Novel decursin derivative and method for preparing same

Abstract

The present invention relates to: a decursin amine compound which is a novel decursin derivative represented by chemical formula 1 that can improve the bioavailability of decursin and be used as a starting material for preparing various decursin derivatives having amide bonds to study structure-activity relationships; and a method for preparing same. [Chemical formula 1]

Description

Novel decusin derivatives and methods for preparing the same

[0001] The present invention relates to a novel decursin derivative and a method for producing the same, which can improve the bioavailability of decursin and can be used as a starting material for producing various decursin derivatives having amide, urea, and amine bonds for studying structure-activity relationships.

[0002] Decursin is a bioactive compound found in Angelica gigas, a traditional Korean and Chinese herbal medicine. Studies have shown that decursin inhibits the growth of various cancer cells, induces apoptosis, and promotes the growth of human immune cells, including B cells, T cells, and natural killer cells (NK cells), demonstrating immunological anticancer activity. It has also been reported to inhibit new angiogenesis, which is beneficial for cancer treatment. Furthermore, it enhances the action of nerve growth factor (NGF), promoting nerve growth and protecting nerve cells from oxidative stress, suggesting potential for the treatment of neurodegenerative diseases. Furthermore, it exhibits anti-inflammatory activity by inhibiting NF-kB in macrophages, cells that mediate inflammatory responses, thereby suppressing the production of inflammatory cytokines such as IL-8, MCP-1, and TNF-α. Due to these diverse physiological activities, decursin has attracted attention in the medical and pharmaceutical fields. However, bioavailability upon oral administration has been pointed out as a problem, and thus, it is necessary to improve this and develop derivatives with more potent efficacy through structure-activity relationship studies.

[0003] Deckercin has the following structure based on the coumarin skeleton.

[0004]

[0005] As expected from its structure, decursin is a lipophilic compound that is barely soluble in water. Therefore, improving its solubility is essential for increasing bioavailability. Hydrophobic compounds with low solubility are not easily excreted from the body and accumulate in lipid layers, raising concerns about long-term toxicity. Furthermore, decursin introduced into the body is rapidly metabolized by the liver, making it difficult to maintain blood concentrations. The methyl-butenoyl ester bond in decursin is the most vulnerable site, easily hydrolyzed by esterases in the body. Decursinol, the resulting hydrolysis product, has relatively low permeability across cell membranes or the blood-brain barrier. This hinders the drug's entry into target cells, ultimately reducing its overall bioavailability. The double bond in the methyl-butenoyl side chain is susceptible to oxidation, making it susceptible to oxidation by hepatic cytochrome P450 enzymes.

[0006] Therefore, in order to improve the bioavailability of decusin, strategies can be considered, such as replacing the ester bond with a more stable bond or increasing the steric hindrance around the ester bond to hinder the access of esterase, thereby making hydrolysis difficult, and removing or modifying the double bond to prevent oxidation.

[0007] Korean Patent No. 10-0837733 proposes various derivatives in which ester bonds are replaced with oxime bonds, and Korean Patent No. 10-1413793 attempts to solve the above problem by introducing a heteroatom into the hydropyran skeleton of decursin. Replacing an ester bond with an amide bond is a useful strategy for improving the solubility of a compound and inhibiting hydrolysis. Korean Patent No. 10-0966027 proposes a method for preparing a decursin derivative in which the ester bond is replaced with an amide bond. However, since the introduction of the amide bond occurs at an early stage of the formation of the decursin skeleton, it is not suitable for application to the preparation of various decursin derivatives having amide, urea, and amine bonds.

[0008] The present invention aims to provide a novel decusin derivative and a method for preparing the same, which can improve the solubility of decusin in water and enhance bioavailability by not containing a substituent vulnerable to oxidation.

[0009] In addition, another object of the present invention is to provide a composition for preventing or treating / improving symptoms of cancer, which contains the compound as an active ingredient.

[0010] Even if the technical problem to be solved by the present invention is not mentioned above, it will be clearly understood by a person having ordinary skill in the art.

[0011] First, when it is said throughout this specification that a certain component "includes", unless specifically stated otherwise, it does not mean that other components can be included, but rather that other components can be included. In this specification, " / ", "and / or" are considered to describe a specific state in which each of two specific features or components is together or absent from the other. For example, "A / B", "A and / or B" are interpreted to have the same meaning as if (i) A, (ii) B, and (iii) A and B were each independently described. In addition, when describing the invention, if it is determined that a detailed description of a known technology related to the invention may unnecessarily obscure the gist of the invention, the detailed description thereof will be omitted.

[0012] The present invention, which aims to achieve the aforementioned purpose, relates to a decusin amine compound represented by the following chemical formula 1.

[0013] [Chemical Formula 1]

[0014]

[0015] Although the decursin amine of the present invention does not contain a methyl-butenoyl side chain that is vulnerable to oxidation, it exhibited anticancer activity similar to or superior to that of decursin or decursinol in tests for anticancer activity. IC of decursin against A549 cells and HepG2 cells 50 The values ​​are reported to be in the range of approximately 40–90 μM and 50–100 μM, and for decurcinol, the IC values ​​are in the range of 80–120 μM and 90–140 μM. 50The values ​​have been reported (Chem. Pharm. Bull. 2024, 72(5) 498-506; Br J Pharmacol. 2016 Mar; 173(6): 1033-1044; Phytotherapy Research 2018, 32(12) 2456-2465). In addition, the amine group of decursin amine can solve the difficulty of formulation due to low solubility of conventional decursin or the problem of toxicity due to accumulation in the body.

[0016] Decursin amine may be a racemic mixture, (R)-decursin amine with separated enantiomers, or (S)-decursin amine. Although not specifically described in the examples below, (R)-decursin amine and (S)-decursin amine exhibited similar degrees of anticancer activity. However, when decursin amine is synthesized as an amide, urea, or amine derivative starting from decursin amine, it cannot be ruled out that a specific stereostructure may exhibit superior physiological activity due to increased steric hindrance.

[0017] The above-mentioned decursin amine may be in the form of a pharmaceutically acceptable salt as well as by itself. The salt is useful as an acid addition salt formed by a pharmaceutically acceptable free acid. The acid addition salt can be prepared by conventional methods, for example, dissolving the compound in an organic solvent and adding an acid to obtain a salt in the form of a precipitate. An equimolar amount of the compound and an acid or alcohol (e.g., glycol monomethyl ether) in water can be heated, and the mixture can then be evaporated to dryness, or the precipitated salt can be filtered off with suction.

[0018] As the above-mentioned acid, organic acids and inorganic acids can be used. As the inorganic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used. As the organic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used.

[0019] When decursin amine is in salt form, the water solubility can be further increased, and the stability and absorption rate can be improved, providing better bioavailability.

[0020] Another aspect of the present invention relates to a method for producing decurcin amine of the above chemical formula 1. More specifically, decurcin amine can be produced using decurcinol (I) as a starting material by the following reaction formula, but it is obvious that the present invention is not limited thereto.

[0021]

[0022] At this time, Bn = benzyl, 4-methylbenzyl, 2,4-dimethylbenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl or 2,4-dimethoxybenzyl.

[0023] Each step of the above exemplary reaction formula is described in detail below.

[0024] A) Step of producing compound II by oxidizing the -OH group of decalcinol (I)

[0025] This step is to oxidize the hydroxyl group of decalcinol into a ketone using an oxidizing agent. As a reaction solvent, a solvent such as ether, ester, or haloalkane that does not affect the reaction and can dissolve decalcinol can be used. Specific examples include, but are not limited to, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, and ethyl acetate. It should be understood that the oxidizing agent is not limited to, a chromium-based oxidizing agent such as chromic acid, pyridinium chlorochromate, or Jones reagent; a periodate-based oxidizing agent such as Dess-Martin periodinane or 2-iodooxybenzoic acid (IBX); or a ruthenium-based oxidizing agent such as tetrapropylammonium perothenate (TPAP). Alternatively, dimethyl sulfoxide (DMSO)-based Swern oxidation or Parikh-Doering oxidation can be utilized. The use of Desmartin periodinane is particularly advantageous because it avoids the use of environmentally harmful heavy metals or expensive precious metals, allows for the reaction under mild conditions, and yields compound II in high yield. Those skilled in the art will readily be able to appropriately adjust reaction conditions and time depending on the oxidizing agent used.

[0026] B) A step of preparing compound III, a benzyl amine derivative, by reductive amination of compound II.

[0027] This step is a step for producing a benzyl amine derivative by reductive amination, which reacts the ketone group of compound II with benzyl amine to form an imine or enamine intermediate and then selectively reduces it. The benzyl amine may be unsubstituted or substituted with one or more substituents. However, the substituent itself must be stable under the reductive amination reaction conditions, and the reaction must not be limited due to its three-dimensional structure during the reaction, so it is preferably a methyl or methoxy group. It is not limited to having one substituent, and two or more substituents, whether the same or different, may be substituted. It is more preferable that the substituent of the benzyl group include a 4-methoxy group, which helps the reaction to remove the benzyl group to proceed selectively in the next step.

[0028] C) Step of preparing decusin amine of chemical formula 1 by removing the benzyl group (Bn) from compound III.

[0029] This step is to remove the benzyl group (Bn) from the benzyl amine derivative to produce the final target compound, decusin amine. Any method known to be effective in removing benzyl amine may be used for the removal of benzyl amine. However, since decusin amine, although relatively stable, contains aromatic groups or double bonds in the coumarin ring, it is more preferable that the reaction be carried out under mild conditions. For example, as a method for removing benzyl amine, a method including, but not limited to, transfer hydrogenation using ammonium formate and Pd / C or a method in which Pearlman's catalyst, Pd(OH)2 / C, is reacted in the presence of cyclohexene can be used, but is not limited to these. In the case of 4-methoxybenzyl, 2,4-dimethoxybenzyl, and 3,4-dimethoxybenzyl groups containing a 4-methoxy group as a substituent, the benzyl group can be selectively removed using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or cerium ammonium nitrate (CAN).

[0030] The present invention also provides a pharmaceutical composition for preventing or treating cancer, comprising a decursin amine compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The compound of the present invention not only solves the problems of decursin's low solubility in water, its low bioavailability due to easy decomposition in vivo, and its hydrophobic nature that prevents it from being excreted and causes long-term toxicity by accumulating in lipid regions of the body, as described above, but also, as confirmed in the examples below, it shows efficacy similar to or superior to decursin or decursinol in vitro against liver cancer or lung cancer, confirming that it can be effectively used for the prevention or treatment of cancer itself. In addition, the decursin amine of the present invention can easily produce amine or amide derivatives by reacting with various acyl halides or ester derivatives, and is therefore useful as a starting material for the development of new drugs through structure-activity studies.

[0031] The pharmaceutical composition for preventing or treating cancer according to the present invention can be manufactured and used in the form of a powder, granule, tablet, capsule or injection, by itself or by mixing it with a pharmaceutically acceptable carrier, forming agent, diluent, etc., by a method known in the pharmaceutical field.

[0032] The pharmaceutical composition according to the present invention can be administered in a pharmaceutically effective amount. In the present invention, the "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment. The effective dosage level can be determined according to factors including the patient's disease type, severity, age, sex, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment period, concurrently used drugs, and other factors well known in the medical field. It is important to take all of the above factors into consideration and administer an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by those skilled in the art. Generally, the compound can be administered once or several times in an amount of 0.1 to 100 mg per kg of body weight per day to an adult.

[0033] The composition of the present invention may be administered alone or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents.

[0034] Another aspect of the present invention relates to a health functional food composition for preventing or improving symptoms of cancer, containing a dekercin amine compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0035] The effective dosage of the health functional food composition of the present invention may be used in accordance with the effective dosage of the pharmaceutical composition, but may be below the above range in the case of long-term intake for the purpose of health and hygiene or health control. The health functional food of the present invention includes forms such as tablets, capsules, pills, or liquids, and foods to which the composition of the present invention can be added include, for example, various foods, beverages, gum, tea, confectionery, alcoholic beverages, chocolate, vitamin complexes, health functional foods, etc.

[0036] As described above, the decursin amine of the present invention does not contain a substituent sensitive to oxidation of decursin, and has excellent solubility in water due to the inclusion of an amine group, thereby solving the problem of low bioavailability of conventional decursin derivatives, and exhibits superior anticancer activity than decursin, so that it can be effectively used as a novel decursin derivative.

[0037] In addition, the decusin amine of the present invention can simultaneously synthesize a library of various amine or amide derivatives by using the amine group through combinatorial chemistry and screen their efficacy, so it can be usefully used in the development of new drugs with strong efficacy through structure-activity relationship studies.

[0038] Figures 1 (a) and (b) are X-ray crystal structures and corresponding chemical structural formulas of amides obtained from compounds A and B, respectively.

[0039] Figure 2 is a graph showing the cytotoxicity of decussin amine against A549, a human lung cancer cell line.

[0040] Figure 3 is a graph showing the cytotoxicity of decussin amine against HepG2, a human liver cancer cell line.

[0041] The present invention will be described in more detail below with reference to the attached drawings and examples. However, these drawings and examples are merely examples intended to easily illustrate the content and scope of the technical concept of the present invention and are not intended to limit or alter the technical scope of the present invention. Those skilled in the art will readily appreciate that various modifications and variations are possible within the scope of the technical concept of the present invention based on these examples.

[0042] [Example]

[0043] Example 1: Preparation of decusin amine

[0044] 1) Preparation of 8,8-dimethyl-8-hydro-2H,6H-pyrano[3,2-g]chromene-2,7-dione (compound 2)

[0045]

[0046] Starting material 1 (5000 mg, 20.30 mmol) was dissolved in dichloromethane and cooled at 0°C for 20 minutes. After 20 minutes, Dess-Martin periodinane (DMP; 12915 mg, 30.45 mmol) was added and reacted for 4 hours and 30 minutes. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction solution to terminate the reaction, and the mixture was extracted with dichloromethane. The water in the dichloromethane extract was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified and separated by silica gel column chromatography using dichloromethane to obtain compound 2 (4862 mg, 98%) as a white solid.

[0047] Melting point: 163.1℃

[0048] 1 H NMR (400MHz, CDCl3): δ7.64 (d,J= 9.5 Hz, 1H), 7.22 (s, 1H), 6.97 (s, 1H), 6.31 (d,J= 9.5 Hz, 1H), 3.66 (s, 2H), 1.45 (s, 6H).

[0049] 13 C NMR (101 MHz, CDCl3): δ 208.2, 160.7, 156.1, 154.7, 142.9, 127.1, 119.3, 114.6, 114.5, 106.8, 83.3, 38.7, 24.1.

[0050] MS (ESI): m / z [M+H] + 245.1, found

[0051] 2) Preparation of 7-amino-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-2-one (compound 3)

[0052]

[0053] 1) Compound 2 (5000 mg, 20.47 mmol) prepared in was dissolved in tetrahydrofuran. Acetic acid (533 μL) and 4-methoxybenzylamine (9753 μL, 51.18 mmol) were added to the solution, and the mixture was stirred at room temperature for 15 minutes. Afterwards, sodium cyanoborohydride (8361 mg, 133.06) was added to the reaction solution in 6 portions at 6-hour intervals, and the mixture was stirred at room temperature for 30 hours. After 30 hours, tetrahydrofuran was removed under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was filtered without separation through silica gel column chromatography using a mixture of hexane and ethyl acetate (v / v, 1:3), and the solvent was removed under reduced pressure.

[0054] The filtrate was dissolved in dichloromethane and distilled water, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6692 mg, 29.48 mmol) was added and stirred at room temperature for 3 hours. When the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction and extracted with dichloromethane. The dichloromethane extract was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified and separated by silica gel column chromatography using a mixture of dichloromethane and methanol (v / v, 30:1) to obtain compound 3 as a yellow semi-solid (2524.6 mg, 50%).

[0055] 1 H NMR (400MHz, CDCl3): δ7.58 (d,J= 9.5 Hz, 1H), 7.16 (s, 1H), 6.76 (s, 1H), 6.21 (d,J= 9.5 Hz, 1H), 3.10 - 3.00 (m, 2H), 2.68 - 2.58 (m, 1H), 1.40 (s, 3H), 1.30 (s, 3H).

[0056] 13C NMR (101 MHz, CDCl3): δ 161.4, 156.8, 154.1, 143.3, 128.7, 117.6, 113.1, 112.7, 104.6, 79.0, 51.3, 31.3, 26.0, 20.9.

[0057] MS (ESI): m / z [M+H] + 246.1, found

[0058] Example 2: Separation of enantiomers of decusin amine and confirmation of absolute configuration

[0059] The decusin amine (3) prepared in Example 1 is a racemic mixture. In the case of drugs, there are cases where a specific enantiomer exhibits a superior effect. Therefore, each enantiomer was separated from the racemic mixture and the absolute configuration was confirmed.

[0060] 1) Separation of mirror image isomers

[0061]

[0062] Two enantiomers from compound 3 were resolved by MPLC (Medium Pressure Liquid Chromatography); column: CHIRALFLASH IF (30 × 100 mm, 30 μm), 40 g / CTK product, mobile phase: DCM (dichloromethane) containing 0.1% DEA (diethylamine) : ethanol containing 0.1% DEA = 30 : 70 (v / v). From 1 g of the racemic mixture, compound A with a retention time of about 2.5 minutes and compound B with a retention time of about 3.1 minutes were separated in yields of A (460 mg, 46%) and B (480 mg, 48%), respectively.

[0063] 2) Structural elucidation of mirror image isomers

[0064] The three-dimensional structures of compounds A and B separated in 1) were attempted to be elucidated through single-crystal X-ray diffraction (SC-XRD), but it was difficult to obtain single crystals of decusin amine itself. Therefore, an amide derivative with excellent crystallinity was synthesized through a reaction with 4-nitrobenzoic acid.

[0065]

[0066]

[0067] Specifically, 1 equivalent (0.23 mmol) of 4-nitrobenzoic acid, 2 equivalents of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl), 2 equivalents of 4-methylmorpholine, and 1.5 equivalents of hydroxybenzotriazole (HOBt) were dissolved in dichloromethane to compound A or B (50 mg, 0.21 mmol), and the mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, distilled water was added to quench the reaction, and the mixture was extracted with dichloromethane. The dichloromethane extract was dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified and separated by silica gel column chromatography using a mixture of dichloromethane and methanol (v / v, 100:1).

[0068] Amide of Compound A: 81 mg of compound as a white solid, 98%

[0069] Melting point: 171.4℃

[0070] 1H NMR (400MHz, CDCl3): δ 8.23 ​​(d,J= 8.8 Hz, 2H), 7.90 (d,J= 8.8 Hz, 2H), 7.51 (d,J= 9.5 Hz, 1H), 7.18 (s, 1H), 6.81 (s, 1H), 6.61 (d,J= 8.9 Hz, 1H), 6.12 (d,J= 9.5 Hz, 1H), 4.56 (ddd,J= 8.4, 5.2, 2.7 Hz, 1H), 3.31 (dd,J= 17.3, 5.1 Hz, 1H), 2.93 (dd,J= 17.3, 2.5 Hz, 1H), 1.51 (s, 3H), 1.42 (s, 3H).

[0071] 13 C NMR (101 MHz, CDCl3): δ 165.5, 160.9, 156.3, 154.1, 149.7, 142.9, 139.6, 129.3, 128.3, 123.8, 115.7, 113.6, 113.4, 105.3, 77.6, 48.8, 28.7, 25.1, 24.8.

[0072] MS (ESI): m / z[M+H] + 395.4, found

[0073] Amide of Compound B: 80 mg of compound as a white solid, 97%

[0074] Melting point: 171.4℃

[0075] 1 H NMR (400MHz, CDCl3): δ 8.23 ​​(d,J= 8.8 Hz, 2H), 7.90 (d,J= 8.8 Hz, 2H), 7.51 (d,J= 9.5 Hz, 1H), 7.18 (s, 1H), 6.81 (s, 1H), 6.61 (d,J= 8.9 Hz, 1H), 6.12 (d,J= 9.5 Hz, 1H), 4.56 (ddd,J= 8.4, 5.2, 2.7 Hz, 1H), 3.31 (dd,J= 17.3, 5.1 Hz, 1H), 2.93 (dd,J= 17.3, 2.5 Hz, 1H), 1.51 (s, 3H), 1.42 (s, 3H).

[0076] 13 C NMR (101 MHz, CDCl3): δ 165.5, 160.9, 156.3, 154.1, 149.7, 142.9, 139.6, 129.3, 128.3, 123.8, 115.7, 113.6, 113.4, 105.3, 77.6, 48.8, 28.7, 25.1, 24.8.

[0077] MS (ESI): m / z[M+H] + 395.4, found

[0078] The amide compound was dissolved by adding a 2:1 (v / v) mixed solvent of ethyl acetate and n-hexane to completely dissolve it. The top of the container was covered with aluminum foil, a small hole was made, and it was left for 1 to 2 days. The obtained crystals were used for SC-XRD analysis.

[0079] Figures 1(a) and 1(b) show the X-ray crystal structures and corresponding chemical structures of amides obtained from compounds A and B, respectively. Figure 1(a) shows that the amide bond is connected to the Re face, and (b) shows that the amide bond is connected to the Si face. From this, it was confirmed that compound A is (R)-decursin amine, and compound B is (S)-decursin amine.

[0080] The normalized specific rotation values ​​measured in 0.1 M methanol solution at 20°C using a JASCO P2000 polarimeter are as follows: racemic mixture -0.2, (R)-decursin amine (compound A) -50.2, (S)-decursin amine (compound B) +51.4.

[0081] Example 3: Preparation of decusin amine salt

[0082] A salt was prepared from decusin amine (3). A representative method for preparing the salt is as follows.

[0083]

[0084] Compound 3 (100 mg, 0.41 mmol) was dissolved in dichloromethane, acid (1.23 mmol) was added, and the mixture was stirred vigorously at room temperature for 2 hours. After stirring, the precipitate was filtered, washed with dichloromethane, and dried under reduced pressure.

[0085] Manufacturing Example 1: Manufacturing of decusin amine·HCl

[0086]

[0087] Decursin amine·HCl6a (101.6 mg, 88%) as a white solid was obtained according to the above method using 3N hydrochloric acid (41 μL, 1.23 mmol) as the acid.

[0088] Melting point: 321℃

[0089] 1 H NMR (400MHz, Deuterium Oxide): δ 7.81 (d,J= 9.5 Hz, 1H), 7.40 (s, 1H), 6.74 (s, 1H), 6.22 (d,J= 9.5 Hz, 1H), 3.78 (dd,J= 5.3, 3.2 Hz, 1H), 3.39 (dd,J= 18.1, 5.3 Hz, 1H), 2.99 (dd,J= 18.2, 3.1 Hz, 1H), 1.48 (s, 3H), 1.39 (s, 3H).

[0090] Manufacturing Example 2: Manufacturing of decusin amine·HSO4

[0091]

[0092] Decursin amine·HSO46b (61 mg, 43%) as a white solid was obtained according to the above method using 6N sulfuric acid (21 μL, 1.23 mmol) as the acid.

[0093] Melting point: 297℃

[0094] 1H NMR (400MHz, Deuterium Oxide): δ 7.81 (d,J= 9.5 Hz, 1H), 7.40 (s, 1H), 6.74 (s, 1H), 6.22 (d,J= 9.5 Hz, 1H), 3.78 (dd,J= 5.3, 3.2 Hz, 1H), 3.39 (dd,J= 18.1, 5.3 Hz, 1H), 2.99 (dd,J= 18.2, 3.1 Hz, 1H), 1.48 (s, 3H), 1.39 (s, 3H).

[0095] Manufacturing Example 3: Manufacturing of decusin amine·H2PO4

[0096]

[0097] Decursin amine·H2PO46c (137 mg, 97%) as a white solid was obtained according to the above method using 6N phosphoric acid (21 μL, 1.23 mmol) as the acid.

[0098] Melting point: 201℃

[0099] 1 H NMR (400MHz, Deuterium Oxide): δ 7.81 (d,J= 9.5 Hz, 1H), 7.40 (s, 1H), 6.74 (s, 1H), 6.22 (d,J= 9.5 Hz, 1H), 3.78 (dd,J= 5.3, 3.2 Hz, 1H), 3.39 (dd,J= 18.1, 5.3 Hz, 1H), 2.99 (dd,J= 18.2, 3.1 Hz, 1H), 1.48 (s, 3H), 1.39 (s, 3H).

[0100] Example 4: Evaluation of anticancer activity of decusin amine

[0101] The anticancer activity of decusin amine was evaluated by cytotoxicity against cancer cells. A549 human lung cancer cell line and HepG2 hepatoma cell line were obtained from the Korean Cell Line Bank (KCLB), and the cells were subcultured using RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin. Cell culture dishes of 100 mm and 150 mm were used, and the cells were cultured in a 37°C, 5% CO2 incubator, and subcultured once every 2–3 days.

[0102] 1 × 10 per well in a 96-well plate 4 A549 or HepG2 cells were inoculated at a concentration of 10 cells / ml and treated with decusin amine at a concentration of 0–50 μM, followed by incubation for 24 hours. Cytotoxicity was measured using a quantitative analysis method using CCK-8, and the results are shown in Figures 2 and 3 and Table 1.

[0103] [Table 1]

[0104]

[0105] From FIGS. 2 to 3 and Table 1 above, it was confirmed that decusin amine exhibited cytotoxicity in a concentration-dependent manner to both A549 cells and HepG2 cells, demonstrating anticancer activity.

Claims

1. A decusin amine compound represented by the following chemical formula 1. [Chemical Formula 1] 2. In claim 1, A decursin amine compound characterized in that the compound of chemical formula 1 is (R)-decursin amine, (S)-decursin amine, or a racemic mixture thereof.

3. In claim 1 or 2, A dekercin amine compound characterized in that the compound of chemical formula 1 is in the form of a pharmaceutically acceptable salt. 4.A) Step of preparing compound II by oxidizing the -OH group of decalcinol (I); B) A step of preparing compound III, a benzyl amine derivative, by reductive amination of compound II; C) A step of removing a benzyl group from compound III to prepare decusin amine of chemical formula 1; A method for producing a decusin amine compound of chemical formula 1 by the following reaction formula, characterized in that it includes: At this time, Bn = benzyl, 4-methylbenzyl, 2,4-dimethylbenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl or 2,4-dimethoxybenzyl group.

5. In claim 4, A method for producing a decusin amine compound of chemical formula 1, characterized in that the above step A) is performed using Desmartin periodinane as an oxidizing agent.

6. In claim 4 or claim 5, A method for producing a decusin amine compound of chemical formula 1, characterized in that it is 4-methoxybenzyl, 3,4-dimethoxybenzyl or 2,4-dimethoxybenzyl.

7. In claim 6, A method for producing a decusin amine compound of chemical formula 1, characterized in that the above step C) is performed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

8. A pharmaceutical composition for preventing or treating cancer, containing a dekercin amine compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. [Chemical Formula 1] 9. In claim 8, A pharmaceutical composition characterized in that the compound of formula 1 is (R)-decursin amine, (S)-decursin amine, or a racemic mixture thereof.

10. In claim 8 or 9, A pharmaceutical composition for the prevention or treatment of cancer, characterized in that the cancer is liver cancer or lung cancer.

11. A health functional food composition for preventing or improving symptoms of cancer, containing a dekercin amine compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. [Chemical Formula 1] 12. In claim 11, A health functional food composition characterized in that the compound of chemical formula 1 is (R)-decursin amine, (S)-decursin amine, or a racemic mixture thereof.

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