (+) - 4- methoxyphenethylcarbamic acid 8,8- -oxo-6,7-dihydro-2H, 8H-pyrano [3,2- g] chromene-7-yl-S Le, (7S) - (+) - carbazole furfuryl acid 8,8- dimethyl-2-oxo-6,7-dihydro - 2H, 8H - pyrano [3,2- g] chromene-7-yl -Ester, (7S) - (+) - benzylcarbamic acid 8,8-dimethyl-2-oxo-6,7-dihydro- 2H, 8H- pyrano [3,2- g ] chromen- ester, (7S) - (+) - (E) -2- (4- chlorophenyl) ethenyl cava acid 8,8- dimethyl-2-oxo-6,7-dihydro-2H, 8H-pyrano [3,2- g] chromene-7-yl-ester, and (7S) - (+) - (E) -2- (3- fluorophenyl) ethenyl cava acid 8,8- dimethyl-2 Oxo-6,7-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-7-yl-ester.

The present invention provides a composition for treating or preventing cancer, comprising the decursinol carbamate derivative of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

The cancer may be selected from the group consisting of lung cancer, stomach cancer, breast cancer, oral cancer, liver cancer, cervical cancer, endometrial cancer, prostate cancer, ovarian cancer, thyroid cancer, esophageal cancer, colorectal cancer, rectum cancer, pancreatic cancer, kidney cancer, .

The present invention provides a composition for treating or preventing cancer, comprising a decursinol carbamate derivative of the above formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

The present invention also provides a health functional food containing the decursinol carbamate derivative of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

Hereinafter, the present invention will be described in detail.

The present invention relates to a decursinol-carbamate derivative of formula (I) or a pharmaceutically acceptable salt thereof.

(I)

In the formula (I)

n is from 0 to 4, m is 0 or 1;

when m is 0, n is from 0 to 4, and R is a phenyl group, a furanyl group, a cyclopentyl group, or a cyclohexyl group substituted or unsubstituted with at least one substituent R ₁ , wherein the substituent R ₁ is a halogen atom, A nitro group, a hydroxy group, an acetyl group, a C1 to C4 lower alkyl group, a C1 to C4 lower alkoxy group, or a naphthyl group;

when m is 1, n is from 0 to 2 and R is a phenyl or furanyl group substituted or unsubstituted with at least one substituent R ₁ wherein the substituent R ₁ is selected from the group consisting of a halogen atom, a nitro group, a hydroxy group, an acetyl group, a C1 To C4 lower alkyl groups, C1 to C4 lower alkoxy groups, or naphthyl groups.

The compounds of formula (I) may be chemically synthesized by the methods shown in the following reaction schemes, but are not limited thereto.

The following reaction schemes illustrate the preparation of representative compounds of the present invention. The compounds of the present invention may be chemically synthesized by the methods shown in the following reaction schemes, but are not limited thereto. That is, various compounds of the present invention can be prepared by a small modification such as changing reagents, solvents and reaction sequence used in the synthesis of Reaction Schemes 1 to 3.

Specifically, Compound 3, corresponding to the case where m is 0 and n is 0 in the above formula (I), can be obtained through the following Reaction Scheme 1.

[Reaction Scheme 1]

The reaction scheme 1 is a process for preparing an isocyanate compound (Compound 2), triethylamine (TEA), and 4- (4-hydroxyphenyl) quinoline by dissolving (+) - decursinol (Compound 1) in dry methylene chloride (Dimethylamino) pyridine (4-DMAP), and the reaction is carried out while refluxing to obtain a decursinol carbamate derivative (Compound 3). The reaction temperature is not particularly limited, but it can be generally carried out at 25 to 50 ° C, preferably at 35 to 45 ° C. The reaction time may be 12 hours to 30 hours, preferably 20 to 28 hours, to synthesize various derivatives of decursinol carbamate (Compound 3).

Compound 5 can also be obtained through the following reaction scheme 2, corresponding to the case where m is 0 and n is 1 to 4 in the above formula (I).

[Reaction Scheme 2]

Reaction Scheme 2 above shows that the isocyanate compound (Compound 4), triethylamine (TEA), 4- (dimethylamino) pyridine (Compound 4) -DMAP) is added and reacted while refluxing to obtain a derivative of the decursinol carbamate (Compound 5). The reaction temperature is not particularly limited, but it can be generally carried out at 25 to 50 ° C, preferably at 35 to 45 ° C. The reaction time may be from 12 hours to 30 hours, preferably from 20 to 28 hours, to synthesize various derivatives of decursinol carbamate (Compound 5).

[Reaction Scheme 3]

In the first step, trans-cinnamic acid (Compound 6) having various substituents is dissolved in dry benzene, and then triethylamine (TEA) and diphenylphosphoryl azide (DPPA) are added and reacted. The reaction temperature is 70 to 90 ° C, and the reaction time is 1 to 5 hours, preferably 75 to 85 ° C for 2 to 5 hours. Thereafter, the reaction mixture is extracted with water and ethyl acetate, and then water is removed. The reaction mixture is concentrated under reduced pressure, and the resulting crude product is dissolved in dry benzene and heated to reflux. At this time, the heating temperature is 70 to 90 ° C, and the reaction time is 6 to 18 hours, preferably 75 to 85 ° C for 10 to 14 hours. Then, (+) - decursinol (Compound 1) was added to the isocyanate compound (Compound 8) having various substituents obtained as the last step, and triethylamine (TEA) and 4- (dimethylamino) pyridine -DMAP) is added and reacted while refluxing. The reaction temperature is not particularly limited, but it can be generally carried out at 25 to 90 ° C, preferably at 35 to 85 ° C. The reaction time may be 1 to 30 hours, preferably 2 to 28 hours, to synthesize various tetracycline carbamate derivatives (9).

The compounds of formula I of the present invention may be prepared in pharmaceutically acceptable salts according to methods conventional in the art. Such pharmaceutically acceptable salts include acid addition salts formed by pharmaceutically acceptable free acids. The acid addition salt can be prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration.

As the free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acids include methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, lactic acid, glycollic acid, gluconic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like. In addition, bases can be used to make the compounds of the invention into pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable to produce sodium, potassium or calcium salt particularly as a metal salt, and the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

The pharmaceutical composition containing the decursinol carbamate derivative of the present invention can be used for prevention or treatment of cancer.

The pharmaceutical composition of the present invention can be applied to general cancer treatment and is preferably used for the treatment of lung cancer, gastric cancer, breast cancer, oral cancer, liver cancer, cervical cancer, endometrial cancer, prostate cancer, ovarian cancer, thyroid cancer, , Pancreatic cancer, kidney cancer, and skin cancer, and more preferably, to the treatment of prostate cancer. In particular, the composition of the present invention may be useful for the treatment of hormone refractory prostate cancer.

The pharmaceutical composition of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method have. Examples of carriers, excipients and diluents that can be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, . In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

The dosage of the pharmaceutical composition of the present invention will depend on the age, sex, body weight of the subject to be treated, the specific disease or condition to be treated, the severity of the disease or condition, the route of administration and the judgment of the prescriber. Dosage determinations based on these factors are within the level of ordinary skill in the art and generally the dosage ranges from 0.01 mg / kg / day to approximately 2000 mg / kg / day. A more preferable dosage is 0.1 mg / kg / day to 500 mg / kg / day. The administration may be carried out once a day or several times. The dose is not intended to limit the scope of the invention in any way. The compounds of the present invention may be administered to mammals such as rats, livestock, humans, and the like in a variety of routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine dural or intracerebral injection.

The present invention also provides a health functional food for preventing or treating cancer, which comprises a decursinol carbamate derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

The health functional food includes forms such as tablets, capsules, pills or liquids, and the health functional foods include dairy products including soups, meats, sausages, breads, candies, snacks, noodles, It may include nutritional products, including beverages, beverages, alcoholic beverages and vitamin complexes.

In addition, a food-acceptable food-aid additive may be added to the health functional food. Examples of additives include proteins, carbohydrates, fats, nutrients, flavoring agents, and flavoring agents. Examples of the above-mentioned carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And polysaccharides such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. As a flavoring agent, natural flavoring agents (tautatin, stevia extract (for example, rebaudioside A and glycyrrhizin)) and synthetic flavors (saccharine, aspartame, etc.) can be advantageously used.

The present invention relates to a novel tetracycline carbamate derivative and a composition for treating or preventing cancer containing the same, wherein the decursinol carbamate derivative has excellent Wnt / β-catenin signaling pathway inhibitory activity, Or a therapeutic pharmaceutical composition or a health functional food. The decursinol carbamate derivatives of the present invention can be usefully used for prevention or treatment of prostate cancer in particular.

FIG. 1 is a graph showing that the Wnt / 3-catenin signal transduction pathway is inhibited by the decursinol carbamate derivative of the present invention in HEK293 cells transformed with a plasmid expressing hFz-1 and TOPFlash, as a Luciferase activity.
Fig. 2 shows the results of evaluation of the concentration dependent Wnt / 3-catenin signaling pathway inhibitory activity of the compounds 3m and 3n of the present invention in comparison with the CGK-062 compound.
FIG. 3 shows the results of confirming the resolving ability of β-catenin when the compounds 3m and 3n of the present invention and the CGK-062 compound were treated in HEK293 cell line.
FIG. 4 shows the cytotoxicity of Compound 3m and 3n of the present invention and CGK-062 compound treated with hormone-resistant prostatic cancer cell line (PC3).

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein but may be embodied in other forms. Rather, the intention is to provide an exhaustive, complete, and complete disclosure of the principles of the invention to those skilled in the art.

A. Example  1 to 15: Decursinol Carbamate  Preparation of derivatives

According to the following Reaction Scheme 1, Compounds 3a to 3o having various substituent groups were prepared.

[Reaction Scheme 1]

Example Compounds 2, 3 R R ₁
(Substituent having R) Example 1 2a, 3a 인 phenyl -4-COCH ₃ Example 2 2b, 3b 인 phenyl -3-NO ₂ Example 3 2c, 3c 인 phenyl -2-NO ₂ Example 4 2d, 3d 인 phenyl -4-NO ₂ Example 5 2e, 3e 인 phenyl -4-Cl Example 6 2f, 3f 인 phenyl -4-OCH ₃ Example 7 2 g, 3 g 인 phenyl - Example 8 2h, 3h 인 phenyl 4-CH ₃ Example 9 2i, 3i 인 phenyl -3-OCH ₃ Example 10 2j, 3j 인 phenyl -2-OCH ₃ Example 11 2k, 3k 인 phenyl -1-naphthyl Example 12 2l, 3l 인 phenyl -2-OH Example 15 2m, 3m -cyclopentyl - Example 13 2n, 3n -cyclohexyl - Example 14 2o, 3o 인 phenyl -4-CH ₂ CH ₃

< Example  1. (7S) - (+) - 4- Acetylphenyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - 4-acetylphenyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: compound 3a)

(+) - decursinol (200 mg, 0.812 mmol) was dissolved in 20 ml of dry methylene chloride (Dry MC), and then 4-acetylphenyl isocyanate (1.827 mmol), tri (DMEA, 59.5 mg, 0.487 mmol) was added to the reaction mixture and reacted at 40 占 폚 for 24 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column separation to obtain the desired product, compound 3a.

Yield: 80.1%;

Ivory solid;

mp: 223.4 캜;

Rf = 0.45 (n-HX: EA = 1: 1);

+110.0667 (c = 0.3, DMSO);

^{1 H NMR (400MHz, DMSO-} d 6): 10.129 (s, NH), 7.931 (d, J = 9.6Hz, 1H), 7.887 (d, J = 8.4Hz, 2H), 7.595 (d, J = 8.4 Hz, 2H), 7.515 (s , 1H), 6.826 (s, 1H), 6.272 (d, J = 9.6Hz, 1H), 5.102 (t, J = 3.4Hz, 1H), 3.295 (dd, J = 4.4 , 17.6 Hz, 1H), 2.973 (dd, J = 3.2, 17.6 Hz, 1H), 2.499 (s, Ac), 1.425 (s, CH3), 1.341 (s, CH3);

IT-TOF / MS 430.1153 [M + Na] &lt; + &gt;.

< Example  2. (7S) - (+) - 3- Nitrophenyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - 3-nitrophenyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: compound 3b)

Compound 3b having the following physical properties was obtained by carrying out the same reaction as in the synthesis of Compound 3a except that 3-nitrophenyl isocyanate was used instead of 4-acetylphenyl isocyanate.

Yield: 68.4%;

Yellow solid;

mp: 138.1 [deg.] C;

Rf = 0.56 (n-HX: EA = 1: 1);

_{+87.0867 (c = 3, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d 6): 10.282 (s, NH), 8.490 (s, 1H), 7.932 (d, J = 9.2Hz, 1H), 7.848 (dd, J = 1.2, 8.0Hz, 1H ), 7.782 (d, J = 7.6Hz, 1H), 7.557 (m, 1H), 7.514 (s, 1H), 6.825 (s, 1H), 6.271 (d, J = 9.6Hz, 1H), 5.127 (t J = 3.4 Hz, 1H), 3.303 (dd, J = 4.4, 17.6 Hz, 1H), 2.985 (dd, J = 3.2, 17.6 Hz, 1H), 1.427 ;

IT-TOF / MS 433.1085 [M + Na] &lt; + &gt;.

< Example  3. (7S) - (+) - 2- Nitrophenyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - Pyrano [3,2- g ] Chromen -7-yl-ester ((7S) - (+) - 2- nitrophenyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro  - 2H, 8H - pyrano [3,2- g ] chromen-7- yl -ester: Preparation of compound 3c)

Compound 3c having the following physical properties was obtained by carrying out the same reaction as in the synthesis of Compound 3a except that 2-nitrophenyl isocyanate was used instead of 4-acetylphenyl isocyanate.

Yield: 90.0%;

Yellow solid;

mp: 113.1 [deg.] C,

Rf = 0.42 (n-HX: EA = 1: 1);

_{+38.2600 (c = 3, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d 6): 10.054 (s, NH), 7.938 (m, 2H), 7.658 (t, J = 7.8Hz, 1H), 7.531 (s, 1H), 7.495 (d, J = 8.4 Hz, 1H), 7.334 (t, J = 7.8 Hz, 1H), 6.830 (d, J = 1.2 Hz, 1H), 6.284 (dd, J = 1.6, 9.6 Hz, 1H) ), 3.270 (dd, J = 4.0, 18.0 Hz, 1H), 2.898 (d, J = 17.2 Hz, 1H), 1.408 (s, CH3), 1.315 (s, CH3);

IT-TOF / MS 433.1078 [M + Na] &lt; + &gt;.

< Example  4. (7S) - (+) - 4- Nitrophenyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - 4-nitrophenyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: compound 3d)

The same reaction as in the synthesis of the compound 3a was carried out except that 4-nitrophenyl isocyanate was used instead of 4-acetylphenyl isocyanate to obtain a compound 3d having the following physical properties.

Yield: 41.1%;

Yellow solid;

mp: 265.7 [deg.] C;

Rf = 0.52 (n-HX: EA = 1: 1);

+131.2000 (c = 0.3, DMSO);

^{1 H NMR (400MHz, DMSO-} d 6): 10.450 (s, NH), 8.217 (d, J = 8.8Hz, 1H), 8.188 (d, J = 9.2Hz, 2H), 7.932 (d, J = 9.6 Hz, 1H), 7.726 (d , J = 9.6Hz, 1H), 7.702 (d, J = 9.2Hz, 2H), 7.512 (s, 1H), 6.827 (s, 1H), 6.273 (d, J = 9.6 Hz, 1H), 5.129 (t , J = 3.2Hz, 1H), 3.296 (dd, J = 4.4, 12.4Hz, 1H), 2.984 (d, J = 15.2Hz, 1H), 1.424 (s, CH3), 1.338 (s, CH3);

IT-TOF / MS 433.1082 [M + Na] &lt; + &gt;.

< Example  5. (7S) - (+) - 4- Chlorophenyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - 4-chlorophenyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester, compound 3e)

Compound 3e having the following physical properties was obtained by carrying out the same reaction as in the synthesis of Compound 3a except that 4-chlorophenyl isocyanate was used instead of 4-acetylphenyl isocyanate.

Yield: 30.5%;

White solid;

mp: 233.5 DEG C;

Rf = 0.62 (n-HX: EA = 1: 1);

+70.8667 (c = 0.3, DMSO);

^{1 H NMR (400MHz, DMSO-} d 6): 9.876 (s, NH), 7.909 (d, J = 9.6Hz, 1H), 7.485 (m, 3H), 7.305 (d, J = 8.8Hz, 2H), 6.807 (s, 1H), 6.260 (d, J = 9.6hz, 1H), 5.074 (t, J = 3.6Hz, 1H), 3.270 (dd, J = 4.0, 8.0Hz, 1H), 2.945 (dd, J = 2.8, 17.6 Hz, 1 H), 1.410 (s, CH 3), 1.326 (s, CH 3);

IT-TOF / MS 422.0786 [M + Na] &lt; + &gt;.

< Example  6. (7S) - (+) - 4- Methoxyphenyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - 4-Methoxyphenyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: compound 3f)

Compound 3f having the following physical properties was obtained by carrying out the same reaction as in the synthesis of 3a except that 4-methoxyphenyl isocyanate was used instead of 4-acetylphenyl isocyanate.

Yield: 65.4%;

White solid;

mp: 180.1 [deg.] C;

Rf = 0.40 (n-HX: EA = 1: 1);

_{+95.4533 (c = 3, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d 6): 9.515 (s, NH), 7.928 (d, J = 9.6Hz, 1H), 7.507 (s, 1H), 7.364 (d, J = 8.0Hz, 2H), 6.835 (d, J = 8.4Hz, 2H), 6.810 (s, 1H), 6.267 (d, J = 9.6Hz, 1H), 5.037 (t, J = 3.8Hz, 1H), 3.262 (dd, J = 4.4 , 17.6 Hz, 1H), 2.926 (dd, J = 3.2, 18.0 Hz, 1H), 1.407 (s, CH3), 1.328 (s, CH3);

IT-TOF / MS 418.1249 [M + Na] &lt; + &gt;.

< Example  7. (7S) - (+) - Phenyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - Phenyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H - pyrano [3,2- g ] chromen -7-yl-ester: compound 3g)

3 g of a compound having the following physical properties was obtained by carrying out the same reaction as in the synthesis of Compound 3a except that 4-acetylphenyl isocyanate was replaced with phenyl isocyanate.

Yield: 57.0%;

Gray-white solid;

mp: 153.7 [deg.] C;

Rf = 0.55 (n-HX: EA = 1: 1);

_{+103.2667 (c = 3, CHCl 3} );

^{1 H NMR (300MHz, DMSO-} d 6): 9.690 (s, NH), 7.917 (d, J = 9.6Hz, 1H), 7.499 (s, 1H), 7.483-7.450 (m, 2H), 7.250 (t , J = 7.8Hz, 2H), 6.974 (t, J = 7.3Hz, 1H), 6.811 (s, 1H), 6.262 (d, J = 9.3Hz, 1H), 5.068 (t, J = 3.75Hz, 1H ), 3.277 (dd, J = 3.9, 17.7 Hz, 1H), 2.942 (dd, J = 3.3, 17.7 Hz, 1H), 1.418 (s, 3H), 1.336 (s, 3H); IT-TOF / MS 388.1135 [M + Na] &lt; + &gt;.

< Example  8. (7S) - (+) - p- Tolylphenyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - p-tolylphenyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: Compound 3h)

Compound 3h having the following physical properties was obtained by carrying out the same reaction as Compound 3a, except that p-tolyl isocyanate was used instead of 4-acetylphenyl isocyanate.

Yield: 35.0%;

White solid;

mp: 215.9 [deg.] C;

Rf = 0.43 (n-HX: EA = 1: 1);

_{+96.7133 (c = 3, CHCl 3} );

^{1 H NMR (300MHz, DMSO-} d 6): 9.576 (s, NH), 7.922 (d, J = 9.6Hz, 1H), 7.503 (s, 1H), 7.335 (d, J = 7.5Hz, 2H), 7.049 (d, J = 8.1Hz, 2H), 6.808 (s, 1H), 6.263 (d, J = 9.6Hz, 1H), 5.043 (t, J = 3.4Hz, 1H), 3.266 (dd, J = 3.9 , 17.7 Hz, 1H), 2.930 (dd, J = 3, 17.7 Hz, 1H), 2.212 (s, 3H), 1.409 (s, 3H), 1.330 (s, 3H);

IT-TOF / MS 402.1296 [M + Na] &lt; + &gt;.

< Example  9. (7S) - (+) - 3- Methoxyphenyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - 3-methoxyphenyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: compound 3i)

Compound 3i having the following physical properties was obtained by carrying out the same reaction as in the synthesis of Compound 3a except that 3-methoxyphenyl isocyanate was used instead of 4-acetylphenyl isocyanate.

Yield: 44.0%;

White solid;

mp: 171 [deg.] C;

Rf = 0.461 (n-HX: EA = 1: 1);

_{+100.4867 (c = 3, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d 6): 9.670 (s, NH), 7.925 (d, J = 9.6Hz, 1H), 7.507 (s, 1H), 7.147 (t, J = 8.2Hz, 2H), 7.019 (d. J = 6.8Hz, 1H), 6.811 (s, 1H), 6.561 (dd, J = 2, 8Hz, 1H), 6.265 (d, J = 9.6Hz, 1H), 5.060 (t, J = 3.8Hz, 1H), 3.686 (s , 3H), 3.274 (dd, J = 4.4, 18Hz, 1H), 2.94 (dd, J = 3.2, 17.6Hz, 1H), 1.412 (s, 3H), 1.334 (s , 3H);

IT-TOF / MS 418.1200 [M + Na] &lt; + &gt;.

< Example  10. (7S) - (+) - 2- Methoxyphenyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - 2-methoxyphenyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: compound 3j)

Compound 3j having the following physical properties was obtained by carrying out the same reaction as in the synthesis of Compound 3a except that 2-methoxyphenyl isocyanate was used instead of 4-acetylphenyl isocyanate.

Yield: 77.6%;

White solid;

mp: 199.1 [deg.] C;

Rf = 0.26 (n-HX: EA = 2: 1);

_{+72.8867 (c = 3, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d 6): 8.466 (s, NH), 7.901 (d, J = 9.6Hz, 1H), 7.617 (s, 1H), 7.473 (s, 1H), 7.054 (t, J = 7.2Hz, 1H), 6.976 ( d, J = 8Hz, 1H), 6.883 (t, J = 7.2Hz, 1H), 6.792 (s, 1H), 6.253 (d, J = 9.2Hz, 1H), 5.010 (t, J = 4Hz, 1H ), 3.743 (s, 3H), 3.244 (dd, J = 4.4, 17.2Hz, 1H), 2.909 (dd, J = 4, 17.6Hz, 1H), 1.394 (s, 3H ), 1.331 (s, 3H);

IT-TOF / MS 418.1222 [M + Na] &lt; + &gt;.

< Example  11. (7S) - (+) - 1- Naphthylphenyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester (7S) - (+) - 1-naphthylphenyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H pyrano [3,2- g ] chromen-7-yl -ester: compound: 3k)

Compound 3k having the following physical properties was obtained by carrying out the same reaction as in the synthesis of 3a except that 1-naphthyl isocyanate was used instead of 4-acetylphenyl isocyanate.

Yield: 47.3%;

Brown solid;

mp: 120.6 DEG C;

_{Rf = 0.281 (MeOH: H 2} O = 5: 1);

_{+43.4667 (c = 3, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d 6): 9.680 (s, NH), 7.994-7.916 (m, 3H), 7.745 (d, J = 7.6Hz, 1H), 7.514 (s, 5H), 6.825 (s , 1H), 6.280 (d, J = 9.2Hz, 1H), 5.091 (s, 1H), 3.293 (d, J = 15.2Hz, 1H), 3.001 (d, J = 16.8Hz, 1H), 1.461 (s , &Lt; / RTI &gt; 3H), 1.352 (s, 3H);

IT-TOF / MS 438.1322 [M + Na] &lt; + &gt;.

< Example  12. (7S) - (+) - 2- Hydroxyphenyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - Pyrano [3,2- g ] Chromen -7-yl-ester ((7S) - (+) - 2- hydroxyphenyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: Compound 3l)

A round flask (7S) - (+) - 2- methoxy-phenylcarbamoyl acid 8,8- dimethyl-2-oxo-6,7-dihydro - 2H, 8H - pyrano [3,2- g] chromene -7-yl-ester (3j, 50mg, 0.126mmol) is dissolved in 20ml of dry methylene chloride (Dry MC). BBr ₃ (46 μl, 0.378 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. After confirming TLC, the reaction mixture was extracted with ethyl acetate (EA) and water to obtain an organic layer. The organic layer was dehydrated and then subjected to column separation to obtain 3l of a compound having the following physical data.

Yield: 72%;

Brown-white solid;

mp: 118.4 [deg.] C;

Rf = 0.41 (n-HX: EA = 1: 1);

_{+71.7000 (C = 1, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d 6): 9.651 (s, NH), 8.347 (s, 1H), 7.929 (d, J = 9.2Hz, 1H), 7.505 (s, 2H), 6.927-6.885 (m , 1H), 6.823-6.800 (m, 2H), 6.738 (t, J = 7.4Hz, 1H), 6.267 (d, J = 9.6Hz, 1H), 4.997 (t, J = 4.2Hz, 1H), 3.253 (dd, J = 4.4, 17.6 Hz, 1H), 2.929 (dd, J = 4, 17.6 Hz, 1H), 1.397 (s, 3H), 1.333 (s, 3H);

IT-TOF / MS 404.1102 [M + Na] &lt; + &gt;.

<Example 13. (7S) - (+) - cyclohexyl-carbazol acid 8,8- dimethyl-2-oxo-6,7-dihydro-2H, 8H-pyrano [3,2- g] chromene- 7-1-ester ((7S) - (+) - cyclohexyl carbamic acid, 8,8-dimethyl-2-oxo-6,7-dihydro- 2H, 8H -pyrano [3,2- g] chromen-7- yl-ester: compound 3n)

Compound 3n having the following physical properties was obtained by carrying out the same reaction as in the synthesis of Compound 3a, except that cyclohexyl isocyanate was used instead of 4-acetylphenyl isocyanate.

Yield: 10.2%;

White solid;

mp: 170.5 C;

Rf = 0.44 (n-HX: EA = 1: 1);

_{+32.1600 (c = 2.5, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d 6): 7.915 (d, J = 9.6Hz, 1H), 7.475 (s, 1H), 7.153 (d, J = 8Hz, 1H), 6.760 (s, 1H), 6.252 (d, J = 9.6Hz, 1H ), 4.904 (t, J = 4Hz, 1H), 3.212-3.155 (m, 2H), 2.807 (dd, J = 4, 17.6Hz, 1H), 1.738-1.473 (m , 10 H), 1.331 (s, 3 H), 1.281 (s, 3 H);

IT-TOF / MS 394.1635 [M + Na] &lt; + &gt;.

<Example 14. (7S) - (+) - 4- ethyl-phenylcarbamoyl acid 8,8- dimethyl-2-oxo-6,7-dihydro - 2H, 8H - pyrano [3,2- g] chroman (7S) - (+) - 4-ethylphenyl carbamic acid, 8,8-dimethyl-2-oxo-6,7-dihydro- 2H, 8H- pyrano [3,2- g ] chromen-7-yl-ester: Compound 3o)

Compound 3o having the following physical properties was obtained by carrying out the same reaction as in the synthesis of Compound 3a except that 4-ethylphenylisocyanate was used instead of 4-acetylphenylisocyanate.

Yield: 85.9%;

White solid;

mp: 133.2 DEG C;

Rf = 0.312 (n-HX: EA = 2: 1);

_{+88.3600 (C = 3, CHCl 3} );

^{1 H NMR (400MHz, acetone-} d 6): 7.858 (d, J = 9.2Hz, 1H), 7.485-7.433 (m, 3H), 7.135 (d, J = 8.8Hz, 2H), 6.721 (s, 1H ), 6.207 (d, J = 9.6Hz, 1H), 5.087 (t, J = 4.4Hz, 1H), 3.309 (dd, J = 4.8, 17.6Hz, 1H), 2.986 (dd, J = 4, 17.6Hz , 1H), 2.575 (q, J = 8Hz, 2H), 1.421 (s, 3H), 1.398 (s, 3H), 1.175 (t, J = 7.6Hz, 3H)

ESI-MS m / z 394.0 [M + H] &lt; ⁺ &gt;.

<Example 15. (7S) - (+) - carbazole-cyclopentyl acid 8,8- dimethyl-2-oxo-6,7-dihydro-2H, 8H-pyrano [3,2- g] chromene- 7-1-ester ((7S) - (+) - cyclopentyl carbamic acid, 8,8-dimethyl-2-oxo-6,7-dihydro- 2H, 8H -pyrano [3,2- g] chromen-7- yl-ester: compound 3m)

The same reaction as in the synthesis of 3a was carried out except that 4-acetylphenyl isocyanate was changed to cyclopentyl isocyanate to obtain 3 m of a compound having the following physical properties.

Yield: 43.2%;

White solid;

mp: 158.5 캜;

Rf = 0.41 (n-HX: EA = 1: 1);

_{+29.0533 (c = 3, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d 6): 7.920 (d, J = 9.6Hz, 1H), 7.475 (s, 1H), 7.254 (d, J = 7.2Hz, 1H), 6.759 (s, 1H), 6.253 (d, J = 9.6Hz, 1H), 4.902 (t, J = 3.8Hz, 1H), 3.827-3.734 (m, 1H), 3.182 (dd, J = 4.4, 17.6Hz, 1H), 2.810 (dd , J = 3.2, 17.6Hz, 1H ), 1.768-1.701 (m, 2H), 1.591-1.511 (m, 3H), 1.484-1.390 (m, 3H), 1.334 (s, 3H), 1.279 (s, 3H );

IT-TOF / MS 380.1468 [M + Na] &lt; + &gt;.

B. Example  16 to 21: Decursinol Carbamate  Preparation of derivatives

Compounds 5a to 5f having various substituents were prepared according to the following Reaction Scheme 2.

[Reaction Scheme 2]

Example Compounds 4, 5 n R  R _One
(Substituent having R) Example 16 4a, 5a 2 인 phenyl - Example 17 4b, 5b 2 인 phenyl -4-OCH ₃ Example 18 4c, 5c One -2-furanyl - Example 19 4d, 5d 3 인 phenyl - Example 20 4e, 5e 4 인 phenyl - Example 21 4f, 5f One 인 phenyl -

< Example  16. (7S) - (+) - Phenylethyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - phenylethyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: Preparation of compound 5a)

The same reaction as in the synthesis of 3a was carried out except that 4-acetylphenyl isocyanate was replaced with phenylethyl isocyanate to obtain compound 5a having the following physical properties.

Yield: 67.6%;

Off-white solid;

mp: 145.5 DEG C;

Rf = 0.46 (n-HX: EA = 1: 1);

_{+27.2800 (c = 3, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d6): 7.934 (d, J = 9.6Hz, 1H), 7.505-7.479 (m, 1H), 7.357 (t, J = 5.2Hz, 1H), 7.270-7.235 (m, 2H), 7.196-7.149 (m, 3H), 6.840-6.767 (m, 1H), 6.263 (d, J = 9.2 Hz, 1H), 4.932-4.889 , 2.890-2.765 (m, 1H), 2.680 (t, J = 7.2 Hz, 2H), 1.312 (s, 3H), 1.271 (s, 3H);

IT-TOF / MS 416.1355 [M + Na] &lt; + &gt;.

< Example  17. (7S) - (+) - 4- Methoxyphenethyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - Pyrano [3,2- g ] Chromen -7-yl-ester ((7S) - (+) - 4- 메틸oxyphenethyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H pyrano [3,2- g ] chromen-7-yl -ester: Compound 5b)

Except that 4-methoxyphenethyl isocyanate was used instead of 4-acetylphenyl isocyanate, compound 5b having the following physical properties was obtained.

Yield: 35.2%;

Ivory solid;

mp: 118.5 [deg.] C;

Rf = 0.56 (n-HX: EA = 1: 1);

_{+21.9933 (c = 3, CHCl 3} );

_{^{1 H NMR (400MHz, CDCl 3}} ): 7.581 (d, J = 9.2Hz, 1H), 7.156 (s, 1H), 7.063 (d, J = 8.0Hz, 2H), 6.804 (d, J = 8.8Hz, 2H), 6.754 (s, 1H), 6.211 (d, J = 9.2 Hz, 1H), 4.960 (t, J = 4.4 Hz, 1H), 4.835 m, 2H), 3.155 (dd, J = 4.4,17.6 Hz, 1H), 2.866 (dd, J = 4.0, 17.2 Hz, 1H), 2.732 (t, J = 6.8Hz, 2H), 1.371 ), 1.326 (s, CH3);

IT-TOF / MS 446.1470 [M + Na] &lt; + &gt;.

< Example  18. (7S) - (+) - Furfuryl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H -blood 3, &lt; / RTI & g ] 7-yl-ester ((7S) - (+) - furfuryl 가사amic  acid, 8,8-dimethyl-2-oxo-6,7-dihydro- 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: Preparation of compound 5c)

The same reaction as in the synthesis of 3a was carried out except that 4-acetylphenyl isocyanate was replaced with furfuryl isocyanate to obtain compound 5c having the following physical properties.

Yield: 65.7%;

Brown solid;

mp: 71.0 [deg.] C;

Rf = 0.35 (n-HX: EA = 1: 1);

+7.6000 (c = 0.3, DMSO);

_{^{1 H NMR (400MHz, CDCl 3}} ): 7.589 (d, J = 9.6Hz, 1H), 7.336 (m, 1H), 7.165 (s, 1H), 6.753 (s, 1H), 6.214 (m, 3H), 5.225 (m, 1H), 5.001 (t, J = 4.2Hz, 1H), 4.346 (d, J = 5.2Hz, 2H), 3.177 (dd, J = 4.4, 17.2Hz, 1H), 2.900 (dd, J = 4.0, 17.2 Hz, 1 H), 1.390 (s, CH 3), 1..336 (s, CH 3);

IT-TOF / MS 392.1118 [M + Na] &lt; + &gt;.

< Example  19. (7S) - (+) - 3- Phenylpropyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - 3-Phenylpropyl 가사amic  acid 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: Compound 5d)

Compound 5d having the following physical properties was obtained by carrying out the same reaction as in the synthesis of Compound 3a except that 3-phenylpropyl isocyanate was used instead of 4-acetylphenyl isocyanate.

Yield: 69.7%;

White solid;

mp: 135.6 [deg.] C;

Rf = 0.35 (n-HX: EA = 1: 1);

_{+31.9733 (C = 3, CHCl 3} );

^{1 H NMR (400MHz, acetone-} d 6): 7.839 (d, J = 10Hz, 1H), 7.399 (s, 1H), 7.286-7.146 (m, 5H), 6.684 (s, 1H), 6.479 (t, J = 6 Hz, 1H), 6.193 (d, J = 9.2 Hz, 1H), 4.968 (t, J = 4.4 Hz, 1H), 3.255-3.138 (m, 3H), 2.909-2.829 (t, J = 7.6 Hz, 2H), 1.813 (quin, J = 7.2 Hz, 2H), 1.363 (s, 3H), 1.353 (s, 3H);

ESI-MS m / z 407.9 [M + H] &lt; ⁺ &gt;.

< Example  20. (7S) - (+) - 4- Phenylbutyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H -blood 3, &lt; / RTI & g ] Chromen-7-yl-ester ((7S) - (+) - 4- Phenylbutyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: Compound 5e)

Except that 4-phenylbutyl isocyanate was used in place of 4-acetylphenyl isocyanate, compound 5e having the following physical properties was obtained.

Yield: 75%;

Light white-yellow semi-solid;

mp: 106.9 캜;

Rf = 0.35 (n-HX: EA = 1: 1);

_{+29.1933 (C = 3, CHCl 3} );

^{1 H NMR (400MHz, acetone-} d 6): 7.797 (d, J = 9.6Hz, 1H), 7.340 (s, 1H), 7.270-7.131 (m, 5H), 6.663 (s, 1H), 6.428 (t J = 5.6 Hz, 1H), 6.179 (d, J = 9.6 Hz, 1H), 4.958 (t, J = 4.4 Hz, 1H), 3.228-3.138 (m, 3H), 2.924-2.831 , 2.602 (t, J = 7.6 Hz, 2H), 1.659-1.582 (m, 2H), 1.561-1.487 (m, 2H), 1.346 (s, 3H), 1.338 (s, 3H);

ESI-MS m / z 422.1 [M + H] &lt; ⁺ &gt;.

< Example  21. (7S) - (+) - benzyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - Benzyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H - pyrano [3,2- g ] chromen -7-yl-ester: compound 5f)

Compound 5f having the following physical properties was obtained by carrying out the same reaction as the synthesis method 3a, except that benzyl isocyanate was used instead of 4-acetylphenyl isocyanate.

Yield: 60.6%;

White solid;

mp: 89.5 DEG C;

Rf = 0.32 (n-HX: EA = 1: 1);

_{+20.6933 (C = 3, CHCl 3} );

^{1 H NMR (300MHz, acetone-} d 6): 7.815 (d, J = 9Hz, 1H), 7.38 (s, 1H), 7.29-7.22 (m, 6H), 6.67 (s, 1H), 6.18 (d, J = 12Hz, 1H), 4.99 (t, J = 6Hz, 1H), 4.37-4.32 (m, 2H), 3.235 (dd, J = 6, 18Hz, 1H), 2.93-2.87 (m, 1H), 1.36 (s, 6 H)

ESI-MS m / z 380.1 [M + H] &lt; ⁺ &gt;.

C. Example  22 to 31: Decursinol Carbamate  Preparation of derivatives

Compounds 9a to 9j having various substituents were prepared according to the following Reaction Scheme 3.

[Reaction Scheme 3]

Example Compounds 6, 7, 8, 9 R R ₁
(Substituent having R) Example 22 6a, 7a, 8a, 9a 인 phenyl - Example 24 6c, 7c, 8c, 9c 인 phenyl -3-OCH ₃ Example 25 6d, 7d, 8d, 9d 인 phenyl -4-OCH ₃ Example 26 6e, 7e, 8e, 9e 인 phenyl -2-OCH ₃ Example 27 6f, 7f, 8f, 9f 인 phenyl -3,4- (OCH _{3) 2} Example 28 6g, 7g, 8g, 9g 인 phenyl -4-Cl Example 29 6h, 7h, 8h, 9h 인 phenyl -3-F Example 30 6i, 7i, 8i, 9i 인 phenyl -3,4,5- (OCH _{3) 3} Example 31 6j, 7j, 8j, 9j - (2-furanyl) -

< Example  22. (7S) - (+) - (E) -2- Phenylethenyl Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - (E) -2-phenylethenyl 가사amic  acid, 8,8- dimethyl -2- oxo -6,7-dihydro- 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: compound 9a)

(500 mg, 3.37 mmol) was dissolved in 20 ml of dry benzene and then triethylamine (TEA, 234 L, 1.683 mmol), diphenyl phosphoryl azide (DPPA, 1.683 mmol), and the mixture was reacted at 80 ° C for 3 hours. The crude product, which was extracted with water and ethyl acetate (EA), then dried with sodium sulfate and concentrated under reduced pressure, was dissolved again in dry benzene and refluxed at 80 ° C for one day. (TEA, 281 쨉 L, 2.019 mmol) and 4- (dimethylamino) pyridine (DMAP, 82 mg, 0.673 mmol) mmol) were added thereto and reacted at 80 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified through silica gel column separation to obtain Compound 9a.

Yield: 13.8%;

Brown-white solid;

mp: 112.4 [deg.] C;

Rf = 0.45 (n-HX: EA = 1: 1);

_{+93.4467 (c = 3, CHCl 3} );

¹ H NMR (400 MHz, DMSO-d6): 9.876 (d, J = 10.4 Hz, NH), 7.928 (d, J = 10.1 Hz, 1H), 7.504 (m, 2H), 6.809 ( s, 1H), 6.269 (d, J = 9.6Hz, 1H), 6.019 (d, J = 14.8Hz, 1H), 5.055 (s, 1H), 3.261 (dd, J = 3.6, 18.0 Hz, 1H), 2.920 (d, J = 17.2 Hz, 1H), 1.392 (s, CH3), 1.322 (s, CH3);

IT-TOF / MS 390.1346 [M + Na] &lt; + &gt;.

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< Example  24. (7S) - (+) - (E) -2- (3- Methoxyphenyl ) Ettenal Carbamic acid  Dimethyl-2-oxo-6,7-dihydro- 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - (E) -2- (3-methoxyphenyl) 가사amic  acid, 8,8-dimethyl-2-oxo-6,7-dihydro- 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: Compound 9c)

Compound 9c having the following physical properties was obtained by carrying out the same reaction as in the synthesis of Compound 9a except that 3-methoxycinnamic acid was used instead of trans-cinnamic acid.

Yield: 31.3%;

Yellow-white solid;

mp: 116.9 [deg.] C;

Rf = 0.39 (n-HX: EA = 1: 1);

_{+109.4333 (c = 3, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d6): 9.895 (d, J = 10.0Hz, NH), 7.926 (d, J = 9.2Hz, 1H), 7.501 (s, 1H), 7.153 (m, 2H), 6.838 (d, J = 7.6Hz, 1H ), 6.809 (s, 1H), 6.685 (dd, J = 2.0, 8.4Hz, 1H), 6.269 (d, J = 9.2Hz, 1H), 5.991 (d, J = 14.8Hz, 1H), 5.058 (t , J = 3.8Hz, 1H), 3.260 (dd, J = 4.0, 18.0Hz, 1H), 2.920 (dd, J = 2.8, 17.6Hz, 1H), 1.390 (s, CH3), 1.320 (s, CH3);

IT-TOF / MS 444.1422 [M + Na] &lt; + &gt;.

< Example  25. (7S) - (+) - (E) -2- (4- Methoxyphenyl ) Ettenal Carbamic acid  8,8-dimethyl-2-oxo-6,7- Dihydro - 2H, 8H - Pyrano [3,2- g ] Chromen -7-yl-ester ((7S) - (+) - (E) -2- (4-methoxyphenyl) 가사amic  acid, 8,8- dimethyl -2- oxo -6,7- dihydro - 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: compound 9d)

Compound 9a having the following physical data was obtained by carrying out the same reaction as in the synthesis of compound 9a except that 4-methoxycinnamic acid was used instead of trans-cinnamic acid.

Yield: 29.0%;

Brown solid;

mp: 107.3 [deg.] C;

Rf = 0.425 (n-HX: EA = 1: 1);

_{+85.3733 (c = 3, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d6): 9.766 (d, J = 10Hz, 1H), 7.926 (d, J = 9.2Hz, 1H), 7.501 (s, 1H), 7.197 (d, J = 8.8Hz, J = 9.6 Hz, 1H), 5.974 (d, J = 14.8 Hz, 1H), 5.042 (t, J) = 3.4 Hz, 1H), 3.711 (s, 3H), 3.254 (dd, J = 4, 17.6 Hz, 1H), 2.910 (dd, J = (s, 3 H);

IT-TOF / MS 444.1419 [M + Na] &lt; + &gt;.

< Example  26. (7S) - (+) - (E) -2- (2- Methoxyphenyl ) Ettenal Carbamic acid  Dimethyl-2-oxo-6,7-dihydro- 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - (E) -2- (2-methoxyphenyl) 가사amic  acid, 8,8-dimethyl-2-oxo-6,7-dihydro- 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: Compound 9e)

Compound 9a having the following physical properties was obtained by carrying out the same reaction as in the synthesis of compound 9a except that 2-methoxycinnamic acid was used instead of trans-cinnamic acid.

Yield: 32.7%;

Brown solid;

mp: 114.7 [deg.] C;

Rf = 0.45 (n-HX: EA = 1: 1);

_{+62.4933 (c = 3, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d6): 9.826 (d, J = 10Hz, 1H), 7.924 (d, J = 9.6Hz, 1H), 7.498 (s, 1H), 7.270 (d, J = 7.2Hz, 3H), 6.256 (m, 2H), 5.040 (s, 1H), 3.763 (s, 3H), 3.254 (dd, J = 4, 18 Hz, 1H), 2.918 (d, J = 15.2 Hz, 1H), 1.389 (s, 3H), 1.320 (s, 3H);

IT-TOF / MS 444.1418 [M + Na] &lt; + &gt;.

< Example  27. (7S) - (+) - (E) -2- (3,4- Dimethoxyphenyl ) Ettenal Carbamic acid  Dimethyl-2-oxo-6,7-dihydro- 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - (E) -2- (3,4-Dimethoxyphenyl) 가사amic  acid, 8,8-dimethyl-2-oxo-6,7-dihydro- 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: compound 9f)

Compound 9f having the following physical properties was obtained by carrying out the same reaction as in the synthesis of 9a, except substituting 3,4-dimethoxycinnamic acid for trans-cinnamic acid.

Yield: 14.6%;

Brown solid;

mp: 108.3 [deg.] C;

Rf = 0.4193 (n-HX: EA = 1: 2);

_{+85.0333 (c = 3, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d6): 9.774 (d, J = 9.6Hz, 1H), 7.929 (d, J = 9.6Hz, 1H), 7.504 (s, 1H), 7.053-6.992 (m, 1H) , 6.877-6.737 (m, 4H), 6.270 (d, J = 9.6Hz, 1H), 5.963 (d, J = 14.4Hz, 1H), 5.049 (t, J = 3.6Hz, 1H), 3.752 (s, (S, 3H), 3.705 (s, 3H), 3.259 (dd, J = 4,18 Hz, 1H), 2.911 (dd, J = ;

IT-TOF / MS 474.1525 [M + Na] &lt; + &gt;.

< Example  28. (7S) - (+) - (E) -2- (4- Chlorophenyl ) Ettenal Carbamic acid  Dimethyl-2-oxo-6,7-dihydro- 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - (E) -2- (4-chlorophenyl) 가사amic  acid, 8,8-dimethyl-2-oxo-6,7-dihydro- 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: compound 9g)

9 g of the compound having the following physical properties was obtained by carrying out the same reaction as in the synthesis of 9a, except that 4-chlorosynnamic acid was used instead of trans-cinnamic acid.

Yield: 30.2%;

Yellow solid;

mp: 103.9 캜;

Rf = 0.48 (n-HX: EA = 1: 1);

_{+89.9067 (c = 3, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d6): 9.932 (d, J = 9.6Hz, 1H), 7.915 (d, J = 9.6Hz, 1H), 7.488 (s, 1H), 7.312-7.257 (m, 4H) J = 9.2 Hz, 1H), 6.004 (d, J = 14.8 Hz, 1H), 5.058 (t, J = 3.6 Hz, 1H), 7.190-7.129 (m, 1H), 3.257 (dd, J = 4, 17.6 Hz, 1H), 2.919 (dd, J = 2.6, 17.6 Hz, 1H), 1.389 (s, 3H), 1.320 (s, 3H);

IT-TOF / MS 448.0929 [M + Na] &lt; + &gt;.

< Example  29. (7S) - (+) - (E) -2- (3- Fluorophenyl ) Ettenal Carbamic acid  Dimethyl-2-oxo-6,7-dihydro- 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - (E) -2- (3-Fluorophenyl) 가사amic  3H-chromen-7-yl-ester: Compound 9h) was prepared in the same manner as in Example 1,

Compound 9h having the following physical properties was obtained by carrying out the same reaction as in the synthesis of compound 9a except that trans-3-fluorosinnamic acid was used instead of trans-cinnamic acid.

Yield: 37.3%;

Yellow solid;

mp: 101.5 C;

Rf = 0.48 (n-HX: EA = 1: 1);

_{+89.1600 (c = 3, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d6): 9.967 (d, J = 10Hz, 1H), 7.896 (d, J = 9.2Hz, 1H), 7.468 (s, 1H), 7.284-7.078 (m, 4H), 6.900 (t, J = 8.4Hz, 1H), 6.792 (s, 1H), 6.253 (d, J = 9.6Hz, 1H), 6.030 (d, J = 14.4Hz, 1H), 5.067 (s, 1H), 3.254 (dd, J = 4, 18 Hz, 1H), 2.925 (d, J = 16 Hz, 1H), 1.393 (s, 3H), 1.321 (s, 3H);

IT-TOF / MS 432.1218 [M + Na] &lt; + &gt;.

< Example  30. (7S) - (+) - (E) -2- (3,4,5- Trimethoxyphenyl ) Ettenal Carbamic acid  Dimethyl-2-oxo-6,7-dihydro- 2H, 8H - pyrano [3,2- g ] Chromen-7-yl-ester ((7S) - (+) - (E) -2- (3,4,5-Trimethoxyphenyl) 가사amic  acid, 8,8-dimethyl-2-oxo-6,7-dihydro- 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: compound 9i)

Compound 9a having the following physical data was obtained by carrying out the same reaction as in the synthesis of compound 9a except that 3,4,5-trimethoxycinnamic acid was used instead of trans-cinnamic acid.

Yield: 79.8%;

Yellow solid;

mp: 59.1 [deg.] C;

Rf = 0.54 (n-HX: EA = 1: 2);

_{+59.5000 (c = 3, CHCl 3} );

^{1 H NMR (400MHz, DMSO-} d6): 9.861 (d, J = 10.4Hz, 1H), 7.928 (d, J = 9.6Hz, 1H), 7.502 (s, 1H), 7.146-7.085 (m, 1H) , 6.809 (s, 1H), 6.549-6.512 (m, 2H), 6.271 (d, J = 9.6Hz, 1H), 5.959 (d, J = 14.4Hz, 1H), 5.060 (t, J = 3.6Hz, (D, J = 6, 18.8 Hz, 1H), 2.916 (dd, J = 3.6, 18 Hz, 1H), 1.392 (s, 3H) , 1.321 (s, 3 H);

IT-TOF / MS 504.1627 [M + Na] &lt; + &gt;.

< Example  31. (7S) - (+) - (E) -2- (Furan-2-yl) Ettenal Carbamic acid  Dimethyl-2-oxo-6,7-dihydro- 2H, 8H - pyrano [3,2- g (7S) - (+) - (E) -2- (furan-2- yl) ethenyl 가사amic  acid, 8,8- dimethyl -2-oxo-6,7-dihydro- 2H, 8H pyrano [3,2- g ] chromen-7-yl-ester: Compound 9j)

Compound 9a having the following physical properties was obtained by carrying out the same reaction as in the synthesis of Compound 9a except that 3- (2-furyl) acrylic acid was used instead of trans-cinnamic acid.

Yield: 69.7%;

Brown solid;

mp: 58.5 DEG C;

Rf = 0.47 (n-HX: EA = 1: 1);

_{+79.6933 (c = 3, CHCl 3} );

^{1 H NMR (300MHz, DMSO-} d6): 9.894 (d, J = 10.2Hz, 1H), 7.920 (d, J = 9.6Hz, 1H), 7.493 (s, 2H), 6.984 (dd, J = 10.2, 14.7Hz, 1H), 6.798 (s , 1H), 6.401-6.383 (m, 1H), 6.264 (d, J = 9.6Hz, 1H), 6.197-6.185 (m, 1H), 5.912 (d, J = 14.4 Hz, 1H), 5.056 (t , J = 3.6Hz, 1H), 3.254 (dd, J = 4.2, 18Hz, 1H), 2.917 (dd, J = 3.3, 17.7Hz, 1H), 1.384 (s, 3H) , 1.313 (s, 3 H);

ESI-MS m / z 382.2 [M + H] &lt; ⁺ &gt;.

< Experimental Example  One. Decursinol Carbamate  Derivative Wnt / β- Catechin  Evaluation of Signal Transduction Pathway Inhibitory Activity>

(1) Preparation of experimental materials and plasmids

The decursinol carbamate derivatives synthesized in the above examples were dissolved in DMSO (Sigma) and LiCl. Human Frizzled cDNA was cloned in each cell by polymerase chain reaction (PCR) and sub-replicated into the pCDN3.1 vector (Invitrogen). The pTOPflash reporter plasmid was purchased from Upstate Biotechnology (Lake Placid, NY, USA) (FEBSLett20054213). Reporter plasmids containing the cyclin D1 promoter were prepared by PCR amplification of promoter residues of TCF-4 response elements secreted by PCR and pRL-null vector insertion, resulting in pCyclin D1-RL.

(2) cell culture, transfection and Lucifer Reyes Assay

HEK293 and Wnt3a-secreting L cell lines were purchased from ATCC (American Type Culture Collection, Manassas, Va.) And cultured in DMEM supplemented with 10% fetal bovine serum (FBS), 120 ug / ml penicillin and 200 ug / ml streptomycin (Dulbecco's modified Eagle's medium). Wnt3a conditioned medium (Wnt3a CM) was prepared by culturing Wnt3a-secreting L cells in DMEM containing 10% [v / v] FBS for 4 days, collecting the cultured DMEM medium, . After addition of new DMEM (10% [v / v] FRB), the cells were further cultured for 3 days and then the medium was collected and combined with the previous medium. Transfection was performed with Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions. Luciferase assays were performed using the Dual Luciferase Assay kit (Promega, Madison, Wis.).

(3) Cell-based  Screening for a Small-Molecule inhibitor of Wnt / β-catenin Signaling)

The HEK 293 reporter (TOP-Flash) cell line was constructed by selecting reciprocal-transformed HEK293 cells with plasmids expressing hFz-1 and TOPFlash using media containing G418 (1 mg / ml). The cell line is replicated and proliferated for 24 hours and cultured in a 96-well plate at 15,000 cells per well. Wnt3a CM was added to each well and a derivative of decursinol carbamate (Compound 3b, 3c, 3d, 3e, 3m, 3n, 5b, 5c, 5f, 9g and 9h) Respectively. After 15 hours, the luciferase activity was measured using a plate.

Namely, HEK293 cells were stably transformed to construct HEK293 reporter cells containing TOPFlash reporter and hFz-1 expression plasmid in order to find a substance that inhibits the signal transduction of Wnt /? -Catenin. When HEK293 reporter cells were incubated with Wnt3a CM, the TOPFlash reporter activity was greatly increased. Thereafter, the inhibitory activity was observed by treating the decursinol carbamate derivative. Controls were analyzed in the presence or absence of Wnt3a CM. The activity of TOPFlash was normalized to the cell titer activity.

As shown in FIG. 1, activity of the ligand (Wnt3a) was increased in the cell line (HEK293) without treating the decursinol carbamate derivative.

(4) Wnt / β- Catechin  Inhibitory activity of signal transduction pathway

As a result of the luciferase assay, the inhibitory activity of the Wnt / 3-catenin pathway was measured and the results are shown in Fig. 1 and Table 4 below.

 &Lt; Result of inhibiting the Wnt /? -Catenin pathway of carbamate-type decursinol derivatives>
(I)

compound m n R R ₁
(Substituent having R) % of inhibition 3b 0 0 phenyl -3-NO ₂ 61.55 3c 0 0 phenyl -2-NO ₂ 71.69 3d 0 0 phenyl -4-NO ₂ 73.43 3e 0 0 phenyl -4-Cl 75.70 3m 0 0 N-cyclopentyl - 92.36 3n 0 0 N-cyclohexyl - 79.57 5b 0 2 phenyl -4-OCH ₃ 49.35 5c 0 One 2-furanyl - 70.01 5f 0 One phenyl - 70.56 9g One 0 phenyl -4-Cl 60.85 9h One 0 phenyl -3-F 47.32

As shown in Table 1, carbamate-type decursinol derivatives exhibited Wnt /? - catenin pathway inhibitory activity. In particular, the compounds 3c, 3d, 3e, 3m, 3n, 5c and 5f exhibited excellent Wnt /? -Catenin pathway inhibitory activity of 70% or more, It was confirmed that the effect of Wnt /? - catenin pathway inhibitory activity was more than 5 times better.

< Experimental Example  2. Decursinol  Concentration-dependent Activity evaluation>

(One) Lucifer Reyes  Activity evaluation

(3 (S) - (3,4-dihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo -3,4-dihydro- 2H, 8H- pyrano [3,2-g] chromen-3-yl-ester. The experiment was carried out in the same manner as in the method for measuring luciferase activity in Experimental Example 1 except that the compounds 3m and 3n and CGK-062 were treated at concentrations of 2.5 μM, 5 μM, 10 μM, 20 μM and 40 μM, respectively.

As shown in Fig. 2, the inhibitory activity was also high at 3 m, especially at a lower concentration than CGK-062 (indicated by "CGK062 " in Figs.

(2) Western Blasting (western blotting)

Western blotting was performed to confirm the level change of the beta -catenin protein with the concentrations of the compounds 3m and 3n. Compounds 3m and 3n and CGK-062 were treated with HEK293 reporter cell lines at concentrations of 2.5 mu M, 5 mu M, 10 mu M, 20 mu M and 40 mu M, respectively, for 15 hours.

The cytoplasmic fraction was prepared in the manner previously described (Nucleic Acids Res. 1983, 11 (5), 14751489) and the protein was isolated from 4-12% gradient SDS-PAGE (Invitrogen) and the nitrocellulose membrane Red, Hercules, CA, USA). The membranes were blocked with 5% nonpackage milk and incubated with anti-beta -catenin antibody (BD Transduction Laboratories, Lexington, KY, USA), anti-Cyclin D1 antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA), and anti-actin antibody (Cell Signaling Technology, Beverly, MA, USA). The membrane was incubated with horseradish peroxidase conjugated anti-mouse IgG antibody (Santa Cruz Biotechnology) and visualized using an ECL system (Santa Cruz Biotechnology).

As can be seen in FIG. 3, the 3m compound in HEK293 reporter cells decreased β-catenin response transcription (CRT) in a dose-dependent manner and down-regulated cytoplasmic β-catenin. These results show that compound 3m exhibits inhibitory activity at lower concentrations when compared to CGK-062, and compound 3m more effectively degrades the? -Catenin to reduce the protein level of? -Catenin Wnt / beta -catenin signaling pathway.

< Experimental Example  3. Prostate cancer cell line Decursinol Carbamate  Cytotoxicity measurement during treatment of derivatives>

Luciferase assay assays may be low due to cell death due to toxicity to chemicals in addition to inhibitory activity. Cell viability test is a method to measure ATP value of living cells. It can be performed with luciferase assay to select a substance that can effectively reduce only β-catenin transcription (CRT) without affecting cell viability do.

Therefore, the CellTiter-Glo Assay was performed to examine cell viability and the method was performed according to the method described in the literature (Mol. Pharmacol. 2006, 70, 960-966).

That is, PC3 cells (prostate cancer cells, purchased from ACTT (American Type Culture Collection)) were inoculated into 96-well plates (5000 cells), and compounds 3m, 3n and GCK-062 were treated for 48 hours. Cell viability of each sample was measured three times using the Cell Titer-Glo assay kit (Cat # G7570, Promega) according to the manufacturer's instructions.

As a result of cell viability analysis, as shown in Fig. 4, the compounds 3m and 3n showed the killing effect of PC3 cells. In particular, the compound 3m decreased the viability of PC3 cells to a degree similar to that of CGK062.

On the other hand, CGK-062 is not only low in solubility in water but also has a problem of being rapidly converted into (+) - decursinol after being administered into an animal by chemical and metabolic instability, But also has chemical and metabolic stability and thus has an advantage of being useful as an anticancer drug.

< Experimental Example  3. Toxicity test>

Experimental Example  3-1. Acute toxicity

The toxicity of the compound of the present invention 3b to 3e, 3m, 3n, 5b, 5c, 5f, 9g and 9h in an animal body in an acute (within 24 hours) This experiment was carried out to make Five mice in the control group and five mice in each experimental group were assigned to the ICR mouse system, which is a general mouse. In the control group, nothing was administered, and the experimental group was treated with the compound 3b to 3e, 3m, 3n, 5b, 5c, 5f, 9g and 9h at a concentration of 2.0 g / kg (about 50 times the amount used in the general animal experiment) Orally. As a result, the control group and the test group administered with the compound 3b to 3e, 3m, 3n, 5b, 5c, 5f, 9g and 9h at the concentration of 2.0g / kg were all survived.

Experimental Example  3- 2 . Experimental group  And control organ organs and tissue toxicity experiments

In order to investigate the effect of C57BL / 6J mice on the organs (tissues) of animals, the test group to which the compounds 3b to 3e, 3m, 3n, 5b, 5c, 5f, 9g, The blood was collected from the animals for 8 weeks and the blood levels of glutamate-pyruvate transferase (GPT) and blood urine nitrogen (BUN) were measured using Select E (Vital Scientific NV, Netherland). As a result, GPT, which is known to be related to hepatotoxicity, and BUN, which is known to be related to renal toxicity, showed no significant difference compared to the control group. In addition, liver and kidney were taken from each animal, and histological observation was carried out with an optical microscope through a conventional tissue section production process. No abnormal abnormalities were observed.

< Formulation example  1. Pharmaceutical preparations>

Formulation example  1-1. Manufacture of tablets

Compound 3m ((7S) of the present invention - (+) - carbazole-cyclopentyl acid 8,8- dimethyl-2-oxo-6,7-dihydro-2H, 8H-pyrano [3,2- g] chromene -7-yl-ester, Example 15) was mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicic acid. To this mixture was added a 10% gelatin solution, which was pulverized and passed through a 14-mesh sieve. This was dried, and a mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into tablets.

Formulation example  1-2. Injection preparation

0.5 g of the compound 3m of the present invention was dissolved in distilled water to make 100 ml. This solution was placed in a bottle and sterilized by heating at 20 DEG C for 30 minutes.

< Formulation example  2. Food Manufacturing>

Formulation example  2-1. Manufacture of cooking seasonings

3 m of the compound of the present invention was adjusted to 0.2 to 10.0% by weight to prepare a cooking sauce for health promotion.

Formulation example  2-2. Manufacture of flour food products

3 m of the present invention was added to wheat flour at a concentration of 0.1-5.0 wt%, and bread, cake, cookies, crackers and noodles were prepared using this mixture to prepare foods for health promotion.

Formulation example  2-3. soup  And gravies

3m of the compound of the present invention was added to soups and juices at 0.1 to 1.0% by weight to prepare health promotion meat products, noodle soups and juices.

Formulation example  2-4. Manufacture of dairy products

The compound 3m of the present invention was added to milk in an amount of 0.1 to 1.0% by weight and various dairy products such as butter and ice cream were prepared using the milk.

Claims (9)

A decrurinol carbamate derivative of the formula (I): &lt; EMI ID =
(I)

In the formula (I)
n is 0 or 1, and m is 0;
when m is 0 and n is 0, R is a phenyl group substituted with at least one substituent R ₁ , or is an unsubstituted cyclopentyl group or a cyclohexyl group, wherein the substituent R ₁ is a halogen atom or a nitro group;
When m is 0 and n is 1, R is an unsubstituted phenyl group or a furanyl group. The method according to claim 1,
The decursinol carbamate derivative of formula (I) can be prepared by reacting (7S) - (+) - 3-nitrophenylcarbamic acid 8,8-dimethyl-2-oxo-6,7-dihydro- 2H, 8H- 3,2- g] chromene-7-yl ester, (7S) - (+) - 2- nitro-phenylcarbamoyl acid 8,8- dimethyl-2-oxo-6,7-dihydro-2H, 8H- (7S) - (+) - 4-nitrophenylcarbamic acid 8,8-dimethyl-2-oxo-6,7-dihydro- 2H -pyran [3,2- g ] chromen- , 8H -pyrano [3,2- g ] chromen-7-yl ester, (7S) - (+) - 4- chlorophenylcarbamic acid 8,8-dimethyl- dihydro-2H, 8H-pyrano [3,2- g] chromene-7-yl ester, (7S) - (+) - cyclohexyl-dimethyl-2-oxo-6,7-carbazole acid 8,8- Dihydro- 2H, 8H -pyrano [3,2- g ] chromen-7-yl ester, (7S) - (+) - cyclopentylcarbamic acid 8,8-dimethyl- 8H -pyrano [3,2- g ] chromen-7-yl ester, (7S) - (+) - furfurylcarbamic acid 8,8- Dihydro- 2H, 8H -pyrano [3,2- g ] chromen-7-yl- Thermal switch, and (7S) - (+) - benzylcarbamoyl acid 8,8- dimethyl-2-oxo-6,7-dihydro - 2H, 8H - pyrano [3,2- g] chromene-7 Wherein said derivative is selected from the group consisting of mono-esters. A pharmaceutical composition for preventing or treating cancer, which comprises the decursinol carbamate derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 3,
The cancer is selected from the group consisting of lung cancer, gastric cancer, breast cancer, oral cancer, liver cancer, cervical cancer, endometrial cancer, prostate cancer, ovarian cancer, thyroid cancer, esophageal cancer, colon cancer, rectal cancer, pancreatic cancer, kidney cancer, Or a pharmaceutically acceptable salt thereof. 5. The method of claim 4,
Wherein the cancer is a prostate cancer. A pharmaceutical composition for preventing or treating cancer, which comprises a decursinol carbamate derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient. A health functional food for preventing or ameliorating cancer, comprising the decursinol carbamate derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 as an active ingredient. 8. The method of claim 7,
The cancer is selected from the group consisting of lung cancer, gastric cancer, breast cancer, oral cancer, liver cancer, cervical cancer, endometrial cancer, prostate cancer, ovarian cancer, thyroid cancer, esophageal cancer, colon cancer, rectal cancer, pancreatic cancer, kidney cancer, A health functional food for preventing or improving cancer. 9. The method of claim 8,
Wherein said cancer is prostate cancer.

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