KR101567940B1 - Novel (tetrahydroquinolin-4-yl)malonate derivatives and anticancer effect thereof - Google Patents

Abstract

The present invention relates to a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof; A method for producing the compound; And a pharmaceutical composition for preventing or treating cancer, which comprises the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
The novel optically active (tetrahydroquinolin-4-yl) malonate derivative compounds of the present invention can be used for the prevention or treatment of cancer diseases by controlling the death, proliferation and metastasis of cancer cells by controlling the Wnt signaling pathway . Also, by using an optically active organic catalyst, the production method of the compound according to the present invention enables eco-friendly production at a lower cost than in the case of using a conventional metal catalyst.

Description

Novel (tetrahydroquinolin-4-yl) malonate derivatives and anticancer effect thereof are disclosed. The novel optically active (tetrahydroquinolin-4-yl) malonate derivatives and their anti-

The present invention relates to an optically active (tetrahydroquinolin-4-yl) malonate derivative compound or a pharmaceutically acceptable salt thereof; A method for producing the compound; And a pharmaceutical composition for preventing or treating cancer, which comprises the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Many molecules produced and / or used in living organisms including naturally occurring amino acids and sugars have optical asymmetry (chirality). Most of the compounds used in vivo show the same chiral properties. For example, most amino acids are of the L type and the sugars are of the D type. Enzymes also have chiral properties and can distinguish two enantiomers of a substrate with chiral properties. For example, supposing an enzyme that envelops the substrate in the form of a bag, when the pouch has an asymmetric structure, depending on the type of substrate, one isomer fits into the asymmetric pocket structure of the enzyme, while the other isomer Due to the structure, it can not enter.

Generally, D-type amino acids are sweet and L-type is tasteless. Spearmint leaves and caraway seeds have L-Carbone and D-Carbone with different fragrances. The reason why the two isomeric molecules give different fragrances is because the human nose is composed of chiral molecules that react differently to enantiomers.

The chiral nature of these molecules is also important in pharmaceuticals. In pharmaceuticals with chiral properties, one isomer has a specific drug effect, while the other isomer has no effect, thus halving the drug efficacy, or even toxic if severe. For example, as thalidomide is a racemic mixture, one enantiomer is effective for mania, while the other enantiomer induces a deformity. While ethambutol is effective on one isomer of tuberculosis, other isomers cause blindness. While naproxen has an analgesic effect on one isomer such as arthritis, the other has no analgesic effect and causes liver toxicity. The action of steroid receptors or penicillin also exhibits stereoselectivity. Therefore, it must be provided with high purity to prevent potential side effects due to mixing of the enantiomers. However, since the enantiomers have the same physicochemical properties such as molecular weight and polarity except for their optical properties, separation is very difficult. Therefore, it is most important to find a synthesis method capable of selectively producing one isomer.

Tetrahydroquinoline is an important component found in therapeutics exhibiting natural products and pharmacological activities of various biological activities. Molecules comprising a tetrahydroquinoline scaffold exhibit a wide range of biological activities such as anti-HIV, antibacterial, antifungal, antimalarial, anti-cancer and cardiovascular activities. The scaffold is also present in antioxidants, dyes and photosensitizers. Furthermore, asymmetric (chiral) tetrahydroquinoline scaffolds are observed in a number of important biologically active natural products and pharmaceutical compounds. For example, potential cholesteryl ester transfer protein inhibitors (cholesteryl ester transfer protein inhibitor) of South American Galicia Piazza operational when flying it (Galipea (+) - Galipinine, which is separated from the trunk bark of the P. officinalis tree, Penicillium Penny presence quinolone separated from simplicissimum) (Peniprequinolone), fungi penny room Solarium janjjeu whiskey (Penicillium Janczewskii ), Torcetrapib (CP-529,414), and Virantmycin with antiviral activity include asymmetric tetrahydroquinoline scaffolds (Fig. 1). Due to the importance of this structure, many methods for the synthesis of tetrahydroquinolines have been reported. Recently, enantioselective synthetic approaches have been developed for the production of asymmetric tetrahydroquinolines that rely primarily on asymmetric hydrogenation of heteroaromatic compounds. Povarov reaction and organic catalytic reaction, which are nucleophilic addition of imine, have been used for the construction of chiral tetrahydroquinoline scaffolds. As a result, the development of efficient enantiomer selective synthetic methods for the production of tetrahydroquinoline scaffolds remains an active area of research.

Accordingly, the present inventors have made extensive efforts to produce optically active (tetrahydroquinolin-4-yl) malonate derivatives having various substituents at a high yield and purity. As a result, it has been found that by using an asymmetric amine compound as an organic catalyst, (Tetrahydroquinolin-4-yl) malonate derivatives can be synthesized from the aminocinnamaldehyde compounds and malonate compounds by high yield and high optical purity by a low-cost, environmentally friendly method. Thereby completing the invention.

It is an object of the present invention to provide a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

Another object of the present invention is to provide a process for producing the above compound.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating cancer diseases comprising the above-mentioned compound as an active ingredient.

In order to solve the above-mentioned problems, the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

Wherein R ₁ is hydrogen (-H) or hydroxy (-OH); R ₂ is hydrogen, C 1 to C 6 alkyl, C 1 to C 6 alkyloxycarbonyl, C 7 to C 12 aralkyloxycarbonyl or tosyl aka toluenesulfonyl); R ₃ and R ₄ are each independently a straight or branched chain C 1 to C 6 alkyl, aryl or C7 to C12 aralkyl; R < ₅ > is hydrogen, halogen or C1 to C6 alkyl.

Preferably, in the above formula, R₃ And R₄May be the same substituent group have.

Preferably, R ₂ may be a C 1 to C 6 alkyloxycarbonyl, a C 7 to C 12 aralkyloxycarbonyl or a tosyloxy compound, more preferably a tert-butyloxycarbonyl, a benzyloxycarbonyl or a tosyl . R ₃ and R ₄ can each independently be methyl, ethyl, isopropyl or benzyl, and R ₅ can be hydrogen, bromine, chlorine or methyl. In this case, R ₅ may be located at any bondable position on the benzene ring.

Preferably, the compound represented by the formula (1)

1) Synthesis of (4R) -dimethyl 2- (N- (benzyloxycarbonyl) -2-hydroxy-1,2,3,4-tetraquinolin-

2) (4R) -dimethyl 2- (N- (benzyloxycarbonyl) -2-hydroxy-8-methyl-1,2,3,4-tetraquinolin-

3) Synthesis of (4R) -dimethyl 2- (N- (benzyloxycarbonyl) -6-chloro-2-hydroxy-1,2,3,4-tetraquinolin-

4) Synthesis of (4R) -dimethyl 2- (N- (benzyloxycarbonyl) -7-chloro-2-hydroxy-1,2,3,4-tetraquinolin-

5) Synthesis of (4R) -dimethyl 2- (N- (benzyloxycarbonyl) -6-bromo-2-hydroxy-1,2,3,4-tetraquinolin-

6) Synthesis of (4R) -dimethyl 2- (N- (benzyloxycarbonyl) -7-bromo-2-hydroxy-1,2,3,4-tetraquinolin-

7) Synthesis of (4R) -diethyl 2- (N- (benzyloxycarbonyl) -2-hydroxy-1,2,3,4-tetraquinolin-

8) Synthesis of (4R) -diisopropyl 2- (N- (benzyloxycarbonyl) -2-hydroxy-1,2,3,4-tetraquinolin-

9) Synthesis of (4R) -dibenzyl 2- (N- (benzyloxycarbonyl) -2-hydroxy-1,2,3,4-tetraquinolin-

10) Synthesis of (4R) -dimethyl 2- (N- (tert-butoxycarbonyl) -2-hydroxy-1,2,3,4-tetraquinolin-

11) Synthesis of (4R) -dimethyl 2- (2-hydroxy-N-tosyl-1,2,3,4-tetraquinolin-

12) (R) -dimethyl 2- (N- (benzyloxycarbonyl) -1,2,3,4-tetraquinolin-4-yl) malonate,

13) Synthesis of (R) -dimethyl 2- (N- (benzyloxycarbonyl) -8-methyl-1,2,3,4-tetraquinolin-

14) Synthesis of (R) -dimethyl 2- (N- (benzyloxycarbonyl) -6-chloro-1,2,3,4-tetraquinolin-

15) Synthesis of (R) -dimethyl 2- (N- (benzyloxycarbonyl) -7-chloro-1,2,3,4-tetraquinolin-

16) Synthesis of (R) -dimethyl 2- (N- (benzyloxycarbonyl) -6-bromo-1,2,3,4-tetraquinolin-

17) Synthesis of (R) -dimethyl 2- (N- (benzyloxycarbonyl) -7-bromo-1,2,3,4-tetraquinolin-

18) (R) -diethyl 2- (N- (benzyloxycarbonyl) -1,2,3,4-tetraquinolin-4-yl) malonate,

19) (R) -diisopropyl 2- (N- (benzyloxycarbonyl) -1,2,3,4-tetraquinolin-4-yl) malonate,

20) (R) -dibenzyl 2- (N- (benzyloxycarbonyl) -1,2,3,4-tetraquinolin-4-yl) malonate,

21) (R) -dimethyl 2- (N- (tert-butoxycarbonyl) -1,2,3,4-tetraquinolin-4-yl) malonate, or

22) (R) -dimethyl 2- (N-tosyl-1,2,3,4-tetrahydroquinolin-4-yl) malonate.

In the specific examples of the present invention, the above 22 compounds were synthesized, and their chemical structural formulas are summarized in Table 1 (Example 1).

In another aspect, the present invention provides a process for preparing a compound represented by formula (1-1), comprising the first step of reacting a compound represented by the following formula (2) with a compound represented by the following formula (3)

[Formula 1-1]

(2)

(3)

Wherein R ₂ to R ₅ are as defined for formula (1).

The present invention also relates to a process for preparing a compound represented by the following general formula (3): And a second step of reacting the product of the first step with triethylsilane in the presence of boron trifluoride etherate to remove the hydroxyl group. Lt; / RTI >

[Formula 1-2]

(2)

(3)

Wherein R ₂ to R ₅ are as defined for formula (1).

In the process for preparing the compound according to the present invention, the first step preferably includes an asymmetric addition-cyclization reaction using a chiral amine compound represented by the following formula (4) as a catalyst:

[Chemical Formula 4]

.

.

Is used in the present invention the catalyst (S) -2- (di-phenyl (trimethylsilyloxy) methyl) pyrrolidine ((S) -2- (diphenyl (trimethylsilyloxy) methyl) pyrrolidine) is an organic catalyst, in the conventional asymmetric The present invention provides an excellent reproducibility and ease of use compared to a metal catalyst used in a sexual reaction. The organic catalysts also have the advantage of being inexpensive, readily available, robust and nontoxic. Thus, the asymmetric reaction using the organic catalyst can be an efficient and environmentally friendly method of producing a single enantiomer having optical activity with high yield and high enantiomeric excess (ee).

Preferably, the molar ratio of the o -amino cinnamaldehyde derivative compound represented by Formula 2 to the malonate derivative compound represented by Formula 3 may be 1: 1 to 1: 5. If the molar ratio of the reactants is lower than 1: 1, the 1,4-addition reaction of the malonate derivative compound does not occur properly, resulting in a low yield. When the molar ratio of the reactants is higher than 1: 5, the yield is not improved.

The reaction using the catalyst is preferably carried out at 0 to 40 DEG C for 4 to 120 hours. It is also preferably carried out with a solvent of methylene chloride, benzene, ethyl acetate, acetonitrile, toluene, tetrahydrofuran, isopropanol, ethanol, methanol, water or mixtures thereof. More preferably, a protic solvent such as isopropanol, ethanol, methanol or water may be used, but is not limited thereto.

When the reaction proceeds at a low temperature of less than 0 ° C, the reaction rate is slowed to prolong the reaction time. When the reaction proceeds at a temperature higher than 40 ° C, the reaction is terminated quickly, and the reaction yield and enantioselectivity may be reduced. The reaction may be carried out more preferably at 20 to 30 占 폚, most preferably at 25 占 폚.

The reaction time may be suitably selected by those skilled in the art depending on the kind of reactant. However, if the reaction time is shorter than 4 hours, the reaction may not be completed. If the reaction time is longer than 120 hours, the reaction may be continued even after the completion of the reaction.

Further, the reaction can further improve the yield or enantiomeric selectivity by carrying out the reaction further comprising an acid or a base. Non-limiting examples of the acid or base include benzoic acid, 2-nitrobenzoic acid, 4-nitrobenzoic acid, acetic acid, dichloroacetic acid, toluenesulfonic acid, lithium acetate and sodium acetate. The concentration of the added acid or base may be optionally controlled by those skilled in the art, but is preferably 15 to 25 mol%, more preferably 20 mol%, based on the amount of the o -amino cinnamaldehyde derivative compound, . ≪ / RTI > When the concentration is lower than the above range, the yield may be decreased. When the concentration is higher than the above range, a side reaction may be involved.

According to the above reaction, a compound represented by the following formula (1-1) wherein R ₁ in the formula ( ₁₎ is a hydroxyl group can be prepared.

[Formula 1-1]

On the other hand, in order to prepare a compound represented by the following general formula (1-2) in which R ₁ in the general formula ( ₁₎ is hydrogen, the reaction of the second step, that is, the product of the first step is reacted with boron trifluoride etherate ) To react with triethylsilane to remove the hydroxyl group. As a result, a compound represented by the general formula (1-2) wherein only the hydroxy group at the R ₁ position is removed while maintaining the optical activity can be obtained.

[Formula 1-2]

In order to increase the purity of the product and reduce the possibility of side reaction, purification of the product of the first step from the reaction mixture may be further carried out before carrying out the reaction of the second step.

Preferably, the reaction of the second step is carried out at -20 to 40 占 폚, more preferably at 0 占 폚. When the reaction is carried out at a temperature lower than -20 ° C, the reaction speed is slowed. Therefore, a longer reaction time is required to complete the reaction. When the reaction proceeds at a temperature higher than 40 ° C, the reaction is terminated early and the yield is decreased . The reaction may be conducted for 10 to 60 minutes, but is not limited thereto and can be controlled by those skilled in the art.

The reaction of the second step may be carried out in the same manner as in the first step using methylene chloride, benzene, ethyl acetate, acetonitrile, toluene, tetrahydrofuran, isopropanol, ethanol, methanol, water or a mixture thereof as a solvent. Preferably, methylene chloride, benzene, ethyl acetate, acetonitrile, toluene, tetrahydrofuran or a mixture thereof can be used, and more preferably methylene chloride can be used.

When the concentration of the reactant is less than 0.05 M, the reaction rate may be slow. When the concentration of the reactant is more than 1.0 M, the reactant may not completely dissolve in the solvent. Therefore, It is preferable to determine the amount of the solvent so as to remain in the range of 0.05 to 1.0 M.

The process according to the invention may further comprise the step of determining the enantiomeric selectivity of the compound produced. For example, this step can be performed by performing HPLC analysis on a chiralcel AD-H column (Chiralcel AD-H column) and an AD-H guard column (1.0 ml / min flow rate, Can be achieved.

In another aspect, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Preferably, the prevention or treatment of the cancer disease is achieved by regulating the death, proliferation, or metastasis of cancer cells by regulating the Wnt signaling pathway in cancer cells.

The term "Wnt signaling pathway" of the present invention is a kind of signal transduction pathway composed of a protein that transmits a signal from the outside of the cell to the inside of the cell through a cell surface receptor. The Wnt signaling pathway is divided into three types: canonical pathway, noncanonical planar cell polarity pathway, and non-normative Wnt / calcium pathway. All of these pathways are activated by the binding of the Wnt-protein ligand to the Frizzled family receptor, which carries a biological signal to the protein Disheveled in the cell. The normative Wnt pathway regulates gene transcription, the non-normal planar polarity pathway controls the cytoskeleton that determines cell morphology, and the non-normative Wnt / calcium pathway regulates intracellular calcium levels. The Wnt signaling pathway uses neighboring cell-cell communication (paracrine) or same-cell communication (autocrine). It is highly evolutionary conservative, meaning that it is similar in many species from fruit flies to humans.

The Wnt signaling has been first identified for its role in carcinogenesis and its role in embryo development has now been revealed. From the recent studies on the clinical significance of the pathway, Or mutations may cause various diseases including cancer. Dr. Moon of the University of Washington has suggested that the Wnt signaling pathway may be a target in cancer therapy because it has a complex role in a variety of cancers (Nat. Rev. Cancer, 2013, 13 (1): 11-26). More specifically, Wnt and its downstream effectors play an important role in the progression of cancer, including tumor initiation, tumor growth, cell senescence, cell death, differentiation and metastasis To control the various processes. In particular, the Wnt pathway can be used to treat breast cancer, lung cancer, colorectal cancer, melanoma, prostate cancer, oesophageal cancer, ovarian cancer, It is also known to be involved in other carcinomas.

The TCF / LEF family is known as a transcription factor involved in the Wnt signal transduction pathway in cancer cells. The TCF / LEF family is a group of transcription factors that bind to DNA through a highly flowable group domain. Specifically, the TCF / LEF family participates in the Wnt signaling pathway by introducing a coactivator beta-catenin to the enhancer element of the target gene. Thus, a TCF / LEF reporter kit is used to monitor the activity of the Wnt signaling pathway in cultured cells.

In a specific embodiment of the present invention, the compound of the present invention was treated and cultured in a human lung cancer cell line into which a TCF / LEF reporter gene was introduced, and luciferase activity was confirmed. As a result, it was confirmed that the TCF / LEF luciferase activity was reduced from 45% to 86% at the highest in the experimental group treated with the compound of the present invention as compared with the untreated group (Table 3).

The compound represented by Formula 1 of the present invention may exist in the form of a pharmaceutically acceptable salt. As the salts, acid addition salts formed by pharmaceutically acceptable free acids are useful. The term "pharmaceutically acceptable salt" of the present invention means a concentration that has a relatively non-toxic and harmless effective action in a patient, wherein the adverse effect due to the salt is an adverse effect of the compound &Quot; means all organic or inorganic addition salts.

The acid addition salt is 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 same 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, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like can be used , But are not limited to these.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal salt 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 salt salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically acceptable to produce sodium, potassium, or calcium salt, but not limited thereto. The corresponding silver salt can also be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

The pharmaceutically acceptable salts of the compounds of formula (1) include, unless otherwise indicated, salts of acidic or basic groups which may be present in the compounds of formula (1). For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of hydroxy groups, and the other pharmaceutically acceptable salts of amino groups include hydrobromides, sulphates, sulphates, phosphates, hydrogen phosphates (Hydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts and the like, ≪ / RTI >

As the salt of the (tetrahydroquinolin-4-yl) malonate derivative of the present invention, a pharmaceutically acceptable salt may be used as the salt of the (tetrahydroquinolin-4-yl) malonate derivative (Tetrahydroquinolin-4-yl) malonate derivatives can be used without limitation.

The term "prevention" of the present invention means all the actions of inhibiting or delaying the development, spread and recurrence of cancer diseases by the administration of the composition of the present invention. The term " Means any act that improves or is beneficially modified.

The composition of the present invention can prevent or treat a cancerous disease by controlling the death, proliferation and / or metastasis of a cell by regulating the Wnt signaling pathway, which is a transcription factor in cancer cells, Can be useful for the prevention or treatment of cancer. Preferably, non-limiting examples of cancer diseases that can be prevented or treated by the compositions of the present invention include breast cancer, lung cancer, colorectal cancer, melanoma, and prostate cancer prostate cancer, oesophageal cancer, ovarian cancer, and the like.

Preferably, the pharmaceutical composition according to the present invention contains 0.1 to 75% by weight, more preferably 1 to 50% by weight, based on the total weight of the composition, of a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient % ≪ / RTI >

The composition of the present invention may be formulated into various forms such as powders, granules, tablets, capsules, oral formulations such as suspensions, emulsions, syrups and aerosols, injections of sterilized injection solutions, and the like, And can be administered via various routes including oral administration or intravenous, intraperitoneal, subcutaneous, rectal, topical administration, and the like. Examples of suitable carriers, excipients or diluents that may be included in such compositions 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. The composition of the present invention may further include a filler, an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, an antiseptic, and the like.

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, lactose, gelatin, Are mixed and formulated. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.

Examples of the oral liquid preparation include suspensions, solutions, emulsions and syrups. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are 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,

Esters and the like can be used. The supplements of suppositories are etwesol, macrogol, tween 61. Cacao butter, laurin, glycerogelatin and the like can be used. On the other hand, injecting agents may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives and the like.

The composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount " of the present invention means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, The type of disease, the severity, the activity of the drug, the sensitivity to the drug, the method of administration, the time of administration, the route of administration and the rate of release, the duration of the treatment, the factors including the drugs used concurrently or concurrently and other factors well known in the medical arts . The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the age, sex and body weight of the patient, and is generally 1 to 100 mg, preferably 5 to 60 mg per kg of body weight, It may be administered one to three times a day. However, the dosage may not be limited in any way because it may be increased or decreased depending on route of administration, severity of disease, sex, weight, age, and the like.

The present invention also provides a method of preventing or treating a cancerous disease in a subject, comprising administering the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

The term "individual" of the present invention means a monkey, a cow, a horse, a sheep, a pig, a chicken, a turkey, a quail, a cat, a dog, a mouse, a rat, a rabbit or a guinea pig, , And the pharmaceutical composition of the present invention can be administered to an individual to effectively prevent or treat the disease. The pharmaceutical composition of the present invention can be administered in parallel with existing therapeutic agents.

The term "administering" of the present invention means providing the patient with the desired substance in any suitable manner, and the administration route of the composition of the present invention may be administered through any conventional route so long as it can reach the target tissue have. But are not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrathecal, rectal. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to the target cell. The preferred modes of administration and formulations are intravenous, subcutaneous, intradermal, intramuscular, and drip injections. The injectable solution may be a non-aqueous solvent such as an aqueous solvent such as a physiological saline solution or a ring gel solution, a vegetable oil, a higher fatty acid ester (e.g., oleic acid), an alcohol (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) (For example, ascorbic acid, sodium hydrogen sulfite, sodium pyrophosphate, BHA, tocopherol, EDTA and the like), an emulsifier, a buffer for pH control, a microbial growth inhibitor And a pharmaceutical carrier such as a preservative (e.g., mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

The term "therapeutically effective amount " used in connection with the active ingredient in the present invention refers to the amount of a (tetrahydroquinolin-4-yl) malonate derivative compound or a pharmaceutically acceptable salt thereof effective to prevent or treat a subject disease it means.

The pharmaceutical composition of the present invention can be used for prevention (prevention) of each known disease other than the (tetrahydroquinolin-4-yl) malonate derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient, depending on the kind of disease to be prevented or treated Or < / RTI > known drugs used in therapy. For example, when it is used for the prophylactic or therapeutic treatment of cancer, it may further comprise a known anticancer agent in addition to the (tetrahydroquinolin-4-yl) malonate derivative compound or its pharmaceutically acceptable salt as an active ingredient, ≪ / RTI > of the invention. Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem cell replacement therapy, other biological therapies, immunotherapy, and the like.

Examples of anticancer agents that can be included in the pharmaceutical composition of the present invention include DNA alkylating agents such as mechloethamine, chlorambucil, phenylalanine, mustard, cyclophosphate, Cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin cisplatin and carboplatin; The anticancer antibiotics include dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitoxantrone, Plicamycin, mitomycin C, and bleomycin; And plant alkaloids such as vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan, And iridotecan, but are not limited thereto.

In another aspect, the present invention provides a food composition for preventing or ameliorating cancer diseases, which comprises a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

The composition may contain, in addition to the active ingredient, a pharmaceutically acceptable food-aid additive.

The term "food-aid additive " as used in the present invention means a component which can be added to foods in a supplementary manner, and it can be appropriately selected and used by those skilled in the art as added to produce health functional foods of each formulation. Examples of food-aid additives include flavors such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and fillers, pectic acid and its salts, alginic acid and its salts, organic acids, , a pH adjusting agent, a stabilizer, a preservative, a glycerin, an alcohol, and a carbonating agent used in a carbonated drink. However, the types of the food auxiliary additives of the present invention are not limited by these examples.

A health functional food may be included in the food composition of the present invention. The term "health functional food " as used in the present invention refers to a food prepared and processed in the form of tablets, capsules, powders, granules, liquids and rings using raw materials and components having useful functions in the human body. Here, 'functional' refers to the structure and function of the human body to obtain nutritional effects and obtain useful effects for health use such as physiological action. The health functional food of the present invention can be prepared by a method commonly used in the art and can be prepared by adding raw materials and ingredients that are conventionally added in the art. In addition, the formulations of the above health functional foods may also be manufactured without limitations as long as they are acceptable as health functional foods. The composition for food of the present invention can be manufactured in various forms, and unlike general pharmaceuticals, it has the advantage that there is no side effect that may occur when a drug is used for a long period of time, and is excellent in portability, Can be ingested as an adjuvant to enhance the effects of anticancer drugs and the like.

The novel optically active (tetrahydroquinolin-4-yl) malonate derivative compounds of the present invention can be used for the prevention or treatment of cancer diseases by controlling the death, proliferation and metastasis of cancer cells by controlling the Wnt signaling pathway . Also, by using an optically active organic catalyst, the production method of the compound according to the present invention enables eco-friendly production at a lower cost than in the case of using a conventional metal catalyst.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows an example of natural products comprising an optically active tetrahydroquinoline scaffold.

Hereinafter, embodiments of the present invention will be described in more detail. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

Example  1: optically active ( Tetrahydroquinoline Yl) Malonate  Synthesis of derivative compounds

1.1. (4 R ) -Dimethyl 2- ( N - ( Benzyloxycarbonyl ) -2-hydroxy-1,2,3,4- Tetraquinoline Yl) Malonate ((4 R ) - dimethyl  2-( N - ( benzyloxycarbonyl )-2- hydroxy -1,2,3,4-tetrahydroquinolin-4-yl) malonate; 1a))

o - N - benzyloxycarbonyl-amino-cinnamaldehyde; as a catalyst (3a 70 mg, 0.25 mmol) (S) -2- ( di-phenyl (trimethylsilyloxy) methyl) pyrrolidine ((S) -2- ( pyrrolidine ( 4 , 0.050 mmol), methanol (0.8 ml) was added, and lithium acetate (0.050 mmol) was added dropwise. Malonate dimethyl at room temperature (dimethyl malonate; 5a, 43 ㎕ , 0.38 mmol) was added and colorless resin of the desired compound to silica gel chromatography in a 20% and then ethyl acetate / hexanes, stirred for 24 hours (gum; 1a; 80 mg, 77% yield, 89% ee ).

^{1 H NMR (400 MHz, CDCl} 3) δ 7.28-7.61 (m, 7H), 7.01-7.24 (m, 3H), 5.86-5.96 (m, 1H), 5.25-5.41 (m, 2H), 4.11 (brs J = 3.6 Hz, 0.3 H), 3.48 (s, 1H), 3.82 (s, (dt, J = 3.2, 9.2 Hz, 0.7 H), 2.45-2.52 (m, 0.3H), 2.18-2.24 (m, 0.7H), 2.00-2.07 (m, 0.7H), 1.88-1.95 (m, 0.3H).

1.2. ( R ) -Dimethyl 2- ( N - ( Benzyloxycarbonyl ) -1,2,3,4- Tetraquinoline Yl) Malonate (( R ) - dimethyl  2-( N - ( benzyloxycarbonyl ) -1,2,3,4- tetrahydroquinoline -4-yl) malonate; 2a))

The embodiment in which (R 4) obtained in the 1-dimethyl-2-words (N (benzyloxycarbonyl) -2-hydroxy-1,2,3,4-tetramethyl-4-yl) carbonate (1a; 62 mg, 0.15 mmol) was dissolved in methylene chloride (1.5 mL) and then boron trifluoride etherate (0.30 mmol) was added at 0 ° C. Then, triethylsilane (0.30 mmol) was added dropwise thereto, followed by stirring for 30 minutes. After the reaction was completed with saturated sodium bicarbonate solution, the reaction product was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 20% ethyl acetate / To obtain the desired compound as a colorless resin ( 2a : 84% yield, 89% ee ).

[a] ²⁴ _D 0.87 (c 1.1, CHCl ₃ );

^{1 H NMR (400 MHz, CDCl} 3) δ 7.72 (d, J = 6.0 Hz, 1H), 7.32-7.45 (m, 5H), 7.22 (td, J = 8.4, 1.2 Hz, 1H), 7.17 (dd, J = 7.6, Hz 0.8, 1H), 7.02 (dd, = J 7.6, 0.8 Hz, 1H), 5.29 (s, 2H), 3.92-4.01 (m, 1H), 3.75 (s, 3H), 3.63-3.78 (m, 3 H), 3.60 (s, 3 H), 2.11 - 2.20 (m, 1 H), 1.93 - 2.04 (m, 1 H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.4, 168.3, 154.6, 137.6, 136.4, 130.4, 128.6, 128.2, 128.1, 127.9, 127.5, 124.2, 123.8, 67.6, 53.9, 52.6, 52.4, 42.3, 37.1, 26.5;

MS (ESI) m / z (%) 398 (M + H ^& lt ^{; +} & gt ^; , 100);

Elemental analysis: C ₂₂ H ₂₃ NO ₆ .H ₂ O: Calculated C, 63.60; H, 6.07; N, 3.37: Meas. Phase C, 63.21; H, 6.08; N, 3.11;

HPLC analysis was performed using a Chiralcel AD-H column and an AD-H guard column (5% ethanol: hexane, 1.0 ml / min flow rate, λ = 220 nm) Determine enantiomeric selectivity; R -isomer t _r = 30.3 min and S -isomer t _r = 34.4 min.

1.3. (4 R ) -Dimethyl 2- ( N - ( Benzyloxycarbonyl ) -2-hydroxy-8- methyl -1,2,3,4- Tetraquinoline Yl) Malonate ((4 R ) - dimethyl  2-( N - ( benzyloxycarbonyl )-2- hydroxy -8-methyl-1,2,3,4-tetrahydroquinolin-4-yl) malonate; 1b))

As the starting material o - N - benzyloxycarbonyl-amino in place of the cinnamaldehyde 3a o - N - benzyloxycarbonyl-amino-3, and the object in the same manner as in Example 1 except for using the compound methyl cinnamaldehyde 3b 1b (74% yield, 93% ee ).

^{1 H NMR (400 MHz, CDCl} 3) 7.25-7.59 (m, 6H), 7.00-7.28 (m, 3H), 5.87-6.06 (m, 1H), 5.20-5.41 (m, 2H), 4.18 (brs, 1H), 3.80 (s, 2.1H ), 3.77 (s, 0.9H), 3.68 (s, 2.1H), 3.65 (s, 0.9H), 3.61 (t, J = 3.2 Hz, 0.3 H), 3.48 ( t, J = 8.8 Hz, 0.7H), 2.45-2.55 (m, 0.3H), 2.37 (s, 3H), 2.16-2.29 (m, 0.7H), 1.98-2.08 1.95 (m, 0.3H).

1.4. ( R ) -Dimethyl 2- ( N - ( Benzyloxycarbonyl )-8- methyl -1,2,3,4- Tetraquinoline -4-yl) malonate (( R ) - dimethyl  2-( N - ( benzyloxycarbonyl )-8- methyl -1,2,3,4-tetrahydroquinolin-4-yl) malonate; 2b))

Obtained in Example 3 as a starting material (4 R) - dimethyl-2- (N - (benzyloxycarbonyl) -2-hydroxy-8-methyl-1,2,3,4-tetrahydro-quinolin-4- yl) words, except that the carbonate of example 2 in the same manner as the desired compound 2b (to obtain a 74% yield, 93% ee).

_{^{[a] 25 D -18.1 (c}} 1.2, CHCl 3);

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.23-7.52 (m, 5H), 7.00-7.18 (m, 3H), 5.20 (s, 2H), 4.26-4.52 (m, 1H), 3.72 (s, 3H) 1H), 2.13 (s, 3H), 1.93-2.03 (m, IH) ;

_{^{13 C NMR (100MHz, CDCl 3}} ) δ 168.5, 168.4, 155.4, 137.7, 134.6, 129.9, 128.5, 128.4, 128.0, 127.9, 127.7, 126.2, 125.7, 67.6, 54.7, 52.6, 52.2, 42.8, 37.9, 27.1, 18.1;

HRMS (ESI): C ₂₃ H ₂₅ NO ₆ Na (M + Na) ⁺ : calculated 434.1580: measured 434.1582;

HPLC analysis was performed using a Chiralcel AD-H column and an AD-H guard column (3% isopropanol: hexane, 1.0 mL / min flow rate, λ = 220 nm) Determine enantiomeric selectivity; R -isomer t _r = 15.0 min and S -isomer t _r = 19.3 min.

1.5. (4 R ) -Dimethyl 2- ( N - ( Benzyloxycarbonyl ) -6- Chloro Hydroxy-1,2,3,4- Tetraquinoline Yl) Malonate ((4 R ) - dimethyl  2-( N - ( benzyloxycarbonyl ) -6- chloro -2-hydroxy-1,2,3,4-tetrahydroquinolin-4-yl) malonate; 1c))

As the starting material o - N - benzyloxycarbonyl-amino in place of the cinnamaldehyde 3a o - N - benzyloxycarbonyl-amino-5-chloro-cinnamaldehyde in Example 1 in the same manner as the target compound but using aldehyde 3c 1c (65% yield, 89% ee ).

(M, 2H), 4.10 (br s, 1H), 7.30-7.30 (m, ), 3.81 (s, 2.1H), 3.78 (s, 0.9H), 3.72 (s, 2.1H), 3.58 (t, J = 4.0 Hz, 0.3H), 3.48 0.7 H), 3.60 (s, 0.9H), 2.45-2.54 (m, 0.3H), 2.18-2.24 (m, 0.7H), 2.00-2.13 (m, 0.7H), 1.87-1.95 );

1.6. ( R ) -Dimethyl 2- ( N - ( Benzyloxycarbonyl ) -6- Chloro -1,2,3,4- Tetraquinoline Yl) Malonate (( R ) - dimethyl  2-( N - ( benzyloxycarbonyl ) -6- chloro -1,2,3,4-tetrahydroquinolin-4-yl) malonate; 2c))

Obtained in Example 5 as a starting material (4 R) - dimethyl-2- (N- (benzyloxycarbonyl) -6-chloro-2-hydroxy-1,2,3,4-tetrahydro-quinolin-4- yl) words, except that the carbonate of example 2 in the same manner to obtain a desired compound 2c (76% yield, 89% ee) and.

_{^{[a] 25 D 29.5 (c}} 0.94, CHCl 3);

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.70 (d, J = 2.0 Hz, 1H), 7.33-7.43 (m, 5H), 7.15-7.21 (m, 2H), 5.28 (s, 2H), 3.89-3.98 (m, 1H), 3.76 (s, 3H), 3.57-3.73 (m, 3H), 3.65 (s, 3H), 2.10-2.19 (m, 1H), 1.92-2.02

¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.1, 168.0, 154.4, 136.2, 136.1, 131.9, 128.8, 128.6, 128.2, 128.1, 128.0, 127.6, 125.4, 67.8, 53.7, 52.8, 52.6, 42.2, 36.9, 29.2;

MS (ESI) m / z (%) 432 (M + H ^& lt ^{; +} & gt ^; , 100);

Elemental analysis C ₂₂ H ₂₂ ClNO ₆ : Calculated C, 61.18; H, 5.13; N, 3.24: Meas. Phase C, 61.34; H, 5.41; N, 3.10;

HPLC analysis was performed using a Chiralcel AD-H column and an AD-H guard column (10% ethanol: hexane, 1.0 ml / min flow rate, λ = 220 nm) Determine enantiomeric selectivity; R -isomer t _r = 21.1 min and S -isomer t _r = 24.6 min.

1.7. (4 R ) -Dimethyl 2- ( N - ( Benzyloxycarbonyl ) -7- Chloro Hydroxy-1,2,3,4- Tetraquinoline Yl) Malonate ((4 R ) - dimethyl  2-( N - ( benzyloxycarbonyl ) -7- chloro -2-hydroxy-1,2,3,4-tetrahydroquinolin-4-yl) malonate; 1d))

As the starting material o - N - benzyloxycarbonyl-amino in place of the cinnamaldehyde 3a o - N - benzyloxycarbonyl-amino-4-chloro-cinnamaldehyde in Example 1 in the same manner as the target compound but using aldehyde 3d 1d (66% yield, 92% ee ).

^{1 H NMR (400 MHz, CDCl} 3) δ 7.24-7.60 (m, 6H), 7.08-7.22 (m, 3H), 5.85-5.93 (m, 1H), 5.25-5.40 (m, 2H), 4.13 (brs , 1H), 3.80 (s, 2.1H), 3.78 (s, 0.9H), 3.73 (s, 2.1H), 3.63 (s, 0.9H), 3.56 (t, J = 3.6 Hz, 0.3 H), 3.48 (dt, J = 3.2, 9.2 Hz, 0.7 H), 2.44-2.54 (m, 0.3H), 2.18-2.24 (m, 0.7H), 2.01-2.15 (m, 0.7H), 1.88-1.95 (m, 0.3H).

1.8. ( R ) -Dimethyl 2- ( N - ( Benzyloxycarbonyl ) -7- Chloro -1,2,3,4- Tetraquinoline Yl) Malonate (( R ) - dimethyl  2-( N - ( benzyloxycarbonyl ) -7- chloro -1,2,3,4-tetrahydroquinolin-4-yl) malonate; 2d))

Obtained in Example 7 as the starting material (4 R) - dimethyl-2- (N - (benzyloxycarbonyl) -7-chloro-2-hydroxy-1,2,3,4-tetrahydro-quinolin-4- yl) words, except that the carbonate is carried out in the same manner as in example 2 the desired compound 2d (to obtain a 83% yield, 92% ee).

_{^{[a] 25 D -17.1 (c}} 0.51, CHCl 3);

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.84 (brs, 1H), 7.34-7.47 (m, 5H), 7.10 (d, J = 8.4 Hz, 1H), 7.00 (dd, J = 8.4, 2.0 Hz, 1H ), 5.30 (s, 2H), 3.87-3.95 (m, IH), 3.76 (s, 3H) 1.91-2.01 (m, 1 H);

¹³ C NMR (100 MHz, CDCl ₃ )? 168.2, 168.1, 154.3, 138.4, 136.0, 133.0, 129.3, 128.6, 128.4, 128.3, 128.0, 124.0, 123.7, 67.9, 53.7, 52.8, 52.6, 42.1, 36.7, 26.1;

HRMS (ESI): C ₂₂ H ₂₂ ClNO ₆ Na (M + Na) ⁺ : Calculated 454.1033: Measured phase 454.1031;

HPLC analysis was performed using a Chiralcel AD-H column and an AD-H guard column (10% ethanol: hexane, 1.0 ml / min flow rate, λ = 220 nm) Determine enantiomeric selectivity; R -isomer t _r = 21.0 min and S -isomer t _r = 39.1 min.

1.9. (4 R ) -Dimethyl 2- ( N - ( Benzyloxycarbonyl ) -6- Bromo Hydroxy-1,2,3,4- Tetraquinoline Yl) Malonate ((4 R ) - dimethyl  2-( N - ( benzyloxycarbonyl ) -6- bromo -2-hydroxy-1,2,3,4-tetrahydroquinolin-4-yl) malonate; 1e))

As the starting material o - N - benzyloxycarbonyl-amino in place of the cinnamaldehyde 3a o - N - and the object in the same manner as in Example 1, except benzyloxycarbonyl-amino-5-bromo to use the thymosin M aldehyde 3e Compound 1e (58% yield, 90% ee ) was obtained.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.24-7.59 (m, 6H), 7.07-7.22 (m, 3H), 5.82-5.90 (m, 1H), 5.25-5.40 (m, 2H), 4.10 (brs , 3.58 (t, J = 4.0 Hz, 0.3H), 3.48 (s, 2H) (dt, J = 3.6, 9.2 Hz, 0.7 H), 2.45-2.56 (m, 0.3H), 2.17-2.24 (m, 0.7H), 1.99-2.13 (m, 0.7H), 1.87-1.95 (m, 0.3H).

1.10. ( R ) -Dimethyl 2- ( N - ( Benzyloxycarbonyl ) -6- Bromo -1,2,3,4- Tetraquinoline Yl) Malonate (( R ) - dimethyl  2-( N - ( benzyloxycarbonyl ) -6- bromo -1,2,3,4-tetrahydroquinolin-4-yl) malonate; 2e))

Obtained in Example 9 as a starting material (4 R) - dimethyl-2- (N - (benzyloxycarbonyl) -6-bromo-2-hydroxy-1,2,3,4-tetrahydro-quinolin -4 - yl) malonate was used in the same manner as in Example 2 to give the desired compound 2e (76% yield, 90% ee ).

[a] ²⁰ _D 39.9 (c 59, CHCl ₃ );

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.64 (brs, 1H), 7.27-7.43 (m, 7H), 5.28 (s, 2H), 3.88-3.99 (m, 1H), 3.76 (s, 3H), 3.65 (s, 3H), 3.57-3.73 (m, 3H), 2.11-2.19 (m, 1H), 1.91-2.02 (m, 1H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.1, 168.0, 154.3, 136.7, 136.1, 132.3, 131.0, 130.5, 128.6, 128.3, 128.0, 125.7, 116.5, 67.8, 53.7, 52.8, 52.6, 42.2, 36.9, 26.1;

MS (ESI) m / z (%) 476 (M + H ^& lt ^{; +} & gt ^; , 100);

Elemental analysis C ₂₂ H ₂₂ BrNO ₆ .1 / 2H ₂ O: Calculated C, 54.45; H, 4.78; N, 2.89: measured phase C, 54.47; H, 4.95; N, 2.65;

HPLC analysis was performed using a Chiralcel AD-H column and an AD-H guard column (20% isopropanol: hexane, 1.0 ml / min flow rate, λ = 220 nm) Determine enantiomeric selectivity; R -isomer t _r = 13.6 min and S -isomer t _r = 15.2 min.

1.11. (4 R ) -Dimethyl 2- ( N - ( Benzyloxycarbonyl ) -7- Bromo Hydroxy-1,2,3,4- Tetraquinoline Yl) Malonate ((4 R ) - dimethyl  2-( N - ( benzyloxycarbonyl ) -7- bromo -2-hydroxy-1,2,3,4-tetrahydroquinolin-4-yl) malonate; 1f))

As the starting material o - N - benzyloxycarbonyl-amino in place of the cinnamaldehyde 3a o - N - and the object in the same manner as in Example 1, except benzyloxycarbonyl-amino-4-bromo the use of thymosin M aldehyde 3f Compound 1f (yield 74%, 93% ee ) was obtained.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.22-7.60 (m, 6H), 7.08-7.18 (m, 3H), 5.85-5.94 (m, 1H), 5.24-5.40 (m, 2H), 4.13 (brs , 1H), 3.81 (s, 2.1H), 3.78 (s, 0.9H), 3.74 (s, 2.1H), 3.63 (s, 0.9H), 3.57 (t, J = 3.6 Hz, 0.3 H), 3.48 (dt, J = 3.2, 8.8 Hz, 0.7 H), 2.44-2.54 (m, 0.3H), 2.17-2.22 (m, 0.7H), 2.01-2.13 (m, 0.7H), 1.88-1.94 (m, 0.3H).

1.12. ( R ) -Dimethyl 2- ( N - ( Benzyloxycarbonyl ) -7- Bromo -1,2,3,4- Tetraquinoline Yl) Malonate (( R ) - dimethyl  2-( N - ( benzyloxycarbonyl ) -7- bromo -1,2,3,4-tetrahydroquinolin-4-yl) malonate; 2f))

Obtained in Example 11 as a starting material (4 R) - dimethyl-2- (N - (benzyloxycarbonyl) -7-bromo-2-hydroxy-1,2,3,4-tetrahydro-quinolin -4 -yl) words, except that the carbonate is carried out in the same manner as in example 2 to give the desired compound 2f (81% yield, 93% ee).

_{^{[a] 24 D -18.0 (c}} 1.6, CHCl 3);

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.98 (brs, 1H), 7.33-7.47 (m, 5H), 7.14 (dd, J = 8.4, 1.6 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H ), 5.30 (s, 2H), 3.87-3.95 (m, IH), 3.76 (s, 3H), 3.62 (s, 3H), 3.58-3.74 1.90-2.01 (m, 1 H);

¹³ C NMR (100 MHz, CDCl ₃ )? 168.2, 168.1, 154.3, 138.6, 136.0, 129.6, 129.0, 128.6, 128.3, 128.0, 126.9, 126.6, 120.9, 67.9, 53.6, 52.8, 52.5, 42.2, 36.7, 26.1;

HRMS (ESI): C ₂₂ H ₂₂ BrNO ₆ Na (M + Na) ⁺ : Calculated 498.0528: found 498.0527;

HPLC analysis was performed using a Chiralcel AD-H column and an AD-H guard column (10% ethanol: hexane, 1.0 ml / min flow rate, λ = 220 nm) Determine enantiomeric selectivity; R -isomer t _r = 20.6 min and S -isomer t _r = 32.9 min.

1.13. (4 R ) - Diethyl  2-( N - ( Benzyloxycarbonyl ) -2-hydroxy-1,2,3,4- Tetraquinoline Yl) Malonate ((4 R ) - diethyl  2-( N - ( benzyloxycarbonyl )-2- hydroxy -1,2,3,4-tetrahydroquinolin-4-yl) malonate; 1g))

Instead of the words dimethyl carbonate 5a as a starting material to obtain Example 1, and the desired compound 1g (45% yield, 66% ee) in the same manner but using the diethyl carbonate 5b words.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.21-7.64 (m, 7H), 7.06-7.15 (m, 3H), 5.85-5.94 (m, 1H), 5.24-5.44 (m, 2H), 4.12-4.22 (m, 5H), 3.57 (t, J = 3.6 Hz, 0.3H), 3.40-3.48 (m, 0.7H), 2.44-2.54 (m, 0.3H), 2.17-2.24 -2.13 (m, 0.7H), 1.88-1.94 (m, 0.3H), 1.18-1.26 (m, 6H).

1.14. ( R ) - Diethyl  2-( N - ( Benzyloxycarbonyl ) -1,2,3,4- Tetraquinoline Yl) Malonate (( R ) - diethyl  2-( N - ( benzyloxycarbonyl ) -1,2,3,4- tetrahydroquinoline -4-yl) malonate; 2g))

Obtained in Example 13 as a starting material (4 R) - Diethyl 2- (N - (benzyloxycarbonyl) -2-hydroxy-1,2,3,4-tetramethyl-4-yl) words 2g (74% yield, 66% ee ) was obtained in the same manner as in Example 2, except that nate was used.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.74 (d, J = 6.0 Hz, 1H), 7.34-7.47 (m, 5H), 7.24 (td, J = 8.4, 1.2 Hz, 1H), 7.16 (dd, J (D, J = 7.6, 0.8 Hz, 1H), 5.33 (s, 2H), 3.90-4.02 J = 7.2, Hz, 3H), 1.20 (t, J = 7.2, Hz, 3H), 3.78 (m, 3H), 2.11-2.22 (m, ;

¹³ C NMR (100 MHz, CDCl ₃ )? 168.7, 168.3, 154.4, 137.4, 136.5, 130.4, 128.6, 128.2, 128.0, 127.8, 127.5, 124.4, 123.9, 67.6, 61.2, 61.0, 53.9, 42.4, 37.2, 14.1;

HPLC analysis was performed using a Chiralcel AD-H column and an AD-H guard column (5% ethanol: hexane, 1.0 ml / min flow rate, λ = 220 nm) Determine enantiomeric selectivity; R-isomer t _r = 30.3 min and S-isomer t _r = 34.4 min.

1.15. (4 R ) - Diisopropyl  2-( N - ( Benzyloxycarbonyl ) -2-hydroxy-1,2,3,4- Tetraquinoline Yl) Malonate ((4 R ) - diisopropyl  2-( N - ( benzyloxycarbonyl )-2- hydroxy -1,2,3,4-tetrahydroquinolin-4-yl) malonate; 1h))

Instead of the words dimethyl carbonate 5a as a starting material was obtained by di-isopropyl malonate and 5c is that of Example 1, the desired compound 1h (44% yield, 49% ee) by the same method except for using the.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.23-7.65 (m, 7H), 7.04-7.14 (m, 3H), 5.85-5.97 (m, 1H), 5.20-5.44 (m, 2H), 4.98-5.05 (m, 2H), 4.12-4.15 (m, 1H), 3.50-3.58 (m, 0.3H), 3.42-3.51 (m, 0.7H), 2.44-2.56 , 0.7H), 2.00-2.15 (m, 0.7H), 1.86-1.94 (m, 0.3H), 1.19-1.30 (m, 12H).

1.16. ( R ) - Diisopropyl  2-( N - ( Benzyloxycarbonyl ) -1,2,3,4- Tetraquinoline -4-yl) malonate (( R ) - diisopropyl  2-( N - ( benzyloxycarbonyl ) -1,2,3,4- tetrahydroquinoline -4-yl) malonate; 2h))

Obtained in Example 15 as a starting material (4 R) - di-isopropyl-2- (N - (benzyloxycarbonyl) -2-hydroxy-1,2,3,4-tetramethyl-4-yl) words to obtain the second embodiment in the same way as the target compound 2h (91% yield, 49% ee), except that the use of alginate.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.77 (d, J = 6.4 Hz, 1H), 7.33-7.47 (m, 5H), 7.22 (td, J = 8.4, 1.2 Hz, 1H), 7.18 (dd, J (M, 2H), 3.63-4.85 (m, 2H), 3.63-4.82 (m, 2H) 3.78 (m, 3H), 2.11-2.22 (m, 1H), 1.93-2.04 (m, 1H), 1.17-1.28 (m, 12H);

_{^{13 C NMR (100MHz, CDCl 3}} ) δ 168.5, 168.3, 154.7, 137.7, 136.4, 130.4, 128.6, 128.3, 128.2, 127.9, 127.5, 124.2, 123.8, 69.3, 69.1, 67.6, 53.9, 42.3, 37.1, 21.7, 21.5;

HPLC analysis was performed using a Chiralcel AD-H column and an AD-H guard column (10% ethanol: hexane, 1.0 ml / min flow rate, λ = 220 nm) Determine enantiomeric selectivity; R-isomer t _r = 9.7 min and S-isomer t _r = 13.7 min.

1.17. (4 R ) - Dibenzyl  2-( N - ( Benzyloxycarbonyl ) -2-hydroxy-1,2,3,4- Tetraquinoline Yl) Malonate ((4 R ) - dibenzyl  2-( N - ( benzyloxycarbonyl )-2- hydroxy -1,2,3,4-tetrahydroquinolin-4-yl) malonate; 1i))

The target compound 1i (59% yield, 92% ee ) was obtained in the same manner as in Example 1, except that dibenzylmalonate 5d was used instead of dimethyl malonate 5a as a starting material.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.02-7.67 (m, 19H), 5.87-5.97 (m, 1H), 5.22-5.47 (m, 2H), 5.04-5.17 (m, 4H), 4.12-4.15 (m, 1H), 3.51-3.58 (m, 0.3H), 3.42-3.51 (m, 0.7H), 2.43-2.56 (m, 0.3H), 2.17-2.28 m, 0.7H), 1.84-1.93 (m, 0.3H).

1.18. ( R ) - Dibenzyl  2-( N - ( Benzyloxycarbonyl ) -1,2,3,4- Tetraquinoline Yl) Malonate (( R ) - dibenzyl  2-( N - ( benzyloxycarbonyl ) -1,2,3,4- tetrahydroquinoline -4-yl) malonate; 2i))

Obtained in Example 17 as a starting material (4 R) - dibenzyl-2- (N - (benzyloxycarbonyl) -2-hydroxy-1,2,3,4-tetramethyl-4-yl) words in the same manner as in example 2 except for using the carbonate to give the desired compound 2i (81% yield, 92% ee).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 6.95-7.77 (m, 19H), 5.35 (s, 2H), 5.10-5.27 (m, 4H), 3.90-4.04 (m, 1H), 4.77-4.95 (m, 2H), 3.64-3.78 (m, 3H), 2.15-2.24 (m, 1H), 1.93-2.06 (m, 1H);

_{^{13 C NMR (100MHz, CDCl 3}} ) δ 168.7, 168.4, 154.9, 137.7, 136.4, 130.4, 129.7, 129.4, 128.8, 128.6, 128.3, 128.2, 128.0, 127.9, 127.5, 125.0, 124.2, 123.8, 67.6, 67.2, 67.1 53.9, 42.3, 37.1;

HPLC analysis was performed using a Chiralcel AD-H column and an AD-H guard column (20% ethanol: hexane, 1.0 ml / min flow rate, λ = 220 nm) Determine enantiomeric selectivity; R-isomer t _r = 22.1 min and S-isomer t _r = 28.8 min.

1.19. (4 R ) -Dimethyl 2- ( N - ( tert - Butoxycarbonyl ) -2-hydroxy-1,2,3,4- Tetraquinoline Yl) Malonate ((4 R ) - dimethyl  2-( N - ( tert - butoxycarbonyl )-2- hydroxy -1,2,3,4-tetrahydroquinolin-4-yl) malonate; 1j))

The procedure of Example 1 was repeated except that o - N- t-butyloxycarbonylaminocinnamaldehyde 3b was used in place of o - N -benzyloxycarbonylaminocinnamaldehyde 3a as the starting material to obtain the desired compound 1j ( 75% yield, 84% ee ).

^{1 H NMR (400 MHz, CDCl} 3) δ 7.04-7.63 (m, 5H), 5.87-5.99 (m, 1H), 4.08 (brs, 1H), 3.87 (s, 2.4H), 3.78 (s, 0.6H ), 3.75 (s, 2.4H), 3.8 (s, 0.6H), 3.58-3.67 (m, 0.2H), 3.40-3.50 (m, 0.8H), 2.45-2.54 2.28 (m, 0.8H), 2.00-2.13 (m, 0.8H), 1.78-1.93 (m, 9.2H).

1.20. ( R ) -Dimethyl 2- ( N - ( tert - Butoxycarbonyl ) -1,2,3,4- Tetraquinoline Yl) Malonate (( R ) - dimethyl  2-( N - ( tert - butoxycarbonyl ) -1,2,3,4- tetrahydroquinoline -4-yl) malonate; 2j))

Obtained in Example 19 as a starting material (4 R) - dimethyl-2- (N - (tert- butoxycarbonyl) -2-hydroxy-1,2,3,4-tetramethyl-4-yl) except for the words use the carbonate in the example 2 in the same manner as the desired compound 2j (12% yield, 84% ee) were obtained.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.27-7.45 (m, 4H), 3.86-4.02 (m, 1H), 3.72 (s, 3H), 3.58-3.78 (m, 3H), 3.61 (s, 3H) , 2.09-2. 21 (m, 1H), 1.73-2.04 (m, 10H);

HPLC analysis was performed using a Chiralcel AD-H column and an AD-H guard column (5% ethanol: hexane, 1.0 ml / min flow rate, λ = 220 nm) Determine enantiomeric selectivity; R-isomer t _r = 20.2 min and S-isomer t _r = 22.5 min.

1.21. (4 R ) -Dimethyl 2- (2-hydroxy- N - tosyl-1,2,3,4- Tetraquinoline Yl) Malonate ((4 R ) - dimethyl  2- (2- hydroxy - N - tosyl -1,2,3,4- tetrahydroquinoline -4-yl) malonate; 1k)

As the starting material o - N - benzyloxycarbonyl-amino-cinnamaldehyde in place of the aldehyde 3a o - N - Example 1, the desired compound 1k in the same manner except that tosyl butyloxycarbonylamino using cinnamaldehyde 3c (75% Yield, 84% ee ).

¹ H NMR (400 MHz, CDCl ₃ )? 7.28-7.82 (m, 4H), 6.97-7.24 (m, 5H), 5.04-5.26 H), 3.77 (s, 0.9H ), 3.68 (s, 2.1H), 3.59 (s, 0.9H), 3.50 (t, J = 3.6 Hz, 0.3 H), 3.44 (m, 0.7 H), 2.45- 2.50 (m, 0.3H), 2.16-2.25 (m, 0.7H), 1.95-2.05 (m, 0.7H), 1.85-1.97 (m, 0.3H).

1.22. ( R ) -Dimethyl 2- ( N - tosyl-1,2,3,4- Tetrahydroquinoline Yl) Malonate (( R ) - dimethyl  2-( N - tosyl -1,2,3,4- tetrahydroquinoline -4- yl ) malonate ; 2k)

But using malonate (tosyl-1,2,3,4-tetrahydro-4-yl 2-hydroxy-2 - - N) - one as a starting material (R 4) obtained in Example 21 Dimethyl 2- in example 2 in the same manner as the desired compound 2k was obtained (83% yield, 94% ee).

[?] _D ²⁰ -55.4 (c 1.7, CHCl ₃ );

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.89 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.22-7.31 (m, 3H), 7.02-7.08 (m, 2H (M, 2H), 3.72 (s, 3H), 3.52 (s, 3H), 3.37-3.42 3H), 1.84-1. 94 (m, 2H);

¹³ C NMR (100 MHz, CDCl ₃ )? 168.2, 167.9, 143.9, 136.4, 135.5, 130.1, 129.7, 128.7, 128.0, 127.1, 124.4, 124.1, 54.7, 52.6, 52.3, 43.5, 36.3, 25.9, 21.5;

HPLC analysis was performed using a Chiralcel AD-H column and an AD-H guard column (10% ethanol: hexane, 1.0 ml / min flow rate, λ = 220 nm) Determine enantiomeric selectivity; R-isomer t _r = 19.9 min and S-isomer t _r = 27.8 min.

The structural formulas of the 22 optically active tetrahydroquinolinium-malonate derivatives synthesized through Examples 1 to 22 are shown in Table 1 below.

Example  2: optically active ( Tetrahydroquinoline Yl) Malonate  Effect of Substituents on the Synthesis Yield and Enantiomeric Selectivity of Derivatives

[Chemical Formula 1]

In order to confirm the effect of the substituent on the asymmetric reaction using the organic catalyst according to the present invention, some compounds having different substituents of the above formula (1) among the compounds synthesized from Examples 1 to 22 were selected and their yield and enantiomeric selectivity (ee) Are shown in Tables 2 and 3 below. Table 2 means that there is no substituent on the benzene ring, R ₅ have been summarized the results for hydrogen in compounds of R ₂ and R ₃ (R ₄ the same as) the other compound, tables and 3, R ₃ (R ₄ The results are summarized for the compound in which each benzene ring has different substituents, that is, each R ₅ is substituted.

compound R ₂ R ₃ & R ₄ Reaction time (hours) yield(%) ee (%) 1a (Example 1) Cbz Me 24 77 89 2a (Example 2) 84 1 g (Example 13) Cbz Meat 24 45 66 2 g (Example 14) 74 1h (Example 15) Cbz i- Pr 36 44 49 2h (Example 16) 91 1i (Example 17) Cbz Bn 36 59 92 2i (Example 18) 81 1j (Example 19) Boc Me 24 75 84 2j (Example 20) 12 1k (Example 21) Ts Me 36 82 94 2k (Example 22) 83

compound R ₂ R ₅ Reaction time (hours) yield(%) ee (%) 1a (Example 1) Cbz H 24 77 89 2a (Example 2) 84 1b (Example 3) Cbz 8-Me 36 74 93 2b (Example 4) 79 1c (Example 5) Cbz 6-Cl 36 65 89 2c (Example 6) 76 1d (Example 7) Cbz 7-Cl 48 66 92 2d (Example 8) 83 1e (Example 9) Cbz 6-Br 48 58 90 2e (Example 10) 76 1f (Example 11) Cbz 7-Br 60 74 93 2f (Example 12) 81 1k (Example 21) Ts H 36 82 94 2k (Example 22) 83

As shown in Table 2, as the electron affinities of the amine substituent (R ₂ ) are increased, the reaction efficiency, that is, the yield in terms of Boc (1j and 2j) <Cbz (1a and 2a) And enantiomeric selectivity ( ee ). The effect of these substituents was similar in the second stage reaction, that is, the removal of the hydroxyl group, and the compound (2j) in which the hydroxyl group was removed from the compound in which Boc was substituted showed a relatively low yield. Furthermore, the yield and ee of the compound obtained by fixing the amine substituent to Cbz and reacting with the different malonate derivatives (different R ₃ and R ₄ ) yields slightly lower yields when benzyl is substituted (long reaction time) (Me>Et> i- Pr), the yield and ee value of the malonate derivatives substituted with an alkyl group were decreased as the substituents were decreased.

As shown in Table 3, when the amine substituent (R ₂ ) was fixed with Cbz and the substituents (R ₃ and R ₄ ) of malonate were fixed with a methyl group and the effect and type of the substituent on the benzene ring were changed, It has been found that the electronic characteristics, i.e., type and position, of the substituent do not show any apparent effect on the asymmetric reaction of?,? - unsaturated aldehyde. The difference is not great, but the reactions according to Examples 11 and 12, which provide 1f and 2f compounds, show the best yield and enantiomeric selectivity.

Example  3: optically active ( Tetrahydroquinoline Yl) Malonate  Effect of Solvent and Acid or Base Additives on the Synthesis of Derivatives

The (S) -2- (di-phenyl (trimethylsilyloxy) methyl) pyrrolidine ((S) -2- (diphenyl (trimethylsilyloxy) methyl) pyrrolidine) to produce the optically active compound used as the asymmetric catalyst an organic In order to confirm the effect of the reaction solvent and / or acid or base additive in the reaction, the reaction of Example 1.1 was carried out while varying kinds of solvents and / or additives, and the yield and the ee value were measured. . When the yield was rather low, the reaction time was confirmed to be suitably increased.

Entry additive menstruum Reaction time (hours) yield(%) ee (%) One - CH ₂ Cl ₂ 72 10 nd 2 NaOAc CH ₂ Cl ₂ 72 20 nd 3 NaOAc MeOH 36 56 87 4 NaOAc EtOH 48 62 60 5 NaOAc i -PrOH 48 65 61 6 LiOAc MeOH 24 77 89 7 - MeOH 60 28 90 8 AcOH MeOH 72 22 97 9 PhCO ₂ H MeOH 72 18 97 10 4-NO ₂ C ₆ H ₄ CO ₂ H MeOH 48 28 96

As shown in Table 4, the type of reaction solvent influenced the conversion efficiency. Regardless of the presence or absence of the additive, aprotic solvents such as methylene chloride were used to obtain racemic mixtures in which the ee value could not be determined, whereas protic solvents such as methanol, ethanol or isopropyl alcohol , The product could be obtained with high enantiomeric selectivity, that is, high ee value, even if the yield was somewhat low. In the case of using similar catalysts (NaOAc) for similar protonic solvents, the yields were somewhat improved and the enantiomeric selectivities were somewhat reduced when ethanol or isopropanol was used, compared with methanol. In the synthesis of compound 1a, the combination of solvent and catalyst providing the best yield and enantiomeric selectivity was confirmed to be the case where LiOAc was used as an additive while using methanol as a solvent. In comparison, when the acidic additive (AcOH, PhCO ₂ H or 4-NO ₂ C ₆ H ₄ CO ₂ H) was used while using the same methanol solvent, the yield was somewhat reduced, but the enantiomeric selectivity was significantly improved (up to 97 % ee ).

Example  4: Human In lung cancer cell lines  About TCF / LEF Luciferase  Activity analysis

A549 cells transfected with a transcription factor (TCF) / reporter gene (LEF) reporter gene were plated on 96-well plates at a density of 1 × 10 ⁴ cells / well in a 10% FBS, 1% antibiotic ), Cultured in a 5% CO 2 incubator at 37 ° C for 24 hours, and then the compound synthesized in Examples 1 to 22 was added to the medium so that the final concentration was 10 μM, followed by culturing for an additional 24 hours Respectively. Then, the medium was removed, and the plate was washed with cold 1 × PBS, followed by the addition of 25 μl of a lysis buffer. After storage at -80 ° C for 30 minutes, the plates were shaken and the cells were lysed for about 1 hour. After dissolution, 10 μl of the sample was collected and transferred to a white 384-well plate, and 25 μl of a mixture of the luciferase assay substrate and buffer was added to each well. The absorbance was measured with a microplate reader and the luciferase activity was calculated in comparison with the control group to which no compound was added. The results are shown in Table 5 below.

compound Luciferase activity (% of control) 1a (Example 1) 76 2a (Example 2) 82 1b (Example 3) 62 2b (Example 4) 53 1c (Example 5) 49 2c (Example 6) 69 1d (Example 7) 64 2d (Example 8) 86 1f (Example 11) 49 2f (Example 12) 69 1k (Example 21) 59 2k (Example 22) 45

The TCF / LEF luciferase assay is used to confirm the activity of the Wnt signaling pathway which regulates the death, proliferation and metastasis of cancer cells. In the experimental groups treated with the compound according to the present invention, Lt; RTI ID = 0.0 &gt; luciferase &lt; / RTI &gt; activity as compared to the control group. This indicates that the compounds according to the present invention regulate the Wnt signal transduction pathway and thus can be usefully used for the prevention or treatment of cancer diseases in which the signal transduction pathway is involved.

Claims (19)

1. A compound represented by the following formula (1): &lt; EMI ID =
[Chemical Formula 1]

In this formula,
R ₁ is hydrogen (-H) or hydroxy (-OH);
R ₂ is hydrogen, C 1 to C 6 alkyloxycarbonyl, C 7 to C 12 aralkyloxycarbonyl or tosyl aka toluenesulfonyl);
R ₃ and R ₄ are each independently a straight or branched chain C 1 to C 6 alkyl or C 7 to C 12 aralkyl;
R &lt; ₅ &gt; is hydrogen, halogen or C1 to C6 alkyl.
The method according to claim 1,
R &lt; ₃ &gt; and R &lt; ₄ &gt; are identical to each other, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R ₂ is C 1 to C 6 alkyloxycarbonyl, C 7 to C 12 aralkyloxycarbonyl or tosyl, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R ₂ is tert-butyloxycarbonyl, benzyloxycarbonyl or tosyl, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R ₃ and R ₄ are each independently methyl, ethyl, isopropyl or benzyl, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
And R &lt; ₅ &gt; is hydrogen, bromine, chlorine or methyl, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
The compound
1) Synthesis of (4R) -dimethyl 2- (N- (benzyloxycarbonyl) -2-hydroxy-1,2,3,4-tetraquinolin-
2) (4R) -dimethyl 2- (N- (benzyloxycarbonyl) -2-hydroxy-8-methyl-1,2,3,4-tetraquinolin-
3) Synthesis of (4R) -dimethyl 2- (N- (benzyloxycarbonyl) -6-chloro-2-hydroxy-1,2,3,4-tetraquinolin-
4) Synthesis of (4R) -dimethyl 2- (N- (benzyloxycarbonyl) -7-chloro-2-hydroxy-1,2,3,4-tetraquinolin-
5) Synthesis of (4R) -dimethyl 2- (N- (benzyloxycarbonyl) -6-bromo-2-hydroxy-1,2,3,4-tetraquinolin-
6) Synthesis of (4R) -dimethyl 2- (N- (benzyloxycarbonyl) -7-bromo-2-hydroxy-1,2,3,4-tetraquinolin-
7) Synthesis of (4R) -diethyl 2- (N- (benzyloxycarbonyl) -2-hydroxy-1,2,3,4-tetraquinolin-
8) Synthesis of (4R) -diisopropyl 2- (N- (benzyloxycarbonyl) -2-hydroxy-1,2,3,4-tetraquinolin-
9) Synthesis of (4R) -dibenzyl 2- (N- (benzyloxycarbonyl) -2-hydroxy-1,2,3,4-tetraquinolin-
10) Synthesis of (4R) -dimethyl 2- (N- (tert-butoxycarbonyl) -2-hydroxy-1,2,3,4-tetraquinolin-
11) Synthesis of (4R) -dimethyl 2- (2-hydroxy-N-tosyl-1,2,3,4-tetraquinolin-
12) (R) -dimethyl 2- (N- (benzyloxycarbonyl) -1,2,3,4-tetraquinolin-4-yl) malonate,
13) Synthesis of (R) -dimethyl 2- (N- (benzyloxycarbonyl) -8-methyl-1,2,3,4-tetraquinolin-
14) Synthesis of (R) -dimethyl 2- (N- (benzyloxycarbonyl) -6-chloro-1,2,3,4-tetraquinolin-
15) Synthesis of (R) -dimethyl 2- (N- (benzyloxycarbonyl) -7-chloro-1,2,3,4-tetraquinolin-
16) Synthesis of (R) -dimethyl 2- (N- (benzyloxycarbonyl) -6-bromo-1,2,3,4-tetraquinolin-
17) Synthesis of (R) -dimethyl 2- (N- (benzyloxycarbonyl) -7-bromo-1,2,3,4-tetraquinolin-
18) (R) -diethyl 2- (N- (benzyloxycarbonyl) -1,2,3,4-tetraquinolin-4-yl) malonate,
19) (R) -diisopropyl 2- (N- (benzyloxycarbonyl) -1,2,3,4-tetraquinolin-4-yl) malonate,
20) (R) -dibenzyl 2- (N- (benzyloxycarbonyl) -1,2,3,4-tetraquinolin-4-yl) malonate,
21) (R) -dimethyl 2- (N- (tert-butoxycarbonyl) -1,2,3,4-tetraquinolin-4-yl) malonate, and
22) (R) -dimethyl 2- (N-tosyl-1,2,3,4-tetrahydroquinolin-4-yl) malonate, or a pharmaceutically acceptable salt thereof. .
Reacting a compound represented by the following formula (2) with a compound represented by the following formula (3): &lt; EMI ID =
[Formula 1-1]

(2)

(3)

In this formula,
R ₂ to R ₅ are as defined in claim 1.
Reacting a compound represented by the following formula (2) with a compound represented by the following formula (3); And
And a second step of reacting the product of the first step with triethylsilane in the presence of boron trifluoride etherate.
[Formula 1-2]

(2)

(3)

In this formula,
R ₂ to R ₅ are as defined in claim 1.
10. The method according to claim 8 or 9,
Wherein the reaction is an asymmetric addition-cyclization reaction using a chiral amine compound represented by the following formula (4) as a catalyst:
[Chemical Formula 4]

.
10. The method according to claim 8 or 9,
Wherein the molar ratio of the compound represented by the formula (2) to the compound represented by the formula (3) is 1: 1 to 1: 5.
10. The method according to claim 8 or 9,
Wherein the reaction is carried out at 0 to &lt; RTI ID = 0.0 &gt; 40 C &lt; / RTI &gt; for 4 to 120 hours.
10. The method according to claim 8 or 9,
Wherein the reaction is carried out on a solvent selected from the group consisting of methylene chloride, benzene, ethyl acetate, acetonitrile, toluene, tetrahydrofuran, isopropanol, ethanol, methanol, water and mixtures thereof.
10. The method according to claim 8 or 9,
Wherein the reaction is carried out further comprising an acid or base.
15. The method of claim 14,
Wherein said acid or base is selected from the group consisting of benzoic acid, 2-nitrobenzoic acid, 4-nitrobenzoic acid, acetic acid, dichloroacetic acid, toluenesulfonic acid, lithium acetate and sodium acetate.
10. The method of claim 9,
And the second step is carried out at -20 to 40 占 폚 for 10 to 60 minutes.
A pharmaceutical composition for preventing or treating cancer, comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.
18. The method of claim 17,
Wherein the prophylactic or therapeutic treatment of cancer is achieved by modulating the death, proliferation, or metastasis of cancer cells by modulating the Wnt signaling pathway in cancer cells.
18. The method of claim 17,
The cancer disease is selected from the group consisting of breast cancer, lung cancer, colorectal cancer, melanoma, prostate cancer, oesophageal cancer and ovarian cancer. &Lt; / RTI &gt;

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