KR20220113067A - Novel sulfonamide compound and Pharmaceutical Composition for Treating or Preventing Cancer comprising the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel sulfonamide compound that inhibits the activity of signal transducer and transcription factor (STAT) protein, particularly STAT3 protein, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient. The compound can significantly inhibit the proliferation and growth of cancer cells by effectively inhibiting the activity of STAT3 protein, and is expected to be useful as an anticancer agent having STAT3 protein inhibitory activity in the future.

Description

Novel sulfonamide compound and a pharmaceutical composition for the prevention or treatment of cancer containing the same as an active ingredient TECHNICAL FIELD

The present invention relates to a novel sulfonamide compound that inhibits the activity of a signal transducer and activator of transcription (STAT) protein, in particular, a STAT3 protein, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient. it's about

Signal transducer and transcription factor (STAT) proteins are one of the DNA binding proteins, and their activity is regulated by stimulation of various cytokines (eg, IL-6, interferon, etc.) or proliferation factors (eg EGF, PDGF, etc.). have. When a cytokine binds to its receptor, JAK (Janus protein tyrosine kinase) kinase is activated and phosphorylates tyrosine in STAT. In addition, when a growth factor binds to its receptor, the tyrosine kinase possessed by the growth factor receptor itself phosphorylates STAT. Phosphorylated 　STAT is activated by forming a dimer via its Src homology 2 (SH2) domain. The activated STAT migrates into the nucleus, specifically recognizes and binds to a specific DNA sequence in the gene promoter region, and induces transcription of many genes. That is, STAT is an essential mediator in the pathway that transmits signals from the cell surface to the nucleus, and is deeply involved in cell proliferation and differentiation.

In STAT, six different members (STAT1, STAT2, STAT3, STAT4, STAT5 and STAT6) and several isoforms (STAT1α, STAT1β, STAT3α and STAT3β) are known.

Among them, STAT3 is known to be expressed in most cell types (PNAS May 24, 1994　91　(11)　4806-4810). In addition, its constitutive activation and overexpression of various cancer cells such as breast cancer, lung cancer, prostate cancer, head and neck cancer, skin cancer, pancreatic cancer, ovarian cancer, myeloma, breast cancer, prostate cancer, brain tumor, head and neck cancer, melanoma, leukemia lymphoma and cancer cells such as multiple myeloma, and proliferation and invasion of these cancer cells is considered to be dependent on STAT3. In addition, it is known that abnormal or constitutive expression of 　STAT3 is also involved in cell transformation (Science, 1995, 269, 81-83). Therefore, STAT3 is considered to be useful as a target molecule for these carcinomas, and therefore, its inhibitor is expected as an anticancer agent.

Strategies for developing STAT3 inhibitors known to date are largely: i) inhibition of phosphorylation of STAT3 protein by IL-6/gp-130/JAK kinase, ii) direct inhibition of dimerization of activated STAT3, and iii) STAT3 dimer It can be divided into inhibition of DNA binding in the nucleus. As low-molecular compounds currently under development as STAT3 inhibitors, OPB-31121, OPB-51602, and OPB-111077, which are being developed by Otsuka Pharmaceutical, are reported to be in clinical trials for solid cancer and hematological cancer patients, and S3I- 201, S3I-M2001, LLL-12, 　Stattic, STA-21, SF-1-066 and STX-0119, etc. have been reported through the literature to show drug efficacy in some cancer cell growth inhibition experiments and anticancer animal models (xenograft model). have. Nevertheless, since many signaling systems are still involved in the development and growth of cancer cells, there are many cases that have not yet led to the development of successful inhibitors. If a novel STAT3 inhibitor capable of regulating this undeveloped cell signaling system is developed, it is expected to improve the therapeutic effect on patients who cannot be treated with anticancer drugs to date.

PNAS　May 24, 1994　91　(11)　4806-4810 Science, 1995, 269, 81-83

It is an object of the present invention to provide a novel sulfonamide compound that inhibits the activity of STAT3 protein, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is for the prevention or treatment of cancer containing a sulfonamide compound of the present invention that inhibits the activity of STAT3 protein, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient To provide a pharmaceutical composition.

Another object of the present invention is to provide a STAT3 inhibitor composition comprising a sulfonamide compound of the present invention, a prodrug thereof, a hydrate thereof, a solvate thereof, or a salt thereof as an active ingredient.

In order to achieve the above object, the present invention provides a compound represented by the following formula (1), a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

[In Formula 1,

R ¹ and R ² are each independently C _1-7 alkyl;

R ³ is C _1-7 alkoxy or halogen;

R ⁴ is hydrogen or halogen;

또는

이고;Het

or

ego;

R ⁵ is haloC _1-7 alkyl.]

In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound of Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a STAT3 inhibitor composition comprising the compound of Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound of Formula 1 according to the present invention can significantly inhibit the proliferation and growth of cancer cells by effectively inhibiting the activity of signal transducers and transcription factor (STAT) proteins, particularly STAT3 proteins, involved in the development and growth of cancer cells. . In addition, the compound of Formula 1 according to the present invention does not exhibit an apoptotic effect on STAT3-independent cancer cells. For this reason, the compound of Formula 1 according to the present invention may be usefully used as an active ingredient of a pharmaceutical composition for preventing or treating diseases for inhibiting the activity of STAT3 protein, specifically, for treating or preventing cancer. it is expected that

Hereinafter, the present invention will be described in more detail. If there is no other definition in the technical and scientific terms used at this time, it has the meaning commonly understood by those of ordinary skill in the art to which this invention belongs, and may unnecessarily obscure the subject matter of the present invention in the following description. Descriptions of possible known functions and configurations will be omitted.

The following terms used in this specification are defined as follows, but these are merely exemplary and are not intended to limit the present invention, application or use.

As used herein, the terms “substituent”, “radical”, “group”, “moiety”, and “fragment” may be used interchangeably.

As used herein, the term "C _A -C _B " means "the number of carbon atoms is greater than or equal to A and less than or equal to B".

As used herein, the term “alkyl” refers to a monovalent straight-chain or branched saturated hydrocarbon radical composed only of carbon and hydrogen atoms.

As used herein, the term “alkoxy” refers to an —O-alkyl radical. Here, "alkyl" is as defined above.

As used herein, the term “halo” or “halogen” refers to a halogen element, and includes, for example, fluoro (F), chloro (Cl), bromo (Br), iodo (I), and the like.

As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted with a halogen atom, wherein alkyl and halogen are as defined above. The haloalkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, perfluoroethyl, and the like.

As used herein, the term "pharmaceutically acceptable" refers to a property that is non-toxic to cells or humans exposed to the composition, and is suitable for use as a pharmaceutical preparation, and generally for such use It is deemed safe and means that it has been officially approved by a national regulatory authority for such use or is listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

As used herein, the term "pharmaceutically acceptable salt" refers to a compound of the present invention at a concentration having an effective action that is relatively non-toxic and harmless to a patient, and side effects due to the salt do not reduce the beneficial efficacy of the compound of the present invention itself. any and all organic or inorganic addition salts of

As used herein, the term “prodrug” is intended to include compounds that, under physiological conditions, convert a compound of the present invention into a therapeutically active agent.

As used herein, the term “hydrate” refers to a pharmaceutically acceptable hydrate.

As used herein, the term “solvate” refers to a pharmaceutically acceptable solvate.

As used herein, the term “cancer” refers to cells characterized by unregulated or dysregulated cell proliferation, reduced cellular differentiation, inappropriate ability to invade surrounding tissue, or ability to establish new growths at ectopic sites. means sexual dysfunction.

As used herein, the term “prevention” refers to any action that inhibits or delays the occurrence, spread, and recurrence of cancer diseases by administration of the composition of the present invention.

As used herein, the term "treatment" refers to any action in which symptoms of cancer are improved or cured by administration of the composition of the present invention.

As used herein, the term “improvement” refers to any action of at least reducing the severity of a parameter, for example, a symptom, associated with a condition to be treated by administration by administration of the composition of the present invention.

As used herein, the term “individual” refers to any animal, including humans, that has or is likely to develop a cancer disease. The animal may be a mammal, such as a cow, a horse, a sheep, a pig, a goat, a camel, an antelope, a dog, a cat, and the like, in need of treatment for symptoms similar to those of a human, but is not limited thereto. In addition, the subject in the present invention may exclude a human, but is not limited thereto.

As used herein, the term “administration” means introducing the composition of the present invention to an individual by any suitable method, and the administration route of the composition of the present invention is administered through various routes, either oral or parenteral, as long as it can reach the target tissue. can be

As used herein, the term “pharmaceutically effective amount” refers to an amount sufficient to treat a disease at a reasonable benefit-risk ratio applicable to medical treatment and not to cause side effects.

Hereinafter, the present invention will be described in detail.

The present invention provides a sulfonamide compound represented by the following formula (1), a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

[In Formula 1,

R ¹ and R ² are each independently C _1-7 alkyl;

R ³ is C _1-7 alkoxy or halogen;

R ⁴ is hydrogen or halogen;

또는

이고;Het

or

ego;

R ⁵ is haloC _1-7 alkyl.]

As described above, activation and overexpression of STAT3 is confirmed in many cancer cells, and it has been reported that the proliferation or invasion of these cancer cells is dependent on STAT3. By inhibiting the function of the STAT3 protein, the compound of Formula 1 according to the present invention may inhibit cancer cell proliferation and induce apoptosis at the same time. That is, the compound of Formula 1 according to the present invention acts as an inhibitor to inhibit STAT3 protein, which is one of the target molecules for various carcinomas, and is expected to be usefully utilized as a therapeutic and preventive agent for cancer. In addition, the compound of Formula 1 according to the present invention has no apoptotic effect in STAT3-independent cell lines [PC-3 (STAT3 null cell), MDA-MB-453 (STAT3 low cell)], etc., and STAT3-dependent cell lines [MDA- MB-468 (STAT3 high cell)], etc., exhibits an apoptotic effect, and thus can be usefully used to prevent and treat diseases related to the activation of STAT3 protein.

In the compound of Formula 1 according to an embodiment of the present invention, R ¹ and R ² may each independently be C _1-3 alkyl.

In the compound of Formula 1 according to an embodiment of the present invention, R ¹ and R ² may be identical to each other C _1-3 alkyl, specifically, methyl or ethyl may be identical to each other.

In the compound of Formula 1 according to an embodiment of the present invention, R ¹ is methyl, ethyl, n-propyl or i-propyl; R ² may be methyl or ethyl.

In the compound of Formula 1 according to an embodiment of the present invention, R ³ is C _1-3 alkoxy or halogen; R ⁴ may be hydrogen or halogen.

In the compound of Formula 1 according to an embodiment of the present invention, R ³ may be methoxy, ethoxy, fluoro, chloro or bromo, and R ⁴ may be hydrogen, fluoro, chloro or bromo.

In the compound of Formula 1 according to an embodiment of the present invention, R ³ is methoxy or ethoxy; R ⁴ may be hydrogen.

In the compound of Formula 1 according to an embodiment of the present invention, R ³ and R ⁴ may each independently be fluoro, chloro or bromo.

로 표시될 수 있으며, 상기 R⁵는 할로C_1-3 알킬인 것일 수 있고, 여기서, 상기 할로는 플루오로인 것일 수 있다. 보다 구체적으로, 상기 R⁵는 트리플루오로메틸 등일 수 있다.In the compound of Formula 1 according to an embodiment of the present invention, Het including R ⁵ is specifically

and R ⁵ may be haloC _1-3 alkyl, where halo may be fluoro. More specifically, R ⁵ may be trifluoromethyl or the like.

It will be apparent to those skilled in the art that the compound of Formula 1 according to an embodiment of the present invention can be prepared by various known methods depending on the type of the substituent, and can be performed using methods known in the art or by appropriately changing them. will be.

Since the compound of Formula 1 according to an embodiment of the present invention can be used in the form of a prodrug, hydrate, solvate, and pharmaceutically acceptable salt to enhance absorption in vivo or increase solubility, the compound of the present invention The scope includes not only the compound of Formula 1 above, but also a prodrug thereof, a hydrate thereof, a solvate thereof or a salt thereof.

The compound of the present invention may be used in the form of a pharmaceutically acceptable salt, and the pharmaceutically acceptable salt is a salt prepared according to a method conventional in the art, and the preparation method thereof is known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable free acids and bases.

A pharmaceutically acceptable salt of the compound of the present invention means a salt prepared according to a method conventional in the art, and the preparation method is known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable inorganic acids and organic acids and bases.

In one embodiment, salts derived from acids are prepared by conventional methods, for example, by dissolving the compound of the present invention in an excess aqueous solution of acid, and dissolving the salt in a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It is prepared by precipitation. It is obtained by heating an equimolar amount of the compound and an acid or alcohol (eg glycol monomethyl ether) in water, followed by evaporation of the mixture to dryness, or by suction filtration of the precipitated salt. At this time, organic acids and inorganic acids can be used as free acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid as organic acids (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used. , but not limited to these.

For example, the salt derived from the base may include a pharmaceutically acceptable metal salt, specifically, an alkali metal salt or an alkaline earth metal salt. In addition, such a metal salt is obtained by a conventional method, for example, by dissolving the compound of the present invention in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt of the present invention, and evaporating and drying the filtrate. In this case, as the metal salt, it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt, but is not limited thereto. Also, 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).

Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group, and other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, and hydrogen phosphate. , dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, and the like, and preparation of salts known in the art It can be prepared through a method.

The hydrate of the compound of the present invention is a compound of the present invention comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces, or means its salt.

A solvate of a compound of the present invention means a compound of the present invention or a salt thereof which contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefor include volatile, non-toxic solvents.

The compound of the present invention may be administered in the form of a prodrug that is decomposed in a human or animal body to provide the compound of the present invention as an active ingredient. Prodrugs can be used to alter or improve the physical or pharmacokinetic profile of the parent compound and can be formed when the parent compound contains suitable groups or substituents that can be derived to form a prodrug.

If a certain compound (prodrug) is isolated in the body to produce a compound of the present invention or a salt thereof, such a compound is also included in the scope of the present invention. As used herein and unless otherwise indicated, the term "prodrug" refers to hydrolyzed, oxidized, and other reactions under biological conditions (either ex vivo or in vivo) to provide an active compound, particularly a compound of the present invention. compounds of the present invention capable of Examples of prodrugs are biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable esters. biohydrolyzable to yield compounds of the present invention, including biohydrolyzable moieties such as ureides and biohydrolyzable phosphate analogs, but in this specific embodiment It is not limited. Preferably, the prodrug of the compound having a carboxyl group is a lower alkyl ester of a carboxylic acid. Carboxylic esters are commonly formed by esterifying a moiety of a carboxylic acid present in a molecule. The prodrug is Burger's Medicinal Chemistry and Drug Discovery 6thed. (Donald J. Abrahamed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound of Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Here, the compound of Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof inhibits the activation of STAT3 protein, thereby preventing, ameliorating, or treating diseases related to activation of STAT3 protein. can be effective. Specifically, according to the present invention, by inhibiting the activity of the STAT3 protein, it is possible to efficiently control the growth of cancer.

For example, the cancer is lung cancer, colorectal cancer, colon cancer, rectal cancer, breast cancer, prostate cancer, bladder cancer, blood cancer, leukemia, myeloid leukemia, lymphoma, cervical cancer, osteosarcoma (osteosarcoma), glioblastoma, It may be melanoma, pancreatic cancer, stomach cancer, liver cancer, kidney cancer, gallbladder cancer, biliary tract cancer, esophageal cancer, ovarian cancer, thyroid cancer, skin cancer or neuroblastoma.

In addition, according to the present invention, autoimmune diseases including rheumatoid arthritis, psoriasis, hepatitis, inflammatory bowel disease, Crohn's disease, diabetes, macular degeneration, papillomavirus infection, tuberculosis, etc. It is useful for prevention or treatment.

The pharmaceutical composition according to an embodiment of the present invention is a conventional formulation in the pharmaceutical field, that is, for oral administration, further comprising an additive selected from a conventional non-toxic pharmaceutically acceptable carrier, excipient, and diluent in addition to the active ingredient. It may be formulated as a preparation or a preparation for parenteral administration.

For example, the pharmaceutically acceptable additives include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl and cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.

The pharmaceutical composition according to an embodiment of the present invention can be prepared in a variety of ways, such as oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and injections of sterile injection solutions, according to conventional methods according to the purpose of use. It can be formulated and used in a form, and it can be administered orally or through various routes including intravenous, intraperitoneal, subcutaneous, rectal, topical administration, and the like.

In addition, the pharmaceutical composition of the present invention may further include a component selected from a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a fragrance, an emulsifier and a preservative.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc. are mixed and formulated. In addition to simple excipients, lubricants such as magnesium stearate and talc may be used.

Liquid formulations for oral use may include suspensions, solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used simple diluents, may be included. can

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, Witepsol, Macrogol, Tween 61, cacao butter, laurin fat, glycerogelatin, and the like can be used. On the other hand, injections may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

The pharmaceutical composition of the present invention may be sterilized, or may further contain adjuvants such as preservatives, stabilizers, thickeners, wetting agents or emulsification accelerators, salts and/or buffers for regulating osmotic pressure, and other therapeutically useful substances. It may also be included, and may be formulated according to conventional methods such as dissolution, dispersion, and gelation.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount, and the pharmaceutical 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 a conventional therapeutic agent. , single or multiple administrations. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum 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 weight of the patient, and generally 1 to 100 mg per kg of body weight, preferably 5 to 60 mg, is administered daily or every other day, or 1 It can be administered in 1 to 3 divided doses per day. However, since it may increase or decrease depending on the route of administration, disease severity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.

In addition, the present invention provides a method for preventing or treating cancer, comprising administering the pharmaceutical composition to an individual having or at risk of developing a cancer disease. In this case, the pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount.

The level of a pharmaceutically effective amount may vary depending on the patient's sex, age, weight, health status, disease type, severity, drug activity, drug sensitivity, administration method, administration time, administration route, and excretion rate, treatment period, It can be readily determined by one of ordinary skill in the art according to factors including drugs used in combination or concomitantly and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.

The route and mode of administration for administering the pharmaceutical composition of the present invention are not particularly limited, and may follow any route and mode of administration as long as the composition including the composition can reach the desired site. Specifically, the composition may be administered through a variety of oral or parenteral routes, and non-limiting examples of the route of administration include oral, rectal, topical, intravenous, intraperitoneal, intramuscular, intraarterial, transdermal, and nasal and those administered intralaterally or through inhalation.

In addition, the cancer prevention or treatment method of the present invention may be combined with surgery, radiation therapy, hormone therapy, chemotherapy, and methods using biological response modifiers.

In addition, the present invention provides a STAT3 inhibitor composition comprising as an active ingredient an effective amount of a compound represented by Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Hereinafter, the present invention will be described in more detail through preferred embodiments. However, this is presented as an example of the present invention, and the scope of the present invention is not limited by this in any sense, and the scope of the present invention is only defined according to the claims described below.

[Example 1]

Synthesis of 3-acetyl-5-methoxy-2-(methylthio)-1-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)quinolin-4( 1H )-one (Compound 1)

3-acetyl-5-methoxy-2-(methylthio)quinolin-4(1 H )-one (3-acetyl-5-methoxy-2-(methylthio)quinolin-4(1 H )-one, A) (0.100 g, 0.38 mmol, 1.00 equiv) and 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (6-(trifluoromethyl)pyridine-3-sulfonyl chloride, 0.112 g, 0.46 mmol, 1.20 equiv) were mixed with CH Dissolved in ₂ Cl ₂ (5.0 ml), Et ₃ N was slowly added dropwise at 0 °C. The reaction mixture was stirred at 0° C. for 30 minutes, and 25 ml of water was added thereto. And after extraction with CH ₂ Cl ₂ 3 times and wiping with brine, the organic layer was dried over anhydrous Na ₂ SO ₄ and the solvent was removed under reduced pressure.

Then, the reaction mixture was purified by column chromatography ( n -hexane : ethyl acetate = 5:1 to 1:1) to obtain 65 mg (36%) of a white solid Compound 1. In addition, the structure and identification data of the prepared compound 1 are shown in Table 1 below.

[Examples 2 to 10]

Compounds 2 to 10 of Table 1 were prepared according to a method similar to Example 1, and the structures and identification data of the prepared compounds are described in Table 1 below.

<Experimental Example 1> Anticancer activity evaluation

The anticancer activity of the compounds of the Examples was evaluated. Specifically, the evaluation includes human breast cancer cells (MDA-MB-231, MDA-MB-468 and MDA-MB-453), prostate cancer cells (PC-3), 96 well plate (COSTAR, 3903 white plate), CellTiter- The Glo® Luminescent Cell Viability Assay kit (Promega) was used.

1) MDA-MB-468, MDA-MB-231, MDA-MB-453 and PC-3 cancer cells that had been stabilized for about a week were placed in a 96-well plate (COSTAR, 3903 white plate) at 8 x 10 ² /100 ul/well. It was very seeded. A well containing only culture media without cells was used as a blank.

2) A chemical solution in DMSO corresponding to X 1,000 of the concentration to be treated was prepared by serial dilution.

3) After 24 hours, the prepared chemical solution was prepared by diluting 500 times in culture media.

4) 100 μl per well was added to the 96 well plate in which the cells were seeded, so that the total vol. 200 μl. The final DMSO was 0.1%, and the concentration of the test substance was X 1/1,000 of the stock solution.

5) Then, the plate was transferred to the incubator.

6) After 72 hours, after removing from the incubator, 50 μl of media was removed from the plate and placed at room temperature (25° C.).

7) After 30 minutes, 50 μl of Celltilter-glo solution was added per well, incubated on a shaker for 20 to 30 minutes, and then measured with a luminometer. At this time, if the incubation time is too short, the S/N ratio is large, and if it is too long, the signal may be saturated. The S/N ratio was set to 200 or more.

<Activity evaluation criteria>

Cell viability assay result (10 μM, MDA-MB-468, MDA-MB-231, MDA-MB-453, PC-3 cells)

0 to less than 30%: ◎

More than 30% to less than 50%: ○

More than 50% and less than 75%: △

75% or more: X

The results are shown in Tables 2 and 3 below.

From the results in Table 2, it was confirmed that the compounds of the present invention significantly induced apoptosis in STAT3-dependent cell lines among prostate cancer cells as well as breast cancer cells at a concentration of 10 μM. Specifically, the compounds of the present invention exhibited more than 50% apoptosis, and the effect was remarkably confirmed in compounds 1, 2, 7, and 8.

More specifically, in order to verify the STAT3 selective inhibitory effect of the compound of the present invention, a STAT3-independent cell line [PC-3 (STAT3 null cell), MDA-MB-453 (STAT3 low cell)] and a STAT3-dependent cell line [MDA-MB] -468 (STAT3 high cell)] was compared. At this time, as a control compound, napabucasin, known as a STAT3 inhibitor, was used. From the results of Table 3, Compound 1 and Compound 8 of the present invention did not show apoptosis in STAT3-independent cell lines (PC-3 and MDA-MB-453), but induced apoptosis in STAT3-dependent cell lines, STAT3-selective It was confirmed that it exhibits a significant effect on apoptosis. However, in the case of napabucacin, a compound of the control group, it was confirmed that the selectivity for the STAT3-dependent cell line was low, considering the results of inducing apoptosis in both STAT3-dependent and non-dependent cell lines.

Based on these results, it was found that the compounds according to the present invention are very effective in anticancer activity by inhibiting the expression of STAT3 protein, which plays an important role in carcinogenesis due to the above-described structural characteristics. In addition, it was found that the compound according to the present invention has excellent selectivity for STAT3-dependent cell lines. Accordingly, the present invention is expected to be usefully used as an anticancer agent having anticancer activity through inhibition of the expression of STAT3 protein.

The present invention is not limited by the above-described embodiments, and it is those skilled in the art that various substitutions, modifications and changes are possible without departing from the technical spirit of the present invention. will be clear to

Claims (6)

A compound represented by the following formula (1), a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
R ¹ and R ² are each independently C _1-7 alkyl;
R ³ is C _1-7 alkoxy or halogen;
R ⁴ is hydrogen or halogen;
Het

or

ego;
R ⁵ is haloC _1-7 alkyl. A pharmaceutical composition for preventing or treating cancer comprising the compound according to claim 1, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. 3. The method of claim 2,
The pharmaceutical composition is
A pharmaceutical composition, characterized in that it inhibits the activity of STAT3 (signal transducer and activator of transcription 3). 3. The method of claim 2,
The cancer is
Lung cancer, colorectal cancer, colon cancer, rectal cancer, breast cancer, prostate cancer, bladder cancer, blood cancer, leukemia, myeloid leukemia, lymphoma, cervical cancer, osteosarcoma, glioblastoma, melanoma, pancreatic cancer, stomach cancer, liver cancer, kidney cancer, gallbladder cancer, biliary tract cancer , esophageal cancer, ovarian cancer, thyroid cancer, skin cancer, brain cancer or neuroblastoma, the pharmaceutical composition. 3. The method of claim 2,
The pharmaceutical composition, further comprising an additive selected from pharmaceutically acceptable carriers, diluents and excipients. A STAT3 inhibitor composition comprising the compound according to claim 1, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.