KR20230012845A - Inhibitors of Cancer Metastasis through Blocking Migration and Invasion of Cancer Cells - Google Patents

Abstract

The present invention relates to: a pharmaceutical composition and a health functional food for preventing or treating cancer metastasis for preventing or treating cancer metastasis, comprising a novel compound that inhibits cancer cell migration and invasion or a pharmaceutically acceptable salt thereof as an active ingredient; and a method for preventing or treating cancer metastasis using the same. An object of the present invention is to provide a compound represented by chemical formula 1, an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof.

Description

Inhibitors of Cancer Metastasis through Blocking Migration and Invasion of Cancer Cells}

The present invention relates to a 2-(cycloalkylmethyl)phenol derivative compound, and specifically, a pharmaceutical composition for preventing or treating cancer metastasis, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient, and preventing or improving cancer metastasis It relates to a health functional food for use, and a method for preventing or treating cancer metastasis, including the step of treating a subject with the pharmaceutical composition.

According to data released by the American Cancer Society, 7.6 million people, or 17% of global deaths, died of cancer in 2008. In Korea, cancer remains the number one cause of death, and the number of deaths in 2016 was 280,827, the highest ever since related statistics were compiled. Cancer ranks first among the 10 causes of death, and the number of deaths from cancer per 100,000 people is 153, which is increasing every year. Due to the enormous social cost, the need for the development of less toxic and highly effective anticancer drugs is gradually increasing. In addition, there is a demand for the development of drugs capable of treating cancer at a low cost because of the enormous social costs caused by cancer.

The biggest cause of life-threatening cancer is the metastasis of cancer cells. Currently, there is a surgical operation as a common cancer treatment method, but since cancer cells metastasize to various places other than the primary cancer site, a complete cure through surgery can be expected only in the early stage.

On the other hand, cancer metastasis, like cancer development, is achieved through the complex action of various genes and factors involved in migration and invasion of cancer cells (Marina Bacac and Ivan Stamenkovic. Annual Review of Pathology: Mechanism of Disease, 3, 221- 247, 2008).

Cancer cell migration plays an important role in cancer metastasis. For example, vascular endothelial cells migrate from the new blood vessels when cancer cells migrate from the initial primary site through the extracellular matrix (ECM) into the blood vessels or out of the blood vessels in the second metastatic tissue. get involved when In migrating cells, polarity is induced by signal receptors activated by cell migration inducers. In addition, the cell membrane in front of the cell is extended forward by polymerization of actin, and the cell attaches to the interstitium through integrin. At this time, a strong contractile force is formed between the actin polymers by myosin bound to the actin polymer, thereby imparting a strong contractile force to the entire cell. Therefore, the direction of cell movement is determined by the difference in adhesion between the front and rear portions of the cell, and the cell moves (Peter Friedl et al., Nature Cancer Review, 2003, 3: 362). Therefore, cell migration inhibitors suppress cancer cell migration to prevent further spread of metastasis, and allow the administration of anticancer drugs that induce the death of cancer cells in a state where migration is inhibited, thereby prolonging the life of cancer patients. approach is considered.

In accordance with these research trends, it is argued that the development of cancer metastasis inhibitors using substances that inhibit the migration of cancer cells, differentiated from existing anticancer drugs or cancer metastasis inhibitors that target cancer cell growth, is a new alternative, and it is named "Migrastatics". (Aneta Gandalovicova et al., Migrastatics-Anti-metastatic and Anti-invasion Drugs: Promises and Challenges, Trends in Cancer 3, 391, 2017).

Many factors are involved in the migration of cancer cells. Among them, protrusions called filopodia are formed that extend from the cytoskeleton or fibrous tissue called lamellipodia around the cells. These protrusions help normal healthy cells to move their position in the tissue to which they belong. However, in malignant cancers, normal healthy cell function is often altered to a destructive excess, resulting in excessive production of lamellipodia and filopodia. If this phenomenon is suppressed, migration of cancer cells can be fundamentally prevented (Stephane R. Gross, Actin binding proteins, Cell Adhesion & Migration 7, 199-213, 2013).

On the other hand, the present inventors have newly invented that a drug called benproperine, which is commercially available as an antitussive expectorant, can effectively inhibit cancer metastasis by blocking cancer cell migration and inhibiting angiogenesis (Korean Patent No. 10- 1323728, US Patent No. 8716288, etc.).

However, since the drug inhibits cancer cell migration at the micromolar (μM) level, development of a drug that inhibits cancer cell migration at the nanomolar (nM) level is required according to the demand for the development of a substance that inhibits cancer metastasis with strong activity. It is necessary.

Under this background, the present inventors have made diligent efforts to develop a method capable of more effectively preventing or inhibiting cancer metastasis by inhibiting migration and invasion of cancer cells, and as a result, not only have the compounds developed new compounds, but also the migration and inhibition of cancer cells. The present invention was completed by confirming that there is an excellent effect of inhibiting permeation at the nanomolar level.

One object of the present invention is to provide a compound represented by Formula 1, an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

n ₁ and n ₂ are each independently an integer of 1 to 3;

R ₁ and R ₂ are each independently hydrogen or C _1-4 alkyl.

Another object of the present invention is a pharmaceutical composition for preventing or treating cancer metastasis, comprising the compound represented by Formula 1, an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. is to provide

Another object of the present invention is a health function for preventing or improving cancer metastasis, comprising the compound represented by Formula 1, an isomer thereof, a racemic mixture thereof, or a food chemically acceptable salt thereof as an active ingredient. to provide food.

Another object of the present invention is to administer to a subject a pharmaceutical composition comprising the compound represented by Formula 1, an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. To provide a method for preventing or treating cancer metastasis, including a.

Each description and embodiment disclosed in the present invention can also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be said that the scope of the present invention is limited by the specific description described below.

In addition, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Also, such equivalents are intended to be included in this invention.

In addition, in the entire specification of the present invention, when a part "includes" a certain component, this means that it may further include other components, not excluding other components unless otherwise stated. it means.

One aspect of the present invention for achieving the above object provides a compound represented by Formula 1 below, an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

n ₁ and n ₂ are each independently an integer of 1 to 3;

R ₁ and R ₂ are each independently hydrogen or C _1-4 alkyl.

The compound of the present invention has two stereocenters (or chiral centers) existing in one molecule at carbons substituted with R ₁ and R ₂ other than hydrogen, as follows:

.

.

Therefore, even if not indicated otherwise, the compound of Formula 1 can be derived from all stereoisomers that can arise therefrom, such as (R,R)-type, (R,S)-type, (S,R)-type, and the (S,S)-type. In addition, (R,R)-type and (S,S)-type, which are enantiomers of each other, and (R,S)-type and (S,R)-type, diastereomers (R,R)-type and (R,S)-type, and racemic mixtures in which (S,R)-type and (S,S)-type are mixed 1:1 are also included in the scope of the present invention. . Furthermore, a compound in which either (R)-type or (S)-type is taken for one stereocenter, but (R)-type and (S)-type are mixed for another stereocenter Of course, both (R)-type and (S)-type are mixed for both stereocenters, that is, the (R,R)-type, (R,S)-type, and (S,R)-type , and randomly mixed mixtures of the (S,S)-type also fall within the scope of the present invention.

For example, the compound of Formula 1 or an isomer thereof or a racemic mixture thereof may be represented by the following formula:

[Formula 2]

; CG650

; CG650

[Formula 3]

; CG651

; CG651

[Formula 4]

; CG652

; CG652

[Formula 5]

; CG653

; CG653

[Formula 6]

; CG654

; CG654

[Formula 7]

; CG655

; CG655

[Formula 8]

; CG656

; CG656

[Formula 9]

; CG657.

; CG657.

Among the bonds located at the stereocenter in the above formula, a bond indicated by a general solid line may mean that it is in the form of a mixture in which all possible stereobonds exist.

The number written on the right side of the above chemical formula is an identification number arbitrarily assigned to easily distinguish synthesized isomers.

Furthermore, including all stereostructures formed at each stereocenter, such as (R,R)-type, (R,S)-type, (S,R)-type, and (S,S)-type This randomly mixed mixture is named CG-653.

Another aspect of the present invention is a first step of reacting 2- (C _5-7 cycloalkylmethyl) phenol and R ₁ -substituted ethylene oxide; A second step of reacting the product obtained from the previous step with methanesulfonyl chloride or mesyl chloride (MsCl); and a third step of reacting the product obtained from the previous step with a 5- to 7-membered heterocyclic compound containing an R ₂ -substituted nitrogen atom.

Each reagent used in the production method of the present invention can be purchased and used commercially available compounds, or prepared by preparing according to a known method can be used.

At this time, among the compounds used, R ₁ -substituted ethylene oxide, R ₂ -substituted 5 to 7 membered heterocyclic compound containing a nitrogen atom, or both are pure (R)-type or (S)-type, or By selecting and using these racemates, various stereoisomers, diastereomers and/or racemates of the compound represented by Formula 1 can be selectively synthesized.

In a specific embodiment of the present invention, the compound represented by Formula 1 is synthesized, but 5 containing 2-(C _5-7 cycloalkylmethyl)phenol, R ₁ -substituted ethylene oxide and R ₂ -substituted nitrogen atom. to 7-membered heterocyclic compounds, or isomers thereof were combined to synthesize various structural isomers, diastereomers, or racemic mixtures.

Specifically, in Example 1, 2-(cyclohexylmethyl)phenol and propylene oxide provided as a racemic mixture with piperidine were used to obtain a racemic mixture designated CG-650. As another example, In Example 2, (R)-(+)-propylene oxide was used instead of propylene oxide, and (R)-2-methylpiperidine was used instead of piperidine to obtain an S,R-type named CG-655. compound was obtained.

For example, the first step may be performed at 100 to 150° C. for 6 to 24 hours in the presence of K ₂ CO ₃ , but is not limited thereto.

For example, the second step may be performed at 10 to 35° C. for 1 to 12 hours by sequentially adding triethylamine (TEA) and methanesulfonyl chloride, but is not limited thereto.

For example, the third step is refluxing at 10 to 35°C for 6 to 24 hours at 100 to 150°C by adding a 5 to 7-membered heterocyclic compound containing an R ₂ -substituted nitrogen atom, and at 10 to 35°C. It may be carried out by further reacting for 10 minutes to 4 hours, but is not limited thereto.

After the reaction of each step, extraction, washing, drying, filtration, concentration, separation, and/or purification may be additionally performed, but is not limited thereto. . Each of the above additional steps may be performed using a conventional method used in the art without limitation.

The compound represented by Formula 1, an isomer thereof, or a racemic mixture thereof may be provided in the form of a pharmaceutically acceptable salt thereof. At this time, a pharmaceutically acceptable salt means a formulation that does not impair the biological activity and physical properties of the administered compound.

The term "pharmaceutically acceptable salt" of the present invention is a concentration that has a relatively non-toxic and harmless effective effect on patients, and any of the compounds represented by Formula 1 do not reduce the beneficial effects of the compound represented by Formula 1 by side effects caused by the salt. means any organic or inorganic addition salt of

The pharmaceutically acceptable salt may include, for example, a non-toxic acid addition salt formed by a free acid containing a pharmaceutically acceptable anion. The acid addition salt is prepared by a conventional method, for example, dissolving the compound represented by Formula 1, its stereoisomers or a mixture thereof in an excess aqueous acid solution, and dissolving the salt in a water-miscible organic solvent such as methanol, ethanol, It is prepared by precipitation using acetone or acetonitrile. Alternatively, heating an equimolar amount of the compound represented by Formula 1, its stereoisomers, or a mixture thereof and an acid or alcohol (eg, glycol monomethyl ether) in water, and then evaporating the mixture to dryness, or precipitated It can be prepared by suction filtration of the salt. The free acid is, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, organic carboxylic acids such as fumaric acid, maleic acid, and salicylic acid; and acid addition salts formed with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, but are not limited thereto. Pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N-methyl-D -Organic salts such as glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine may be included.

In addition, the pharmaceutically acceptable salt may include a pharmaceutically acceptable metal salt prepared using a base. The alkali metal salt or alkaline earth metal salt may be obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable for preparing a sodium, potassium, or calcium salt, but is not limited thereto. In addition, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

The pharmaceutically acceptable salt may include any organic or inorganic addition salt of the compound represented by Formula 1, stereoisomers thereof, or mixtures thereof, in addition to the above-mentioned salts.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer metastasis, comprising a compound having the structure of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound having the structure of Formula 1 or a pharmaceutically acceptable salt thereof is as described above.

In the examples of the present invention, it was confirmed that CG-655, which corresponds to a representative example of a chiral compound, effectively inhibits the migration of representative cancer cell lines such as colon cancer cells, pancreatic cancer cells, skin cancer cells, and lung cancer cells (FIG. 2). . In addition, it was confirmed that CG-655 has an activity of inhibiting the migration of colon cancer cells and pancreatic cancer cells by more than 50% at the nanomolar level (FIG. 3), and inhibiting the invasion of these cancer cells by more than 50% at the nanomolar level. It was confirmed that there was activity (FIG. 4). In addition, for several compounds represented by Formula 1 other than CG-655, concentrations that inhibited migration of DLD-1, a colorectal cancer cell, by 50% were calculated and summarized in FIG. 5 .

From these results, it was shown that CG-655 can exhibit an effective cancer cell migration inhibitory activity even at a concentration 10 times lower than that of the previously known benproperine drug, which indicates that an excellent cancer metastasis inhibitory drug with a new structure can be developed in the future. This is an indicative result.

In another embodiment of the present invention, it was confirmed that CG-655 had no effect on the migration and growth of normal cells, thereby indirectly verifying the possibility of developing a drug that inhibits cancer metastasis with less toxicity (FIG. 6).

In addition, in another embodiment of the present invention, it was confirmed at the cellular level that CG-655 inhibits the process of forming protrusions called lamellipodia and filopodia, which are one of the important processes for cancer cell migration. It was verified that there would be no effect on normal cells (FIG. 7). In addition, the effect of CG-655 on the mobility of single cells was confirmed using HoloMonitor M4 (Phase Holographic Imaging), a real-time cell migration imaging and analysis equipment. It was confirmed that cell migration increased (FIG. 8).

In addition to the above, in another embodiment of the present invention, CG-655 is very strongly cancerous by oral administration at 5 or 10 mg/kg in an animal model transplanted with human-derived pancreatic cancer luminescent cell line (AsPC-1 luciferase) to evaluate cancer metastasis efficacy. It was confirmed that metastasis was inhibited (FIG. 9). Therefore, the pharmaceutical composition of the present invention can effectively suppress cancer metastasis in animal models of cancer metastasis as well as inhibit migration or invasion of cancer cells, and thus can be usefully used for preventing or treating various cancer metastases.

As used herein, the term "cancer" refers to a disease that abnormally proliferates due to a problem in the normal division, differentiation, and death control function of cells, infiltrates surrounding tissues and organs, forms cancerous tissues, and destroys or transforms existing structures. means state. The cancer is divided into primary cancer existing at the site of occurrence and metastatic cancer that has spread to other organs of the body from the site of occurrence.

The cancers include, for example, colorectal cancer, pancreatic cancer, gastric cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer, parathyroid cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, and hematological cancer. , bladder cancer, kidney cancer, ovarian cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine adenocarcinoma , adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureteric cancer, renal cell carcinoma, renal pelvic carcinoma, CNS central nervous system tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, or pituitary adenoma. It may, but is not limited thereto. The melanoma may occur in the skin, eye, mucous membrane, or central nervous system.

The migration of cancer cells is formed by spreading cancer cells through blood circulation or lymph circulation, and usually forms new tumors after moving to other organs through blood circulation.

Invasion of the cancer cells means that cancer cells proliferate while burrowing into the tissue surrounding the site where the cancer first occurred, and that the cancer cells directly migrate and invade neighboring tissues.

As used herein, the term "prevention" refers to the occurrence, growth, proliferation, migration, and invasion of cancer cells by administering a compound having the structure of Formula 1 according to the present invention, or a pharmaceutically acceptable salt thereof, to a subject. It can mean any action that inhibits or delays

As used herein, the term "treatment" may refer to any activity that improves symptoms of cancer or benefits by administering the composition of the present invention to a subject suspected of having cancer.

The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent.

As used herein, the term "pharmaceutically acceptable carrier" may refer to a carrier or diluent that does not inhibit the biological activity and properties of the injected compound without irritating living organisms. The type of the carrier that can be used in the present invention is not particularly limited, and any carrier commonly used in the art and pharmaceutically acceptable can be used. Non-limiting examples of the carrier include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and the like. These may be used alone or in combination of two or more. In addition, if necessary, other conventional additives such as antioxidants, buffers, and/or bacteriostatic agents may be added and used. The pharmaceutical composition may be formulated into a unit dosage form or prepared by being incorporated into a multi-dose container. For example, the pharmaceutical composition is from the group consisting of tablets, pills, powders, granules, capsules, suspensions, internal solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. It may have any one formulation selected, and may be various oral or parenteral formulations. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in one or more compounds, for example, starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, and syrups. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. can Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.

The pharmaceutical composition of the present invention can also be used as a single agent. In addition, it may be prepared and used as a combination preparation by further including one or more anticancer agents. The anticancer agent may be at least one selected from the group consisting of DNA alkylating agents, anti-cancer antibiotics, and plant alkaloids, but is not limited thereto. For example, the anticancer agent is mechloethamine, chlorambucil, phenylalanine, mustard, cyclophosphamide, ifosfamide, carmustine ( carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin, carboplatin, dactinomycin (actinomycin) D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitoxantrone, plicamycin, mitomycin, C breomycin (C Bleomycin); In the group consisting of vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan and iridotecan It may be one or more selected ones.

Another aspect of the present invention is a health functional food for preventing or improving cancer metastasis, comprising a compound having the structure of Formula 1, its stereoisomers, a mixture thereof, or a food chemically acceptable salt thereof as an active ingredient. provides

The compound having the structure of Formula 1 is as described above.

The term "health functional food" of the present invention refers to food prepared and processed in the form of tablets, capsules, powders, granules, liquids and pills using raw materials or ingredients having useful functionalities for the human body. Here, functional means obtaining useful effects for health purposes such as adjusting nutrients for the structure and function of the human body or physiological functions. 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 components commonly added in the art during the preparation. In addition, unlike general drugs, there is an advantage in that there is no side effect that may occur when taking a drug for a long time by using food as a raw material, and it can be excellent in portability.

The mixing amount of the active ingredient may be appropriately determined according to the purpose of use (prevention, health or therapeutic treatment). Generally, the compound of the present invention is added in an amount of 1 to 10% by weight, preferably 5 to 10% by weight, of the raw material composition during food preparation. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount below the above range may be used.

The health functional food of the present invention may be for preventing or improving cancer metastasis.

Another aspect of the present invention includes the step of administering to a subject a pharmaceutical composition comprising a compound having the structure of Formula 1, its stereoisomers, a mixture thereof, or a pharmaceutically acceptable salt thereof as an active ingredient To provide a method for preventing or treating cancer metastasis.

The pharmaceutical composition refers to a pharmaceutical composition for preventing or treating cancer, including the compound having the structure of Formula 1, stereoisomers thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

As used herein, the term "individual" may refer to all animals, including humans, except for humans who have or are likely to develop cancer. The animal may be not only humans but also mammals such as cattle, horses, sheep, pigs, goats, camels, antelopes, dogs, and cats that require treatment for similar symptoms, but are not limited thereto.

Specifically, the preventive or therapeutic method of the present invention may include administering an effective amount of the composition to a subject who has or is at risk of developing cancer.

The "effective amount" is a pharmacologically effective amount, and means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective amount level is the type and severity of the subject, age, sex, drug activity, It may be determined according to factors including sensitivity to the drug, administration time, route of administration and excretion rate, duration of treatment, drugs used concurrently, and other factors well known in the medical field. For example, an amount of 0.01 to 100 mg/kg, preferably 0.5 to 10 mg/kg, and more preferably 1 to 5 mg/kg may be divided and administered once or several times a day. 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 it can be single or multiple administrations.

It is important to administer the amount that can obtain the maximum effect with the minimum amount without side effects in consideration of all the above factors, and can be easily determined by those skilled in the art. The preferred dosage of the composition of the present invention may vary depending on the condition and body weight of the patient, the severity of the disease, the type of drug, the route and duration of administration. Administration may be administered once a day, or may be administered in several divided doses. In addition, it is preferable to apply differently according to various factors including drugs used together with a specific composition or concurrently used and similar factors well known in the medical field. The composition can be administered to various mammals such as rats, livestock, and humans by various routes, and the method of administration includes, but is not limited to, conventional methods in the art, but oral administration is preferred.

As used herein, the term "administration" means introducing the pharmaceutical composition of the present invention to a patient by any suitable method, and the route of administration of the composition of the present invention is oral or parenteral as long as it can reach the target tissue. It can be administered through various routes. The administration method of the pharmaceutical composition according to the present invention is not particularly limited, and may follow a method commonly used in the art. As a non-limiting example of the administration method, the composition may be administered by oral administration or parenteral administration. The pharmaceutical composition according to the present invention may be prepared in various formulations depending on the desired administration method.

The frequency of administration of the composition of the present invention is not particularly limited thereto, but may be administered once a day or administered several times by dividing the dose.

In one embodiment of the present invention, it was confirmed that CG-655 has an activity to inhibit cell migration of representative cancer cell lines, such as colon cancer cells, pancreatic cancer cells, skin cancer cells, and lung cancer cells. In particular, CG-655 is a known drug, Benpro. Results suggesting that it can exhibit effective cancer metastasis inhibitory activity even at concentrations 10 times or more lower than that of ferrin were confirmed (FIGS. 3 to 5). In addition, in another embodiment of the present invention, it was confirmed that CG-655 inhibits cancer metastasis by more than 50% even at a dose (10 mg/kg) that is 5 times less than benproperine (50 mg/kg) in animal experiments (Fig. 9). Therefore, the pharmaceutical composition of the present invention can inhibit the migration or invasion of cancer cells and suppress cancer metastasis in animal experiments, and thus can be usefully used for preventing or treating various cancers in animals including humans.

The term CG-655, cancer, prevention, or improvement of the present invention is as described above.

The novel compound of the present invention or a pharmaceutically acceptable salt thereof has excellent inhibitory effects on the migration and invasion of various cancer cells and, in particular, exhibits superior cancer metastasis inhibitory effects compared to previously known benproperine, It can be usefully used as a pharmaceutical composition for preventing or treating cancer metastasis, and a method for preventing or treating cancer metastasis using the same.

1 shows the ¹ H-NMR of (R)-1-((R)-1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl)-2-methylpiperidine (CG-655). It is a diagram showing the spectrum.
Figure 2 is a diagram showing the migration inhibitory activity of GC655 on various cancer cells (colorectal cancer cell line DLD-1, pancreatic cancer cell lines AsPc-1, CFPAC-1, PANC-1, skin cancer cell line A375-p, lung cancer cell line HCC-827). to be.
3 is a diagram showing the migration inhibitory activity of GC655 on colon cancer cell line DLD-1 and pancreatic cancer cell line AsPc1 and its concentration dependence.
FIG. 4 is a diagram showing the structural formulas of benproperine as a control group and compounds according to Examples of the present invention and IC ₅₀ values for migration of these compounds in the colon cancer cell line DLD-1.
5 is a diagram showing cancer cell invasion inhibitory activity of GC655 against colon cancer cell line DLD-1 and pancreatic cancer cell line AsPc1.
Figure 6 is a diagram showing the absence of the effect of GC655 on the migration and invasion of normal cell lines MCF-10A and HFF.
7 is a diagram showing the selective inhibitory effect of GC655 on the formation of lamellipodia on the colon cancer cell line DLD-1 and the pancreatic cancer cell line AsPc-1 compared to the normal cell line MCF-10A.
8 is a diagram showing the migration inhibitory effect of GC655 on the colorectal cancer cell line DLD-1 confirmed through real-time monitoring.
9 is a diagram showing the effect of suppressing cancer metastasis in an experimental animal model of pancreatic cancer by oral administration of GC655.

Hereinafter, the configuration and effects of the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.

Example 1: Synthesis of CG-650

As a representative example of the compound of Formula 1, compound CG-650 was synthesized in the same manner as in Scheme 1 below:

[Scheme 1]

.

.

Step 1: Synthesis of 1-(2-(cyclohexylmethyl)phenoxy)propan-2-ol

After mixing 2-(cyclohexylmethyl)phenol (1.5 g, 7.88 mmol) with N,N-dimethylformamide (DMF, 25mL), K ₂ CO ₃ at room temperature. (1.2 g, 8.68 mmol) was added. After 30 minutes, propylene oxide (2-methyloxirane, 550 mg, 9.48 mmol) was rapidly added to the mixture using a syringe. Thereafter, the solution was heated to 120° C. and stirred for 12 hours. After cooling the reaction solution to room temperature, water was added to terminate the reaction, followed by extraction with ethyl acetate and water three times. Thereafter, the organic layer was washed three times with water and then washed once more with brine. After drying with MgSO ₄ , filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (EA:Hex=1:9) to obtain the title compound (1-(2-(cyclohexylmethyl)phenoxy)propan-2-ol, 1.78 g, 91.2%) as a light yellow oil. In order to identify the compound, ¹ H-NMR and ¹³ C-NMR were analyzed, and the results are as follows.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.27-7.10 (m, 2H), 6.93-6.82 (m, 2H), 4.23 (m, 1H), 3.94 (m, 1H), 3.81 (m, 1H), 2.52 (d, J = 6.9 Hz, 2H), 1.71–0.96 (m, 11H), 1.32 (d, J = 6.3 Hz, 3H);

¹³ C-NMR (75 MHz, CDCl ₃ ) δ 156.40, 131.09, 129.94, 126.89, 120.62, 111.38, 73.16, 66.53, 38.77, 38.15, 33.51,33.43, 26.56, 26.86, 18.

Step 2: Synthesis of 1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl methanesulfonate

1-(2-(cyclohexylmethyl)phenoxy)propan-2-ol (2.48 g. 10 mmol) was dissolved in 50 mL of methylene chloride (MC). Then, TEA (triethylamine, 1.5 mL, 11.1 mmol) and MsCl (methylsulfonyl chloride, 1.26 g, 11 mmol) were sequentially added, followed by stirring at room temperature for 6 hours. After the reaction was terminated by adding water, the mixture was extracted three times with MC (methylene chloride) and water. Thereafter, the MC layer was washed twice with water and washed once more with saline. After drying with MgSO ₄ , filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (EA:Hex=1:9) to obtain the title compound (1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl methanesulfonate, 2.86 g, 87.7%) as a brown oil. In order to identify the compound, ¹ H-NMR and ¹³ C-NMR were analyzed, and the results are as follows.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.10-7.01 (m, 2H), 6.85-6.71 (m, 2H), 5.03 (m, 1H), 4.03 (m, 1H), 3.94 (m, 1H), 2.96 (s, 3H), 2.42 (m, 2H), 1.59–0.86 (m, 11H), 1.47 (d, J = 6.3 Hz, 3H);

¹³ C-NMR (75 MHz, CDCl ₃ ) δ 156.06, 131.28, 130.01, 121.02, 120.62, 111.43, 77.29, 70.29, 38.55, 38.36, 38.05,33.43, 33.35, 26.39, 218.39, 26.35.

Step 3: Synthesis of 1-(1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl)piperidine (CG-650)

After dissolving 1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl methanesulfonate (3.27 g, 10 mmol) in DMF (30 mL), piperidine (0.65 mL, 0.65 mL, 21.2 mmol) was added and refluxed at 120° C. for 12 hours. Then, the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with methanol and then concentrated under reduced pressure to remove excess piperidine. Thereafter, 1M sodium hydroxide (NaOH, 43 mL) was added to form a basic condition, followed by extraction with ethyl acetate and water three times. Then, the ethyl acetate layer was washed with brine. After drying with MgSO ₄ , filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (EA:Hex=1:1) to yield the title compound (1-(1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl)piperidine; CG-650, 1.28 as a brown oil. g, 38.8%). In order to identify the compound, ¹ H-NMR and ¹³ C-NMR were analyzed, and the results are as follows.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.16-7.03 (m, 2H), 6.79-6.72 (m, 2H), 3.96 (m, 1H), 3.80 (m, 1H), 2.96 (m, 1H), 2.97-2.37 (m, 6H), 1.60-1.21 (m, 20H);

¹³ C-NMR (75MHz, CDCL ₃ ) δ 156.90, 130.99, 129.91, 126.80, 1119.92, 110.92, 69.72, 59.14, 50.58, 38.45, 38.26, 33.50, 33.42

Example 2: Synthesis of (R)-1-((R)-1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl)-2-methylpiperidine (CG-655)

(R)-(+)-propylene oxide instead of propylene oxide in step 1, (R)-2-methylpiperidine instead of piperidine in step 3 (R) -2-methylpiperidine) was reacted in a similar manner to Example 1, except that the title compound ((R)-1-((R)-1-(2-(cyclohexylmethyl)phenoxy)propan -2-yl)-2-methylpiperidine) was obtained. The ¹ H-NMR spectrum of CG-655 synthesized as described above is shown in FIG. 1 .

[α] ²⁵ _D - 56.8° (c1, MeOH), molecular formula C ₂₂ H ₃₆ NO ESI-MS 330.2796 (Calc. Mass 330.2797);

1H ^- NMR (300MHz, CDCl ₃ ) δ 7.09-6.98 (m, 2H), 6.80-6.72 (m, 2H), 3.96 (m, 1H), 3.75 (m, 1H), 3.53 (m, 1H), 2.97 (m, 1H), 2.71 (m, 1H), 2.45-2.21 (m, 3H), 1.58-0.81 (23H);

¹³ C-NMR (75MHz, CDCL ₃ ) δ 156.99, 131.11, 129.99, 126.79, 1119.93, 110.72, 67.45, 56.46, 51.73, 45.67, 38.43, 38.19, 35.82, 33.48, 33.39, 26.83, 26.44 , 20.21, 16.84.

Experimental example 1: Analysis of cancer cell migration inhibitory activity

In order to analyze the cancer cell migration inhibitory activity of CG-655 as a representative compound prepared in Example, colorectal cancer cell line DLD-1 (ATCC-CCL-221); pancreatic cancer cell lines AsPc-1 (ATCC-CCL-1682), CFPAC-1 (ATCC-CCL-1918), Panc-1 (ATCC-CCL-1469); skin cancer cell line A375-P (ATCC-CCL-3224); and lung cancer cell line HCC-827 (ATCC-CCL-2868); cell migration inhibitory activity was measured using a trans-well (trans-well).

First, DLD-1 cells were counted using a hemocytometer in RPMI medium without FBS. Then, trans-wells were placed on a 24-well plate and 8×10 ⁴ cells/200 μl of cells were added. 500 μl of RPMI medium containing 10% FBS containing CG-655 was added to the empty space of the trans-well on the well plate, and incubated at 37° C. for 16 hours in a CO ₂ incubator. After incubation, 500 μl of crystal violet (5 mg/ml in 20% MeOH) was added to each well of the 24-well plate and the trans-well was stained for 30 minutes at room temperature. The stained trans-well was washed with PBS, and cells on the non-migrated side were wiped off with a cotton swab. After taking a picture of the prepared sample with an inverted microscope equipped with a digital camera (TE 300, Nikon, Japan), the number of migrating cells was counted. Compared to the control group (DMSO), the cell migration inhibition was calculated by Equation 1 for the sample-treated group:

[Equation 1]

.

.

In Equation 1, 'the number of cell migration in the sample treatment area' means the number of migrated cells measured after treatment with CG-655 of Example 1, and 'the number of migration of cells in the control sample' is 1 instead of the compound. It means the number of migrated cells measured after treatment with only % dimethyl sulfoxide (DMSO).

As a result, as shown in FIG. 2, treatment with 200 nM CG-655 inhibited the migration of colon cancer cell DLD-1 and pancreatic cancer cell line AsPc-1 by more than 50%, and treatment with 5 μM CG-655 inhibited pancreatic cancer. It was confirmed that the migration of cells CFPAC-1 and PANC-1, lung cancer cells A549, and skin cancer cell line A375P could be significantly inhibited.

In addition, the concentration dependence of the compound CG-655 on cancer cell migration in the colon cancer cell line DLD-1 and the pancreatic cancer cell line AsPc-1 was confirmed, and the results are shown in FIG. 3 . As shown in FIG. 3, as the concentration of CG-655 administered increased, better cancer cell migration inhibitory activity was exhibited.

Furthermore, the effect of inhibiting migration of colon cancer cell line DLD-1 was confirmed for a series of compounds synthesized according to the examples of the present invention, and the IC ₅₀ values measured for each are summarized in FIG. 4 . As shown in FIG. 4, all of the compounds synthesized according to the examples of the present invention exhibited cancer cell migration inhibitory activity against colon cancer cell lines, although to varying degrees, and CG-655 exhibited the best inhibitory activity among them. In this case, it was confirmed that a 50% migration inhibitory effect equivalent to that of benproperrin can be achieved even when treated at a concentration of 100 nM, which is 1/20 of that of benproperine, a known cancer cell migration inhibitor. This indicates that the compound CG-655 of the present invention exerts a superior cancer cell migration inhibitory activity compared to benproperine, a known cancer cell migration inhibitor.

Experimental Example 2: cancer cells Invasion inhibition activity assay

In order to analyze the cancer cell invasion inhibitory activity of CG-655 prepared in Example 2, colon cancer cell line DLD-1 cells and pancreatic cancer cell line AsPc-1 cells were used in a trans-well. Invasion inhibition activity was measured.

Matrigel was diluted 1/5 in RPMI medium without FBS, and then 200 μl was added to the inside of the trans-well. It was coated in a CO ₂ incubator for 2 hours. DLD-1 cells were counted using a hemocytometer in RPMI medium without FBS. Then, the coated trans-well was placed on a 24-well plate and 8×10 ⁴ cells/200 μl of cells were added. 500 μl of RPMI medium containing 10% FBS containing CG-655 was added to the empty space on the trans-well of the well plate, and incubated at 37° C. for 16 hours in a CO ₂ incubator. After incubation, 500 μl of crystal violet (5 mg/ml in 20% MeOH) was added to each well of the 24-well plate and the trans-well was stained for 30 minutes at room temperature. The stained trans-well was washed with PBS, and cells on the non-migrated side were wiped off with a cotton swab. After taking a picture of the prepared sample with an inverted microscope (TE300, Nikon, Japan) equipped with a digital camera, the number of migrating cells was counted. Compared to the control group (DMSO), cancer cell invasion inhibition was calculated for the sample-treated group.

As a result, as shown in FIG. 5 , it was confirmed that when the colorectal cancer cell line DLD-1 and the pancreatic cancer cell line AsPc-1 were treated with 200 nM of CG-655, cell invasion was inhibited by more than 50% compared to the DMSO-treated control sample. Compared to the previously published results of benproperine, which inhibited cell invasion by 50% only when treated with 5 μM, it was found that CG-655 strongly inhibited cell invasion even at a very low concentration.

As described above, it was confirmed that CG-655 effectively inhibits not only cancer cell migration but also cancer cell invasion. This suggests that a composition containing CG-655 or a pharmaceutically acceptable salt thereof can be usefully used for preventing or treating metastasis of various cancers.

Furthermore, in order to confirm that the cell invasion inhibitory effect is an effect selectively for cancer cells, normal cell lines MCF-10A and HFF were treated with 2 μM of CG-655 to confirm the degree of cell invasion in the same manner as above. Results are shown in FIG. 6 . As shown in Figure 6, cell migration in both MCF-10A and HFF, which are normal cell lines, was not affected by CG-655 treatment, indicating that the cell invasion inhibitory effect of CG-655 on cancer cells This implies that it is selectively acted upon.

Experimental Example 3: Imaging and analysis of inhibition of lamellipodia formation

Human colon cancer cell line DLD-1 cells (0.8×10 ⁵ cells), human pancreatic cancer cell line AsPc-1 (0.8×10 ⁵ cells), and normal cells MCF10A (0.6×10 ⁵ cells) were each placed on a 35 mm dish (ibid GmbH, Am Klopferspitz, Germany), and the cells were treated with DMSO and CG-655 (0.5 M and 1 M) for 24 hours. Then washed with PBS, and fixed with 4% paraformaldehyde for 10 minutes at room temperature. The fixed cells were permeabilized with 2% Triton X-100 for 10 minutes at room temperature and then blocked with 1% BSA for 1 hour. Cells prepared as above were stained with antibody Alexa Fluor ^® 488-conjugated phalloidin (Cell signaling, Danvers, MA, USA) for 24 hours, and then stained with 2 g/mL DAPI (4',6'-diamidino-2-phenylindole , Santa Crus Biotechnology), and the nuclei were stained. All images of the cells stained as described above were obtained with a laser scanning confocal microscope (LSM 510 META, Carl Zeiss Vision, St. Cloud, NM, USA) and are shown in FIG. 7 . The acquired images were analyzed with the analysis program LSM Version 3.2 software (Carl Zeiss).

As shown in Figure 7, CG-655 effectively inhibited the formation of lamellipodia in DLD-1 and AsPC-1 cells, which are cancer cells, but had no effect on the formation of lamellipodia in normal cells, MCF10A. . This indicates that the inhibitory effect of CG-655 on lamellipodia formation is also expressed specifically in cancer cells.

Experimental Example 4: Real-time cell migration imaging and analysis

The effect of the drug on the mobility of single cells was confirmed using HoloMonitor M4 (Phase Holographic Imaging), a real-time cell migration imaging and analysis equipment. was performed within Experiments were performed by dispensing cells into a μ-slide microscopy chamber (Ibidi) to prevent water vapor generated during long-term imaging of cells from interfering with imaging. To analyze the mobility of single cells, cells to be analyzed (2.5×10 ⁵ cells/mL) were dispensed in an amount of 0.2 mL into a μ-slide microscopy chamber, and the cells were cultured for 12 hours or more. After the cells were fully adhered to their original shape, the drug was treated, and the cell migration was measured in real time after designating the desired location for analysis.

Cell migration was measured at 5-minute intervals for 24 hours, and 25 cell migration per group was analyzed. Using the HoloMonitor tracking software, the total distance the cells moved during the measured time, the straight line distance from the starting point to the ending point, the speed of movement, and the direction were quantitatively analyzed, and the movement of a single cell was visualized with a Wind-Rose plot (FIG. 8). ). As shown in Figure 8, the movement of cells in the CG-655-administered group was significantly restricted compared to the control group, and this phenomenon increased in a concentration-dependent manner, indicating that the movement of cells was more restricted when treated with a higher concentration of CG-655. .

Experimental example 5: to the rat Acute toxicity test for oral administration

After dividing 6-week-old SPF SD-based rats into two groups per group, CG-655 prepared in Example 2 was dissolved in distilled water for injection and orally administered at a dose of 500 mg/kg to each rat. After administration of the test substance, mortality, clinical symptoms, and weight changes of the animals were observed, hematological and blood biochemical tests were performed, and after autopsy, abnormalities in the abdominal organs and thoracic organs were observed with the naked eye.

As a result, there were no remarkable clinical symptoms or dead animals in all animals administered with the test substance, and no toxic changes were observed in weight change, hematological and blood biochemical tests, and autopsy findings.

Therefore, since CG-655 did not show any toxicity change up to 500 mg/kg in all rats, it was determined to be a safe substance with an oral administration minimum lethal dose (LD50) of 500 mg/kg or more.

Experimental example 6: Verification of cancer metastasis inhibitory activity of CG-655 in a liver metastasis model using nude mice

In this experiment, using a mouse tail vein transplantation metastasis model of AsPC-1-luc (AsPc-1 luciferase), a human-derived pancreatic cancer cell line, to verify the cancer metastasis inhibition activity by oral administration of CG-655 using a live animal imaging system did As animals, Athymic-NCr NCr-nu specific pathogen-free (SPF) 5-week-old nude mice supplied by Coretech (Pyeongtaek-si, Gyeonggi-do) were used. The cancer cell concentration was adjusted to 1×10 ⁶ cells/mL, and 30 μl of the cell culture medium was injected per mouse using a syringe using a tail vein injection. CG-655, a drug, was dissolved at a concentration of 5 mg/kg or 10 mg/kg using 0.5% Tween80, and then orally administered to mice in a 10 mL/kg volume 5 times a week for a total of 20 times.

A total of 5 images were taken from the day after cancer cell transplantation until the end of the experiment on the 28th, and 50 μl of luciferin was intraperitoneally administered to both sides of the animal's abdomen at a concentration of 15 mg/mL during imaging, and then optical imaging System (IVIS-spectrum CT, PerkinElmer) was used (FIG. 9), and the values of all measurement items were tested for statistical significance by comparing the solvent control group and the drug administration group using the t-TEST statistical method. As shown in FIG. 9, cancer metastasis inhibition effects of 35.1% and 59.2% were observed in the CG-655 5 mg/kg and 10 mg/kg administration groups, respectively.

Overall, it was confirmed that CG-655 inhibited migration and invasion of cancer cells and effectively inhibited cancer metastasis in animal models. This suggests that a composition containing CG-655 or a pharmaceutically acceptable salt thereof can be usefully used for preventing or treating metastasis of various cancers.

From the above description, those skilled in the art to which the present invention pertains will be able to understand that the present invention may be embodied in other specific forms without changing its technical spirit or essential features. In this regard, the embodiments described above should be understood as illustrative in all respects and not limiting. The scope of the present invention should be construed as including all changes or modifications derived from the meaning and scope of the claims to be described later and equivalent concepts rather than the detailed description above are included in the scope of the present invention.

Claims (13)

A compound represented by Formula 1, an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
n ₁ and n ₂ are each independently an integer of 1 to 3;
R ₁ and R ₂ are each independently hydrogen or C _1-4 alkyl.
According to claim 1,
n ₁ and n ₂ are both 1, and R ₁ and R ₂ are each independently hydrogen or methyl, a compound, an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
The compound
1. 1-(1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl)piperidine;
2. 1-(1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl)-2-methylpiperidine;
3. 1-(2-(2-(cyclohexylmethyl)phenoxy)ethyl)piperidine;
4. 1-(2-(2-(cyclohexylmethyl)phenoxy)ethyl)-2-methylpiperidine, or
5. A compound which is 1-(1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl)-3-methylpiperidine, an isomer thereof, a racemic mixture thereof, or a pharmaceutical thereof an acceptable salt.
According to claim 1,
The compound
1. 1-(1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl)piperidine;
2. (R)-1-(1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl)piperidine;
3. (S)-1-(1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl)piperidine;
4. 1-(1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl)-2-methylpiperidine;
5. 1-((R)-1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl)-2-methylpiperidine;
6. (R)-1-((R)-1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl)-2-methylpiperidine;
7. 1-((S)-1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl)-2-methylpiperidine, or
8. A compound which is 1-((R)-1-(2-(cyclohexylmethyl)phenoxy)propan-2-yl)-3-methylpiperidine, isomers thereof, racemic mixtures thereof, or a pharmaceutically acceptable salt thereof.
A first step of reacting 2-(C _5-7 cycloalkylmethyl)phenol with R ₁ -substituted ethylene oxide;
A second step of reacting the product obtained from the previous step with methanesulfonyl chloride or mesyl chloride (MsCl); and
A method for producing the compound of claim 1 comprising a third step of reacting the product obtained from the previous step with a 5- to 7-membered heterocyclic compound containing an R ₂ -substituted nitrogen atom.
A pharmaceutical composition for preventing or treating cancer metastasis, comprising the compound of claim 1, an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
According to claim 6,
The cancers include colorectal cancer, pancreatic cancer, gastric cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer, parathyroid cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, blood cancer, bladder cancer, Kidney cancer, ovarian cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, adrenal cancer , soft tissue sarcoma, urethral cancer, penile cancer, ureteric cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma, and pituitary adenoma. To, the composition.
According to claim 6,
The composition further comprises a pharmaceutically acceptable carrier, excipient or diluent, the composition.
According to claim 6,
The composition further comprises an anti-cancer agent, the composition.
According to claim 9,
Wherein the anticancer agent is at least one selected from the group consisting of DNA alkylating agents, anticancer antibiotics, and plant alkaloids.
According to claim 9,
The anticancer agent is mechloethamine, chlorambucil, phenylalanine, mustard, cyclophosphamide, ifosfamide, carmustine (BCNU) ), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin, carboplatin, dactinomycin (actinomycin D) , doxorubicin (adriamycin), daunorubicin, idarubicin, mitoxantrone, plicamycin, mitomycin, C breomycin (C Bleomycin); In the group consisting of vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan and iridotecan Any one or more selected, the pharmaceutical composition.
A health functional food for preventing or improving cancer metastasis, comprising the compound of claim 1, an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
Preventing or treating cancer metastasis, comprising administering a pharmaceutical composition comprising the compound of claim 1, an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof as an active ingredient to a non-human subject Way.

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